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Sample records for models il-22 induces

  1. Immune modulatory effects of IL-22 on allergen-induced pulmonary inflammation.

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    Ping Fang

    Full Text Available IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox induction, IL-22 protein was readily detected in the large (CC10 promoter and small (SPC promoter airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL, and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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...

  7. IL-22 Protects against Tissue Damage during Cutaneous Leishmaniasis.

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    Ciara Gimblet

    Full Text Available Cutaneous leishmaniasis is a disease characterized by ulcerating skin lesions, the resolution of which requires an effective, but regulated, immune response that limits parasite growth without causing permanent tissue damage. While mechanisms that control the parasites have been well studied, the factors regulating immunopathologic responses are less well understood. IL-22, a member of the IL-10 family of cytokines, can contribute to wound healing, but in other instances promotes pathology. Here we investigated the role of IL-22 during leishmania infection, and found that IL-22 limits leishmania-induced pathology when a certain threshold of damage is induced by a high dose of parasites. Il22-/- mice developed more severe disease than wild-type mice, with significantly more pathology at the site of infection, and in some cases permanent loss of tissue. The increased inflammation was not due to an increased parasite burden, but rather was associated with the loss of a wound healing phenotype in keratinocytes. Taken together, these studies demonstrate that during cutaneous leishmaniasis, IL-22 can play a previously unappreciated role in controlling leishmania-induced immunopathology.

  8. Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4+T cells from a BTBR T+Itpr3tf/J mouse model of autism.

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    Ahmad, Sheikh F; Ansari, Mushtaq A; Nadeem, Ahmed; Bakheet, Saleh A; Almutairi, Mashal M; Attia, Sabry M

    2017-10-15

    Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T + Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders. We investigated the effects of the A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on IL-21, IL-22, T-bet, T-box transcription factor (T-bet), GATA3 (GATA Binding Protein 3), and CD152 (CTLA-4) expression in BTBR mice. Our results showed that BTBR mice treated with SCH had increased CD4 + IL-21 + , CD4 + IL-22 + , CD4 + GATA3 + , and CD4 + T-bet + and decreased CD4 + CTLA-4 + expression in spleen cells compared with BTBR control mice. Moreover, CGS efficiently decreased CD4 + IL-21 + , CD4 + IL-22 + , CD4 + GATA3 + , and CD4 + T-bet + and increased CD4 + CTLA-4 production in spleen cells compared with SCH-treated and BTBR control mice. Additionally, SCH treatment significantly increased the mRNA and protein expression levels of IL-21, IL-22, GATA3, and T-bet in brain tissue compared with CGS-treated and BTBR control mice. The augmented levels of IL-21/IL-22 and GATA3/T-bet could be due to altered A2AR signaling. Our results indicate that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of autistic and neuroimmune dysfunctions. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor

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    Joseph Franz

    2015-01-01

    Full Text Available Interleukin- (IL- 22 signaling is protective in animal models of pneumonia and bacteremia by Klebsiella pneumoniae and mediates tissue recovery from influenza and Staph aureus infection. We recently described processing of mouse lung epithelial IL-22 receptor (IL-22R by ubiquitination on the intracellular C-terminal. To identify cellular factors that regulate human IL-22R, we screened receptor abundance while overexpressing constituents of the ubiquitin system and identify that IL-22R can be shuttled for degradation by multiple previously uncharacterized F-box protein E3 ligase subunits. We observe that in human cells IL-22R is destabilized by FBXW12. FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro. FBXW12 knockdown with shRNA increases IL-22R abundance and STAT3 phosphorylation in response to IL-22 cytokine treatment. FBXW12 shRNA increases human epithelial cell growth and cell cycle progression with enhanced constitutive activity of map kinases JNK and ERK. These findings indicate that the heretofore-undescribed protein FBXW12 functions as an E3 ligase constituent to ubiquitinate and degrade IL-22R and that therapeutic FBXW12 inhibition may enhance IL-22 signaling and bolster mucosal host defense and infection containment.

  10. 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.

  11. 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).

  12. 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.

  13. IL-22 regulation of functional gene expression in salivary gland cells

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    Tegan N. Lavoie

    2016-03-01

    Full Text Available TH17 cells and their associated signature cytokines, IL-17 and IL-22, are highly elevated in primary Sjögren's syndrome (pSjS. The levels of IL-22 present in sera showed significant correlations with many disease parameters, specifically hyposalivation, anti-SSB, anti-SSA/SSB, hypergammaglobulinemia and rheumatoid factor. The present study aims to examine the biological function of IL-22 on human salivary glands. To accomplish the goal, microarray analysis using the HumanHT-12 v4 Expression BeadChip was utilized to determine the biological function of IL-22. Differential expression analyses were conducted using the LIMMA package from the Bioconductor project. MTT assay, flow cytometry and Western blotting were used to identify the function of IL-22 on human salivary gland cells. Results indicate an extensive effect of IL-22 on many major molecular functions including activation of antimicrobial genes and downregulation of immune-associated pathways. Functional studies performed in-vitro using human salivary gland cells treated with IL-22 indicated a direct effect of IL-22 on cell cycling, specifically reducing cellular proliferation at the G2-M phase by activation of STAT3. These results suggest the important role of IL-22 in the salivary gland function. The present study suggests that IL-22 might be involved in regulating inflammation and controlling the cell proliferation in SjS.

  14. In vivo analysis of helper T cell responses in patients with autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy provides evidence in support of an IL-22 defect.

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    Laakso, Sini M; Kekäläinen, Eliisa; Heikkilä, Nelli; Mannerström, Helga; Kisand, Kai; Peterson, Pärt; Ranki, Annamari; Arstila, T Petteri

    2014-12-01

    Autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune regulator (AIRE) gene and is associated with neutralizing anti-cytokine autoantibodies. We have used an in vivo challenge model to analyze antigen-specific CD4(+) T cell responses. Bacille Calmette-Guérin (BCG)-vaccinated patients and controls were injected tuberculin intradermally, skin blisters were induced by suction on the indurations and on unexposed skin, and the infiltrating cells harvested. The patients had a quantitatively normal CD4(+) T cell response and no significant abnormalities in the expression of T helper type (Th) 1- or Th2-related genes. The expression of interleukin (IL)-22, in contrast, was lower in the patients. Two patients, both with a pre-existing ocular keratopathy, experienced a relapse of keratoconjunctivitis, suggesting a possible immunological basis for this APECED component. Our in vivo data are compatible with a selective IL-22 defect in the activated CD4(+) T cells of APECED patients, affecting also unexposed skin in steady-state conditions.

  15. Conventional NK cells can produce IL-22 and promote host defense in Klebsiella pneumoniae pneumonia.

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    Xu, Xin; Weiss, Ido D; Zhang, Hongwei H; Singh, Satya P; Wynn, Thomas A; Wilson, Mark S; Farber, Joshua M

    2014-02-15

    It was reported that host defense against pulmonary Klebsiella pneumoniae infection requires IL-22, which was proposed to be of T cell origin. Supporting a role for IL-22, we found that Il22(-/-) mice had decreased survival compared with wild-type mice after intratracheal infection with K. pneumoniae. Surprisingly, however, Rag2(-/-) mice did not differ from wild-type mice in survival or levels of IL-22 in the lungs postinfection with K. pneumoniae. In contrast, K. pneumoniae-infected Rag2(-/-)Il2rg(-/-) mice failed to produce IL-22. These data suggested a possible role for NK cells or other innate lymphoid cells in host defense and production of IL-22. Unlike NK cell-like innate lymphoid cells that produce IL-22 and display a surface phenotype of NK1.1(-)NKp46(+)CCR6(+), lung NK cells showed the conventional phenotype, NK1.1(+)NKp46(+)CCR6(-). Mice depleted of NK cells using anti-asialo GM1 showed decreased survival and higher lung bacterial counts, as well as increased dissemination of K. pneumoniae to blood and liver, compared with control-treated mice. NK cell depletion also led to decreased production of IL-22 in the lung. Within 1 d postinfection, although there was no increase in the number of lung NK cells, a subset of lung NK cells became competent to produce IL-22, and such cells were found in both wild-type and Rag2(-/-) mice. Our data suggest that, during pulmonary infection of mice with K. pneumoniae, conventional NK cells are required for optimal host defense, which includes the production of IL-22.

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

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    Dyring-Andersen, Beatrice; Skov, Lone; Løvendorf, Marianne B; Bzorek, Michael; Søndergaard, Knud; Lauritsen, Jens-Peter H; Dabelsteen, Sally; Geisler, Carsten; Bonefeld, Charlotte Menné

    2013-06-01

    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. To determine 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. Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6 controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes. We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine-producing CLA(+) T cell subtypes in nickel-allergic patients as compared with controls. In nickel-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. CD4(+) T cells producing IL-17, IL-22 and IFN-γ are important effector cells in the eczematous reactions of nickel-induced allergic contact dermatitis in humans. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Human mast cells are major IL-22 producers in patients with psoriasis and atopic dermatitis.

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    Mashiko, Shunya; Bouguermouh, Salim; Rubio, Manuel; Baba, Nobuyasu; Bissonnette, Robert; Sarfati, Marika

    2015-08-01

    Psoriasis is a systemic inflammatory disease in which IL-17 and IL-22 levels are markedly increased in the skin and blood. The prevalent concept, using skin cells that are isolated from psoriatic plaques and examined after cell expansion and in vitro stimulation, is that IL-17 and IL-22 production essentially results from T cells and the rare type 3 innate lymphoid cells. We sought to examine the cellular source of IL-17A and IL-22 at the protein and transcriptional single-cell level immediately after ex vivo skin cell isolation from psoriatic plaques. Skin biopsy specimens were collected from patients with psoriasis, as well as from patients with atopic dermatitis. Cell suspensions were prepared by combining mild enzymatic digestion and mechanical dissociation and analyzed for cytokine expression without prior in vitro culture and stimulation. Expression of IL-17 and IL-22 was quantified at the protein and mRNA single-cell level by using flow cytometry. IL-22 is predominantly expressed by CD3(-)c-Kit(+) cells relative to CD3(+) T cells in lesional skin of patients with psoriasis and patients with atopic dermatitis. Strikingly, we identified c-Kit(+)FcεRI(+) mast cells as major IL-22 producers. The proportion of mast cells that produce IL-22 ranges from 20% to 80% in patients with psoriasis or those with atopic dermatitis. Skin mast cells express IL-22 and IL-17 mRNA. Conversely, IL-17-producing T cells outnumber IL-17-producing mast cells, which also express IL-17 receptor. Human skin mast cells are previously unrecognized IL-22 producers. We further established that skin mast cells express IL-17. Thus mast cells might play an important role in the physiopathology of chronic inflammatory skin disorders. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  18. Restriction of IL-22-producing T cell responses and differential regulation of regulatory T cell compartments by zinc finger transcription factor Ikaros.

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    Heller, Jennifer J; Schjerven, Hilde; Li, Shiyang; Lee, Aileen; Qiu, Ju; Chen, Zong-Ming E; Smale, Stephen T; Zhou, Liang

    2014-10-15

    Proper immune responses are needed to control pathogen infection at mucosal surfaces. IL-22-producing CD4(+) T cells play an important role in controlling bacterial infection in the gut; however, transcriptional regulation of these cells remains elusive. In this study, we show that mice with targeted deletion of the fourth DNA-binding zinc finger of the transcription factor Ikaros had increased IL-22-producing, but not IL-17-producing, CD4(+) T cells in the gut. Adoptive transfer of CD4(+) T cells from these Ikaros-mutant mice conferred enhanced mucosal immunity against Citrobacter rodentium infection. Despite an intact in vivo thymic-derived regulatory T cell (Treg) compartment in these Ikaros-mutant mice, TGF-β, a cytokine well known for induction of Tregs, failed to induce Foxp3 expression in Ikaros-mutant CD4(+) T cells in vitro and, instead, promoted IL-22. Aberrant upregulation of IL-21 in CD4(+) T cells expressing mutant Ikaros was responsible, at least in part, for the enhanced IL-22 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor, but not RORγt, was required for aberrant IL-22 expression by Ikaros-mutant CD4(+) T cells, whereas forced expression of Foxp3 was sufficient to inhibit this aberrant cytokine production. Together, our data identified new functions for Ikaros in maintaining mucosal immune homeostasis by restricting IL-22 production by CD4(+) T cells. Copyright © 2014 by The American Association of Immunologists, Inc.

  19. Early Production of IL-22 but Not IL-17 by Peripheral Blood Mononuclear Cells Exposed to live Borrelia burgdorferi: The Role of Monocytes and Interleukin-1

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    Rudloff, Ina; Goren, Itamar; Holdener, Martin; Christen, Urs; Darsow, Nicole; Hunfeld, Klaus-Peter; Koehl, Ulrike; Kind, Peter; Pfeilschifter, Josef; Kraiczy, Peter; Mühl, Heiko

    2010-01-01

    If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection. PMID:20976193

  20. Early production of IL-22 but not IL-17 by peripheral blood mononuclear cells exposed to live Borrelia burgdorferi: the role of monocytes and interleukin-1.

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    Malte Bachmann

    Full Text Available If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection.

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

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    Pichavant, Muriel; Sharan, Riti; Le Rouzic, Olivier; Olivier, Cécile; Hennegrave, Florence; Rémy, Gaëlle; Pérez-Cruz, Magdiel; Koné, Bachirou; Gosset, Pierre; Just, Nicolas; Gosset, Philippe

    2015-11-01

    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.

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

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    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.

  3. Autonomous cure of damaged human intestinal epithelial cells by TLR2 and TLR4-dependent production of IL-22 in response to Spirulina polysaccharides.

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    Tominaga, Akira; Konishi, Yuko; Taguchi, Takahiro; Fukuoka, Satoshi; Kawaguchi, Tokuichi; Noda, Tetsuo; Shimizu, Keiji

    2013-12-01

    In order to analyze the damage of human epithelial cells, we used human quasi-normal FPCK-1-1 cells derived from a colonic polyp in a patient with familial adenomatous polyposis as a monolayer, which is co-cultured with peptidoglycan (PGN)-stimulated THP-1 cells. Co-cultured FPCK-1-1 cells showed a decreased transepithelial electrical resistance (TER) and the lower level of claudin-2. When Spirulina complex polysaccharides were added one day before the start of the co-culture, there was no decrease of TER and claudin-2 (early phase damage). In contrast, when Spirulina complex polysaccharides were added to FPCK-1-1 cells after the level of TER had decreased, there was no recovery at the level of claudin-2, though the TER level recovered (late phase damage). The mucosa reconstitution is suggested to be involved in the recovery from the damaged status. Interestingly, autonomous recovery of FPCK-1-1 cells from both the early and late phase damage requires the production of IL-22, because anti-IL-22 antibodies inhibited recovery in these cases. Antibodies against either TLR2 or TLR4 inhibited the production of IL-22 from FPCK-1-1 colon epithelial cells, suggesting that signals through TLR2 and TLR4 are necessary for autonomous recovery of FPCK-1-1 colon epithelial cells by producing IL-22. In conclusion, we have established a useful model for the study of intestinal damage and recovery using human colon epithelial cells and our data suggest that damage to human colon epithelial cells can, at least in part, be recovered by the autonomous production of IL-22 in response to Spirulina complex polysaccharides. © 2013.

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

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    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.

  5. IL-17 and IL-22 in Cerebrospinal Fluid and Plasma Are Elevated in Guillain-Barré Syndrome

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    Shujuan Li

    2012-01-01

    Full Text Available Guillain-Barré syndrome (GBS is an acute autoimmune-mediated inflammatory demyelinating disease that causes rapidly progressing paralysis and occasionally respiratory failure. We hypothesized that interleukin (IL-17 and IL-22 are elevated in GBS and participate in the autoimmune inflammatory response of GBS. We used sandwich enzyme-linked immunosorbent assay (ELISA to measure the IL-17 and IL-22 levels in the CSF, and plasma from 22 GBS patients at the acute phase and 18 healthy controls (HC. The results show that CSF and plasma levels of IL-17 and IL-22 are elevated in GBS patients compared with HC. IL-17 and IL-22 levels in CSF, respectively, are correlated with GBS disability scale scores (GDSs. Meanwhile, IL-17 and IL-22 levels in CSF, IL-22 in CSF, and plasma of GBS patients have positive correlation, respectively. The increased levels of IL-17 and IL-22 in CSF may be explained by the disruption of blood-brain barrier (BBB and peripheral nervous system (PNS local inflammation in GBS. Meanwhile, the elevated levels of these two cytokines in plasma suggest the activation of Th17 and Th22 cells in the systemic immune response of GBS. Our data provide preliminary evidence that GBS is associated with high levels of IL-17 and IL-22 in CSF and plasma. These cytokines display pathogenic potential and may serve as useful biomarkers for GBS.

  6. 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

  7. A higher frequency of circulating IL-22(+CD4(+ T cells in Chinese patients with newly diagnosed Hashimoto's thyroiditis.

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    Hui Guo

    Full Text Available BACKGROUND: IL-22 and IL-17A are implicated in the pathogenesis of autoimmune diseases. However, the role of IL-22(+ and IL-17A(+ CD4(+ T cells in the pathogenesis of Hashimoto's thyroiditis (HT is not fully understood. This study investigates serum IL-22 and IL-17A levels and determines the frequency of circulating IL-22(+ CD4(+ T cells in HT patients to understand their roles in the pathogenesis of HT. METHODS: The levels of serum IL-22, IL-17A and IFN-γ and the frequency of circulating IL-22(+CD4(+ and IL-17A(+CD4(+ T cells in 17 HT patients and 17 healthy controls (HC were determined by enzyme-linked immunosorbent assay (ELISA and flow cytometry. The levels of serum free triiodothyronine (FT4, free thyroxine (FT3, thyroid stimulating hormone (TSH, anti-thyroid peroxidase (TPO and anti-thyroglobulin antibodies (TgAb by chemiluminescent enzyme immunoassay and radioimmunoassay. RESULTS: The percentages of circulating IL-22(+CD4(+ and IL-17(+CD4(+ T cells (p<0.0001, p<0.0001 and the levels of serum IL-22, IL-17A and IFN-γ (p<0.0001, p<0.0001, p = 0.0210 in the HT patients were significantly higher than that in the HC. The percentages of IL-22(+CD4(+ T cells were positively correlated with Th17 cells (r = 0.8815, p<0.0001 and IL-17A(+IL-22(+CD4(+ T cells (r = 0.8914, p<0.0001, but were negatively correlated with Th1 cells (r = -0.6110, p<0.0092 in the HT patients. The percentages of Th22 cells, Th17 cells and IL-17A(+IL-22(+CD4(+ T cells were negatively correlated with the levels of serum TSH in the HT patients (r = -0.8402, p<0.0001; r = -0.8589, p<0.0001; r = -0.8289 p<0.0001, respectively. CONCLUSIONS: A higher frequency of circulating IL-22(+CD4(+ and IL-17A(+CD4(+ T cells may be associated with the development of HT in Chinese patients.

  8. Evidence for Involvement of IL-9 and IL-22 in Cows' Milk Allergy in Infants.

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    Barros, Karina V; Flor Silveira, Vera L; Laranjeira, Marisa S; Wandalsen, Neusa F; Passeti, Susana; de Oliveira, Roberta; Munekata, Regina V; Noakes, Paul S; Miles, Elizabeth A; Calder, Philip C

    2017-09-21

    Although allergic inflammation is characterized by a T helper (Th) 2-dominant immune response, the discovery of a role for new T cell subsets in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogeneses of allergic diseases. We evaluated plasma cytokine profiles in infants with cows' milk allergy (CMA), who were being treated with an elimination diet. In a prospective, randomized and controlled study, infants (aged 8.4 ± 3.9 months) with CMA were treated with an elimination diet for 120 days, which replaced cows' milk with a hydrolysed soy protein formula ( n = 26) or a free amino acid formula ( n = 20). Blood samples were collected before treatment during active disease (T0) and after 120 days, when symptoms were absent (T1). Plasma cytokine concentrations were measured. Infants with CMA had higher plasma concentrations of interleukin (IL)-4 and IL-13 and lower concentrations of IL-9, IL-17A and interferon-γ, compared with healthy breast-fed infants. At T0, there was a positive correlation between blood eosinophil numbers and plasma concentrations of IL-4, IL-9, IL-17A and IL-22. Treatment with a cows' milk elimination diet resulted in a decrease in plasma IL-4, IL-9, IL-13 and IL-22 and an increase in plasma IL-17A. We conclude that IL-4 and IL-13 are elevated in active CMA. The association of IL-9 and IL-22 with eosinophilia, and the decrease in these two cytokines with cows' milk elimination, suggests that they both play a role in the symptoms observed in CMA and may be important targets for future interventions.

  9. Effect of IL-22 on DNA vaccine encoding LACK gene of Leishmania major in BALB/c mice.

    Science.gov (United States)

    Hezarjaribi, Hajar Ziaee; Ghaffarifar, Fatemeh; Dalimi, Abdolhosein; Sharifi, Zohreh; Jorjani, Ogholniaz

    2013-07-01

    In the present study, the effect of IL-22 together with the plasmid encoding LACK (Leishmania homolog of receptors for activated C-kinase) gene of Leishmania major on the trend of leishmaniasis in BALB/c mice was evaluated. Evaluation of the cellular and humoral immunity was performed by measurement of IL-4 and IFN-γ, culture of splenocytes and MTT assay, and measurement of total IgG, IgG1, and IgG2a in the control and immunized groups. Clinical evaluations were also carried out by measurement of the lesion size, survival rate, and body weight of mice. Comparison of the mean size of lesions in the LACK and LACK+IL-22 groups demonstrated that the mean size of lesions of the two groups was significantly different from week four (pLACK gene), and pcLACK+IL-22 groups were 20%, 40%, 60%, and 80%, respectively. According to the results of IFN-γ, IL-4, total IgG, IgG1, and IgG2a measurement and the MTT assay, IL-22 obviously caused an increase in IFN-γ production and a decrease in IL-4 production before and after the challenge (p<0.05). The results showed the effectiveness of IL-22 in DNA vaccine. It showed that IL-22 brought about Th1 cytokine responses and high survival rate of mice. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. 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.

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

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    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.

  12. IL22 in Egyptian SLE patients, could it reflect disease activity, skin or renal involvement or is it only an expensive ESR?

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    Iman Ibrahim El-Gazzar

    2017-01-01

    Conclusion: Our data suggest that increased serum IL-22 may contribute to the pathogenesis of SLE. Its elevated serum level allows discrimination between patients with different clinical and laboratory measures and indicates the potential of IL-22 as an additional tool for assessment of activity in SLE. IL22 in serum seems to be a significant index reflecting skin and renal involvement in SLE.

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

    International Nuclear Information System (INIS)

    Murano, Tatsuro; Okamoto, Ryuichi; Ito, Go; Nakata, Toru; Hibiya, Shuji; Shimizu, Hiromichi; Fujii, Satoru; Kano, Yoshihito; Mizutani, Tomohiro; Yui, Shiro; Akiyama-Morio, Junko; Nemoto, Yasuhiro; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Watanabe, Mamoru

    2014-01-01

    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

  14. 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.

  15. Co-expression of S. Typhi GroEL and IL-22 gene augments immune responses against Salmonella infection.

    Science.gov (United States)

    Kaur, Gurpreet; STS, Chitradevi; Nimker, Charu; Singh, Mrinalini; Saraswat, Deepika; Saxena, Shweta; Bansal, Anju

    2013-01-01

    Recombinant DNA vaccines represent a novel method for generating in situ expression of vaccine antigens. Intramuscular injections of naked DNA are able to elicit potent humoral and cellular immune responses but still numerous factors limit the immunogenicity of DNA vaccines. Co-expression of cytokines with antigen encoding genes in DNA vectors can improve the immune responses and modify Th1/Th2 balance. In this study, the immunomodulatory effect of Interleukin 22 (IL-22) as an adjuvant was studied by DNA vaccination with S. Typhi Heat shock protein 60 (HSP60/GroEL) in mice. Further, DNA construct of IL-22 gene fused with GroEL was developed and immunization studies were carried out in mice. DNA vaccination with GroEL alone stimulated humoral and cell-mediated immune responses. Co-immunization (IL-22+GroEL) further resulted in increase in T-cell proliferative responses, antibody titres (IgG, IgG1, IgG2a) and secretion of IFNγ (Th1), IL-1β and Th2 (IL-4, IL-6) cytokines. Co-expression (IL-22-GroEL DNA) also promoted antibody titres and cytokine levels were significantly higher as compared to co-immunized group. A reduction in bacterial load in spleen, liver and intestine was seen in all the immunized groups as compared to control, with least organ burden in fusion DNA construct group (co-expression). Improved protective efficacy (90%) against lethal challenge by Salmonella was observed with IL-22-GroEL co-expressing DNA vector as compared with plasmid encoding GroEL only (50-60%) or co-immunization group (75-80%). This study thus shows that co-expression of IL-22 and GroEL genes enhances the immune responses and protective efficacy, circumventing the need of any adjuvant.

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

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    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.

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

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    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.

  18. 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.

  19. 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.

  20. 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.

  1. Role of group 3 innate lymphoid cells during experimental otitis media in a rat model.

    Science.gov (United States)

    Cho, Chang Gun; Gong, Sung Ho; Kim, Hee-Bok; Song, Jae-Jun; Park, Joo Hyun; Lim, Yun-Sung; Park, Seok-Won

    2016-09-01

    The objective of this study was to evaluate the role of group 3 innate lymphoid cells (ILC3) in the middle ear (ME) mucosal response to bacterial infection in a rat model. To confirm the role of ILC3 in bacterially induced otitis media (OM), the serum concentrations of IL-17 and IL-22 were determined by ELISA, and the tissue expression of IL-17 and IL-22 in infected ME mucosa was assessed by immunohistochemical staining. Immunohistochemical staining of specific cell surface markers was also assessed to confirm the origin of the cells expressing IL-17 and IL-22. Twenty Sprague-Dawley rats were used in the surgically-induced animal model of OM. OM was induced by inoculation of non-typeable Haemophilus influenzae into the ME cavity of the rats. The rats were divided into four experimental groups: three infected groups and one control group. Infected groups were subdivided into sets of 5 rats, one for each of the three time points (1, 4 and 7 days post-inoculation). For determination of rat IL-17 and IL-22 levels in infected rats and control rats, infected or control ME mucosa sections were analyzed by immunohistochemistry with specific antibodies directed against IL-17 and IL-22. Immunohistochemical staining for CD3, RORγt, and NKp46 were also conducted on the samples to confirm the origin of cells expressing IL-17 and IL-22. IL-17 and IL-22 serum concentrations were significantly increased in the infected rats compared to control rats. Immunohistochemical staining revealed increased IL-17 and IL-22 expressions in all infected ME mucosae from the first day after inoculation. In addition, the results of tissue staining for the specific surface markers were negative for CD3 and NKp46, but were highly positive for RORγt. IL-17 and IL-22 revealed their association with the bacterially induced proliferative and hyperplastic responses of ME mucosa, which are characteristic features in pathogenesis of OM. Surface marker examination showed that the source cells for IL-17

  2. 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...... controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes. Results We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine-producing CLA(+) T cell subtypes in nickel-allergic patients as compared with controls. In nickel......-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...

  3. 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.

  4. IL-22 mRNA Expression in Blood Samples as a Useful Biomarker for Assessing the Adverse Health Effects of PCBs on Allergic Children

    Directory of Open Access Journals (Sweden)

    Mayumi Tsuji

    2012-11-01

    Full Text Available To facilitate the assessment of adverse effects of very low concentrations of air pollutants on general populations, we planned to establish a reliable biomarker that is also useful in identifying vulnerable populations. For this purpose we monitored several inflammation markers in blood samples from 2 year old Japanese children (N = 30, and found that those children living close to major highways (<50 m show higher levels of mRNA expression IL-22 in their blood samples than those living further away (+50 m. This tendency was more pronounced among subjects showing positive IgE against egg and milk. We further examined association between IL-22 mRNA expression and PCB residues and found a number of significant positive correlations between each individual PCB congener and IL-22 expression. To identify the most vulnerable population among those children we selected asthma as a typical allergy-related disease, and could show that there are significant differences in the levels of IL-22 mRNA expression between IgE negative non-asthmatic subject and asthmatic children showing positive IgE reaction toward egg or milk, again. These observations support our main conclusion that IL-22 expression is a sensitive biomarker which is useful in identifying sub-populations of children who are especially vulnerable to air pollution.

  5. 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.

  6. 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.

  7. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health

    Science.gov (United States)

    Dietary supplementation with fermentable fiber is thought to suppress metabolic syndrome via production of short-chain fatty acids (SCFA), which activate the free fatty acid receptors including GPR43. However, herein, we demonstrate that fermentable (inulin), but not insoluble (cellulose) fiber, mar...

  10. 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

  11. Interleukin-23 (IL-23), independent of IL-17 and IL-22, drives neutrophil recruitment and innate inflammation during Clostridium difficile colitis in mice.

    Science.gov (United States)

    McDermott, Andrew J; Falkowski, Nicole R; McDonald, Roderick A; Pandit, Chinmay R; Young, Vincent B; Huffnagle, Gary B

    2016-01-01

    Our objective was to determine the role of the inflammatory cytokine interleukin-23 (IL-23) in promoting neutrophil recruitment, inflammatory cytokine expression and intestinal histopathology in response to Clostridium difficile infection. Wild-type (WT) and p19(-/-) (IL-23KO) mice were pre-treated with cefoperazone in their drinking water for 5 days, and after a 2-day recovery period were challenged with spores from C. difficile strain VPI 10463. Interleukin-23 deficiency was associated with significant defects in both the recruitment of CD11b(High) Ly6G(H) (igh) neutrophils to the colon and the expression of neutrophil chemoattractants and stabilization factors including Cxcl1, Cxcl2, Ccl3 and Csf3 within the colonic mucosa as compared with WT animals. Furthermore, the expression of inflammatory cytokines including Il33, Tnf and Il6 was significantly reduced in IL-23-deficient animals. There was also a trend towards less severe colonic histopathology in the absence of IL-23. The induction of Il17a and Il22 was also significantly abrogated in IL-23KO mice. Inflammatory cytokine expression and neutrophilic inflammation were not reduced in IL-17a-deficient mice or in mice treated with anti-IL-22 depleting monoclonal antibody. However, induction of RegIIIg was significantly reduced in animals treated with anti-IL-22 antibody. Taken together, these data indicate that IL-23, but not IL-17a or IL-22, promotes neutrophil recruitment and inflammatory cytokine and chemokine expression in the colon in response to C. difficile infection. © 2015 John Wiley & Sons Ltd.

  12. Multiparameter grouping delineates heterogeneous populations of human IL-17 and/or IL-22 T-cell producers that share antigen specificities with other T-cell subsets.

    Science.gov (United States)

    Larsen, Martin; Arnaud, Laurent; Hié, Miguel; Parizot, Christophe; Dorgham, Karim; Shoukry, Mohamed; Kemula, Mathilde; Barete, Stéphane; Derai, David; Sauce, Delphine; Amoura, Zahir; Pène, Jérôme; Yssel, Hans; Gorochov, Guy

    2011-09-01

    The ontogenic relationship between pro-inflammatory populations of interleukin-17 (IL-17A)- and/or IL-22-producing T cells and other T-cell subsets is currently unclear in humans. To appreciate T helper cell-lineage commitment, we combined cytokine production profiles of in vitro expanded T-cell clones with T-cell receptor (TCR) clonotypic signatures. Moreover, ex vivo cytokine production profiles at the single-cell level were analyzed using an original approach based on the hierarchical cluster analysis of multiparametric flow cytometry data. These combined approaches enabled the delineation of distinct functional T-cell subsets, including Th1, Th2, Tr1, Th17 cells and a highly polyfunctional IL-22-producing T-cell population. Cluster analysis highlighted that the IL-22-producing T-cell population should be considered independently from the Th17 and Th1 subsets, although it was more closely related to the former. In parallel, we observed extensive TCRαβ sharing across all five subsets defined. The strategy described here allows the objective definition of cellular subsets and an unbiased insight into their similarities. Together, our results underscore the ontogenic plasticity of CD4(+) T-cell progenitors, which can adopt a differentiation profile irrespective of antigen specificity. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Interleukin-22 protects rat PC12 pheochromocytoma cells from serum deprivation-induced cell death.

    Science.gov (United States)

    Liu, Yongchun; Pan, Wenyan; Yang, Shengmei; Wu, Xiaoying; Wu, Jianfu; Ma, Jun; Yuan, Zengqiang; Meng, Songshu

    2012-12-01

    Interleukin-22 (IL-22), an IL-10 family cytokine, mediates the crosstalk between leukocytes and epithelial cells. Previous studies reported that IL-22 expresses in mouse brain, and the rat PC12 cells are responsive to IL-22 stimulation. However, the biological roles of IL-22 in neuronal cells remain largely unknown. We show here that IL-22 activates Stat3, p38 mitogen-activated protein kinases (MAPK), and Akt pathways and inhibits Erk/MAPK pathway in naïve PC12 cells. We further demonstrate that IL-22 protects naïve PC12 cells from serum starvation-induced cell death via the Jak1/Stat3 and Akt pathways. We also show that IL-22 has no effects on naïve PC12 cell proliferation and cannot protect naïve PC12 cells from 1-methyl-4-phenylpyridinium (MPP(+))-induced cytotoxicity. However, IL-22 exerts a dose-dependent protective effect on MPP(+)-induced neurodegeneration in nerve growth factor-differentiated PC12 cells. Overall, our data suggest that IL-22 might play a role in neurological processes. To our knowledge, this is the first report showing that IL-22 confers a neuroprotective function, which may provide a new therapeutic option for treatment of neurodegenerative diseases.

  14. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    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.

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

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    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.

  16. 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.

  17. Modeling Explosion Induced Aftershocks

    Science.gov (United States)

    Kroll, K.; Ford, S. R.; Pitarka, A.; Walter, W. R.; Richards-Dinger, K. B.

    2017-12-01

    Many traditional earthquake-explosion discrimination tools are based on properties of the seismic waveform or their spectral components. Common discrimination methods include estimates of body wave amplitude ratios, surface wave magnitude scaling, moment tensor characteristics, and depth. Such methods are limited by station coverage and noise. Ford and Walter (2010) proposed an alternate discrimination method based on using properties of aftershock sequences as a means of earthquakeexplosion differentiation. Previous studies have shown that explosion sources produce fewer aftershocks that are generally smaller in magnitude compared to aftershocks of similarly sized earthquake sources (Jarpe et al., 1994, Ford and Walter, 2010). It has also been suggested that the explosion-induced aftershocks have smaller Gutenberg- Richter b-values (Ryall and Savage, 1969) and that their rates decay faster than a typical Omori-like sequence (Gross, 1996). To discern whether these observations are generally true of explosions or are related to specific site conditions (e.g. explosion proximity to active faults, tectonic setting, crustal stress magnitudes) would require a thorough global analysis. Such a study, however, is hindered both by lack of evenly distributed explosion-sources and the availability of global seismicity data. Here, we employ two methods to test the efficacy of explosions at triggering aftershocks under a variety of physical conditions. First, we use the earthquake rate equations from Dieterich (1994) to compute the rate of aftershocks related to an explosion source assuming a simple spring-slider model. We compare seismicity rates computed with these analytical solutions to those produced by the 3D, multi-cycle earthquake simulator, RSQSim. We explore the relationship between geological conditions and the characteristics of the resulting explosion-induced aftershock sequence. We also test hypothesis that aftershock generation is dependent upon the frequency

  18. Matrix models of induced QCD

    International Nuclear Information System (INIS)

    Makeenko, Yu.

    1994-01-01

    I review recent works on the problem of inducing large-N QCD by matrix fields. In the first part of the talk I describe the matrix models which induce large-N QCD and present the results of studies of their phase structure by the standard lattice technology (in particular, by the mean field method). The second part is devoted to the exact solution of these models in the strong coupling region by means of the loop equations. I describe the solution of the Kazakov-Migdal model with the quadratic and logarithmic potentials as well as that of analogous fermionic models with the quadratic potential. (orig.)

  19. CD8+ T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-γ, IL-13, IL-17 and IL-22

    Science.gov (United States)

    Hijnen, DirkJan; Knol, Edward F.; Gent, Yoony Y.; Giovannone, Barbara; Beijn, Scott; Kupper, Thomas S.; Bruijnzeel-Koomen, Carla A.F.M.; Clark, Rachael A.

    2013-01-01

    Although CD4+ T cells are known to contribute to the pathology of atopic dermatitis (AD) and psoriasis, the role of CD8+ T cells in these diseases remains poorly characterized. The aim of this study was to characterize the cytokine production of T cells from AD and psoriasis skin. We found that CD4+ T cells isolated from AD skin were largely Th2-biased, in agreement with prior reports. However, we also observed large numbers of CD8+ T cells producing IL-13, IFN-γ and IL-22. We observed increased numbers of CD8+ T cells isolated from AD skin, and immunohistochemistry studies confirmed the presence of CD8+ T cells in the dermis and epidermis of AD skin lesions. Surprisingly, T cell cytokine production was similar in the lesional and non-lesional skin of patients with AD. T cells from psoriatic lesional skin predominantly produced IFN-γ, IL-17 and IL-22, in agreement with prior studies. However, in addition to Th17 cells, we observed high percentages of CD8+ T cells that produced both IL-22 and IL-17 in psoriatic skin lesions. Our findings demonstrate that CD8+ T cells are a significant and previously unappreciated source of inflammatory cytokine production in both AD and psoriasis. PMID:23223131

  20. Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22- secreting neutrophils at early stages of Citrobacter rodentium infection.

    Science.gov (United States)

    Lee, Yong-Soo; Yang, Hyungjun; Yang, Jin-Young; Kim, Yeji; Lee, Su-Hyun; Kim, Ji Heui; Jang, Yong Ju; Vallance, Bruce A; Kweon, Mi-Na

    2015-08-01

    Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli in humans and Citrobacter rodentium in mice, raise serious public health concerns. Here we demonstrate that interleukin-1 receptor (IL-1R) signaling is indispensable for protection against C. rodentium infection in mice. Four days after infection with C. rodentium, there were significantly fewer neutrophils (CD11b+ Ly6C+ Ly6G+) in the colons of IL-1R−/− mice than in wild-type mice. Levels of mRNA and protein of KC/CXCL1 were also significantly reduced in colon homogenates of infected IL-1R−/− mice relative to wild-type mice. Of note, infiltrated CD11b+ Ly6C+ Ly6G+ neutrophils were the main source of IL-22 secretion after C. rodentium infection. Interestingly, intestinal stromal cells isolated from IL-1R−/− mice secreted lower levels of KC/CXCL1 than stromal cells from wild-type mice during C. rodentium infection. Similar effects were found when mouse intestinal stromal cells and human nasal polyp stromal cells were treated with IL-1R antagonists (i.e., anakinra) in vitro. These results suggest that IL-1 signaling plays a pivotal role in activating mucosal stromal cells to secrete KC/CXCL1, which is essential for infiltration of IL-22-secreting neutrophils upon bacterial infection.

  1. 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

  2. Psychological stress promotes neutrophil infiltration in colon tissue through adrenergic signaling in DSS-induced colitis model.

    Science.gov (United States)

    Deng, Que; Chen, Hongyu; Liu, Yanjun; Xiao, Fengjun; Guo, Liang; Liu, Dan; Cheng, Xiang; Zhao, Min; Wang, Xiaomeng; Xie, Shuai; Qi, Siyong; Yin, Zhaoyang; Gao, Jiangping; Chen, Xintian; Wang, Jiangong; Guo, Ning; Ma, Yuanfang; Shi, Ming

    2016-10-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition. Psychological stress has been postulated to affect the clinical symptoms and recurrence of IBD. The exact molecular mechanisms are not fully understood. In the present study, we demonstrate that psychological stress promotes neutrophil infiltration into colon tissues in dextran sulfate sodium (DSS)-induced colitis model. The psychological stress resulted in abnormal expression of the proinflammatory cytokines (IL-1β, IL-6, IL-17A, and IL-22) and neutrophil chemokines (CXCL1 and CXCL2) and overactivation of the STAT3 inflammatory signaling pathway. Under chronic unpredictable stress, the adrenergic nervous system was markedly activated, as the expression of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, in bone marrow and colonic epithelium was enhanced, especially in the myenteric ganglia. The β-AR agonist isoproterenol mimicked the effects of psychological stress on neutrophilia, neutrophil infiltration, and colonic damage in DSS-induced colitis. The β1-AR/β2-AR inhibitor propranolol reduced the numbers of the neutrophils in the circulation, suppressed neutrophil infiltration into colonic tissues, and attenuated the colonic tissue damage promoted by chronic stress. Propranolol also abolished stress-induced upregulation of proinflammatory cytokines and neutrophil chemokines. Our data reveal a close linkage between the β1-AR/β2-AR activation and neutrophil trafficking and also suggest the critical roles of adrenergic nervous system in exacerbation of inflammation and damage of colonic tissues in experimental colitis. The current study provides a new insight into the mechanisms underlying the association of psychological stress with excessive inflammatory response and pathophysiological consequences in IBD. The findings also suggest a potential application of neuroprotective agents to prevent relapsing immune activation in the treatment of IBD

  3. Computational modeling of induced emotion using GEMS

    NARCIS (Netherlands)

    Aljanaki, Anna; Wiering, Frans; Veltkamp, Remco

    2014-01-01

    Most researchers in the automatic music emotion recognition field focus on the two-dimensional valence and arousal model. This model though does not account for the whole diversity of emotions expressible through music. Moreover, in many cases it might be important to model induced (felt) emotion,

  4. 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

  5. Animal Models of Chemotherapy-induced Mucositis

    DEFF Research Database (Denmark)

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

    2018-01-01

    of CIM, and how to prevent it. Animal models allow highly controlled experimental conditions, detailed organ (e.g. GIT) insights, standardized, clinically-relevant treatment regimens and discovery of new biomarkers. Still, surprisingly few results from animal models have been translated into clinical CIM......Chemotherapy for cancer patients induces damaging tissue reactions along the epithelium of the gastrointestinal tract (GIT). This chemotherapy-induced mucositis (CIM) is a serious side effect of cytotoxic drugs and several animal models of CIM have been developed to help understand the progression...... mangement and treatments. The results obtained from specific animal models can be difficult to translate to the diverse range of CIM manifestations in patients that vary according to the antineoplastic drugs, dose, underlying (cancer) disease and patient characteristics (e.g. age, genetics, body...

  6. 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.

  7. Modeling of Laser-Induced Metal Combustion

    Energy Technology Data Exchange (ETDEWEB)

    Boley, C D; Rubenchik, A M

    2008-02-20

    Experiments involving the interaction of a high-power laser beam with metal targets demonstrate that combustion plays an important role. This process depends on reactions within an oxide layer, together with oxygenation and removal of this layer by the wind. We present an analytical model of laser-induced combustion. The model predicts the threshold for initiation of combustion, the growth of the combustion layer with time, and the threshold for self-supported combustion. Solutions are compared with detailed numerical modeling as benchmarked by laboratory experiments.

  8. Sugar-induced molten-globule model.

    Science.gov (United States)

    Davis-Searles, P R; Morar, A S; Saunders, A J; Erie, D A; Pielak, G J

    1998-12-01

    Proteins denature at low pH because of intramolecular electrostatic repulsions. The addition of salt partially overcomes this repulsion for some proteins, yielding a collapsed conformation called the A-state. A-states have characteristics expected for the molten globule, a notional kinetic protein folding intermediate. Here we show that the addition of neutral sugars to solutions of acid-denatured equine ferricytochrome c induces formation of the A-state in the absence of added salt. We characterized the structure and stability of the sugar-induced A-state with circular dichroism spectropolarimetry (CD) and NMR-monitored hydrogen-deuterium exchange experiments. We also examined the stability of the sugar-induced A-state as a function of sugar size and concentration. The results are interpreted using several models and we conclude that the stabilizing effect is consistent with increased steric repulsion between the protein and the sugar solutions.

  9. Continental scale modelling of geomagnetically induced currents

    Directory of Open Access Journals (Sweden)

    Sakharov Yaroslav

    2012-09-01

    Full Text Available The EURISGIC project (European Risk from Geomagnetically Induced Currents aims at deriving statistics of geomagnetically induced currents (GIC in the European high-voltage power grids. Such a continent-wide system of more than 1500 substations and transmission lines requires updates of the previous modelling, which has dealt with national grids in fairly small geographic areas. We present here how GIC modelling can be conveniently performed on a spherical surface with minor changes in the previous technique. We derive the exact formulation to calculate geovoltages on the surface of a sphere and show its practical approximation in a fast vectorised form. Using the model of the old Finnish power grid and a much larger prototype model of European high-voltage power grids, we validate the new technique by comparing it to the old one. We also compare model results to measured data in the following cases: geoelectric field at the Nagycenk observatory, Hungary; GIC at a Russian transformer; GIC along the Finnish natural gas pipeline. In all cases, the new method works reasonably well.

  10. 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.

  11. A novel BLK-induced tumor model

    DEFF Research Database (Denmark)

    Petersen, David Leander; Berthelsen, Jens; Willerslev-Olsen, Andreas

    2017-01-01

    -hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells...... expressing wild type BLK nor non-transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK-induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing...... tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK-driven lymphomagenesis and screening of novel BLK inhibitors in vivo....

  12. 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......-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...... of corrosion products affects both the time-to cover cracking and the crack width at the concrete surface....

  13. 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.

  14. 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.

  15. Numerical modeling of tunneling-induced seismicity

    Science.gov (United States)

    Rinaldi, Antonio Pio; Urpi, Luca

    2017-04-01

    Removal of rock mass in mining environment has been associated since long-time with seismic event of magnitude 3 and above, with the potential to cause damage to the infrastructures or even loss of human life. Although with similarities with mining, relatively unknown up to now are seismic events induced by tunneling. However with modern mechanized tunneling techniques, making possible to digging deeper and longer underground infrastructure, the risk is not negligible. As an example, the excavation of the 57km long Gotthard Base Tunnel has been associated more than hundred seismic events, with the largest one having magnitude of ML 2.4, damaging the tunnel infrastructures. For future scenario of deep geological storage of nuclear waste, tunneling will constitute the primary activity during site construction. Hence, it will be crucial to understand the risk associated with the underground construction operation that can reactivate seismogenic features nearby the future location of emplacement tunnels. Here we present numerical simulation aimed at understanding the potential for inducing seismicity during tunnel construction. The stress changes and their evolution during the excavation are evaluated with a finite element solver (FLAC3d). A strain-softening friction model is then used to simulate the occurrence of a sudden slip on a fault zone (if critical conditions for reactivation are reached). We also present a sensitivity analysis of the potential for inducing different seismic events by different tunnel sizes at varying distance from a nearby failure plane, with the final purpose of evaluating safety of a potential nuclear repository site on the short- and long-term.

  16. Modeling Keratoconus Using Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Joseph, Roy; Srivastava, Om P; Pfister, Roswell R

    2016-07-01

    To model keratoconus (KC) using induced pluripotent stem cells (iPSC) generated from fibroblasts of both KC and normal human corneal stroma by a viral method. Both normal and KC corneal fibroblasts from four human donors were reprogramed directly by delivering reprogramming factors in a single virus using 2A "self-cleaving" peptides, using a single polycistronic lentiviral vector coexpressing four transcription factors (Oct 4, Sox2, Klf4, and Myc) to yield iPSC. These iPS cells were characterized by immunofluorescence detection using of stem cell markers (SSEA4, Oct4, and Sox2). The mRNA sequencing was performed and the datasets were analyzed using ingenuity pathways analysis (IPA) software. The generated stem cell-like clones expressed the pluripotency markers, SSEA4, Oct4, Sox2, Tra-1-60, and also expressed pax6. Our transcriptome analysis showed 4300 genes, which had 2-fold change and 870 genes with a q-value of iPSC compared to normal iPSC. One of the genes that showed difference in KC iPSC was FGFR2 (down-regulated by 2.4 fold), an upstream target of Pi3-Kinase pathway, was further validated in keratoconus corneal sections and also KC iPSC-derived keratocytes (down regulated by 2.0-fold). Both normal and KC-derived keratocytes expressed keratocan, signature marker for keratocytes. KC iPSC-derived keratocytes showed adverse growth and proliferation and was further confirmed by using Ly2924002, a PI3k inhibitor, which severely affected the growth and differentiation in normal iPSC. Based on our result, we propose a model for KC in which inhibition FGFR2-Pi3-Kinase pathway affects the AKT phosphorylation, and thus affecting the keratocytes survival signals. This inhibition of the survival signals could be a potential mechanism for the KC-specific decreased cell survival and apoptosis of keratocytes.

  17. 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.

  18. Modeling fluid injection induced microseismicity in shales

    Science.gov (United States)

    Carcione, José M.; Currenti, Gilda; Johann, Lisa; Shapiro, Serge

    2018-02-01

    Hydraulic fracturing in shales generates a cloud of seismic—tensile and shear—events that can be used to evaluate the extent of the fracturing (event clouds) and obtain the hydraulic properties of the medium, such as the degree of anisotropy and the permeability. Firstly, we investigate the suitability of novel semi-analytical reference solutions for pore pressure evolution around a well after fluid injection in anisotropic media. To do so, we use cylindrical coordinates in the presence of a formation (a layer) and spherical coordinates for a homogeneous and unbounded medium. The involved differential equations are transformed to an isotropic diffusion equation by means of pseudo-spatial coordinates obtained from the spatial variables re-scaled by the permeability components. We consider pressure-dependent permeability components, which are independent of the spatial direction. The analytical solutions are compared to numerical solutions to verify their applicability. The comparison shows that the solutions are suitable for a limited permeability range and moderate to minor pressure dependences of the permeability. Once the pressure evolution around the well has been established, we can model the microseismic events. Induced seismicity by failure due to fluid injection in a porous rock depends on the properties of the hydraulic and elastic medium and in situ stress conditions. Here, we define a tensile threshold pressure above which there is tensile emission, while the shear threshold is obtained by using the octahedral stress criterion and the in situ rock properties and conditions. Subsequently, we generate event clouds for both cases and study the spatio-temporal features. The model considers anisotropic permeability and the results are spatially re-scaled to obtain an effective isotropic medium representation. For a 3D diffusion in spherical coordinates and exponential pressure dependence of the permeability, the results differ from those of the classical

  19. Mechanically induced residual stresses: Modelling and characterisation

    Science.gov (United States)

    Stranart, Jean-Claude E.

    Accurate characterisation of residual stress represents a major challenge to the engineering community. This is because it is difficult to validate the measurement and the accuracy is doubtful. It is with this in mind that the current research program concerning the characterisation of mechanically induced residual stresses was undertaken. Specifically, the cold expansion of fastener holes and the shot peening treatment of aerospace alloys, aluminium 7075 and titanium Ti-6Al-4V, are considered. The objective of this study is to characterise residual stresses resulting from cold working using three powerful techniques. These are: (i) theoretical using three dimensional non-linear finite element modelling, (ii) semi-destructive using a modified incremental hole drilling technique and (iii) nondestructive using a newly developed guided wave method supplemented by traditional C-scan measurements. The three dimensional finite element results of both simultaneous and sequential cold expansion of two fastener holes revealed the importance of the separation distance, the expansion level and the loading history upon the development and growth of the plastic zone and unloading residual stresses. It further showed that the commonly adopted two dimensional finite element models are inaccurate and incapable of predicting these residual stresses. Similarly, the dynamic elasto-plastic finite element studies of shot peening showed that the depth of the compressed layer, surface and sub-surface residual stresses are significantly influenced by the shot characteristics. Furthermore, the results reveal that the separation distance between two simultaneously impacting shots governs the plastic zone development and its growth. In the semi-destructive incremental hole drilling technique, the accuracy of the newly developed calibration coefficients and measurement techniques were verified with a known stress field and the method was used to measure peening residual stresses. Unlike

  20. Experimentally Induced Mammalian Models of Glaucoma

    Directory of Open Access Journals (Sweden)

    Makoto Ishikawa

    2015-01-01

    Full Text Available A wide variety of animal models have been used to study glaucoma. Although these models provide valuable information about the disease, there is still no ideal model for studying glaucoma due to its complex pathogenesis. Animal models for glaucoma are pivotal for clarifying glaucoma etiology and for developing novel therapeutic strategies to halt disease progression. In this review paper, we summarize some of the major findings obtained in various glaucoma models and examine the strengths and limitations of these models.

  1. Effects of Induced Stress on Seismic Forward Modelling and Inversion

    Science.gov (United States)

    Tromp, Jeroen; Trampert, Jeannot

    2018-01-01

    We demonstrate how effects of induced stress may be incorporated in seismic modelling and inversion. Our approach is motivated by the accommodation of prestress 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 wavespeeds; 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 2D propagation of SH waves and related Fréchet derivatives based on a spectral-element method.

  2. The farming environment protects mice from allergen-induced skin contact hypersensitivity.

    Science.gov (United States)

    Frossard, C P; Lazarevic, V; Gaïa, N; Leo, S; Doras, C; Habre, W; Schrenzel, J; Burger, D; Eigenmann, P A

    2017-06-01

    Being born and raised in a farm provides a long-lasting protection for allergies. The microbial environment provided by farm animals is crucial to induce this protective effect, although underlying immune mechanisms remain elusive. To establish a mouse model of global exposure to the farming environment and to study immunologic changes linked to protection of allergy. Mice colonies were bred in parallel in a farm cowshed and the university animal facility (AF). Mice from both locations were subjected to a skin contact allergy model. Peripheral blood cells and cell cytokine production were assessed in both populations. In addition, the gut microbiome at various ages was characterized. Mice born in the farm were less prone to develop allergy than mice bred in the AF. Mice transfers between the AF and the farm showed a better protection when mice were moved to the farm early in life. As compared to AF-bred mice, farm mice displayed early immune activation with higher CD4 + T cell population, in particular CD4 + CD25 + FoxP3 - (activated cells). The cytokine profile of mice from the farm was skewed towards an IL-17 and IL-22 secreting cell profile accompanied by increased IL-10 secretion. These differences were mostly seen within a specific age window between birth and 8 weeks of age. Microbiome analysis showed differences between 4 and 20 weeks old mice and between farm and AF mice with an increased number of Murine mastadenovirus B in young farm mice exclusively. The farming environment provides a strong, allergy protective IL-22 stimulus and generates activated CD4+ T cells. Exposure to the farm environment early in their life may also provide a better protection for contact skin allergy. Whether a viral trigger might decisively influence protection for allergies remains to be determined. © 2017 John Wiley & Sons Ltd.

  3. Hepatoprotective and anti-fibrotic functions of interleukin-22: therapeutic potential for the treatment of alcoholic liver disease.

    Science.gov (United States)

    Kong, Xiaoni; Feng, Dechun; Mathews, Stephanie; Gao, Bin

    2013-08-01

    Interleukin-22 (IL-22) plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces by binding to the receptors IL-22R1, which is generally thought to be expressed exclusively in epithelial cells, and IL-10R2. Our laboratory previously demonstrated that IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22R1 and IL-10R2. Recently, we have identified high expression levels of IL-22R1 and IL-10R2 in liver progenitor cells and hepatic stellate cells (HSCs). Overexpression of IL-22 in vivo or treatment with IL-22 in vitro promotes proliferation of liver progenitor cells via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. IL-22 treatment also prevents HSC apoptosis in vitro and in vivo. Surprisingly, overexpression of IL-22, via either gene targeting or exogenous administration of adenovirus expressing IL-22, reduces liver fibrosis and accelerates the resolution of liver fibrosis during recovery. The anti-fibrotic effects of IL-22 are mediated via the activation of STAT3 in HSCs and subsequent induction of suppressor of cytokine signaling 3, which induces HSC senescence. Taken together, the hepatoprotective, mitogenic, and anti-fibrotic effects of IL-22 are beneficial in ameliorating alcoholic liver injury. Importantly, due to the restricted expression of IL-22R1, IL-22 therapy is expected to have few side effects, thus making IL-22 a potential candidate for treatment of alcoholic liver disease. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  4. A model for proton-induced SEU

    International Nuclear Information System (INIS)

    Bion, T.; Bourrieau, J.

    1989-01-01

    This paper presents a method for predicting proton-induced single event effect (SEE) rates in devices exposed to given proton fluxes, within a particular spacecraft shielding. The approach uses heavy-ion cross section experimental data, combined with nuclear reaction calculations, in order to determine proton-induced SEE cross section versus proton energy relationship. Calculations for two devices, the Fairchild 932422 RAM and the Intel 2164A dRAM, for which heavy-ion test data was available, are presented and compared with the results of Bendel and with ground based experimental data. Available on-orbit SEE data are used and compared with the authors predictions. A comparison of predicted SEE rates for both protons and cosmic rays at various 60 degrees circular orbits is discussed. Good agreement is found in all cases

  5. 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)

  6. 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...

  7. 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...

  8. Laser induced fluorescence model of human goiter

    Science.gov (United States)

    Jaliashvili, Z. V.; Medoidze, T. D.; Mardaleishvili, K. M.; Ramsden, J. J.; Melikishvili, Z. G.

    2008-03-01

    Laser induced fluorescence (LIF) with wide area surveillance for resected thyroid tissue solid chunks is presented. The characteristic LIF spectra of goiter were established. The state of tissue at each point represents a superposition of normal and pathology states. To our knowledge two co-existing pathological effects were observed optically for the first time. It is demonstrated that the LIF spectral functions and their intensities well-labeled such areas and represent a good tool for medical diagnostics of goiter and for the definition of the degree of abnormality and geometrical sizes of these areas.

  9. Dispersion and emission modelling of traffic induced road dust

    OpenAIRE

    Berger, Janne

    2010-01-01

    This thesis is concerned with the evaluation and development of models related to the emissions and dispersion of traffic induced road dust. Road traffic is a highly important source of a range of pollutants having adverse health and environmental effects. Development of models describing traffic related emissions and dispersion of pollutants will in the end lead to robust models that well reproduce available air quality measurements. Furthermore, such models will aid the analysis of existing...

  10. A Mouse Model for Laser-induced Choroidal Neovascularization.

    Science.gov (United States)

    Shah, Ronil S; Soetikno, Brian T; Lajko, Michelle; Fawzi, Amani A

    2015-12-27

    The mouse laser-induced choroidal neovascularization (CNV) model has been a crucial mainstay model for neovascular age-related macular degeneration (AMD) research. By administering targeted laser injury to the RPE and Bruch's membrane, the procedure induces angiogenesis, modeling the hallmark pathology observed in neovascular AMD. First developed in non-human primates, the laser-induced CNV model has come to be implemented into many other species, the most recent of which being the mouse. Mouse experiments are advantageously more cost-effective, experiments can be executed on a much faster timeline, and they allow the use of various transgenic models. The miniature size of the mouse eye, however, poses a particular challenge when performing the procedure. Manipulation of the eye to visualize the retina requires practice of fine dexterity skills as well as simultaneous hand-eye-foot coordination to operate the laser. However, once mastered, the model can be applied to study many aspects of neovascular AMD such as molecular mechanisms, the effect of genetic manipulations, and drug treatment effects. The laser-induced CNV model, though useful, is not a perfect model of the disease. The wild-type mouse eye is otherwise healthy, and the chorio-retinal environment does not mimic the pathologic changes in human AMD. Furthermore, injury-induced angiogenesis does not reflect the same pathways as angiogenesis occurring in an age-related and chronic disease state as in AMD. Despite its shortcomings, the laser-induced CNV model is one of the best methods currently available to study the debilitating pathology of neovascular AMD. Its implementation has led to a deeper understanding of the pathogenesis of AMD, as well as contributing to the development of many of the AMD therapies currently available.

  11. 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.

  12. Hypoxia-induced metastasis model in embryonic zebrafish

    DEFF Research Database (Denmark)

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

    2010-01-01

    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...

  13. 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 o...

  14. 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.

  15. 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...

  16. 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.

  17. Modeling of movement-induced and flow-induced fluid forces in fast switching valves

    DEFF Research Database (Denmark)

    Roemer, Daniel Beck; Johansen, Per; Schmidt, Lasse

    2015-01-01

    Fast switching fluid power valves set strict requirements on performance, size and energy efficiency and simulation models are therefore needed to obtain good designs of such components. The valve moving member is subject to fluid forces depending on the valve flow rate and movement of the valve...... member itself. These fluid forces may be accurately simulated using Computational Fluid Dynamics (CFD) analysis, but such models suffer from being computationally expensive and is not suited for optimization routines. In this paper, a computationally inexpensive method for modeling the fluid forces...... is proposed, which includes both the flow-induced fluid forces and the movement-induced fluid forces resulting from movement of the valve moving member. The movement-induced fluid force model is based on a known solution to the linearized Navier-Stokes equations. A method for accurately simulating the flow...

  18. Assessing a 3D smoothed seismicity model of induced earthquakes

    Science.gov (United States)

    Zechar, Jeremy; Király, Eszter; Gischig, Valentin; Wiemer, Stefan

    2016-04-01

    As more energy exploration and extraction efforts cause earthquakes, it becomes increasingly important to control induced seismicity. Risk management schemes must be improved and should ultimately be based on near-real-time forecasting systems. With this goal in mind, we propose a test bench to evaluate models of induced seismicity based on metrics developed by the CSEP community. To illustrate the test bench, we consider a model based on the so-called seismogenic index and a rate decay; to produce three-dimensional forecasts, we smooth past earthquakes in space and time. We explore four variants of this model using the Basel 2006 and Soultz-sous-Forêts 2004 datasets to make short-term forecasts, test their consistency, and rank the model variants. Our results suggest that such a smoothed seismicity model is useful for forecasting induced seismicity within three days, and giving more weight to recent events improves forecast performance. Moreover, the location of the largest induced earthquake is forecast well by this model. Despite the good spatial performance, the model does not estimate the seismicity rate well: it frequently overestimates during stimulation and during the early post-stimulation period, and it systematically underestimates around shut-in. In this presentation, we also describe a robust estimate of information gain, a modification that can also benefit forecast experiments involving tectonic earthquakes.

  19. 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....

  20. 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

  1. Cancer Immunology in an Inducible Model of Breast Cancer

    Science.gov (United States)

    2005-04-01

    AD Award Number: DAMD17-02-1-0361 TITLE: Cancer Immunology in an Inducible Model of Breast Cancer PRINCIPAL INVESTIGATOR: Khashayarsha Khazaie, Ph.D...Leave blank) April 2005 Final (1 Apr 2002 - 31 Mar 2005) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Cancer Immunology in an Inducible Model of Breast Cancer...ndont Pvn~rlrn~ntq Chen t al. PNAS I January 11, 2005 I vol. 102 I no. 2 I 421 a CT4400) "T26("-) b a % H- pem b man -sdal-n q!" N,~ CD8 T celia

  2. 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.)

  3. Xenobiotic Induced Model of Primary Biliary Cirrhosis

    Directory of Open Access Journals (Sweden)

    Arsenijevic Aleksandar

    2014-10-01

    Full Text Available Primarna bilijarna ciroza (PBC je autoimunska bolest jetre koju karakteriše destrukcija intrahepatičnih žučnih kanalića i prisistvo antimitohondrijalnih antitela (AMAs. Poslednjih godina je razvijeno nekoliko mišjih modela PBC koji imaju slične serološke, biohemijske i histološke karakteristike kao i humana PBC. Ovi animalni modeli su omogućili ispitivanje etiologije i mehanizama uključenih u patogenezu PBC. U PBC imunski odgovor je usmeren na E2 komponentu 2-okso-kiseline dehidrogenaza familije enzima koji su locirani u mitohondrijama, a imunodominantni epitop je peptidna sekvenca sa lipidima koja je zajednička za ove enzime. Imunizacija miševa 2-oktinoičnom kisleinom vezanom za goveđi serumski albumin (2-OA-BSA, antigenom koji je strukturno sličan E2 subjedinici kompleksa piruvat dehidrogenaze (PDC-E2, omogućava razvoj histoloških promena koje karakterišu PBC kod ljudi. Ovaj model PBC indukovan ksenobiotikom je pogodan za ispitivanje početnih događaja u patogenezi PBC i za razvoj novih lekova za PBC.

  4. 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

  5. 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.

  6. 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

  7. Left Ventricular Systolic Dysfunction Induced by Ventricular Ectopy: a Novel Model for PVC-induced Cardiomyopathy

    Science.gov (United States)

    Huizar, Jose F.; Kaszala, Karoly; Potfay, Jonathan; Minisi, Anthony J.; Lesnefsky, Edward J.; Abbate, Antonio; Mezzaroma, Eleonora; Chen, Qun; Kukreja, Rakesh C.; Hoke, Nicholas N.; Thacker, Leroy R.; Ellenbogen, Kenneth A.; Wood, Mark A.

    2011-01-01

    Background Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathological abnormalities. Methods and Results Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n=7) or no PVCs (control, n=6). Continuous 24-hr Holter corroborated ventricular bigeminy in the PVC group (PVC 49.8% vs. control PVC group developed cardiomyopathy with a significant reduction in left ventricular (LV) ejection fraction (PVC 39.7±5.4% vs. control 60.7±3.8%, PPVC 33.3±3.5mm vs. control 23.7±3.6mm, PPVC group. PVC-induced cardiomyopathy was resolved within 2-4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy. Conclusions This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced CM lacks gross histopathological and mitochondrial abnormalities seen in other canine models of CM. PMID:21576277

  8. 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

  9. Modeling Aggressive Medulloblastoma Using Human Induced Pluripotent Stem Cells

    Science.gov (United States)

    2017-09-01

    Determine if AngII promotes MB cell tumorigenicity through a AT1R-MYC positive feedback loop. This aim will build on our working model that AngII...AWARD NUMBER: W81XWH-14-1-0176 TITLE: Modeling Aggressive Medulloblastoma Using Human-Induced Pluripotent Stem Cells PRINCIPAL INVESTIGATOR...DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response

  10. 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...

  11. Modeling laser-induced periodic surface structures: an electromagnetic approach

    NARCIS (Netherlands)

    Skolski, J.Z.P.

    2014-01-01

    This thesis presents and discusses laser-induced periodic surface structures (LIPSSs), as well as a model explaining their formation. LIPSSs are regular wavy surface structures with dimensions usually in the submicrometer range, which can develop on the surface of many materials exposed to laser

  12. Nuclear-induced XeBr/asterisk/ photolytic laser model

    Science.gov (United States)

    Wilson, J. W.

    1980-01-01

    Parameters for a photolytically pumped alkyl iodide lasant gas by the nuclear-induced XeBr excimer fluorescence are calculated according to a detailed kinetic model. High gain on the atomic iodine 2P1/2 state is estimated and 100-mJ pulses with an average power output on the order of 1 kW appear possible.

  13. Hypoxia-inducible factor-1alpha DNA induced angiogenesis in a rat cerebral ischemia model.

    Science.gov (United States)

    Matsuda, Takeshi; Abe, Tatsuya; Wu, Jian Liang; Fujiki, Minoru; Kobayashi, Hidenori

    2005-07-01

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. It consists of a regulatory subunit HIF-1alpha, which accumulates under hypoxic conditions, and a constitutively expressed subunit, HIF-1beta. In this study, we investigated HIF-1alpha naked DNA-induced angiogenesis in a cerebral ischemic model in vivo. We utilized a rat encephalo-myo-synangiosis (EMS) model and inoculated HIF-1alpha DNA into the brain surface or the temporal muscle. We analysed whether HIF-1alpha induced angiogenic factors and collateral circulation. A histological section treated with HIF-1alpha DNA showed an increased expression of HIF1 a and VEGF with collateral circulation, in comparison with control DNA (p angiogenesis development. These results suggest the feasibility of a novel approach for therapeutic collateral circulation of cerebral ischemia in which neovascularization may be achieved indirectly using a transcriptional regulatory strategy.

  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. 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.

  16. 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).

  17. Expression of interleukin-22/STAT3 signaling pathway in ulcerative colitis and related carcinogenesis

    Science.gov (United States)

    Yu, Lian-Zhen; Wang, Hai-Yang; Yang, Shu-Ping; Yuan, Zhi-Ping; Xu, Fang-Yuan; Sun, Chao; Shi, Rui-Hua

    2013-01-01

    AIM: To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS: Biopsy specimens were obtained from patients with inactive (n = 10), mild-to-moderately active (n = 30), severely active (n = 34), initial (n = 30), and chronic UC (n = 44), as well as UC patients with dysplasia (n = 10). Specimens from patients without colonic abnormalities (n = 20) served as controls. Chronic colitis in experimental mice was induced by 2.5% dextran sodium sulfate. The expression levels of IL-22, IL-23, IL-22R1 and phosphorylated STAT3 (p-STAT3) were determined by immunohistochemistry. Bcl-2, cyclin D1 and survivin expression was detected by Western blotting. RESULTS: Patients with active UC had significantly more IL-22, IL-23, IL-22R1 and p-STAT3-positive cells than the patients with inactive UC and normal controls. Furthermore, IL-22 and related proteins were closely related to the severity of the colitis. The expression of IL-22 and IL-22R1 in the tissue of initial UC was stronger than in that of chronic UC, whereas the expression of p-STAT3 was significantly increased in chronic UC tissues. In dysplasia tissues, the expression level of IL-22 and related proteins was higher compared with controls. Mouse colitis model showed that expression of IL-22, IL-22R1 and IL-23 was increased with time, p-STAT3 and the downstream gene were also remarkably upregulated. CONCLUSION: IL-22/STAT3 signaling pathway may be related to UC and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC. PMID:23674871

  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. 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.

  20. Radiation induced genome instability: multiscale modelling and data analysis

    Science.gov (United States)

    Andreev, Sergey; Eidelman, Yuri

    2012-07-01

    Genome instability (GI) is thought to be an important step in cancer induction and progression. Radiation induced GI is usually defined as genome alterations in the progeny of irradiated cells. The aim of this report is to demonstrate an opportunity for integrative analysis of radiation induced GI on the basis of multiscale modelling. Integrative, systems level modelling is necessary to assess different pathways resulting in GI in which a variety of genetic and epigenetic processes are involved. The multilevel modelling includes the Monte Carlo based simulation of several key processes involved in GI: DNA double strand breaks (DSBs) generation in cells initially irradiated as well as in descendants of irradiated cells, damage transmission through mitosis. Taking the cell-cycle-dependent generation of DNA/chromosome breakage into account ensures an advantage in estimating the contribution of different DNA damage response pathways to GI, as to nonhomologous vs homologous recombination repair mechanisms, the role of DSBs at telomeres or interstitial chromosomal sites, etc. The preliminary estimates show that both telomeric and non-telomeric DSB interactions are involved in delayed effects of radiation although differentially for different cell types. The computational experiments provide the data on the wide spectrum of GI endpoints (dicentrics, micronuclei, nonclonal translocations, chromatid exchanges, chromosome fragments) similar to those obtained experimentally for various cell lines under various experimental conditions. The modelling based analysis of experimental data demonstrates that radiation induced GI may be viewed as processes of delayed DSB induction/interaction/transmission being a key for quantification of GI. On the other hand, this conclusion is not sufficient to understand GI as a whole because factors of DNA non-damaging origin can also induce GI. Additionally, new data on induced pluripotent stem cells reveal that GI is acquired in normal mature

  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. Transgenic Mouse Models of SV40-Induced Cancer.

    Science.gov (United States)

    Hudson, Amanda L; Colvin, Emily K

    2016-01-01

    The SV40 viral oncogene has been used since the 1970s as a reliable and reproducible method to generate transgenic mouse models. This seminal discovery has taught us an immense amount about how tumorigenesis occurs, and its success has led to the evolution of many mouse models of cancer. Despite the development of more modern and targeted approaches for developing genetically engineered mouse models of cancer, SV40-induced mouse models still remain frequently used today. This review discusses a number of cancer types in which SV40 mouse models of cancer have been developed and highlights their relevance and importance to preclinical research. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Noise-induced divisive gain control in neuron models.

    Science.gov (United States)

    Longtin, André; Doiron, Brent; Bulsara, Adi R

    2002-01-01

    A recent computational study of gain control via shunting inhibition has shown that the slope of the frequency-versus-input (f-I) characteristic of a neuron can be decreased by increasing the noise associated with the inhibitory input (Neural Comput. 13, 227-248). This novel noise-induced divisive gain control relies on the concommittant increase of the noise variance with the mean of the total inhibitory conductance. Here we investigate this effect using different neuronal models. The effect is shown to occur in the standard leaky integrate-and-fire (LIF) model with additive Gaussian white noise, and in the LIF with multiplicative noise acting on the inhibitory conductance. The noisy scaling of input currents is also shown to occur in the one-dimensional theta-neuron model, which has firing dynamics, as well as a large scale compartmental model of a pyramidal cell in the electrosensory lateral line lobe of a weakly electric fish. In this latter case, both the inhibition and the excitatory input have Poisson statistics; noise-induced divisive inhibition is thus seen in f-I curves for which the noise increases along with the input I. We discuss how the variation of the noise intensity along with inputs is constrained by the physiological context and the class of model used, and further provide a comparison of the divisive effect across models.

  4. Toxin-Induced and Genetic Animal Models of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Shin Hisahara

    2011-01-01

    Full Text Available Parkinson's disease (PD is a common progressive neurodegenerative disorder. The major pathological hallmarks of PD are the selective loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal aggregates termed Lewy bodies (LBs, but the pathophysiological mechanisms are not fully understood. Epidemiologically, environmental neurotoxins such as pesticides are promising candidates for causative factors of PD. Oxidative stress and mitochondrial dysfunction induced by these toxins could contribute to the progression of PD. While most cases of PD are sporadic, specific mutations in genes that cause familial forms of PD have led to provide new insights into its pathogenesis. This paper focuses on animal models of both toxin-induced and genetically determined PD that have provided significant insight for understanding this disease. We also discuss the validity, benefits, and limitations of representative models.

  5. 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

  6. Modelling laser-induced phase transformations in semiconductors

    Czech Academy of Sciences Publication Activity Database

    Gatskevich, E.; Přikryl, Petr; Ivlev, G.

    2007-01-01

    Roč. 76, č. 1 (2007), s. 65-72 ISSN 0378-4754. [MODELLING 2005. Plzeň, 04.07.2005-08.07.2005] R&D Projects: GA ČR GA201/04/1503 Institutional research plan: CEZ:AV0Z10190503 Keywords : laser-induced phase transitions * moving boundary problem * non-equilibrium phase changer Subject RIV: BA - General Mathematics Impact factor: 0.738, year: 2007

  7. A murine model of inflammation-induced cerebral microbleeds

    OpenAIRE

    Sumbria, Rachita K.; Grigoryan, Mher Mahoney; Vasilevko, Vitaly; Krasieva, Tatiana B.; Scadeng, Miriam; Dvornikova, Alexandra K.; Paganini-Hill, Annlia; Kim, Ronald; Cribbs, David H.; Fisher, Mark J.

    2016-01-01

    Background Cerebral microhemorrhages (CMH) are tiny deposits of blood degradation products in the brain and are pathological substrates of cerebral microbleeds. The existing CMH animal models are ?-amyloid-, hypoxic brain injury-, or hypertension-induced. Recent evidence shows that CMH develop independently of hypoxic brain injury, hypertension, or amyloid deposition and CMH are associated with normal aging, sepsis, and neurodegenerative conditions. One common factor among the above pathologi...

  8. Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Kenny Bielen

    2017-06-01

    Full Text Available Biofilm-producing strains of Pseudomonas aeruginosa are a major cause of morbidity and mortality in cystic fibrosis (CF patients. In these patients, increased levels of IL-17 as well as of IL-5 and IL-13 along with arginase (Arg-positive macrophages have been observed in bronchoalveolar lavage fluid. While IL-17 is a strong proinflammatory cytokine associated with host defense against bacterial and fungal infections and is also elevated in several autoimmune diseases, IL-5/IL-13 and Arg1-positive M2 macrophages are part of the anti-inflammatory type 2 (Th2 immunity. To study whether increased IL-5 and IL-13 levels are related to biofilm formation, which is frequently observed in CF patients colonized by P. aeruginosa, we utilized an agarose bead-embedded P. aeruginosa rat model commonly employed in in vivo biofilm studies. We showed that “sterile” agarose bead instillation in rat notably increased lung transcript levels of IL-5 and IL-13 at two post-instillation study-points, day 1 and day 3. Concurrently, increased infiltration of type 2 innate cells such as eosinophils and Arg1 positive M2 activated macrophages (Arg1+CD68+ was also observed both at day 1 and day 3 while the proportion of M1 activated macrophages (iNOS+CD68+ at these time-points decreased. In contrast, P. aeruginosa-loaded beads caused a drastic elevation of proinflammatory Th1 (IFNγ, TNFα, IL-12a and antibacterial Th17 (IL-17a, IL-17f, IL-22, IL-23a cytokines along with a high influx of neutrophils and M1 macrophages, while Th2 cytokines (IL-5 and IL-13 drastically declined at day 1 post-infection. Interestingly, at day 3 post-infection, both Th1 and Th17 cytokines sharply declined and corroborated with decreased M1 and increased M2 macrophages. These data suggest that while IL-17 is linked to episodes of acute exacerbations of infection in CF patients, the increased Th2 cytokines and M2 macrophages observed in these patients are largely due to the biofilm matrix. The

  9. Cryo-Induced Thermal Wounds: A Human Acute Wound Model.

    Science.gov (United States)

    Vivas, Alejandra; Fox, Joshua D; Baquerizo Nole, Katherine L; Maderal, Andrea D; Badiavas, Evangelos; Cargill, D Innes; Slade, Herbert B; Feldman, Steven R; Kirsner, Robert S

    2015-07-01

    Clinical models are invaluable in studying wound healing. Challenges in studying human wounds include heterogeneity of patients and wounds, as well as prolonged study time, resulting in high costs. Animal models are an efficient method to study wound healing, but often lack correlation with human acute wound healing. Human wound models can be created using sharp instruments, suction, acids, heat and cold. In this observational study, we propose a practical human acute wound model where partial thickness wounds are induced by cryosurgery to create wounds that could facilitate wound healing research and development. On forearms of 8 healthy adult volunteers, freeze injuries were induced using liquid nitrogen spray delivered onto a target area of a 1 cm circular opening at a distance from the cryo-device to the skin of 0.5-1 cm. Several freeze-thaw time cycles were implemented by administering pulses ranging from 3 to 12 seconds. Clinical evaluation was performed at a 24-hour follow-up period. Blister roofs were histologically analyzed by a blinded dermatophathologist. Clinical assessment of time to heal was determined. Freeze-times greater than 5 seconds caused a majority of subjects to develop blisters, and freeze-times greater than 8 seconds resulted in uniform blister formation. Consistent histology of full thickness necrotic epidermis with intact detached basement membrane with minimal acute neutrophilic inflammatory infiltrate was observed in all blister specimens examined. The 8-second freeze-time group had a time to heal of 13-14 days, while the 12-second freeze-time group required 3 weeks to heal. After healing, an area of hypopigmented skin and slightly hypertrophic scarring remained. This novel cryo-induced wound model is a potential simple, efficient and reliable model for studying the dynamic processes involved in acute wound healing and to aid in the development of new wound healing therapies. Clinicaltrials.gov identifier: NCT01253135.

  10. 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.

  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. 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...

  13. Induced pluripotent stem cell models of lysosomal storage disorders

    Directory of Open Access Journals (Sweden)

    Daniel K. Borger

    2017-06-01

    Full Text Available Induced pluripotent stem cells (iPSCs have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models. Examples are provided to illustrate how iPSC-derived models can be employed to develop new therapeutic strategies for these disorders. We also discuss how models of these rare diseases could contribute to an enhanced understanding of more common neurodegenerative disorders such as Parkinson’s disease, and discuss key challenges and opportunities in this area of research.

  14. 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.

  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. Modeling Microgravity Induced Fluid Redistribution Autoregulatory and Hydrostatic Enhancements

    Science.gov (United States)

    Myers, J. G.; Werner, C.; Nelson, E. S.; Feola, A.; Raykin, J.; Samuels, B.; Ethier, C. R.

    2017-01-01

    Space flight induces a marked cephalad (headward) redistribution of blood and interstitial fluid potentially resulting in a loss of venous tone and reduction in heart muscle efficiency upon introduction into the microgravity environment. Using various types of computational models, we are investigating how this fluid redistribution may induce intracranial pressure changes, relevant to reported reductions in astronaut visual acuity, part of the Visual Impairment and Intracranial Pressure (VIIP) syndrome. Methods: We utilize a lumped parameter cardiovascular system (CVS) model, augmented by compartments comprising the cerebral spinal fluid (CSF) space, as the primary tool to describe how microgravity, and the associated lack of hydrostatic gradient, impacts fluid redistribution. Models of ocular fluid pressures and biomechanics then accept the output of the above model as boundary condition input to allow more detailed, local analysis (see IWS Abstract by Ethier et al.). Recently, we enhanced the capabilities our previously reported CVS model through the implementation of robust autoregulatory mechanisms and a more fundamental approach to the implementation of hydrostatic mechanisms. Modifying the approach of Blanco et al., we implemented auto-regulation in a quasi-static manner, as an averaged effect across the span of one heartbeat. This approach reduced the higher frequency perturbations from the regulatory mechanism and was intended to allow longer simulation times (days) than models that implement within-beat regulatory mechanisms (minutes). A more fundamental approach to hydrostatics was implemented by a quasi-1D approach, in which compartment descriptions include compartment length, orientation and relative position, allowed for modeling of body orientation, relative body positioning and, in the future, alternative gravity environments. At this time the inclusion of hydrostatic mechanisms supplies additional capabilities to train and validate the CVS model

  17. Modeling Genomic Imprinting Disorders Using Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Chamberlain, Stormy J; Germain, Noelle D; Chen, Pin-Fang; Hsiao, Jack S; Glatt-Deeley, Heather

    2016-01-01

    Induced pluripotent stem cell (iPSC) technology has allowed for the invaluable modeling of many genetic disorders including disorders associated with genomic imprinting. Genomic imprinting involves differential DNA and histone methylation and results in allele-specific gene expression. Most of the epigenetic marks in somatic cells are erased and reestablished during the process of reprogramming into iPSCs. Therefore, in generating models of disorders associated with genomic imprinting, it is important to verify that the imprinting status and allele-specific gene expression patterns of the parental somatic cells are maintained in their derivative iPSCs. Here, we describe three techniques: DNA methylation analysis, allele-specific PCR, and RNA FISH, which we use to analyze genomic imprinting in iPSC models of neurogenetic disorders involving copy number variations of the chromosome 15q11-q13 region.

  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. 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.

  20. 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.

  1. 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.

  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. 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.

  4. 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.

  5. A Mathematical Model of Quorum Sensing Induced Biofilm Detachment.

    Science.gov (United States)

    Emerenini, Blessing O; Hense, Burkhard A; Kuttler, Christina; Eberl, Hermann J

    2015-01-01

    Cell dispersal (or detachment) is part of the developmental cycle of microbial biofilms. It can be externally or internally induced, and manifests itself in discrete sloughing events, whereby many cells disperse in an instance, or in continuous slower dispersal of single cells. One suggested trigger of cell dispersal is quorum sensing, a cell-cell communication mechanism used to coordinate gene expression and behavior in groups based on population densities. To better understand the interplay of colony growth and cell dispersal, we develop a dynamic, spatially extended mathematical model that includes biofilm growth, production of quorum sensing molecules, cell dispersal triggered by quorum sensing molecules, and re-attachment of cells. This is a highly nonlinear system of diffusion-reaction equations that we study in computer simulations. Our results show that quorum sensing induced cell dispersal can be an efficient mechanism for bacteria to control the size of a biofilm colony, and at the same time enhance its downstream colonization potential. In fact we find that over the lifetime of a biofilm colony the majority of cells produced are lost into the aqueous phase, supporting the notion of biofilms as cell nurseries. We find that a single quorum sensing based mechanism can explain both, discrete dispersal events and continuous shedding of cells from a colony. Moreover, quorum sensing induced cell dispersal affects the structure and architecture of the biofilm, for example it might lead to the formation of hollow inner regions in a biofilm colony.

  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. 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

  8. 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

  9. Inhalation toxicology models of endotoxin- and bioaerosol-induced inflammation.

    Science.gov (United States)

    Thorne, P S

    2000-11-02

    Inhalation toxicology studies in rodents have proven their usefulness for furthering our understanding of the causal agents, mechanisms, and pathology associated with exposures to environmental endotoxins and bioaerosols. Inhalation animal models are used to determine which components of a mixture are the most important toxicants for inducing the observed adverse outcome. They are used to obtain exposure-response relationships for allergens and pro-inflammatory agents to help elucidate disease mechanisms and contribute quantitative data to the risk assessment process. Inhalation models serve as important adjuncts to epidemiology studies and human exposure studies. They are also useful for establishing phenotype in studies of genetic polymorphisms and disease susceptibility and are widely applied for evaluation of safety and efficacy for potential therapeutic agents. In order to produce reliable data, rigorous exposure chamber design, aerosol generation systems, exposure quantitation and experimental protocols must be utilized.

  10. 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.

  11. 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

  12. Comparison of methods for modelling geomagnetically induced currents

    Science.gov (United States)

    Boteler, D. H.; Pirjola, R. J.

    2014-09-01

    Assessing the geomagnetic hazard to power systems requires reliable modelling of the geomagnetically induced currents (GIC) produced in the power network. This paper compares the Nodal Admittance Matrix method with the Lehtinen-Pirjola method and shows them to be mathematically equivalent. GIC calculation using the Nodal Admittance Matrix method involves three steps: (1) using the voltage sources in the lines representing the induced geoelectric field to calculate equivalent current sources and summing these to obtain the nodal current sources, (2) performing the inversion of the admittance matrix and multiplying by the nodal current sources to obtain the nodal voltages, (3) using the nodal voltages to determine the currents in the lines and in the ground connections. In the Lehtinen-Pirjola method, steps 2 and 3 of the Nodal Admittance Matrix calculation are combined into one matrix expression. This involves inversion of a more complicated matrix but yields the currents to ground directly from the nodal current sources. To calculate GIC in multiple voltage levels of a power system, it is necessary to model the connections between voltage levels, not just the transmission lines and ground connections considered in traditional GIC modelling. Where GIC flow to ground through both the high-voltage and low-voltage windings of a transformer, they share a common path through the substation grounding resistance. This has been modelled previously by including non-zero, off-diagonal elements in the earthing impedance matrix of the Lehtinen-Pirjola method. However, this situation is more easily handled in both the Nodal Admittance Matrix method and the Lehtinen-Pirjola method by introducing a node at the neutral point.

  13. Comparison of methods for modelling geomagnetically induced currents

    Directory of Open Access Journals (Sweden)

    D. H. Boteler

    2014-09-01

    Full Text Available Assessing the geomagnetic hazard to power systems requires reliable modelling of the geomagnetically induced currents (GIC produced in the power network. This paper compares the Nodal Admittance Matrix method with the Lehtinen–Pirjola method and shows them to be mathematically equivalent. GIC calculation using the Nodal Admittance Matrix method involves three steps: (1 using the voltage sources in the lines representing the induced geoelectric field to calculate equivalent current sources and summing these to obtain the nodal current sources, (2 performing the inversion of the admittance matrix and multiplying by the nodal current sources to obtain the nodal voltages, (3 using the nodal voltages to determine the currents in the lines and in the ground connections. In the Lehtinen–Pirjola method, steps 2 and 3 of the Nodal Admittance Matrix calculation are combined into one matrix expression. This involves inversion of a more complicated matrix but yields the currents to ground directly from the nodal current sources. To calculate GIC in multiple voltage levels of a power system, it is necessary to model the connections between voltage levels, not just the transmission lines and ground connections considered in traditional GIC modelling. Where GIC flow to ground through both the high-voltage and low-voltage windings of a transformer, they share a common path through the substation grounding resistance. This has been modelled previously by including non-zero, off-diagonal elements in the earthing impedance matrix of the Lehtinen–Pirjola method. However, this situation is more easily handled in both the Nodal Admittance Matrix method and the Lehtinen–Pirjola method by introducing a node at the neutral point.

  14. Stress induced obesity: lessons from rodent models of stress

    Science.gov (United States)

    Patterson, Zachary R.; Abizaid, Alfonso

    2013-01-01

    Stress was once defined as the non-specific result of the body to any demand or challenge to homeostasis. A more current view of stress is 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 lose 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

  15. 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

  16. 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

  17. Auraptene induces oligodendrocyte lineage precursor cells in a cuprizone-induced animal model of demyelination.

    Science.gov (United States)

    Nakajima, Mitsunari; Shimizu, Risei; Furuta, Kohei; Sugino, Mami; Watanabe, Takashi; Aoki, Rui; Okuyama, Satoshi; Furukawa, Yoshiko

    2016-05-15

    We investigated the effects of auraptene on mouse oligodendroglial cell lineage in an animal model of demyelination induced by cuprizone. Auraptene, a citrus coumarin, was intraperitoneally administered to mice fed the demyelinating agent cuprizone. Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone reduced immunoreactivity for myelin-basic protein, a marker of myelin, whereas it increased immunoreactivity to platelet derived-growth factor receptor-α, a marker of oligodendrocyte precursor cells. Administration of auraptene enhanced the immunoreactivity to oligodendrocyte transcription factor 2, a marker of oligodendrocyte precursor cells and oligodendrocyte lineage precursor cells, but had no effect on immunoreactivity to myelin-basic protein or platelet-derived growth factor receptor-α. These findings suggest that auraptene promotes the production of oligodendrocyte lineage precursor cells in an animal model of demyelination and may be useful for individuals with demyelinating diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. 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

  19. 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

  20. Numerical Modelling of the Mining Induced Horizontal Displacement

    Directory of Open Access Journals (Sweden)

    Tajduś Krzysztof

    2015-12-01

    Full Text Available The paper presents results of numerical calculations and modeling of mining-induced surface deformation based on Finite Element Method (FEM. Applying the numerical method discussed to calculations allows us to assume a larger number of factors, such as rock mass structure, fracture network, rock properties, etc., which essentially affect the results obtained. On the basis of an elastic transversely isotropic model, an analysis of horizontal displacement distribution and surface subsidence was carried out for two sample regions of mines. The results of numerical calculations were later compared with the measured values. Such an analysis proved that the applied numerical model properly described distribution and values of subsidence and slope of subsidence trough, though there were serious differences in the values of calculated horizontal displacement, especially in areas of far influence range. In order to improve the matching, the influence of boundary conditions of the model on the value of calculated horizontal displacement was analyzed. The results are presented in graphs.

  1. Transmissibility of adenovirus-induced adiposity in a chicken model.

    Science.gov (United States)

    Dhurandhar, N V; Israel, B A; Kolesar, J M; Mayhew, G; Cook, M E; Atkinson, R L

    2001-07-01

    We previously reported that human adenovirus Ad-36 induces adiposity and paradoxically lower levels of serum cholesterol (CHOL) and triglycerides (TG) in animals. To evaluate the transmissibility of Ad-36 and Ad-36 induced adiposity using a chicken model. Experiment 1--four chickens were housed (two per cage) and one from each cage was inoculated with Ad-36. Duration of presence of Ad-36 DNA in the blood of all chickens was monitored. Experiment 2--two groups of chickens were intranasally inoculated with Ad-36 (infected donors, I-D) or media (control donors, C-D). Blood drawn 36 h later from I-D and C-D groups was inoculated into wing veins of recipient chickens (infected receivers, I-R, and control receivers, C-R, respectively). On sacrifice, 5 weeks post-inoculation, blood was drawn, body weight noted and visceral fat was separated and weighed. Experiment 1--Ad-36 DNA appeared in the blood of the inoculated chickens and that of uninoculated chickens (cage mates) within 12 h of inoculation and the viral DNA persisted up to 25 days in the blood. Experiment 2--compared with C-D, visceral and total body fat were significantly greater and CHOL significantly lower for the I-D and I-R. TG were significantly lower for the I-D. Ad-36 was isolated from 12 out of 16 blood samples of the I-D that were used for inoculating I-R chickens. Ad-36 DNA was present in the blood and the adipose tissue of the I-D and I-R but not in the skeletal muscles of animals selected randomly for testing. As seen in experiment 1, Ad-36 infection can be transmitted horizontally from an infected chicken to another chicken sharing the cage. Additionally, experiment 2 demonstrated blood-borne transmission of Ad-36-induced adiposity in chickens. Transmissibility of Ad-36-induced adiposity in chicken model raises serious concerns about such a possibility in humans that needs further investigation.

  2. 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.

  3. 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...

  4. A rat model of early stage osteonecrosis induced by glucocorticoids

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    Kerachian Mohammad

    2011-12-01

    Full Text Available Abstract Background Glucocorticoid (GC-induced osteonecrosis (ON is an important complication of medical therapy. The exact pathomechanisms of ON has not been clearly elucidated. There is a need for a reproducible animal model that better approximates the clinical scenario. Methods To determine the genetic susceptibility of rats to develop GC-induced femoral head ON, we evaluated 5 different inbred strains of rats (Spontaneous Hypertensive Rat, Wistar Kyoto, Wistar Furth, SASCO Fisher and Lewis. Prednisone pellets (dosage of 1.82-2.56 mg/kg/day were implanted subcutaneously for 90. After 90 days, the femurs were resected and examined histologically and radiographically. Pathological and histological examination was performed. Hematoxylin and eosin (H & E staining was used to delineate the femoral head osteonecrosis lesions as well as abnormalities of articular cartilage and growth plate. Results The greatest differences in H & E staining were seen in the Wistar Kyoto and Wistar Furth groups. In these groups 4 out of 5 and 3 out of 5, respectively, steroid-induced rats revealed growth plate disruption with acellular areas. The TUNEL apoptosis staining assay for apoptosis revealed that 4 out of 5 of Wistar Kyoto rats, 5 out of 5 of Wistar Furth, 2 out of 4 of surviving Lewis and 2 out of 2 of the surviving spontaneous hypertensive rats had apoptotic osteocytes in trabeculae, whereas none of the Fisher rats showed apoptotic osteocytes. Conclusions We postulate that Wistar Kyoto, Wistar Furth and spontaneous hypertensive rats may be strains of rats more susceptible to develop ON of the femoral head while Fisher rats were the most resistant.

  5. Leptin deficiency in mice counteracts imiquimod (IMQ)-induced psoriasis-like skin inflammation while leptin stimulation induces inflammation in human keratinocytes.

    Science.gov (United States)

    Stjernholm, Theresa; Ommen, Pernille; Langkilde, Ane; Johansen, Claus; Iversen, Lars; Rosada, Cecilia; Stenderup, Karin

    2017-04-01

    Leptin is an adipocyte-derived cytokine secreted mostly by adipose tissue. Serum leptin levels are elevated in obese individuals and correlate positively with body mass index (BMI). Interestingly, serum leptin levels are also elevated in patients with psoriasis and correlate positively with disease severity. Psoriasis is associated with obesity; patients with psoriasis have a higher incidence of obesity, and obese individuals have a higher risk of developing psoriasis. Additionally, obese patients with psoriasis experience a more severe degree of psoriasis. In this study, we hypothesised that leptin may link psoriasis and obesity and plays an aggravating role in psoriasis. To investigate leptin's role in psoriasis, we applied the widely accepted imiquimod (IMQ)-induced psoriasis-like skin inflammation mouse model on leptin-deficient (ob/ob) mice and evaluated psoriasis severity. Moreover, we stimulated human keratinocytes with leptin and investigated the effect on proliferation and expression of pro-inflammatory proteins. In ob/ob mice, clinical signs of erythema, infiltration and scales in dorsal skin and inflammation in ear skin, as measured by ear thickness, were attenuated and compared with wt mice. Moreover, IL-17A and IL-22 mRNA expression levels, as well as increased epidermal thickness, were significantly less induced. In vitro, the effect of leptin stimulation on human keratinocytes demonstrated increased proliferation and induced secretion of several pro-inflammatory proteins; two hallmarks of psoriasis. In conclusion, leptin deficiency attenuated IMQ-induced psoriasis-like skin inflammation in a mouse model, and leptin stimulation induced a pro-inflammatory phenotype in human keratinocytes, thus, supporting an aggravating role of leptin in psoriasis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Modeling Microscale Electro-thermally Induced Vortex Flows

    Science.gov (United States)

    Paul, Rajorshi; Tang, Tian; Kumar, Aloke

    2017-11-01

    In presence of a high frequency alternating electric field and a laser induced heat source, vortex flows are generated inside micro-channels. Such electro-thermally influenced micro-vortices can be used for manipulating nano-particles, programming colloidal assemblies, trapping biological cells as well as for fabricating designed bacterial biofilms. In this study, a theoretical model is developed for microscale electro-thermally induced vortex flows with multiple heat sources. Semi-analytical solutions are obtained, using Hankel transformation and linear superposition, for the temperature, pressure and velocity fields. The effect of material properties such as electrical and thermal conductivities, as well as experimental parameters such as the frequency and strength of the alternating electric field, and the intensity and heating profile of the laser source, are systematically investigated. Resolution for a pair of laser sources is determined by analyzing the strength of the micro-vortices under the influence of two heating sources. Results from this work will provide useful insights into the design of efficient optical tweezers and Rapid Electrokinetic Patterning techniques.

  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. Streptozotocin-Induced Diabetes Models: Pathophysiological Mechanisms and Fetal Outcomes

    Directory of Open Access Journals (Sweden)

    D. C. Damasceno

    2014-01-01

    Full Text Available Glucose homeostasis is controlled by endocrine pancreatic cells, and any pancreatic disturbance can result in diabetes. Because 8% to 12% of diabetic pregnant women present with malformed fetuses, there is great interest in understanding the etiology, pathophysiological mechanisms, and treatment of gestational diabetes. Hyperglycemia enhances the production of reactive oxygen species, leading to oxidative stress, which is involved in diabetic teratogenesis. It has also been suggested that maternal diabetes alters embryonic gene expression, which might cause malformations. Due to ethical issues involving human studies that sometimes have invasive aspects and the multiplicity of uncontrolled variables that can alter the uterine environment during clinical studies, it is necessary to use animal models to better understand diabetic pathophysiology. This review aimed to gather information about pathophysiological mechanisms and fetal outcomes in streptozotocin-induced diabetic rats. To understand the pathophysiological mechanisms and factors involved in diabetes, the use of pancreatic regeneration studies is increasing in an attempt to understand the behavior of pancreatic beta cells. In addition, these studies suggest a new preventive concept as a treatment basis for diabetes, introducing therapeutic efforts to minimize or prevent diabetes-induced oxidative stress, DNA damage, and teratogenesis.

  9. A Mouse Model of Hypospadias Induced by Estradiol Benzoate.

    Science.gov (United States)

    He, Hou-Guang; Han, Cong-Hui; Zhang, Wei

    2015-12-01

    We wished to establish a mouse model of hypospadias using injections of estradiol benzoate for investigating the molecular mechanisms of hypospadias. Fifty timed pregnant mice were randomly divided into five study groups: A, B, C, D, and E. These groups were injected subcutaneously with estradiol benzoate mixed with sesame oil at, respectively, the doses of 0, 0.1, 0.5, 2.5, or 12.5 mg kg(-1) days(-1) from gestation day (GD) 12 to GD 16. The pups' mortality was recorded on the day of delivery. Urethras and positions of testes were examined on postnatal day 28. The numbers of live pups were significantly lower in the study groups D and E compared to study group A (p Hypospadias was seen in groups C (3.3 %; 1/30), D (18.2 %; 4/22), and E (21.4 %; 3/14), while cryptorchidism was observed in groups C (10 %; 3/30), D (31.8 %; 7/22), and E (57.1 %; 8/14) on postnatal day 28. The experimental model of hypospadias induced by estradiol benzoate in the group D (2.5 mg kg(-1) days(-1)) was more reliable considering high mortality of the study group E. The dose of estradiol benzoate used in the group D is suitable for establishing mouse model of hypospadias.

  10. Considerations for skin carcinogenesis experiments using inducible transgenic mouse models.

    Science.gov (United States)

    Popis, Martyna C; Wagner, Rebecca E; Constantino-Casas, Fernando; Blanco, Sandra; Frye, Michaela

    2018-01-24

    This study was designed to estimate the percentage of non-malignant skin tumours (papillomas) progressing to malignant squamous cell carcinomas (SCCs) in a carcinogenesis study using established transgenic mouse models. In our skin cancer model, we conditionally induced oncogenic point mutant alleles of p53 and k-ras in undifferentiated, basal cells of the epidermis. Upon activation of the transgenes through administration of tamoxifen, the vast majority of mice (> 80%) developed skin papillomas, yet primarily around the mouth. Since these tumours hindered the mice eating, they rapidly lost weight and needed to be culled before the papillomas progressed to SCCs. The mouth papillomas formed regardless of the route of application, including intraperitoneal injections, local application to the back skin, or subcutaneous insertion of a tamoxifen pellet. Implantation of a slow releasing tamoxifen pellet into 18 mice consistently led to papilloma formation, of which only one progressed to a malignant SCC. Thus, the challenges for skin carcinogenesis studies using this particular cancer mouse model are low conversion rates of papillomas to SCCs and high frequencies of mouth papilloma formation.

  11. 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.

  12. 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.

  13. Can inducible resistance in plants cause herbivore aggregations? Spatial patterns in an inducible plant/herbivore model

    OpenAIRE

    Anderson, KE; Inouye, BD; Underwood, N

    2015-01-01

    © 2015 by the Ecological Society of America. Many theories regarding the evolution of inducible resistance in plants have an implicit spatial component, but most relevant population dynamic studies ignore spatial dynamics. We examined a spatially explicit model of plant inducible resistance and herbivore population dynamics to explore how realistic features of resistance and herbivore responses influence spatial patterning. Both transient and persistent spatial patterns developed in all model...

  14. 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.

  15. 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)

  16. 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)

  17. Modelling primaquine-induced haemolysis in G6PD deficiency.

    Science.gov (United States)

    Watson, James; Taylor, Walter Rj; Menard, Didier; Kheng, Sim; White, Nicholas J

    2017-02-04

    Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose-dependent acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd). As testing for G6PDd is often unavailable, this limits the use of primaquine for radical cure. A compartmental model of the dynamics of red blood cell production and destruction was designed to characterise primaquine-induced haemolysis using a holistic Bayesian analysis of all published data and was used to predict a safer alternative to the currently recommended once weekly 0.75 mg/kg regimen for G6PDd. The model suggests that a step-wise increase in daily administered primaquine dose would be relatively safe in G6PDd. If this is confirmed, then were this regimen to be recommended for radical cure patients would not require testing for G6PDd in areas where G6PDd Viangchan or milder variants are prevalent.

  18. Modeling Neurological Disorders by Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Tanut Kunkanjanawan

    2011-01-01

    Full Text Available Studies of human brain development are critical as research on neurological disorders have been progressively advanced. However, understanding the process of neurogenesis through analysis of the early embryo is complicated and limited by a number of factors, including the complexity of the embryos, availability, and ethical constrains. The emerging of human embryonic stem cells (hESCs and induced pluripotent stem cells (iPSCs has shed light of a new approach to study both early development and disease pathology. The cells behave as precursors of all embryonic lineages; thus, they allow tracing the history from the root to individual branches of the cell lineage tree. Systems for neural differentiation of hESCs and iPSCs have provided an experimental model that can be used to augment in vitro studies of in vivo brain development. Interestingly, iPSCs derived from patients, containing donor genetic background, have offered a breakthrough approach to study human genetics of neurodegenerative diseases. This paper summarizes the recent reports of the development of iPSCs from patients who suffer from neurological diseases and evaluates the feasibility of iPSCs as a disease model. The benefits and obstacles of iPSC technology are highlighted in order to raising the cautions of misinterpretation prior to further clinical translations.

  19. Induced pluripotent stem cells and Parkinson's disease: modelling and treatment.

    Science.gov (United States)

    Xu, Xiaoyun; Huang, Jinsha; Li, Jie; Liu, Ling; Han, Chao; Shen, Yan; Zhang, Guoxin; Jiang, Haiyang; Lin, Zhicheng; Xiong, Nian; Wang, Tao

    2016-02-01

    Many neurodegenerative disorders, such as Parkinson's disease (PD), are characterized by progressive neuronal loss in different regions of the central nervous system, contributing to brain dysfunction in the relevant patients. Stem cell therapy holds great promise for PD patients, including with foetal ventral mesencephalic cells, human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Moreover, stem cells can be used to model neurodegenerative diseases in order to screen potential medication and explore their mechanisms of disease. However, related ethical issues, immunological rejection and lack of canonical grafting protocols limit common clinical use of stem cells. iPSCs, derived from reprogrammed somatic cells, provide new hope for cell replacement therapy. In this review, recent development in stem cell treatment for PD, using hiPSCs, as well as the potential value of hiPSCs in modelling for PD, have been summarized for application of iPSCs technology to clinical translation for PD treatment. © 2016 John Wiley & Sons Ltd.

  20. Physical model studies of seismically induced deformations in slopes

    Science.gov (United States)

    Wartman, Joseph

    Physical model experiments were conducted on a 1-g shaking table with the goals of: (1) investigating the mechanisms of seismically induced permanent deformations in slopes and embankments, (2) assessing the accuracy and applicability of the popular "Newmark-type" procedures for estimating deformations in slopes, and (3) developing a suite of fully defined "model-scale" case histories for calibration of existing numerical procedures for predicting seismic slope deformations and for the future development of advanced numerical analyses. The inclined plane experiments indicated that the Newmark (1965) sliding block procedure generally provides unconservative estimates of deformation when the predominant frequency of the input motion is 0.2 to 1.5 times the natural frequency of the sliding mass. Conversely, the procedure was found to be generally conservative when the frequency ratio is in the range of about 1.5 to 2.2. The inclined plane tests also suggest that one-dimensional decoupled deformation analyses are generally conservative, with decoupled analyses overpredicting measured deformations by about 10% to 20% for the tests analyzed. The model slopes were commonly observed to displace along two or more localized shear surfaces. The multiple shear surfaces were typically of the same orientation and generally located within relatively close proximity of each other. Surface deformations varied over the length of each model, with the largest displacements occurring at the toe or along the face of the slope. Newmark's (1965) assumption that deformation occurs along a single surface reasonably approximated the actual deformation behavior for tests where multiple shear surfaces developed in close proximity to each other. For approximately half the tests, however, the single surface assumption proved to be an oversimplification. Accuracy was improved when the Newmark (1965) procedure was modified by using the acceleration-time history recorded in the soil immediately

  1. 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;…

  2. A mathematical model for the chemical reactions induced by radiation

    International Nuclear Information System (INIS)

    Negron M, A.; Ramos B, S.; Frias, D.; Sanchez M, G.

    2007-01-01

    Full text: Ferrous sulfate salt in acid solutions is one of the systems most extensively studied and most widely used. This dosimeter has received considerable attention because of its high sensitivity to X-rays and gamma radiation. With care this dosimetry is capable of a 0.1% precision for Co gamma rays. It is an easily available commercial product and can easily be prepared. However, our experimental results have shown that kinetics of the reaction mechanism initiated by radiolysis is strongly affected by changes in the temperature of irradiation. To evaluate energy deposited by gamma radiation on samples irradiated below room temperature is a truly difficult task. In fact, irradiating iron salts with gamma rays at different decreasing temperatures keeping constant the rest of irradiation conditions, we have observed a diminution of the rate of conversions of Fe 2+ into Fe 3+ . Several factors can contribute in order that the same absorbed dose will produce different amount of production of Fe 3+ . In the present paper, we present some experimental results of the response of ferrous sulfate in frozen solutions as a function of the irradiation temperature. The considered values were from 77 K, 198 K, 273 K, and 300 K. However this aim of e article concerns with the implementation of a theoretical model framework. This is a computational numerical simulation of the kinetics of reaction induced by radiation via radiolysis and the comparison with our experimental results which allowed the study of the effect of low temperature in such contexts. We also describe the mathematical model for the reaction kinetics as well as haw is obtained the temperature dependent yield by radiolysis tem. On the other hand it is detailed the computational approach. Finally a comparison between both experimental and theoretical results was compared in order to verify the reproducibility of our results from our theoretical model. (Author)

  3. Diet-induced metabolic syndrome model in rats

    Directory of Open Access Journals (Sweden)

    Reza Homayounfar

    2013-03-01

    Full Text Available Background & Objective: Risk for heart disease, diabetes, and stroke increases with the number of the metabolic risk factors. In general, a person who has the metabolic syndrome is twice as likely to develop heart disease and five times as likely to develop diabetes as someone who does not have the metabolic syndrome. High-calorie-diet rodent models have contributed significantly to the analysis of the pathophysiology of the metabolic syndrome, but their phenotype varies distinctly between different studies and maybe is not very similar to a model of the metabolic syndrome in humans. We sought to create a model in this study close to the disease in humans.   Materials & Methods: Twenty male, Wistar rats were randomly assigned to the high-calorie diet group with 416 calories per 100 grams (researcher made or the control diet group for 12 weeks. Weight changes, lipid profile, glucose, insulin levels, and QUICKI index (an indicator of insulin sensitivity were measured. Weight changes were compared using the repeated measures and the independent t-test, and serum factors were compared using the independent t-test.   Results: There was a significant change in weight, glucose, insulin, and lipid profile except for HDL at the end of the study. The QUICKI index (0.34 ± 0.02 vs. 0.40 ± 0.01; p value <0.0001 suggested that insulin resistance had been created in the high-calorie diet group.   Conclusion: The present study demonstrates the ability to make diet-induced metabolic syndrome domestically.

  4. Laser induced x-ray `RADAR' particle physics model

    Science.gov (United States)

    Lockley, D.; Deas, R.; Moss, R.; Wilson, L. A.; Rusby, D.; Neely, D.

    2016-05-01

    The technique of high-power laser-induced plasma acceleration can be used to generate a variety of diverse effects including the emission of X-rays, electrons, neutrons, protons and radio-frequency radiation. A compact variable source of this nature could support a wide range of potential applications including single-sided through-barrier imaging, cargo and vehicle screening, infrastructure inspection, oncology and structural failure analysis. This paper presents a verified particle physics simulation which replicates recent results from experiments conducted at the Central Laser Facility at Rutherford Appleton Laboratory (RAL), Didcot, UK. The RAL experiment demonstrated the generation of backscattered X-rays from test objects via the bremsstrahlung of an incident electron beam, the electron beam itself being produced by Laser Wakefield Acceleration. A key initial objective of the computer simulation was to inform the experimental planning phase on the predicted magnitude of the backscattered X-rays likely from the test objects. This objective was achieved and the computer simulation was used to show the viability of the proposed concept (Laser-induced X-ray `RADAR'). At the more advanced stages of the experimental planning phase, the simulation was used to gain critical knowledge of where it would be technically feasible to locate key diagnostic equipment within the experiment. The experiment successfully demonstrated the concept of X-ray `RADAR' imaging, achieved by using the accurate timing information of the backscattered X-rays relative to the ultra-short laser pulse used to generate the electron beam. By using fast response X-ray detectors it was possible to derive range information for the test objects being scanned. An X-ray radar `image' (equivalent to a RADAR B-scan slice) was produced by combining individual X-ray temporal profiles collected at different points along a horizontal distance line scan. The same image formation process was used to generate

  5. Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Liu, Lin L; Brumbaugh, Justin; Bar-Nur, Ori; Smith, Zachary; Stadtfeld, Matthias; Meissner, Alexander; Hochedlinger, Konrad; Michor, Franziska

    2016-12-20

    Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is typically an inefficient and asynchronous process. A variety of technological efforts have been made to accelerate and/or synchronize this process. To define a unified framework to study and compare the dynamics of reprogramming under different conditions, we developed an in silico analysis platform based on mathematical modeling. Our approach takes into account the variability in experimental results stemming from probabilistic growth and death of cells and potentially heterogeneous reprogramming rates. We suggest that reprogramming driven by the Yamanaka factors alone is a more heterogeneous process, possibly due to cell-specific reprogramming rates, which could be homogenized by the addition of additional factors. We validated our approach using publicly available reprogramming datasets, including data on early reprogramming dynamics as well as cell count data, and thus we demonstrated the general utility and predictive power of our methodology for investigating reprogramming and other cell fate change systems. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Modafinil improves monocrotaline-induced pulmonary hypertension rat model.

    Science.gov (United States)

    Lee, Hyeryon; Kim, Kwan Chang; Cho, Min-Sun; Suh, Suk-Hyo; Hong, Young Mi

    2016-07-01

    Pulmonary arterial hypertension (PAH) progressively leads to increases in pulmonary vasoconstriction. Modafinil plays a role in vasorelaxation and blocking KCa3.1 channel with a result of elevating intracellular cyclic adenosine monophosphate (cAMP) levels. The purpose of this study is to evaluate the effects on modafinil in monocrotaline (MCT)-induced PAH rat. The rats were separated into three groups: the control group, the monocrotaline (M) group (MCT 60 mg/kg), and the modafinil (MD) group (MCT 60 mg/kg + modafinil). Reduced right ventricular pressure (RVP) was observed in the MD group. Right ventricular hypertrophy was improved in the MD group. Reduced number of intra-acinar pulmonary arteries and medial wall thickness were noted in the MD group. After the administration of modafinil, protein expressions of endothelin-1 (ET-1), endothelin receptor A (ERA) and KCa3.1 channel were significantly reduced. Modafinil suppressed pulmonary artery smooth muscle cell (PASMC) proliferation via cAMP and KCa3.1 channel. Additionally, we confirmed protein expressions such as Bcl-2-associated X, vascular endothelial growth factor, tumor necrosis factor-α, and interleukin-6 were reduced in the MD group. Modafinil improved PAH by vasorelaxation and a decrease in medial thickening via ET-1, ERA, and KCa3.1 down regulation. This is a meaningful study of a modafinil in PAH model.

  7. 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

  8. ORBIT modelling of fast particle redistribution induced by sawtooth instability

    Science.gov (United States)

    Kim, Doohyun; Podestà, Mario; Poli, Francesca; Princeton Plasma Physics Laboratory Team

    2017-10-01

    Initial tests on NSTX-U show that introducing energy selectivity for sawtooth (ST) induced fast ion redistribution improves the agreement between experimental and simulated quantities, e.g. neutron rate. Thus, it is expected that a proper description of the fast particle redistribution due to ST can improve the modelling of ST instability and interpretation of experiments using a transport code. In this work, we use ORBIT code to characterise the redistribution of fast particles. In order to simulate a ST crash, a spatial and temporal displacement is implemented as ξ (ρ , t , θ , ϕ) = ∑ξmn (ρ , t) cos (mθ + nϕ) to produce perturbed magnetic fields from the equilibrium field B-> , δB-> = ∇ × (ξ-> × B->) , which affect the fast particle distribution. From ORBIT simulations, we find suitable amplitudes of ξ for each ST crash to reproduce the experimental results. The comparison of the simulation and the experimental results will be discussed as well as the dependence of fast ion redistribution on fast ion phase space variables (i.e. energy, magnetic moment and toroidal angular momentum). Work supported by the U.S. Department of Energy, Office of Science, Office of Fusion Energy Sciences under Contract Number DE-AC02-09CH11466.

  9. Geomagnetically induced currents in Uruguay: Sensitivity to modelling parameters

    Science.gov (United States)

    Caraballo, R.

    2016-11-01

    According to the traditional wisdom, geomagnetically induced currents (GIC) should occur rarely at mid-to-low latitudes, but in the last decades a growing number of reports have addressed their effects on high-voltage (HV) power grids at mid-to-low latitudes. The growing trend to interconnect national power grids to meet regional integration objectives, may lead to an increase in the size of the present energy transmission networks to form a sort of super-grid at continental scale. Such a broad and heterogeneous super-grid can be exposed to the effects of large GIC if appropriate mitigation actions are not taken into consideration. In the present study, we present GIC estimates for the Uruguayan HV power grid during severe magnetic storm conditions. The GIC intensities are strongly dependent on the rate of variation of the geomagnetic field, conductivity of the ground, power grid resistances and configuration. Calculated GIC are analysed as functions of these parameters. The results show a reasonable agreement with measured data in Brazil and Argentina, thus confirming the reliability of the model. The expansion of the grid leads to a strong increase in GIC intensities in almost all substations. The power grid response to changes in ground conductivity and resistances shows similar results in a minor extent. This leads us to consider GIC as a non-negligible phenomenon in South America. Consequently, GIC must be taken into account in mid-to-low latitude power grids as well.

  10. Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Lin L. Liu

    2016-12-01

    Full Text Available Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs is typically an inefficient and asynchronous process. A variety of technological efforts have been made to accelerate and/or synchronize this process. To define a unified framework to study and compare the dynamics of reprogramming under different conditions, we developed an in silico analysis platform based on mathematical modeling. Our approach takes into account the variability in experimental results stemming from probabilistic growth and death of cells and potentially heterogeneous reprogramming rates. We suggest that reprogramming driven by the Yamanaka factors alone is a more heterogeneous process, possibly due to cell-specific reprogramming rates, which could be homogenized by the addition of additional factors. We validated our approach using publicly available reprogramming datasets, including data on early reprogramming dynamics as well as cell count data, and thus we demonstrated the general utility and predictive power of our methodology for investigating reprogramming and other cell fate change systems.

  11. Bonnet monkey model for pancreatic changes in induced malnutrition.

    Science.gov (United States)

    Sandhyamani, S; Vijayakumari, A; Balaraman Nair, M

    1999-01-01

    Pancreatic degenerative lesions of identical nature could be induced in bonnet monkeys (Macaca radiata) fed protein-deficient tapioca or cassava starch-based and corn-starch-based diets for 3 or 5 months. Marked to severe lobular and acinar cell atrophy in animals fed low-protein diets resembled human pancreatic atrophy resulting from protein deficiency. Animals fed low-protein, high-carbohydrate diets showed lesions akin to tropical chronic calculus pancreatopathy with diabetes mellitus. The pancreatic lesions comprised moderate to marked acinar cell atrophy, marked islet hyperplasia or nesidioblastosis with hypertrophy and mucoid metaplasia of the duct epithelium. Mucoid vasculopathy of the pancreatic artery and arterioles was observed in all animals given protein-deficient diets. It was enhanced in those given additional carbohydrate. Identical lesions were observed after using either source of carbohydrate. This excluded the role of toxic factors such as cyanoglycosides or heavy metals from a tapioca source in initiating the lesions. The study establishes monkey models for the spectrum of human pancreatic changes associated with malnutrition owing to protein deficiency and nutritional imbalance with low-protein, high-starch diets. The experiments demonstrate the dual effects of similar diets on the parenchyma and vasculature of the pancreas.

  12. 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...

  13. Flow induced orientation in carbon nanotube suspensions: Modeling and experiments

    Science.gov (United States)

    Natale, Giovanniantonio

    Due to their unique properties, carbon nanotubes (CNTs) hold remarkable promise for the next generation of materials, with potential applications in organic electronics, reinforced and electrically conducting plastic composites, new alloys, and even new types of biological sensors and devices. Despite these promises and potentialities, carbon nanotube composites and suspensions are inherently difficult to process, and efficient processing schemes are only just starting to be formulated. The success of CNTs, in all potential applications, depends on the understanding and ability to control the microstructure evolution during processing. During flow, CNTs dispersed in a polymeric matrix orient and interact, inducing spatial and orientation correlations. Agglomerates can also break if the hydrodynamic forces are sufficient, increasing the probability of contact between different nanotubes and improving the interactions with the matrix and the flowability of the composite. At rest, the microstructure of the CNT suspension keeps changing due to Brownian motion and van der Waals attractive forces, and the CNTs diffuse in the suspending fluid and eventually form a network of particles. To analyze such a complex system, a low viscosity epoxy was used as the matrix to disperse the multiwall carbon nanotubes (MWCNTs). Nearly Newtonian polymers are particularly useful because they can impart significant shear stress to break the CNT agglomerates and facilitate their dispersion, while their Newtonian behavior does not mask the viscoelastic properties of the overall system. From dilute to concentrated regimes, CNT suspensions were rheologically probed to obtain information ranging from the orientation and transport of individual carbon nanotubes to the viscoelastic properties of dense and isotropic network of rods. Rheology was used to understand the microstructure evolution under flow and in static conditions. The effects of flow history, shearing velocity, rest time and

  14. 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.

  15. 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

  16. BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

    Science.gov (United States)

    Banuelos, J.; Shin, S.; Cao, Y.; Bochner, B. S.; Morales-Nebreda, L.; Budinger, G. R. S.; Zhou, L.; Li, S.; Xin, J.; Lingen, M. W.; Dong, C.; Schleimer, R. P.; Lu, N. Z.

    2016-01-01

    Background Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. Methods Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. Results Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. Conclusion Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma. PMID:26752231

  17. Pazopanib-Induced Hepatotoxicity in an Experimental Rat Model.

    Science.gov (United States)

    Cetin, Bulent; Yılmaz, Guldal Esendagli; Armagan, Berkan; Afsar, Baris; Demirci, Umut; Gulbahar, Ozlem; Gumusay, Ozge; Bilgetekin, Irem; Ozet, Ahmet; Uner, Aytug

    2018-01-01

    Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow-brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity. © 2018 S. Karger AG, Basel.

  18. 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.

  19. Can inducible resistance in plants cause herbivore aggregations? Spatial patterns in an inducible plant/herbivore model.

    Science.gov (United States)

    Anderson, Kurt E; Inouye, Brian D; Underwood, Nora

    2015-10-01

    Many theories regarding the evolution of inducible resistance in plants have an implicit spatial component, but most relevant population dynamic studies ignore spatial dynamics. We examined a spatially explicit model of plant inducible resistance and herbivore population dynamics to explore how realistic features of resistance and herbivore responses influence spatial patterning. Both transient and persistent spatial patterns developed in all models examined, where patterns manifested as wave-like aggregations of herbivores and variation in induction levels. Patterns arose when herbivores moved away from highly induced plants, there was a lag between damage and deployment of induced resistance, and the relationship between herbivore density and strength of the induction response had a sigmoid shape. These mechanisms influenced pattern formation regardless of the assumed functional relationship between resistance and herbivore recruitment and mortality. However, in models where induction affected herbivore mortality, large-scale herbivore population cycles driven by the mortality response often co-occurred with smaller scale spatial patterns driven by herbivore movement. When the mortality effect dominated, however, spatial pattern formation was completely replaced by spatially synchronized herbivore population cycles. Our results present a new type of ecological pattern formation driven by induced trait variation, consumer behavior, and time delays that has broad implications for the community and evolutionary ecology of plant defenses.

  20. 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)

  1. Development of an Animal Model of Thoracolumbar Burst Fracture-Induced Acute Spinal Cord Injury

    Science.gov (United States)

    2016-07-01

    spinal cord impactor and sustained balloon compression. 2. Keywords Spinal cord injury, spine trauma , burst fracture, large animal model 3...AWARD NUMBER: W81XWH-14-2-0013 TITLE: DEVELOPMENT OF AN ANIMAL MODEL OF THORACOLUMBAR BURST FRACTURE-INDUCED ACUTE SPINAL CORD INJURY...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER DEVELOPMENT OF AN ANIMAL MODEL OF THORACOLUMBAR BURST FRACTURE-INDUCED ACUTE SPINAL CORD INJURY 5b. GRANT

  2. 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)

  3. 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.

  4. 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.

  5. A novel gingival overgrowth mouse model induced by the combination of CsA and ligature-induced inflammation.

    Science.gov (United States)

    Okanobu, Ai; Matsuda, Shinji; Kajiya, Mikihito; Fujita, Tsuyoshi; Kittaka, Mizuho; Shiba, Hideki; Kurihara, Hidemi

    2017-06-01

    Drug-induced gingival overgrowth (DIGO) is a side effect of the enlargement of gingival tissue by phenytoin, nifedipine, and cyclosporine A (CsA). Gingival inflammation has been identified as a key factor that initiates DIGO. However, a sufficient animal model for clarifying the role of inflammation in DIGO has not yet been generated. We herein describe a novel CsA-induced gingival overgrowth mouse model to evaluate the role of inflammation. A ligature was placed around the second molar in maxillae for 7days to induce gingival inflammation, and CsA (50mg/kg/day) was administered to mice during each experimental period. The severity of gingival overgrowth and mRNA expression of inflammatory cytokines in gingiva were assessed by the gingival overgrowth degree, histological analyses, and RT-PCR. The administration of CsA for 28days in combination with ligation significantly increased the gingival overgrowth degree and expanded the connective tissue area. Increases in the gingival overgrowth degree continued in a time-dependent manner until 21days. Furthermore, the cessation of CsA reduced gingival overgrowth. Thin ligatures (7-0 size) induced weaker tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 mRNA expression and less gingival overgrowth than thick ligatures (5-0 ligature). Moreover, the administration of an antibiotic cocktail, which suppressed the expression of these inflammatory cytokines in gingiva, attenuated gingival overgrowth induced by ligatures and CsA. These results suggest that inflammation in gingival tissue plays a role in initiating CsA-induced gingival overgrowth. This gingival overgrowth mouse model has potential for elucidating the etiology of DIGO from the view point of gingival inflammation. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Flow induced noise modelling for industrial piping systems

    NARCIS (Netherlands)

    Gijrath, H.; Ǎbom, M.

    2003-01-01

    Noise from e.g. gas-transport piping systems becomes more and more a problem for plants located close to urban areas. Too high noise levels are unacceptable and will put limitations on the plant capacity. Flow-induced noise of valves, orifices and headers installed in the installation plays a

  7. 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....

  8. A genetically inducible porcine model of intestinal cancer

    DEFF Research Database (Denmark)

    Callesen, Morten M.; Árnadóttir, Sigrid S.; Lyskjær, Iben

    2017-01-01

    of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase-inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT - which inhibits p53 - and pRB and (b) a 4-hydroxytamoxifen (4-OHT...

  9. 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

  10. 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)

  11. 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

  12. FINITE ELEMENT MODELS FOR COMPUTING SEISMIC INDUCED SOIL PRESSURES ON DEEPLY EMBEDDED NUCLEAR POWER PLANT STRUCTURES.

    Energy Technology Data Exchange (ETDEWEB)

    XU, J.; COSTANTINO, C.; HOFMAYER, C.

    2006-06-26

    PAPER DISCUSSES COMPUTATIONS OF SEISMIC INDUCED SOIL PRESSURES USING FINITE ELEMENT MODELS FOR DEEPLY EMBEDDED AND OR BURIED STIFF STRUCTURES SUCH AS THOSE APPEARING IN THE CONCEPTUAL DESIGNS OF STRUCTURES FOR ADVANCED REACTORS.

  13. 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)

  14. 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...

  15. 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

  16. 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.

  17. Parametric analysis of a phenomenological model for vortex-induced motions of monocolumn platforms

    OpenAIRE

    ROSETTI, Guilherme F.; GONÇALVES, Rodolfo T.; FUJARRA, André L. C.; NISHIMOTO, Kazuo

    2011-01-01

    Phenomenological models are an important branch in VIV (Vortex-Induced Vibrations) and in VIM (Vortex-Induced Motions) studies to complement the results achieved via CFD (Computational Fluid Dynamics), as the latter tool is not presently a suitable tool for intense use in engineering analysis, due to high computer power requirements. A phenomenological model for evaluating the VIM on monocolumn platforms is presented and its results are compared with experimental ones. The main objective is t...

  18. A Computational and Mathematical Model for Device Induced Thrombosis

    Science.gov (United States)

    Wu, Wei-Tao; Aubry, Nadine; Massoudi, Mehrdad; Antaki, James

    2015-11-01

    Based on the Sorenson's model of thrombus formation, a new mathematical model describing the process of thrombus growth is developed. In this model the blood is treated as a Newtonian fluid, and the transport and reactions of the chemical and biological species are modeled using CRD (convection-reaction-diffusion) equations. A computational fluid dynamic (CFD) solver for the mathematical model is developed using the libraries of OpenFOAM. Applying the CFD solver, several representative benchmark problems are studied: rapid thrombus growth in vivo by injecting Adenosine diphosphate (ADP) using iontophoretic method and thrombus growth in rectangular microchannel with a crevice which usually appears as a joint between components of devices and often becomes nidus of thrombosis. Very good agreements between the numerical and the experimental results validate the model and indicate its potential to study a host of complex and practical problems in the future, such as thrombosis in blood pumps and artificial lungs.

  19. 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.

  20. 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

  1. 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......)(0) for each of the 67 months of Orsted and CHAMP data that have been used. We discuss the advantage of this new parameterization of external and induced field for geomagnetic field modeling, and describe the derivation of candidate models for IGRF 2005....

  2. 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.

  3. Modeling and Manipulating Human Diseases with Induced Pluripotent Stem Cells, Pig Models and Precision Gene Editing.

    Directory of Open Access Journals (Sweden)

    Yonglun Luo

    2016-06-01

    Full Text Available We have developed systems, e.g. C-Check, that can be used to rapidly select and quantify CRISPR/Cas9 nuclease activity and enrichment of genetically modified cells with desired mutations (Zhou et al., 2016. To facilitate the simultaneous manipulation of multiple genes in cells, we have developed a system that allows concordant delivery of up to 30 sgRNAs into one cell [Johan Vad-Nielsen et al., under review]. Targeted insertion, fluorescent tagging or correction of endogenous genes is of great interest but greatly hampered by the technical difficulties and relatively low homology directed repair efficiency compared to the higher efficiency of NHEJ. Thus, we have developed systems for rapid generation of gene targeting vectors (Luo et al., 2014, lentivirus-mediated gene targeting [Yujia Cai et al., Elife, in revision], and recombinant Cas9s to enhance HDR in mammalian cells. Furthermore, to recapitulate the pathogenesis of human diseases, we have developed pig models of breast cancer and diabetes using gene editing and SCNT, as well as human induced pluripotent stem cell models of MCADD.

  4. A lattice model exhibiting radiation-induced anomalous conductivity

    OpenAIRE

    Kimball, J. C.; Lee, Keeyung

    2003-01-01

    A lattice-based model exhibits an unusual conductivity when it is subjected to both a static magnetic field and electromagnetic radiation. This conductivity anomaly may explain some aspects of the recently observed "zero-resistance states". PACS: 72.40+w, 73.40-c, 73.63 Keywords: Zero-resistance states, negative conductivity, lattice model

  5. 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

  6. 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

    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...

  7. 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

  8. 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.

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

    DEFF Research Database (Denmark)

    Poon, Anna; Zhang, Yu; Chandrasekaran, Abinaya

    2017-01-01

    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...... 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...

  10. Modelling blast induced damage from a fully coupled explosive charge

    Science.gov (United States)

    Onederra, Italo A.; Furtney, Jason K.; Sellers, Ewan; Iverson, Stephen

    2015-01-01

    This paper presents one of the latest developments in the blasting engineering modelling field—the Hybrid Stress Blasting Model (HSBM). HSBM includes a rock breakage engine to model detonation, wave propagation, rock fragmentation, and muck pile formation. Results from two controlled blasting experiments were used to evaluate the code’s ability to predict the extent of damage. Results indicate that the code is capable of adequately predicting both the extent and shape of the damage zone associated with the influence of point-of-initiation and free-face boundary conditions. Radial fractures extending towards a free face are apparent in the modelling output and matched those mapped after the experiment. In the stage 2 validation experiment, the maximum extent of visible damage was of the order of 1.45 m for the fully coupled 38-mm emulsion charge. Peak radial velocities were predicted within a relative difference of only 1.59% at the nearest history point at 0.3 m from the explosive charge. Discrepancies were larger further away from the charge, with relative differences of −22.4% and −42.9% at distances of 0.46 m and 0.61 m, respectively, meaning that the model overestimated particle velocities at these distances. This attenuation deficiency in the modelling produced an overestimation of the damage zone at the corner of the block due to excessive stress reflections. The extent of visible damage in the immediate vicinity of the blasthole adequately matched the measurements. PMID:26412978

  11. Carbon monoxide inhalation induces headache in a human headache model

    DEFF Research Database (Denmark)

    Arngrim, Nanna; Schytz, Henrik Winther; Britze, Josefine

    2018-01-01

    Introduction Carbon monoxide (CO) is an endogenously produced signalling molecule that has a role in nociceptive processing and cerebral vasodilatation. We hypothesized that inhalation of CO would induce headache and vasodilation of cephalic and extracephalic arteries. Methods In a randomized......, double-blind, placebo-controlled crossover design, 12 healthy volunteers were allocated to inhalation of CO (carboxyhemoglobin 22%) or placebo on two separate days. Headache was scored on a verbal rating scale from 0-10. We recorded mean blood velocity in the middle cerebral artery (VMCA) by transcranial...... Doppler, diameter of the superficial temporal artery (STA) and radial artery (RA) by high-resolution ultrasonography and facial skin blood flow by laser speckle contrast imaging. Results Ten volunteers developed headache after CO compared to six after placebo. The area under the curve for headache (0...

  12. Arsenic-induced bladder cancer in an animal model

    International Nuclear Information System (INIS)

    Cohen, Samuel M.; Ohnishi, Takamasa; Arnold, Lora L.; Le, X. Chris

    2007-01-01

    Dimethylarsinic acid (DMA V ) is carcinogenic to the rat urinary bladder, but not in mice. The carcinogenic mode of action involves cytotoxicity followed by regenerative cell proliferation. Dietary DMA V does not produce urinary solids or significant alterations in urinary composition. The cytotoxicity is due to formation of a reactive metabolite, likely dimethylarsinous acid (DMA III ), concentrated and excreted in the urine. Urinary concentrations of DMA III are dose-dependent, and the urinary concentrations are at cytotoxic levels based on in vitro studies. The no observed effect level (NOEL) in these rat dietary studies for detectable levels of DMA III , cytotoxicity, and proliferation is 2 ppm, with marginal changes at 10 ppm. The tumorigenic dose is 100 ppm. Recent investigations have demonstrated that arsenicals administered to the rat result in binding to a specific cysteine in the hemoglobin alpha chain as DMA III , regardless of the arsenical being administered. Monomethylarsonic acid (MMA V ) is not carcinogenic in rats or mice. In short term experiments (≤ 10 weeks), sodium arsenate in the drinking water induces significant cytotoxicity and regenerative proliferation. There is little evidence that the cytotoxicity produced following administration of arsenicals is caused by oxidative damage, as antioxidants show little inhibitory activity of the cytotoxicity of the various arsenicals either in vitro or in vivo. In summary, the mode of action for DMA V -induced bladder carcinogenesis in the rat involves generation of a reactive metabolite (DMA III ) leading to cytotoxicity and regenerative proliferation, is a non-linear process, and likely involves a threshold. Extrapolation to human risk needs to take this into account along with the significant differences in toxicokinetics and toxicodynamics that occur between different species

  13. 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.

  14. Experimentation and numerical modeling of forging induced bending (FIB) process

    Science.gov (United States)

    Naseem, S.; van den Boogaard, A. H.

    2016-10-01

    Accurate prediction of the final shape using numerical modeling has been a top priority in the field of sheet and bulk forming. Better shape prediction is the result of a better estimation of the physical stress and strain state. For experimental and numerical investigations of such estimations, simple benchmark processes are used. In this paper a benchmark process involving forging (flattening) of sheet metal between punch and die with negative clearance is proposed. The introduced material flow results in bending. Easy measurability of the angle of this bend makes this process suitable for validation purpose. Physical experiments are performed to characterize this bending angle due to flattening. Furthermore a numerical model is developed to capture this phenomenon. The main focus of this paper is the validation of the numerical model in terms of accurate prediction of the physical results.

  15. 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.

  16. Towards Quantitative Systems Pharmacology Models of Chemotherapy-Induced Neutropenia.

    Science.gov (United States)

    Craig, M

    2017-05-01

    Neutropenia is a serious toxic complication of chemotherapeutic treatment. For years, mathematical models have been developed to better predict hematological outcomes during chemotherapy in both the traditional pharmaceutical sciences and mathematical biology disciplines. An increasing number of quantitative systems pharmacology (QSP) models that combine systems approaches, physiology, and pharmacokinetics/pharmacodynamics have been successfully developed. Here, I detail the shift towards QSP efforts, emphasizing the importance of incorporating systems-level physiological considerations in pharmacometrics. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  17. Time fractional capital-induced labor migration model

    Science.gov (United States)

    Ali Balcı, Mehmet

    2017-07-01

    In this study we present a new model of neoclassical economic growth by considering that workers move from regions with lower density of capital to regions with higher density of capital. Since the labor migration and capital flow involves self-similarities in long range time, we use the fractional order derivatives for the time variable. To solve this model we proposed Variational Iteration Method, and studied numerically labor migration flow data from Turkey along with other countries throughout the period of 1966-2014.

  18. 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.

  19. 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.

  20. 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.

  1. 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

    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 at the reinforce...... 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.......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...... 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...

  2. 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

    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...

  3. 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.

  4. A Model for Breast Cancer-Induced Angiogenesis

    Science.gov (United States)

    1996-09-01

    new vessels occurs primarily during disease processes, therapeutic modalities which target new vessels selectively inhibit tumor growth without... mammoplasties . The adipose tissue which comprises most of the specimen is translucent under bright light allowing identification of large vessel which...targets of therapeutic intervention. Finally, we are proposing to develop an organ culture model system in which to examine the angiogenic effect of

  5. 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 ...

  6. 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.

  7. 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)

  8. 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

  9. Inflammatory bowel disease: a model of chronic inflammation-induced cancer.

    Science.gov (United States)

    Yang, Guang-Yu; Taboada, Sofia; Liao, Jie

    2009-01-01

    Chronic inflammation is a well-recognized risk factor for the development of human cancer. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a typical longstanding inflammatory disease of the colon with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic inflammatory process may contribute to multistage progression of human cancer development, including the overproduction of reactive oxygen and nitrogen species, overproduction/activation of key arachidonic acid metabolites and cytokines/growth factors, and immunity system dysfunction. Multiple animal models of IBD have been established, and in general, these models can be mainly categorized into chemically induced, genetically engineered (transgenic or gene knock-out), spontaneous, and adoptive transferring animal models. This chapter mainly focuses on (1) epidemiologic and molecular evidence on IBD and risk of colorectal cancer, (2) molecular pathogenesis of IBD-induced carcinogenesis, and (3) modeling of IBD-induced carcinogenesis in rodents and its application.

  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. 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.

  12. Crustaceans as a model for microgravity-induced muscle atrophy

    Science.gov (United States)

    Mykles, D. L.

    Atrophy of skeletal muscles is a serious problem in a microgravity environment. It is hypothesized that the unloading of postural muscles, which no longer must resist gravity force, causes an accelerated breakdown of contractile proteins, resulting in a reduction in muscle mass and strength. A crustacean model using the land crab, Gecarcinus lateralis, to assess the effects of spaceflight on protein metabolism is presented. The model is compared to a developmentally-regulated atrophy in which a premolt reduction in muscle mass allows the withdrawal of the large claws at molt. The biochemical mechanisms underlying protein breakdown involves both Ca^2+-dependent and multicatalytic proteolytic enzymes. Crustacean claw muscle can be used to determine the interactions between shortening and unloading at the molecular level.

  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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...

  18. 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.

  19. 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

  20. Modeling and Mechanism of Rain-Wind Induced Vibration of Bundled Conductors

    Directory of Open Access Journals (Sweden)

    Chao Zhou

    2016-01-01

    Full Text Available Under the certain rain-wind conditions, bundled conductors exhibit a rain-wind induced large-amplitude vibration. This type of vibration can cause the fatigue fractures of conductors and fatigue failures of spacers, which threaten the safety operation and serviceability of high-voltage transmission line. To reveal the mechanism of rain-wind induced vibration of bundled conductors, a series of 2-dimensional CFD models about the twin bundled conductors with rivulets are developed to obtain the curves of aerodynamic coefficients with the upper rivulet angle. The influences of the forward conductor’s aerodynamic shielding and the upper rivulet’s aerodynamic characteristics on the leeward conductor are discussed. Furthermore, a 2-dimensional 3DOF model for the rain-wind induced vibration of the leeward conductor is established. The model is solved by finite element method and Newmark method, and the effects of the wind velocity and the upper rivulet’s motion on vibration amplitude of the leeward conductor are analyzed. By contrast with the wake-induced vibration, it can easily find that the characteristics of rain-wind vibration are obviously different from those of the wake-induced vibration, and the main reason of the rain-induced vibration may be due to the upper rivulet’s motion.

  1. 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.

  2. 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.

  3. 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.

  4. Approaches to modelling irradiation-induced processes in transmission electron microscopy.

    Science.gov (United States)

    Skowron, Stephen T; Lebedeva, Irina V; Popov, Andrey M; Bichoutskaia, Elena

    2013-08-07

    The recent progress in high-resolution transmission electron microscopy (HRTEM) has given rise to the possibility of in situ observations of nanostructure transformations and chemical reactions induced by electron irradiation. In this article we briefly summarise experimental observations and discuss in detail atomistic modelling of irradiation-induced processes in HRTEM, as well as mechanisms of such processes recognised due to modelling. Accurate molecular dynamics (MD) techniques based on first principles or tight-binding models are employed in the analysis of single irradiation-induced events, and classical MD simulations are combined with a kinetic Monte Carlo algorithm to simulate continuous irradiation of nanomaterials. It has been shown that sulphur-terminated graphene nanoribbons are formed inside carbon nanotubes as a result of an irradiation-selective chemical reaction. The process of fullerene formation in HRTEM during continuous electron irradiation of a small graphene flake has been simulated, and mechanisms driving this transformation analysed.

  5. 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

  6. 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

  7. 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.

  8. 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

  9. Establishment of tensile failure induced sanding onset prediction model for cased-perforated gas wells

    Directory of Open Access Journals (Sweden)

    Mohammad Tabaeh Hayavi

    2017-04-01

    Full Text Available Sand production is a challenging issue in upstream oil and gas industry, causing operational and safety problems. Therefore, before drilling the wells, it is essential to predict and evaluate sanding onset of the wells. In this paper, new poroelastoplastic stress solutions around the perforation tunnel and tip based on the Mohr–Coulomb criterion are presented firstly. Based on the stress models, a tensile failure induced sanding onset prediction model for cased-perforated gas wells is derived. Then the analytical model is applied to field data to verify its applicability. The results from the perforation tip tensile failure induced sanding model are very close to field data. Therefore, this model is recommended for forecasting the critical conditions of sand production analysis. Such predictions are necessary for providing technical support for sand control decision-making and predicting the production condition at which sanding onset occurs.

  10. 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)

  11. 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.

  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.

    1991-01-01

    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.)

  13. 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.

  14. Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis.

    Directory of Open Access Journals (Sweden)

    Takeshi Okinami

    Full Text Available Lower urinary tract symptoms (LUTS include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS. Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1, one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation.

  15. Dislocation-induced superfluidity in a model supersolid

    Energy Technology Data Exchange (ETDEWEB)

    Goswami, Debajit [Universitaet des Saarlandes, Saarbruecken (Germany); Dasbiswas, Kinjal; Dorsey, Alan [University of Florida, Gainesville, FL (United States); Yoo, Chi-Deuk [University of Minnesota, Minneapolis, MN (United States)

    2012-07-01

    Motivated by recent experiments on the supersolid behavior of {sup 4}He, we study the effect of an edge dislocation in promoting superfluidity in a Bose crystal. Using Landau theory, we couple the elastic strain field of the dislocation to the superfluid density, and use a linear analysis to show that superfluidity nucleates on the dislocation before occurring in the bulk of the solid. Moving beyond the linear analysis, we develop a systematic perturbation theory in the weakly nonlinear regime, and use this method to integrate out transverse degrees of freedom and derive a one-dimensional Landau equation for the superfluid order parameter. We then extend our analysis to a network of dislocation lines, and derive an XY model for the dislocation network by integrating over fluctuations in the order parameter. Our results show that the ordering temperature for the network has a sensitive dependence on the dislocation density, consistent with numerous experiments that find a clear connection between the sample quality and the supersolid response.

  16. Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia.

    Science.gov (United States)

    Vigano, Daniela; Guidali, Cinzia; Petrosino, Stefania; Realini, Natalia; Rubino, Tiziana; Di Marzo, Vincenzo; Parolaro, Daniela

    2009-06-01

    Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and schizophrenia. Our studies showed that chronic-intermittent phencyclidine (PCP) treatment of rats, an animal model of schizophrenia-like cognitive deficit, impaired recognition memory in the novel object recognition (NOR) test and induced alterations in CB1 receptor functionality and in endocannabinoid levels mainly in the prefrontal cortex. In this region, we observed a significant reduction in GTPgammaS binding (-41%) accompanied by an increase in the levels of the endocannabinoid 2-AG (+38%) in PCP-treated rats, suggesting that a maladaptation of the endocannabinoid system might contribute to the glutamatergic-related cognitive symptoms encountered in schizophrenia disorders. Moreover, we evaluated the ability of the main psychoactive ingredient of marijuana, Delta9-tetrahydrocannabinol (THC), to modulate the cognitive dysfunctions and neuroadaptations in the endocannabinoid system induced by PCP. Chronic THC co-treatment worsened PCP-induced cognitive impairment, without inducing any effect per se, and in parallel, it provoked a severe reduction in the levels of the other endocannabinoid, AEA, vs. either vehicle (-73%) or PCP (-64%), whereas it reversed the PCP-induced increase in 2-AG levels. These results point to the involvement of the endocannabinoid system in this pharmacological model of cognitive dysfunction, with a potentially different role of AEA and 2-AG in schizophrenia-like behaviours and suggest that prolonged cannabis use might aggravate cognitive performances induced by chronic PCP by throwing off-balance the endocannabinoid system.

  17. The Involvement of the Oxidative Stress in Murine Blue LED Light-Induced Retinal Damage Model.

    Science.gov (United States)

    Nakamura, Maho; Kuse, Yoshiki; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

    2017-01-01

    The aim of study was to establish a mouse model of blue light emitting diode (LED) light-induced retinal damage and to evaluate the effects of the antioxidant N-acetylcysteine (NAC). Mice were exposed to 400 or 800 lx blue LED light for 2 h, and were evaluated for retinal damage 5 d later by electroretinogram amplitude and outer nuclear layer (ONL) thickness. Additionally, we investigated the effect of blue LED light exposure on shorts-wave-sensitive opsin (S-opsin), and rhodopsin expression by immunohistochemistry. Blue LED light induced light intensity dependent retinal damage and led to collapse of S-opsin and altered rhodopsin localization from inner and outer segments to ONL. Conversely, NAC administered at 100 or 250 mg/kg intraperitoneally twice a day, before dark adaptation and before light exposure. NAC protected the blue LED light-induced retinal damage in a dose-dependent manner. Further, blue LED light-induced decreasing of S-opsin levels and altered rhodopsin localization, which were suppressed by NAC. We established a mouse model of blue LED light-induced retinal damage and these findings indicated that oxidative stress was partially involved in blue LED light-induced retinal damage.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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)

  3. Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease.

    Science.gov (United States)

    F Hernández, Ledia; Castela, Ivan; Ruiz-DeDiego, Irene; Obeso, Jose A; Moratalla, Rosario

    2017-04-01

    Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno-associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6-hydroxydopamine lesion but l-dopa naïve rats induced involuntary movements similar to l-dopa-induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l-dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l-dopa-induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine-depleted hemisphere. Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6-hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato-nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l-dopa-induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  4. 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.

  5. Noise-Induced Transitions in a Population Growth Model Based on Size-Dependent Carrying Capacity

    Directory of Open Access Journals (Sweden)

    Neeme Lumi

    2014-01-01

    Full Text Available The stochastic dynamics of a population growth model with size-dependent carrying capacity is considered. The effect of a fluctuating environment on population growth is modeled as a multiplicative dichotomous noise. At intermediate values of population size the deterministic counterpart of the model behaves similarly to the Von Foerster model for human population, but at small and very large values of population size substantial differences occur. In the stochastic case, an exact analytical solution for the stationary probability distribution is found. It is established that variation of noise correlation time can cause noise-induced transitions between three different states of the system characterized by qualitatively different behaviors of the probability distributions of the population size. Also, it is shown that, in some regions of the system parameters, variation of the amplitude of environmental fluctuations can induce single unidirectional abrupt transitions of the mean population size.

  6. A kinetic-based model of radiation-induced intercellular signalling.

    Directory of Open Access Journals (Sweden)

    Stephen J McMahon

    Full Text Available It is now widely accepted that intercellular communication can cause significant variations in cellular responses to genotoxic stress. The radiation-induced bystander effect is a prime example of this effect, where cells shielded from radiation exposure see a significant reduction in survival when cultured with irradiated cells. However, there is a lack of robust, quantitative models of this effect which are widely applicable. In this work, we present a novel mathematical model of radiation-induced intercellular signalling which incorporates signal production and response kinetics together with the effects of direct irradiation, and test it against published data sets, including modulated field exposures. This model suggests that these so-called "bystander" effects play a significant role in determining cellular survival, even in directly irradiated populations, meaning that the inclusion of intercellular communication may be essential to produce robust models of radio-biological outcomes in clinically relevant in vivo situations.

  7. 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.

  8. Integrated Modeling of Spatial and Temporal Heterogeneities and Decisions Induced by Catastrophic Events

    OpenAIRE

    Ermolieva, T.Y.; Fischer, G.; Obersteiner, M.

    2003-01-01

    This paper discusses an integrated model capable of dealing with spatial and temporal heterogeneities induced by extreme events, in particular weather related catastrophes. The model can be used for quite different problems which take explicitly into account the specifics of catastrophic risks: highly mutually dependent losses, inherent capacity of information, the need for long-term perspectives (temporal heterogeneity) and geographically explicit analyses (spatial heterogeneity) with respec...

  9. Analytical Model of Underground Train Induced Vibrations on Nearby Building Structures in Cameroon: Assessment and Prediction

    OpenAIRE

    Lezin Seba MINSILI; He XIA; Robert Medjo EKO

    2013-01-01

    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...

  10. Establishment of tensile failure induced sanding onset prediction model for cased-perforated gas wells

    OpenAIRE

    Mohammad Tabaeh Hayavi; Mohammad Abdideh

    2017-01-01

    Sand production is a challenging issue in upstream oil and gas industry, causing operational and safety problems. Therefore, before drilling the wells, it is essential to predict and evaluate sanding onset of the wells. In this paper, new poroelastoplastic stress solutions around the perforation tunnel and tip based on the Mohr–Coulomb criterion are presented firstly. Based on the stress models, a tensile failure induced sanding onset prediction model for cased-perforated gas wells is derived...

  11. 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: ...

  12. Fenugreek Prevents the Development of STZ-Induced Diabetic Nephropathy in a Rat Model of Diabetes

    Directory of Open Access Journals (Sweden)

    Yingli Jin

    2014-01-01

    evidently reduced by fenugreek treatment. Furthermore, the upregulation of TGF-β1 and CTGF at a transcriptional and translational level in DN rats was distinctly inhibited by fenugreek. Consequently, fenugreek prevents DN development in a STZ-induced diabetic rat model.

  13. Modeling Proton- and Light Ion-Induced Reactions at Low Energies in the MARS15 Code

    Energy Technology Data Exchange (ETDEWEB)

    Rakhno, I. L. [Fermi National Accelerator Lab. (FNAL), Batavia, IL (United States); Mokhov, N. V. [Fermi National Accelerator Lab. (FNAL), Batavia, IL (United States); Gudima, K. K. [National Academy of Sciences, Cisineu (Moldova)

    2015-04-25

    An implementation of both ALICE code and TENDL evaluated nuclear data library in order to describe nuclear reactions induced by low-energy projectiles in the Monte Carlo code MARS15 is presented. Comparisons between results of modeling and experimental data on reaction cross sections and secondary particle distributions are shown.

  14. Meanfield modeling of propofol-induced changes in spontaneous EEG rhythms

    NARCIS (Netherlands)

    Hindriks, Rikkert; van Putten, Michel Johannes Antonius Maria

    2012-01-01

    During the maintenance period of propofol-induced general anesthesia, specific changes in spontaneous EEG rhythms can be observed. These comprise increased delta and theta power and the emergence of alpha oscillations over frontal regions. In this study we use a meanfield model of the

  15. 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.

  16. Prevention of injury by resveratrol in a rat model of adenine-induced ...

    African Journals Online (AJOL)

    1Department of Nephrology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, 2Clinical. Medicine ... tubule swelling and expansion induced by adenine administration. Conclusion: ... administration in a rat model of CKD by inhibiting FGF-23, parathyroid hormone, and phosphate. Thus,.

  17. Mechanistic constitutive model for wormlike micelle solutions with flow-induced structure formation

    Science.gov (United States)

    Dutta, Sarit; Graham, Michael

    2017-11-01

    We present a tensor constitutive model for stress and flow-induced structure formation in dilute wormlike micellar solutions. The fluid is treated as a dilute suspension of rigid Brownian rods whose length varies dynamically. Consistent with the mechanism of Turner and Cates, flow-induced alignment of the rods is assumed to promote increase of rod length that corresponds to the formation of flow-induced structures observed in experiments. At very high deformation rate, hydrodynamic stresses cause the rod length to decrease. These mechanisms are implemented in a phenomenological equation governing the evolution of rod length, with the number density of rods appropriately modified to ensure conservation of surfactant mass. The model leads first to an increase in both shear and extensional viscosity as deformation rate increases and then to a decrease at higher rates. If the rate constant for flow-induced rod growth is sufficiently large, the model predicts a multivalued relation between stress and deformation rate in both shear and uniaxial extension in agreement with experimental results. By design, the model is simple enough to serve as a tractable constitutive relation for computational fluid dynamics studies.

  18. A Combined Mathematical-Physical Model of Laser-Induced Thermotherapy (LITT)

    DEFF Research Database (Denmark)

    Enevoldsen, Marie Sand; Skovgaard, Ove; Andersen, Peter E.

    2009-01-01

    Laser{induced thermo therapy (LITT) is an alternative, gentle therapy of cancer. In this work a new computa- tional model (3D space and time) of LITT is presented. Using an arbitrary small number (<20) of optical ¯bers, multiple low energy laser light sources are applied internal to an arbitrary ...

  19. Dynamical-model analysis of intermediate mechanisms in /sup 32/S-induced reactions

    Energy Technology Data Exchange (ETDEWEB)

    Gentili, M.; Massa, I.; Vannini, G. (Bologna Univ. (Italy). Ist. di Fisica; Istituto Nazionale di Fisica Nucleare, Bologna (Italy)); Boccaccio, P.; Reffo, F.; Vannucci, L. (Istituto Nazionale di Fisica Nucleare, Padua (Italy). Lab. di Legnaro); Ricci, R.A. (Padua Univ. (Italy). Ist. di Fisica; Istituto Nazionale di Fisica Nucleare, Padua (Italy). Lab. di Legnaro); Iori, I. (Milan Univ. (Italy). Ist. di Fisic

    1984-08-18

    In this letter the results of calculations for /sup 32/S-induced collisions on /sup 59/Co and /sup 76/Ge are reported. In addition to the diffusion model, in the present calculations the statistical decay of the nuclear system and the contribution of a totally mass-equilibrated component are taken into account.

  20. Portal vein embolization induces more liver regeneration than portal vein ligation in a standardized rabbit model

    NARCIS (Netherlands)

    van den Esschert, Jacomina W.; van Lienden, Krijn P.; de Graaf, Wilmar; Maas, Martinus A. W.; Roelofs, Joris J. T. H.; Heger, Michal; van Gulik, Thomas M.

    2011-01-01

    Background. Portal vein ligation (PVL) and portal vein embolization (PVE) are used to induce hypertrophy of the future remnant liver before major liver resection. The aim of our study was to compare the hypertrophy response of the liver after PVL versus PVE in a rabbit model. Methods. Twenty rabbits

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

    NARCIS (Netherlands)

    Boomsma, Marjolein J.; Bijl, Hendrik P.; Christianen, Miranda E. M. C.; Beetz, Ivo; Chouvalova, Olga; Steenbakkers, Roel J. H. M.; van der Laan, Bernard F. A. M.; 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

  2. Detailed seismic modeling of induced seismicity at the Groningen gas field

    NARCIS (Netherlands)

    Paap, B.F.; Steeghs, T.P.H.; Kraaijpoel, D.A.

    2016-01-01

    We present the results of a detailed seismic modeling study of induced seismicity observed at the Groningen gas field, situated in the North-eastern part of the Netherlands. Seismic simulations are valuable to support the interpretation of observed earthquake waveforms recordings and to increase the

  3. Radiation-induced decomposition of the purine bases within DNA and related model compounds

    International Nuclear Information System (INIS)

    Cadet, J.; Berger, M.

    1985-01-01

    This survey focuses on recent developments in the radiation chemistry of purine bases in nucleic acids and related model compounds. Both direct and indirect effects of ionizing radiation are investigated with special emphasis on the structural characterization of the final decomposition products of nucleic acid components. Available assays for monitoring radiation-induced base lesions are critically reviewed. (author)

  4. 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

  5. Prevention of injury by resveratrol in a rat model of adenine-induced ...

    African Journals Online (AJOL)

    Purpose: To investigate the preventive effect of resveratrol against renal pathological changes in a rat model of chronic kidney disease (CKD). Methods: CKD was induced by daily intragastric administration of adenine (200 mg/kg) for 1 month. The effect of 10, 15, and 20 mg/kg doses of resveratrol on the levels of ...

  6. Benefits and applications of laser-induced sparks in real scale model measurements

    DEFF Research Database (Denmark)

    Gómez-Bolaños, Javier; Delikaris-Manias, Symeon; Pulkki, Ville Topias

    2015-01-01

    The characteristics of using a laser-induced spark as a monopole source in scale model measurements were assessed by comparison with an electric spark and a miniature spherical loudspeaker. Room impulse responses of first order directivity sources were synthesized off-line using six spatially dis...

  7. Process-oriented modelling to identify main drivers of erosion-induced carbon fluxes

    Science.gov (United States)

    Wilken, Florian; Sommer, Michael; Van Oost, Kristof; Bens, Oliver; Fiener, Peter

    2017-05-01

    Coupled modelling of soil erosion, carbon redistribution, and turnover has received great attention over the last decades due to large uncertainties regarding erosion-induced carbon fluxes. For a process-oriented representation of event dynamics, coupled soil-carbon erosion models have been developed. However, there are currently few models that represent tillage erosion, preferential water erosion, and transport of different carbon fractions (e.g. mineral bound carbon, carbon encapsulated by soil aggregates). We couple a process-oriented multi-class sediment transport model with a carbon turnover model (MCST-C) to identify relevant redistribution processes for carbon dynamics. The model is applied for two arable catchments (3.7 and 7.8 ha) located in the Tertiary Hills about 40 km north of Munich, Germany. Our findings indicate the following: (i) redistribution by tillage has a large effect on erosion-induced vertical carbon fluxes and has a large carbon sequestration potential; (ii) water erosion has a minor effect on vertical fluxes, but episodic soil organic carbon (SOC) delivery controls the long-term erosion-induced carbon balance; (iii) delivered sediments are highly enriched in SOC compared to the parent soil, and sediment delivery is driven by event size and catchment connectivity; and (iv) soil aggregation enhances SOC deposition due to the transformation of highly mobile carbon-rich fine primary particles into rather immobile soil aggregates.

  8. Modelling biological and chemically induced precipitation of calcium phosphate in enhanced biological phosphorus removal systems.

    Science.gov (United States)

    Barat, R; Montoya, T; Seco, A; Ferrer, J

    2011-06-01

    The biologically induced precipitation processes can be important in wastewater treatment, in particular treating raw wastewater with high calcium concentration combined with Enhanced Biological Phosphorus Removal. Currently, there is little information and experience in modelling jointly biological and chemical processes. This paper presents a calcium phosphate precipitation model and its inclusion in the Activated Sludge Model No 2d (ASM2d). The proposed precipitation model considers that aqueous phase reactions quickly achieve the chemical equilibrium and that aqueous-solid change is kinetically governed. The model was calibrated using data from four experiments in a Sequencing Batch Reactor (SBR) operated for EBPR and finally validated with two experiments. The precipitation model proposed was able to reproduce the dynamics of amorphous calcium phosphate (ACP) formation and later crystallization to hydroxyapatite (HAP) under different scenarios. The model successfully characterised the EBPR performance of the SBR, including the biological, physical and chemical processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. 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.

  10. Two-dimensional and three-dimensional models for studying atherosclerosis pathogenesis induced by periodontopathogenic microorganisms.

    Science.gov (United States)

    Gualtero, D F; Lafaurie, G I; Fontanilla, M R

    2018-02-01

    Epidemiological studies have established a clinical association between periodontal disease and atherosclerosis. Bacteremia and endotoxemia episodes in patients with periodontitis appear to link these two diseases by inducing a body-wide production of cardiovascular markers. The presence of oral bacteria in atherosclerotic lesions in patients with periodontitis suggests that bacteria, or their antigenic components, induce alterations in the endothelium associated with atherosclerosis. Therefore, a causal mechanism explaining the association between both diseases can be constructed using in vitro models. This review presents current experimental approaches based on in vitro cell models used to shed light on the mechanism by which periodontal pathogenic microorganisms, and their antigenic components, induce proatherosclerotic endothelial activity. Monolayer cultures of endothelial vascular or arterial cells have been used to assess periodontal pathogenic bacteria and their antigenic compounds and endothelial activation. However, these models are not capable of reflecting the physiological characteristics of the endothelium inside vascularized tissue. Therefore, the shift from two-dimensional (2D) cellular models toward three-dimensional (3D) models of endothelial cells resembling an environment close to the physiological environment of the endothelial cell within the endothelium is useful for evaluating the physiological relevance of results regarding the endothelial dysfunction induced by periodontopathogens that are currently obtained from 2D models. The use of in vitro 3D cellular models can also be relevant to the search for therapeutic agents for chronic inflammatory diseases such as atherosclerosis. Here, we present some strategies for the assembly of 3D cultures with endothelial cells, which is useful for the study of periodontopathogen-mediated disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Optimal clearance of Sporothrix schenckii requires an intact Th17 response in a mouse model of systemic infection.

    Science.gov (United States)

    Ferreira, Lucas Souza; Gonçalves, Amanda Costa; Portuondo, Deivys Leandro; Maia, Danielle Cardoso Geraldo; Placeres, Marisa Campos Polesi; Batista-Duharte, Alexander; Carlos, Iracilda Zeppone

    2015-08-01

    The discovery of Th17 cells, along with many other Th cell subsets in the recent years, has expanded the Th1/Th2 paradigm that had persisted since its proposition by Mosmann in 1986. Defined by the characteristic expression of the transcription factor retinoic-related orphan receptor γt (RORγt) and production of IL-17A (IL-17), Th17 cells are powerful inducers of tissue inflammation with a recognized role against extracellular bacteria and fungi. Despite this, the interest in their study came from the pivotal role they play in the development and maintenance of major chronic inflammatory conditions such as multiple sclerosis, rheumatoid arthritis and Crohn's disease, hence they have been the target of promising new anti-Th17 therapies. Accordingly, the identification of opportunistic pathogens whose clearance relies on the Th17 response is of huge prophylactic importance. As shown here for the first time, this applies to Sporothrix schenckii, a thermo-dimorphic fungus and the causative agent of sporotrichosis. Our results show that both Th17 and Th1/Th17 mixed cells are developed during the S. schenckii systemic mice infection, which also leads to augmented production of IL-17 and IL-22. Also, by using an antibody-mediated IL-23 depletion model, we further demonstrate that optimal fungal clearance, but not survival, depends on an intact Th17 response. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. 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.

  13. Paraquat Induces Epigenetic Changes by Promoting Histone Acetylation in Cell Culture Models of Dopaminergic Degeneration

    Science.gov (United States)

    Song, C.; Kanthasamy, A.; Jin, H.; Anantharam, V.; Kanthasamy, A. G.

    2012-01-01

    Environmental neurotoxic exposure to agrochemicals has been implicated in the etiopathogenesis of Parkinson’s disease (PD). The widely used herbicide paraquat is among the few environmental chemicals potentially linked with PD. Since epigenetic changes are beginning to emerge as key mechanisms in neurodegenerative diseases, herein we examined the effects of paraquat on histone acetylation, a major epigenetic change in chromatin that can regulate gene expression, chromatin remodeling, cell survival and cell death. Exposure of N27 dopaminergic cells to paraquat induced histone H3 acetylation in a time-dependent manner. However, paraquat did not alter acetylation of another core histone H4. Paraquat-induced histone acetylation was associated with decreased total histone deacetylase (HDAC) activity and HDAC4 and 7 protein expression levels. To determine if histone acetylation plays a role in paraquat-induced apoptosis, the novel HAT inhibitor anacardic acid was used. Anacardic acid treatment significantly attenuated paraquat-induced caspase-3 enzyme activity, suppressed proteolytic activation and kinase activity of protein kinase C delta (PKCδ) and also blocked paraquat-induced cytotoxicity. Together, these results demonstrate that the neurotoxic agent paraquat induced acetylation of core histones in cell culture models of PD and that inhibition of HAT activity by anacardic acid protects against apoptotic cell death, indicating that histone acetylation may represent key epigenetic changes in dopaminergic neuronal cells during neurotoxic insults. PMID:21777615

  14. 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.

  15. 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

  16. 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

  17. Hydro-mechanical modelling of induced seismicity during the deep geothermal project in St. Gallen, Switzerland

    Science.gov (United States)

    Zbinden, Dominik; Rinaldi, Antonio Pio; Kraft, Toni; Diehl, Tobias; Wiemer, Stefan

    2017-04-01

    The St. Gallen deep geothermal project in 2013 was the second geothermal project in Switzerland with the objective of power production after the Enhanced Geothermal System in Basel in 2006. In St. Gallen, the seismic risk was expected to be smaller than in Basel, since the hydrothermal resource was an aquifer at a depth of about 4 km, not expected to require permeability enhancement and associated hydroshearing of the rock. However, after an injectivity test and two acid stimulations, unexpected gas release from an unidentified source forced the operators to inject drilling mud into the well to fight the gas kick. Subsequently, several seismic events were induced, the largest one having a local magnitude of 3.5, which was distinctly felt by the nearby living population. Even though the induced seismicity could not be handled properly, the community still strongly supported the geothermal project. The project was however halted because the target formation was not as permeable as required to deliver sufficient power. Still, controlling induced seismicity during deep geothermal projects is a key factor to successfully operate future geothermal projects. Hence, it is crucial to understand the physical relations of fluid injection, pressure and stress response at reservoir depth as well as associated induced seismicity. To date, these processes are yet not fully understood. In this study, we aim at developing a hydro-mechanical model reproducing the main features of the induced seismic sequence at the St. Gallen geothermal site. Here, we present the conceptual model and preliminary results accounting for hydraulic and mechanical parameters from the geothermal well, geological information from a seismic survey conducted in the St. Gallen region, and actual fluid injection rates from the injectivity tests. In a future step, we are going to use this model to simulate the physical interaction of injected fluid, gas release, hydraulic response of the rock, and induced

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. A remanent and induced magnetization model of Magsat vector anomalies over the west African craton

    Science.gov (United States)

    Toft, P. B.; Haggerty, S. E.

    1986-01-01

    Scalar and vector Magsat anomalies over the west African craton are analyzed by forward and inverse models. A forward model of the Man shield is based on Liberia. Induced magnetization contrasts due to sporadic iron-formations and to regional metamorphic rocks, and a contrast in remanent magnetization within the lower crust are included. This combination reproduces the location, magnitude and adopted local zero level of anomalies in the initial Magsat maps. An inverse model of the Reguibat shield estimates the magnetization contrast of its lithosphere, and when magnetism is restricted to shallower than 75 km both shields can be represented by a susceptibility contrast of +0.02. A residual anomaly between the shields involves a relative deficiency of induced magnetization along with other causes.

  4. Animal models for glucocorticoid-induced postmenopausal osteoporosis: An updated review.

    Science.gov (United States)

    Zhang, Zhida; Ren, Hui; Shen, Gengyang; Qiu, Ting; Liang, De; Yang, Zhidong; Yao, Zhensong; Tang, Jingjing; Jiang, Xiaobing; Wei, Qiushi

    2016-12-01

    Glucocorticoid-induced postmenopausal osteoporosis is a severe osteoporosis, with high risk of major osteoporotic fractures. This severe osteoporosis urges more extensive and deeper basic study, in which suitable animal models are indispensable. However, no relevant review is available introducing this model systematically. Based on the recent studies on GI-PMOP, this brief review introduces the GI-PMOP animal model in terms of its establishment, evaluation of bone mass and discuss its molecular mechanism. Rat, rabbit and sheep with their respective merits were chosen. Both direct and indirect evaluation of bone mass help to understand the bone metabolism under different intervention. The crucial signaling pathways, miRNAs, osteogenic- or adipogenic- related factors and estrogen level may be the predominant contributors to the development of glucocorticoid-induced postmenopausal osteoporosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  5. Statistically induced topological phase transitions in a one-dimensional superlattice anyon-Hubbard model

    Science.gov (United States)

    Zuo, Zheng-Wei; Li, Guo-Ling; Li, Liben

    2018-03-01

    We theoretically investigate topological properties of the one-dimensional superlattice anyon-Hubbard model, which can be mapped to a superlattice bose-Hubbard model with an occupation-dependent phase factor by fractional Jordan-Wigner transformation. The topological anyon-Mott insulator is identified by topological invariant and edge modes using exact diagonalization and the density matrix renormalization group algorithm. When only the statistical angle is varied and all other parameters are fixed, a statistically induced topological phase transition can be realized, which provides insights into the topological phase transitions. What's more, we give an explanation of the statistically induced topological phase transition. The topological anyon-Mott phases can also appear in a variety of superlattice anyon-Hubbard models.

  6. 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

    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...... normalised ratio (INR), and cardiovascular failure were used to derive an initial predictive model, with a second (day 2) model including additional changes in INR and lactate. FINDINGS: We developed and validated new high-performance statistical models to support decision making in patients with paracetamol...

  7. 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.

  8. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model

    Directory of Open Access Journals (Sweden)

    Banu Taskin

    2017-01-01

    Full Text Available The most severe side effect of prolonged MTX treatment is hepatotoxicity. The aim of this study is to investigate the effect of lactulose treatment on MTX-induced hepatotoxicity in a rat model. Twenty-four male rats were included in the study. Sixteen rats were given a single dose of 20 mg/kg MTX to induce liver injury. Eight rats were given no drugs. 16 MTX-given rats were divided into two equal groups. Group 1 subjects were given lactulose 5 g/kg/day, and group 2 subjects were given saline 1 ml/kg/day for 10 days. The rats were then sacrificed to harvest blood and liver tissue samples in order to determine blood and tissue MDA, serum ALT, plasma TNF-α, TGF-β, and PTX3 levels. Histological specimens were examined via light microscopy. Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by relatively worse histopathological scores and increased biochemical marker levels. Lactulose treatment significantly reduced the liver enzyme ALT, plasma TNF-α, TGF-β, PTX3, and MDA levels and also decreased histological changes in the liver tissue with MTX-induced hepatotoxicity in the rat model. We suggest that lactulose has anti-inflammatory and antifibrotic effects on an MTX-induced liver injury model. These effects can be due to the impact of intestinal microbiome.

  9. Hyperphosphatemia-induced hyperparathyroidism in 5/6 nephrectomized rats: development of a new animal model.

    Science.gov (United States)

    Jiang, Ying; Wang, Mei

    2008-12-05

    We require a stable model to understand the molecular mechanism by which isolated hyperphosphatemia induces hyperparathyroidism secondary to chronic renal failure. The present study established a rat model of hyperphosphatemia-induced secondary hyperparathyroidism in chronic renal failure. Twenty-nine rats with 5/6 nephrectomy (Nx) were divided into three groups and were fed for 10 weeks on a high phosphate diet (1.2% phosphate) starting from three different post-Nx time points. Parathyroid hormone mRNA in parathyroid gland was measured by real-time PCR and parathyroid cell hyperplasia was tested by proliferating cell nuclear antigen (PCNA) assay. The 10 rats fed a high phosphate diet starting from the fourth week post-Nx had isolated hyperphosphatemia and excess synthesis/secretion of parathyroid hormone, and hyperplasia of the parathyroid glands were induced (r = 0.86 - 0.97, P rat model of hyperphosphatemia-induced secondary hyperparathyroidism in chronic renal failure was established by 5/6 Nx and 10 weeks-high phosphate diet starting from the fourth week post-Nx.

  10. Modeling of alpha-particle-induced soft error rate in DRAM

    International Nuclear Information System (INIS)

    Shin, H.

    1999-01-01

    Alpha-particle-induced soft error in 256M DRAM was numerically investigated. A unified model for alpha-particle-induced charge collection and a soft-error-rate simulator (SERS) was developed. The author investigated the soft error rate of 256M DRAM and identified the bit-bar mode as one of dominant modes for soft error. In addition, for the first time, it was found that trench-oxide depth has a significant influence on soft error rate, and it should be determined by the tradeoff between soft error rate and cell-to-cell isolation characteristics

  11. Pharmacodynamic modeling of propofol-induced tidal volume depression in children.

    Science.gov (United States)

    Hahn, Jin-Oh; Khosravi, Sara; Dosani, Maryam; Dumont, Guy A; Mark Ansermino, J

    2011-08-01

    This investigation aimed to develop a pediatric pharmacodynamic model of propofol-induced tidal volume depression towards an ultimate goal of developing a dosing schedule that would preserve spontaneous breathing following a loading dose of propofol. Fifty two ASA 1 and 2 children aged 6-15 year presenting for gastrointestinal endoscopy were enrolled. Subjects were administered a loading dose of 4 mg/kg of propofol intravenously at a constant infusion rate determined by a randomization schedule. Respiratory parameters including tidal volume, respiratory rate, minute volume, and end-tidal CO(2) were recorded at 5 s intervals. Using the predicted plasma concentration, based on the Paedfusor pharmacokinetic model, propofol-induced tidal volume depression was modeled by 3 different approaches (2-stage, pooled, and mixed effects) and results were compared using prediction residual, median percentage errors, median absolute percentage errors, and root-mean-squared normalized errors. The effects of age and body weight as covariates were examined. Respiratory rate and end-tidal CO(2) did not show clear dependence on the predicted plasma concentration. The pharmacodynamic models for tidal volume derived from different modeling approaches were highly consistent. The 2-stage, pooled, and mixed effects approaches yielded k(e0) of 1.06, 1.24, and 0.72 min(-1); γ of 1.10, 0.83, and 0.93; EC50 of 3.18, 3.44, and 3.00 mcg/ml. Including age and body weight as covariates did not significantly improve the predictive performance of the models. A pediatric pharmacodynamic model of propofol-induced tidal volume depression was developed. Models derived from 3 different approaches were shown to be consistent with each other; however, the individual pharmacodynamic parameters exhibited significant inter-individual variability without strong dependence on age and body weight. This would suggest the desirability of adapting the pharmacodynamic model to each subject in real time.

  12. 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.

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

    Science.gov (United States)

    Spincemaille, Pieter; Pham, Duc-Hung; Chandhok, Gursimran; Verbeek, Jef; Zibert, Andree; Libbrecht, Louis; Schmidt, Hartmut; Esguerra, Camila V; de Witte, Peter A M; Cammue, Bruno P A; Cassiman, David; Thevissen, Karin

    2014-10-15

    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. 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. OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B(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. OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. 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.

  15. 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...

  16. A Micro-Mechanically Based Continuum Model for Strain-Induced Crystallization in Natural Rubber

    Science.gov (United States)

    Mistry, Sunny Jigger

    Recent experimental results show that strain-induced crystallization can substantially improve the crack growth resistance of natural rubber. While this might suggest superior designs of tires or other industrial applications where elastomers are used, a more thorough understanding of the underlying physics of strain-induced crystallization in natural rubber has to be developed before any design process can be started. The objective of this work is to develop a computationally-accessible micro-mechanically based continuum model, which is able to predict the macroscopic behavior of strain crystallizing natural rubber. While several researchers have developed micro-mechanical models of partially crystallized polymer chains, their results mainly give qualitative agreement with experimental data due to a lack of good micro-macro transition theories or the lack of computational power. However, recent developments in multiscale modeling in polymers provide new tools to continue this early work. In this thesis, a new model is proposed to model strain-induced crystallization in natural rubber. To this end, a micro-mechanical model of a constrained partially crystallized polymer chain with an extended-chain crystal is derived and connected to the macroscopic level using the non-affine micro-sphere model. On the macroscopic level, a thermodynamically consistent framework for strain-crystallizing materials is developed, and a description of the crystallization kinetics is introduced. For that matter, an evolution law for crystallization based on the gradient of the macroscopic Helmholtz free energy function (chemical potential) in combination with a simple threshold function is used. A numerical implementation of the model is proposed and its predictive performance assessed using published data.

  17. 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)

  18. Novel Markov model of induced pluripotency predicts gene expression changes in reprogramming

    Directory of Open Access Journals (Sweden)

    Hu Zhirui

    2011-12-01

    Full Text Available Abstract Background Somatic cells can be reprogrammed to induced-pluripotent stem cells (iPSCs by introducing few reprogramming factors, which challenges the long held view that cell differentiation is irreversible. However, the mechanism of induced pluripotency is still unknown. Methods Inspired by the phenomenological reprogramming model of Artyomov et al (2010, we proposed a novel Markov model, stepwise reprogramming Markov (SRM model, with simpler gene regulation rules and explored various properties of the model with Monte Carlo simulation. We calculated the reprogramming rate and showed that it would increase in the condition of knockdown of somatic transcription factors or inhibition of DNA methylation globally, consistent with the real reprogramming experiments. Furthermore, we demonstrated the utility of our model by testing it with the real dynamic gene expression data spanning across different intermediate stages in the iPS reprogramming process. Results The gene expression data at several stages in reprogramming and the reprogramming rate under several typically experiment conditions coincided with our simulation results. The function of reprogramming factors and gene expression change during reprogramming could be partly explained by our model reasonably well. Conclusions This lands further support on our general rules of gene regulation network in iPSC reprogramming. This model may help uncover the basic mechanism of reprogramming and improve the efficiency of converting somatic cells to iPSCs.

  19. Refinement of canine pancreatitis model: inducing pancreatitis by using endoscopic retrograde cholangiopancreatography.

    Science.gov (United States)

    Ruben, Dawn S; Scorpio, Diana G; Gabrielson, K L; Simon, B W; Buscaglia, Jonathan M

    2009-02-01

    The causes and treatments of pancreatitis have been studied in diverse species, but the canine pancreatitis model has been used most often due to its similarities to the condition in humans. Although pancreatitis in dogs can be induced readily by numerous methods, managing these dogs can be difficult because they often develop severe abdominal pain, vomiting, inappetance, and lethargy. In an effort to study pancreatitis, we performed a pilot study to determine whether an endoscopic pancreatic procedure would be possible in a dog and whether, through various manipulations, a new method of inducing pancreatitis could be developed. The model uses endoscopic retrograde cholangiopancreatography (ERCP), a common procedure in human gastroenterology that has been associated with postprocedural pancreatitis. Although all 8 dogs used in developing the ERCP model had both biochemical and histologic changes consistent with pancreatitis, 7 of the 8 dogs remained free of classic clinical signs of the disease. This method is presented as a refinement of a canine model and presents an alternative method of inducing pancreatitis, with decreased risk of developing associated clinical signs.

  20. Establishment of hydrochloric acid/lipopolysaccharide-induced pelvic inflammatory disease model

    Science.gov (United States)

    Oh, Yeonsu; Lee, Jaehun; Kim, Hyeon-Cheol; Hahn, Tae-Wook; Yoon, Byung-Il; Han, Jeong-Hee; Kwon, Yong-Soo; Park, Joung Jun; Koo, Deog-Bon; Rhee, Ki-Jong

    2016-01-01

    Pelvic inflammatory disease (PID), which is one of the most problematic complications experienced by women with sexually transmitted diseases, frequently causes secondary infections after reproductive abnormalities in veterinary animals. Although the uterus is self-protective, it becomes fragile during periods or pregnancy. To investigate PID, bacteria or lipopolysaccharide (LPS) extracted from gram negative bacteria has been used to induce the disease in several animal models. However, when LPS is applied to the peritoneum, it often causes systemic sepsis leading to death and the PID was not consistently demonstrated. Hydrochloric acid (HCl) has been used to induce inflammation in the lungs and stomach but not tested for reproductive organs. In this study, we developed a PID model in mice by HCl and LPS sequential intracervical (i.c.) administration. The proinflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, were detected in the mouse uterus by western blot analysis and cytokine enzyme-linked immunosorbent assay after HCl (25 mg/kg) administration i.c. followed by four LPS (50 mg/kg) treatments. Moreover, mice exhibited increased infiltration of neutrophils in the endometrium and epithelial layer. These results suggest that ic co-administration of HCl and LPS induces PID in mice. This new model may provide a consistent and reproducible PID model for future research. PMID:26726020

  1. Modeling Geomagnetically Induced Currents From Magnetometer Measurements: Spatial Scale Assessed With Reference Measurements

    Science.gov (United States)

    Butala, Mark D.; Kazerooni, Maryam; Makela, Jonathan J.; Kamalabadi, Farzad; Gannon, Jennifer L.; Zhu, Hao; Overbye, Thomas J.

    2017-10-01

    Solar-driven disturbances generate geomagnetically induced currents (GICs) that can result in power grid instability and, in the most extreme cases, even failure. Magnetometers provide direct measurements of the geomagnetic disturbance (GMD) effect on the surface magnetic field and GIC response can be determined from the power grid topology and engineering parameters. This paper considers this chain of models: transforming surface magnetic field disturbance to induced surface electric field through an electromagnetic transfer function and, then, induced surface electric field to GIC using the PowerWorld simulator to model a realistic power grid topology. Comparisons are made to transformer neutral current reference measurements provided by the American Transmission Company. Three GMD intervals are studied, with the Kp index reaching 8- on 2 October 2013, 7 on 1 June 2013, and 6- on 9 October 2013. Ultimately, modeled to measured GIC correlations are analyzed as a function of magnetometer to GIC sensor distance. Results indicate that modeling fidelity during the three studied GMD intervals is strongly dependent on both magnetometer to substation transformer baseline distance and GMD intensity.

  2. Establishment of hydrochloric acid/lipopolysaccharide-induced pelvic inflammatory disease model.

    Science.gov (United States)

    Oh, Yeonsu; Lee, Jaehun; Kim, Hyeon-Cheol; Hahn, Tae-Wook; Yoon, Byung-Il; Han, Jeong-Hee; Kwon, Yong-Soo; Park, Joung Jun; Koo, Deog-Bon; Rhee, Ki-Jong; Jung, Bae Dong

    2016-09-30

    Pelvic inflammatory disease (PID), which is one of the most problematic complications experienced by women with sexually transmitted diseases, frequently causes secondary infections after reproductive abnormalities in veterinary animals. Although the uterus is self-protective, it becomes fragile during periods or pregnancy. To investigate PID, bacteria or lipopolysaccharide (LPS) extracted from gram negative bacteria has been used to induce the disease in several animal models. However, when LPS is applied to the peritoneum, it often causes systemic sepsis leading to death and the PID was not consistently demonstrated. Hydrochloric acid (HCl) has been used to induce inflammation in the lungs and stomach but not tested for reproductive organs. In this study, we developed a PID model in mice by HCl and LPS sequential intracervical (i.c.) administration. The proinflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, were detected in the mouse uterus by western blot analysis and cytokine enzyme-linked immunosorbent assay after HCl (25 mg/kg) administration i.c. followed by four LPS (50 mg/kg) treatments. Moreover, mice exhibited increased infiltration of neutrophils in the endometrium and epithelial layer. These results suggest that ic co-administration of HCl and LPS induces PID in mice. This new model may provide a consistent and reproducible PID model for future research.

  3. High-fat high-sugar diet induces polycystic ovary syndrome in a rodent model.

    Science.gov (United States)

    Roberts, Jacob S; Perets, Ron A; Sarfert, Kathryn S; Bowman, John J; Ozark, Patrick A; Whitworth, Gregg B; Blythe, Sarah N; Toporikova, Natalia

    2017-01-27

    Obesity has been linked with a host of metabolic and reproductive disorders including polycystic ovary syndrome (PCOS). While a clear association exists between obesity and PCOS, the exact nature of this relationship remains unexplained. The primary symptoms of PCOS include hyperandrogenism, anovulation, and polycystic ovaries. Most animal models utilize androgen treatments to induce PCOS. However, these models often fail to address the underlying causes of the disease and do not effectively reproduce key metabolic features such as hyperinsulinemia. Here, we present a novel rodent model of diet-induced obesity that recapitulates both the metabolic and reproductive phenotypes of human PCOS. Rats on a high-fat high-sugar (HFHS) diet not only demonstrated signs of metabolic impairment, but they also developed polycystic ovaries and experienced irregular estrous cycling. Though hyperandrogenism was not characteristic of HFHS animals as a group, elevated testosterone levels were predictive of high numbers of ovarian cysts. Alterations in steroidogenesis and folliculogenesis gene expression were also found via RNA sequencing of ovarian tissue. Importantly, the PCOS-like symptoms induced in these rats may share a similar etiology to PCOS in humans. Therefore, this model offers a unique opportunity to study PCOS at its genesis rather than following the development of disease symptoms.

  4. Earthquake Rate Models for Evolving Induced Seismicity Hazard in the Central and Eastern US

    Science.gov (United States)

    Llenos, A. L.; Ellsworth, W. L.; Michael, A. J.

    2015-12-01

    Injection-induced earthquake rates can vary rapidly in space and time, which presents significant challenges to traditional probabilistic seismic hazard assessment methodologies that are based on a time-independent model of mainshock occurrence. To help society cope with rapidly evolving seismicity, the USGS is developing one-year hazard models for areas of induced seismicity in the central and eastern US to forecast the shaking due to all earthquakes, including aftershocks which are generally omitted from hazards assessments (Petersen et al., 2015). However, the spatial and temporal variability of the earthquake rates make them difficult to forecast even on time-scales as short as one year. An initial approach is to use the previous year's seismicity rate to forecast the next year's seismicity rate. However, in places such as northern Oklahoma the rates vary so rapidly over time that a simple linear extrapolation does not accurately forecast the future, even when the variability in the rates is modeled with simulations based on an Epidemic-Type Aftershock Sequence (ETAS) model (Ogata, JASA, 1988) to account for earthquake clustering. Instead of relying on a fixed time period for rate estimation, we explore another way to determine when the earthquake rate should be updated. This approach could also objectively identify new areas where the induced seismicity hazard model should be applied. We will estimate the background seismicity rate by optimizing a single set of ETAS aftershock triggering parameters across the most active induced seismicity zones -- Oklahoma, Guy-Greenbrier, the Raton Basin, and the Azle-Dallas-Fort Worth area -- with individual background rate parameters in each zone. The full seismicity rate, with uncertainties, can then be estimated using ETAS simulations and changes in rate can be detected by applying change point analysis in ETAS transformed time with methods already developed for Poisson processes.

  5. Severity of sepsis-induced acute kidney injury in a novel mouse model is age dependent.

    Science.gov (United States)

    Maddens, Bert; Vandendriessche, Benjamin; Demon, Dieter; Vanholder, Raymond; Chiers, Koen; Cauwels, Anje; Meyer, Evelyne

    2012-09-01

    Despite extensive research, the mortality rate of patients with sepsis-induced acute kidney injury (AKI) is unacceptably high, especially in the elderly. Current sepsis models have difficulties in reproducing AKI. This study aimed to develop a novel, clinically relevant mouse model for sepsis-induced AKI by uterine ligation and inoculation of bacteria. In addition, the age dependency of the severity of sepsis and sepsis-induced AKI was studied by validating this model in three different age categories. Experimental animal investigation. University research laboratory. Young (12-14 wks), aged (46-48 wks), and old (70-72 wks) C57BL/6 female mice were used as models for adolescent, adult premenopausal, and elderly postmenopausal women, respectively. Uterine ligation and inoculation with 10 colony forming unit Escherichia coli or saline (sham) was performed; in vivo imaging with a luminescent Escherichia coli strain documented the course of infection. All mice had established Escherichia coli sepsis at 48 hrs postinfection, with higher mortality rate in old (43%) compared to aged (23%) or young (9%) mice. Infected mice had elevated serum or plasma cytokine, chemokine (tumor necrosis factor, interleukin-6, keratinocyte-derived chemokine, monocyte chemoattractant protein 1, and interleukin-10), and NOx concentrations compared to sham mice. AKI was confirmed by renal histology. Serum creatinine concentrations at 48 hrs increased with age (mean ± SEM; controls 0.18 ± 0.03 mg/dL, young 0.28 ± 0.03 mg/dL, aged 0.38 ± 0.05 mg/dL, and old 0.44 ± 0.06 mg/dL). The uterine ligation and inoculation model for sepsis-induced AKI starts from a real infectious focus and shows an age-dependent severity of septic AKI that resembles AKI in humans.

  6. Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Models.

    Science.gov (United States)

    Perros, Frédéric; Günther, Sven; Ranchoux, Benoit; Godinas, Laurent; Antigny, Fabrice; Chaumais, Marie-Camille; Dorfmüller, Peter; Hautefort, Aurélie; Raymond, Nicolas; Savale, Laurent; Jaïs, Xavier; Girerd, Barbara; Cottin, Vincent; Sitbon, Olivier; Simonneau, Gerald; Humbert, Marc; Montani, David

    2015-09-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD. We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats. MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease. © 2015 American Heart Association, Inc.

  7. Hippocampal neurogenesis dysfunction linked to depressive-like behaviors in a neuroinflammation induced model of depression.

    Science.gov (United States)

    Tang, Ming-Ming; Lin, Wen-Juan; Pan, Yu-Qin; Guan, Xi-Ting; Li, Ying-Cong

    2016-07-01

    Our previous work found that triple central lipopolysaccharide (LPS) administration could induce depressive-like behaviors and increased central pro-inflammatory cytokines mRNA, hippocampal cytokine mRNA in particular. Since several neuroinflammation-associated conditions have been reported to impair neurogenesis, in this study, we further investigated whether the neuroinflammation induced depression would be associated with hippocampal neurogenesis dysfunction. An animal model of depression induced by triple central lipopolysaccharide (LPS) administration was used. In the hippocampus, the neuroinflammatory state evoked by LPS was marked by an increased production of pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-α. It was found that rats in the neuroinflammatory state exhibited depressive-like behaviors, including reduced saccharin preference and locomotor activity as well as increased immobility time in the tail suspension test and latency to feed in the novelty suppressed feeding test. Adult hippocampal neurogenesis was concomitantly inhibited, including decreased cell proliferation and newborn cell survival. We also demonstrated that the decreased hippocampal neurogenesis in cell proliferation was significantly correlated with the depressive-like phenotypes of decreased saccharine preference and distance travelled, the core and characteristic symptoms of depression, under neuro inflammation state. These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of biological mechanisms underlying depression induced by neruoinflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. 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.

  9. 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.

  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. Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity.

    Science.gov (United States)

    Pecoraro, Michela; Ciccarelli, Michele; Fiordelisi, Antonella; Iaccarino, Guido; Pinto, Aldo; Popolo, Ada

    2018-03-07

    Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), a specific opener of mitochondrial K ATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg/kg i.p.) was administered 30 min before DOXO (10 mg/kg i.p.) in C57BL/6j female mice for 1-3 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca 2+ -signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43.

  12. Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

    Directory of Open Access Journals (Sweden)

    Michela Pecoraro

    2018-03-01

    Full Text Available Doxorubicin (DOXO administration induces alterations in Connexin 43 (Cx43 expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX, a specific opener of mitochondrial KATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg/kg i.p. was administered 30 min before DOXO (10 mg/kg i.p. in C57BL/6j female mice for 1–3 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco/endoplasmic reticulum Ca2+-ATPase (SERCAII and a reduction in phospholamban (PLB amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca2+-signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43.

  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. 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

  15. Fusobacterium nucleatum and Tannerella forsythia Induce Synergistic Alveolar Bone Loss in a Mouse Periodontitis Model

    Science.gov (United States)

    Settem, Rajendra P.; El-Hassan, Ahmed Taher; Honma, Kiyonobu; Stafford, Graham P.

    2012-01-01

    Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late-colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-κB activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single-species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model. PMID:22547549

  16. 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

    We have developed a synthetic multiparametric modeling and inversion exercise undertaken to study the robustness of inverting airborne time-domain electromagnetic (TDEM) data to extract Cole-Cole parameters. The following issues were addressed: nonuniqueness, ill posedness, dependency on manual...... 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...... by a shallower chargeable target, became possible only when full Cole-Cole modeling was used in the inversion. Lateral constraints improved the recoverability of model parameters. Finally, modeling IP effects increased the accuracy of recovered electrical resistivity models....

  17. Modeling of radiation-induced bystander effect using Monte Carlo methods

    Science.gov (United States)

    Xia, Junchao; Liu, Liteng; Xue, Jianming; Wang, Yugang; Wu, Lijun

    2009-03-01

    Experiments showed that the radiation-induced bystander effect exists in cells, or tissues, or even biological organisms when irradiated with energetic ions or X-rays. In this paper, a Monte Carlo model is developed to study the mechanisms of bystander effect under the cells sparsely populated conditions. This model, based on our previous experiment which made the cells sparsely located in a round dish, focuses mainly on the spatial characteristics. The simulation results successfully reach the agreement with the experimental data. Moreover, other bystander effect experiment is also computed by this model and finally the model succeeds in predicting the results. The comparison of simulations with the experimental results indicates the feasibility of the model and the validity of some vital mechanisms assumed.

  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. 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...... provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides......-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...

  1. Use of Animal Models in Understanding Cancer-induced Bone Pain

    Directory of Open Access Journals (Sweden)

    Lauren M. Slosky

    2015-01-01

    Full Text Available Many common cancers have a propensity to metastasize to bone. Although malignancies often go undetected in their native tissues, bone metastases produce excruciating pain that severely compromises patient quality of life. Cancer-induced bone pain (CIBP is poorly managed with existing medications, and its multifaceted etiology remains to be fully elucidated. Novel analgesic targets arise as more is learned about this complex and distinct pain state. Over the past two decades, multiple animal models have been developed to study CIBP's unique pathology and identify therapeutic targets. Here, we review animal models of CIBP and the mechanistic insights gained as these models evolve. Findings from immunocompromised and immunocompetent host systems are discussed separately to highlight the effect of model choice on outcome. Gaining an understanding of the unique neuromolecular profile of cancer pain through the use of appropriate animal models will aid in the development of more effective therapeutics for CIBP.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Decrease of plasma platelet-activating factor acetylhydrolase activity in lipopolysaccharide induced mongolian gerbil sepsis model.

    Directory of Open Access Journals (Sweden)

    Junwei Yang

    Full Text Available Platelet-activating factor (PAF plays an important role in the pathogenesis of sepsis, and the level of plasma PAF acetylhydrolase (pPAF-AH, which inactivates PAF, decreases in sepsis patients except for the sepsis caused by severe leptospirosis. Usually, increase of pPAF-AH activity was observed in lipopolysaccharide (LPS-induced Syrian hamster and rat sepsis models, while contradictory effects were reported for mouse model in different studies. Here, we demonstrated the in vivo effects of LPS upon the change of pPAF-AH activity in C57BL/6 mice and Mongolian gerbils. After LPS-treatment, the clinical manifestations of Mongolian gerbil model were apparently similar to that of C57BL/6 mouse sepsis model. The pPAF-AH activity increased in C57BL/6 mice after LPS induction, but decreased in Mongolian gerbils, which was similar to that of the human sepsis. It thus suggests that among the LPS-induced rodent sepsis models, only Mongolian gerbil could be used for the study of pPAF-AH related to the pathogenesis of human sepsis. Proper application of this model might enable people to clarify the underline mechanism accounted for the contradictory results between the phase II and phase III clinical trials for the administration of recombinant human pPAF-AH in the sepsis therapy.

  7. 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.

  8. Optimization of Multi-Cluster Fracturing Model under the Action of Induced Stress in Horizontal Wells

    Directory of Open Access Journals (Sweden)

    Shanyong Liu

    2016-05-01

    Full Text Available Volume fracturing in shale gas forms complex fracture networks and increases stimulated reservoir volume through large-scale fracturing operation with plug-perforation technology. However, some perforation clusters are stimulated unevenly after fracturing. This study aims to solve this problem by analyzing the shortcomings of the conventional fracturing model and developing a coupled model based on the 2D fracture motion equation, energy conservation law, linear elastic mechanics, and stress superposition principle. First, a multi-fracture in-situ stress model was built by studying the induced stress produced by the fracture initiation to deduce the multi-fracture induced stress impact factor on the basis of the stress superposition principle. Then, the classical Perkins–Kern–Nordgren model was utilized with the crustal stress model. Finally, a precise fracturing design method was used to optimize perforation and fracturing parameters under the new model. Results demonstrate that the interference effect among fractures is the major factor causing the non-uniform propagation of each fracture. Compression on the main horizontal stress increases the net pressure. Therefore, both the degree of operation difficulty and the complexity of fracture geometry are improved. After applying the optimal design, the production is increased by 20%, and the cost is reduced by 15%.

  9. 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

  10. Modeling Radiation-Induced Degradation in Top-Gated Epitaxial Graphene Field-Effect-Transistors (FETs

    Directory of Open Access Journals (Sweden)

    Jeong-S. Moon

    2013-07-01

    Full Text Available This paper investigates total ionizing dose (TID effects in top-gated epitaxial graphene field-effect-transistors (GFETs. Measurements reveal voltage shifts in the current-voltage (I-V characteristics and degradation of carrier mobility and minimum conductivity, consistent with the buildup of oxide-trapped charges. A semi-empirical approach for modeling radiation-induced degradation in GFETs effective carrier mobility is described in the paper. The modeling approach describes Coulomb and short-range scattering based on calculations of charge and effective vertical field that incorporate radiation-induced oxide trapped charges. The transition from the dominant scattering mechanism is correctly described as a function of effective field and oxide trapped charge density. Comparison with experimental data results in good qualitative agreement when including an empirical component to account for scatterer transparency in the low field regime.

  11. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

  12. 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...

  13. Refinement of Canine Pancreatitis Model: Inducing Pancreatitis by Using Endoscopic Retrograde Cholangiopancreatography

    OpenAIRE

    Ruben, Dawn S; Scorpio, Diana G; Buscaglia, Jonathan M

    2009-01-01

    The causes and treatments of pancreatitis have been studied in diverse species, but the canine pancreatitis model has been used most often due to its similarities to the condition in humans. Although pancreatitis in dogs can be induced readily by numerous methods, managing these dogs can be difficult because they often develop severe abdominal pain, vomiting, inappetance, and lethargy. In an effort to study pancreatitis, we performed a pilot study to determine whether an endoscopic pancreatic...

  14. 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

  15. Prediction models for drug-induced hepatotoxicity by using weighted molecular fingerprints

    OpenAIRE

    Kim, Eunyoung; Nam, Hojung

    2017-01-01

    Background Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. Results In this study, we used 881 bits of molecular fingerpri...

  16. Experimental investigation of lateral forces induced by flow through model labyrinth glands

    Science.gov (United States)

    Leong, Y. M. M. S.; Brown, R. D.

    1984-01-01

    The lateral forces induced by flow through model labyrinth glands were investigated. Circumferential pressure distributions, lateral forces and stiffness coefficients data obtained are discussed. The force system is represented as a negative spring and a tangential force orthogonal to eccentricity. The magnitude of these forces are dependent on eccentricity, entry swirl, rotor peripheral velocity and seal size. A pressure equalization chamber at midgland tests should in significantly reduced forces and stiffness coefficients.

  17. 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.

  18. Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models

    Science.gov (United States)

    Williams, Jonathan M.

    2017-01-01

    ABSTRACT 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. PMID:28151409

  19. 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.

  20. 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

  1. 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.

  2. Effect of melatonin on cytokine levels in a hyperthermia-induced febrile seizure model.

    Science.gov (United States)

    Aydin, Leyla; Yurtcu, Erkan; Korkmaz, Yeşim; Sezer, Taner; Ogus, Ersin

    2017-11-30

    Higher serum cytokine levels have been reported in children admitted with febrile seizures and in some experimental models. However, other studies have shown that cytokine levels are influenced by melatonin. In this study, we investigated serum cytokine levels in a hyperthermia-induced febrile rat seizure model and the effect of melatonin. A total of 28 male Sprague-Dawley rats were divided into four groups: the control (C) group, healthy melatonin (MT) group, and hyperthermia-induced febrile seizure groups with (HIFS-MT) and without (HIFS) administration of melatonin. Melatonin (80 mg/kg) was given intraperitoneally 15 min before the seizure. HIFS was induced by placing the rats in 45°C water. The rats were sacrificed under anesthesia after the seizure. Blood samples were drawn by transcardiac puncture to measure serum cytokine and melatonin levels. Serum interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α levels were lower in the HIFS group than those in the C group (p = 0.005, p = 0.200, p = 0.011, and p = 0.016, respectively). All serum cytokine levels of rats in the MT and HIFS-MT groups were similar to those in the C group. This experimental rat model demonstrated that serum cytokine levels decrease with HIFS and that administering melatonin maintains serum cytokine levels. These results suggest that cytokines may play role in the anticonvulsive activity of melatonin in rats with febrile seizures.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Modeling the induced mutation process in bacterial cells with defects in excision repair system

    Science.gov (United States)

    Bugay, A. N.; Vasilyeva, M. A.; Krasavin, E. A.; Parkhomenko, A. Yu.

    2015-12-01

    A mathematical model of the UV-induced mutation process in Escherichia coli cells with defects in the uvrA and polA genes has been developed. The model describes in detail the reaction kinetics for the excision repair system. The number of mismatches as a result of translesion synthesis is calculated for both wild-type and mutant cells. The effect of temporal modulation of the number of single-stranded DNA during postreplication repair has been predicted. A comparison of effectiveness of different repair systems has been conducted.

  8. Mixing-Induced CP Asymmetries in Radiative B Decays in and beyond the Standard Model

    International Nuclear Information System (INIS)

    Atwood, D.; Gronau, M.; Soni, A.

    1997-01-01

    In the standard model (SM) the photon in radiative B 0 and B s decays is predominantly left handed. Thus, mixing-induced CP asymmetries in b→sγ and b→dγ are suppressed by m s /m b and m d /m b , respectively, and are very small. In many extensions of the SM, such as the left-right symmetric model (LRSM), the amplitude of right-handed photons grows proportional to the virtual heavy fermion mass, which can lead to large asymmetries. In the LRSM, asymmetries larger than 50% are possible even when radiative decay rate measurements agree with SM predictions. copyright 1997 The American Physical Society

  9. Uniform flow around a square cylinder using the Self-induced angular Moment Method turbulence model

    DEFF Research Database (Denmark)

    Johansson, Jens; Nielsen, Mogens Peter; Nielsen, Leif Otto

    2012-01-01

    or explicit filtering is performed. The model is, in all its simplicity, a modification of the classical constitutive equations of fluids to which a term is added that accounts for the transfer for angular momentum between parts of the fluid.The time-mean and fluctuating force coefficients, pressure......The uniform flow around a square cylinder at Reynolds number 1e5 is simulated in a threedimensional domain by means of the newly developed Self-induced angular Moment Method, SMoM. The model does not utilize Reynolds averaging. No additional transport equations are introduced and no implicit...

  10. Refinement of the Collagen Induced Arthritis Model in Rats by Infrared Thermography

    DEFF Research Database (Denmark)

    Jasemian, Yousef; Deleuran, Bent Winding; Svendsen, Pia

    2011-01-01

    Aims: Collagen induced arthritis in rats is an important model for human rheumatoid arthritis. This study was designed to improve and refine this model by use of infrared thermography by measuring surface temperature of hind feet. Our hypothesis is that the local temperature on the feet correlates...... correlation between temperature and clinical scores. Conclusion: The thermographic response appeared prior to the clinical signs, suggesting that thermography may be used as a predictive sign for the development of disease. This technique could be a non-invasive, objective, rapid, and reproducible method...

  11. 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

  12. 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...

  13. 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.

  14. 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.

  15. Distinguishing relative and absolute risk models for radiation-induced cancers

    International Nuclear Information System (INIS)

    Muirhead, C.R.; Darby, S.C.

    1987-01-01

    Methods for distinguishing between the goodness-of-fit of relative and absolute risk models are applied to mortality data from atomic bomb survivors at Hiroshima for the disease grouping consisting of all cancers other than leukaemia. The effect of allowing the radiation-induced risk to depend on variables such as sex, age at exposure and/or time since exposure is illustrated. Predicted numbers of deaths and numbers of years of life lost in an irradiated population are calculated for those models that fit the data well. Problems in extrapolating beyond the period for which follow-up data are currently available are emphasized. (author)

  16. 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 ...External Pulsed Electromagnetic Irradiation 5a. CONTRACT NUMBER FA9451-15-C-0004 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6 . AUTHOR(S) David...microcontroller (µC) subjected to external irradiation by a narrowband electromagnetic (EM) pulse . In our model, the state of a µC is completely specified by

  17. 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

  18. 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.

  19. Antibiotic activity against naive and induced Streptococcus pneumoniae biofilms in an in vitro pharmacodynamic model.

    Science.gov (United States)

    Vandevelde, Nathalie M; Tulkens, Paul M; Van Bambeke, Françoise

    2014-01-01

    Biofilms play a role in the pathogenicity of pneumococcal infections. A pharmacodynamic in vitro model of biofilm was developed that allows characterization of the activity of antibiotics against viability and biomass by using in parallel capsulated (ATCC 49619) and noncapsulated (R6) reference strains. Naive biofilms were obtained by incubating fresh planktonic cultures for 2 to 11 days in 96-well polystyrene plates. Induced biofilms were obtained using planktonic bacteria collected from the supernatant of 6-day-old naive biofilms. Biomass production was more rapid and intense in the induced model, but the levels were similar for both strains. Full concentration responses fitting sigmoidal regressions allowed calculation of maximal efficacies and relative potencies of drugs. All antibiotics tested (amoxicillin, clarithromycin, solithromycin, levofloxacin, and moxifloxacin) were more effective against young naive biofilms than against old or induced biofilms, except macrolides/ketolides, which were as effective at reducing viability in 2-day-old naive biofilms and in 11-day-old induced biofilms of R6. Macrolides/ketolides, however, were less potent than fluoroquinolones against R6 (approximately 5- to 20-fold-higher concentrations needed to reduction viability of 20%). However, at concentrations obtainable in epithelial lining fluid, the viabilities of mature or induced biofilms were reduced 15 to 45% (amoxicillin), 17 to 44% (macrolides/ketolides), and 12 to 64% (fluoroquinolones), and biomasses were reduced 5 to 45% (amoxicillin), 5 to 60% (macrolides/ketolides), and 10 to 76% (fluoroquinolones), with solithromycin and moxifloxacin being the most effective and the most potent agents (due to lower MICs) in their respective classes. This study allowed the ranking of antibiotics with respect to their potential effectiveness in biofilm-related infections, underlining the need to search for still more effective options.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. A physics-based probabilistic forecasting model for rainfall-induced shallow landslides at regional scale

    Science.gov (United States)

    Zhang, Shaojie; Zhao, Luqiang; Delgado-Tellez, Ricardo; Bao, Hongjun

    2018-03-01

    Conventional outputs of physics-based landslide forecasting models are presented as deterministic warnings by calculating the safety factor (Fs) of potentially dangerous slopes. However, these models are highly dependent on variables such as cohesion force and internal friction angle which are affected by a high degree of uncertainty especially at a regional scale, resulting in unacceptable uncertainties of Fs. Under such circumstances, the outputs of physical models are more suitable if presented in the form of landslide probability values. In order to develop such models, a method to link the uncertainty of soil parameter values with landslide probability is devised. This paper proposes the use of Monte Carlo methods to quantitatively express uncertainty by assigning random values to physical variables inside a defined interval. The inequality Fs forecasting model for rainfall-induced shallow landslides. The prediction ability of this model was tested in a case study, in which simulated forecasting of landslide disasters associated with heavy rainfalls on 9 July 2013 in the Wenchuan earthquake region of Sichuan province, China, was performed. The proposed model successfully forecasted landslides in 159 of the 176 disaster points registered by the geo-environmental monitoring station of Sichuan province. Such testing results indicate that the new model can be operated in a highly efficient way and show more reliable results, attributable to its high prediction accuracy. Accordingly, the new model can be potentially packaged into a forecasting system for shallow landslides providing technological support for the mitigation of these disasters at regional scale.

  6. Fatigue Modeling via Mammalian Auditory System for Prediction of Noise Induced Hearing Loss.

    Science.gov (United States)

    Sun, Pengfei; Qin, Jun; Campbell, Kathleen

    2015-01-01

    Noise induced hearing loss (NIHL) remains as a severe health problem worldwide. Existing noise metrics and modeling for evaluation of NIHL are limited on prediction of gradually developing NIHL (GDHL) caused by high-level occupational noise. In this study, we proposed two auditory fatigue based models, including equal velocity level (EVL) and complex velocity level (CVL), which combine the high-cycle fatigue theory with the mammalian auditory model, to predict GDHL. The mammalian auditory model is introduced by combining the transfer function of the external-middle ear and the triple-path nonlinear (TRNL) filter to obtain velocities of basilar membrane (BM) in cochlea. The high-cycle fatigue theory is based on the assumption that GDHL can be considered as a process of long-cycle mechanical fatigue failure of organ of Corti. Furthermore, a series of chinchilla experimental data are used to validate the effectiveness of the proposed fatigue models. The regression analysis results show that both proposed fatigue models have high corrections with four hearing loss indices. It indicates that the proposed models can accurately predict hearing loss in chinchilla. Results suggest that the CVL model is more accurate compared to the EVL model on prediction of the auditory risk of exposure to hazardous occupational noise.

  7. Fatigue Modeling via Mammalian Auditory System for Prediction of Noise Induced Hearing Loss

    Directory of Open Access Journals (Sweden)

    Pengfei Sun

    2015-01-01

    Full Text Available Noise induced hearing loss (NIHL remains as a severe health problem worldwide. Existing noise metrics and modeling for evaluation of NIHL are limited on prediction of gradually developing NIHL (GDHL caused by high-level occupational noise. In this study, we proposed two auditory fatigue based models, including equal velocity level (EVL and complex velocity level (CVL, which combine the high-cycle fatigue theory with the mammalian auditory model, to predict GDHL. The mammalian auditory model is introduced by combining the transfer function of the external-middle ear and the triple-path nonlinear (TRNL filter to obtain velocities of basilar membrane (BM in cochlea. The high-cycle fatigue theory is based on the assumption that GDHL can be considered as a process of long-cycle mechanical fatigue failure of organ of Corti. Furthermore, a series of chinchilla experimental data are used to validate the effectiveness of the proposed fatigue models. The regression analysis results show that both proposed fatigue models have high corrections with four hearing loss indices. It indicates that the proposed models can accurately predict hearing loss in chinchilla. Results suggest that the CVL model is more accurate compared to the EVL model on prediction of the auditory risk of exposure to hazardous occupational noise.

  8. 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.

  9. 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

    2017-12-01

    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 data set 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%.

  10. Loop-induced decays of Higgs boson in the left-right twin Higgs model

    International Nuclear Information System (INIS)

    Yao-Bei, Liu; Xue-Lei, Wang; Yao-Bein, Liu; Xue-Lei, Wang

    2009-01-01

    We analyze the loop-induced decays of the Higgs boson into pairs of gluons and photons in the left-right twin Higgs model. The study shows that the deviation of the partial widths for these decays relative to their Standard Model (SM) values scales with 1/f 2 , where f ∼ TeV is the symmetry breaking scale in the model. For the mass mixing parameter M equals 150 GeV, the LHC and a linear e + e - collider would be sensitive to the deviation in Γ(H → gg) for f ≤ 770(660) GeV at the 1(2) σ level. So the Higgs boson processes at the LHC can be a sensitive probe for the left-right twin Higgs model. (authors)

  11. 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

    2017-01-01

    The effect of wind waves on water level and currents during two storms in the North Sea is investigated using a high-resolution Nucleus for European Modelling of the Ocean (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, 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.

  12. Agent-based computational model investigates muscle-specific responses to disuse-induced atrophy

    Science.gov (United States)

    Martin, Kyle S.; Peirce, Shayn M.

    2015-01-01

    Skeletal muscle is highly responsive to use. In particular, muscle atrophy attributable to decreased activity is a common problem among the elderly and injured/immobile. However, each muscle does not respond the same way. We developed an agent-based model that generates a tissue-level skeletal muscle response to disuse/immobilization. The model incorporates tissue-specific muscle fiber architecture parameters and simulates changes in muscle fiber size as a result of disuse-induced atrophy that are consistent with published experiments. We created simulations of 49 forelimb and hindlimb muscles of the rat by incorporating eight fiber-type and size parameters to explore how these parameters, which vary widely across muscles, influence sensitivity to disuse-induced atrophy. Of the 49 muscles modeled, the soleus exhibited the greatest atrophy after 14 days of simulated immobilization (51% decrease in fiber size), whereas the extensor digitorum communis atrophied the least (32%). Analysis of these simulations revealed that both fiber-type distribution and fiber-size distribution influence the sensitivity to disuse atrophy even though no single tissue architecture parameter correlated with atrophy rate. Additionally, software agents representing fibroblasts were incorporated into the model to investigate cellular interactions during atrophy. Sensitivity analyses revealed that fibroblast agents have the potential to affect disuse-induced atrophy, albeit with a lesser effect than fiber type and size. In particular, muscle atrophy elevated slightly with increased initial fibroblast population and increased production of TNF-α. Overall, the agent-based model provides a novel framework for investigating both tissue adaptations and cellular interactions in skeletal muscle during atrophy. PMID:25722379

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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.

  18. An EOQ Model for Phase Inventory with Induced Demand and Periodic Cycle Time

    Directory of Open Access Journals (Sweden)

    Sujit Kumar De

    2014-01-01

    Full Text Available This paper deals with a stock flow of an inventory problem over induced demand. The inventory is consumed through “core customer” or chain marketing system in an induced environment (inductance to exhaust all the items of the stock inventory in an indefinite time. The demand rate is depicted due to induced factor which is generated from the same inventory presented nearby. The inventory cycle time is split into several periodic times due to oscillatory feature of the inventory which is called phase inventory. Considering uniform demand, this cycle time splits into two basic parts, namely, “first shift” (phase and “second shift” (phase. Since the process dampens over time, so the whole inventory will exhaust after few periods. A cost function consisted of inventory cost, setup cost, and loss for induced items is minimized to obtain optimal order quantity and replenishment time. The multivariate lagrange interpolation (MLI over the average values of the postsensitivity analysis is developed here. Finally, graphical illustrations are made to justify the model.

  19. A rat model of picornavirus-induced airway infection and inflammation

    Directory of Open Access Journals (Sweden)

    Szakaly Renee J

    2009-08-01

    Full Text Available Abstract Background Infection of the lower airways by rhinovirus, a member of the picornavirus family, is an important cause of wheezing illnesses in infants, and plays an important role in the pathogenesis of rhinovirus-induced asthma exacerbations. Given the absence of natural rhinovirus infections in rodents, we investigated whether an attenuated form of mengovirus, a picornavirus whose wild-type form causes systemic rather than respiratory infections in its natural rodent hosts, could induce airway infections in rats with inflammatory responses similar to those in human rhinovirus infections. Results After inoculation with 107 plaque-forming units of attenuated mengovirus through an inhalation route, infectious mengovirus was consistently recovered on days 1 and 3 postinoculation from left lung homogenates (median Log10 plaque-forming units = 6.0 and 4.8, respectively and right lung bronchoalveolar lavage fluid (median Log10 plaque-forming units = 5.8 and 4.0, respectively. Insufflation of attenuated mengovirus, but not vehicle or UV-inactivated virus, into the lungs of BN rats caused significant increases (P P Conclusion Attenuated mengovirus caused a respiratory infection in rats with several days of viral shedding accompanied by a lower airway inflammatory response consisting of neutrophils and lymphocytes. These features suggest that mengovirus-induced airway infection in rodents could be a useful model to define mechanisms of rhinovirus-induced airway inflammation in humans.

  20. Piplartine induces genotoxicity in eukaryotic but not in prokaryotic model systems.

    Science.gov (United States)

    Bezerra, Daniel P; Vasconcellos, Marne C; Machado, Miriana S; Villela, Izabel V; Rosa, Renato M; Moura, Dinara J; Pessoa, Cláudia; Moraes, Manoel O; Silveira, Edilberto R; Lima, Mary Anne S; Aquino, Nayara C; Henriques, João Antonio P; Saffi, Jenifer; Costa-Lotufo, Letícia V

    2009-01-01

    Piplartine {5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propen-1-yl]-2(1H)-pyridinone} is an alkamide present in Piper species that exhibits promising anticancer properties. It was previously shown that piplartine is mutagenic in yeast and cultured mammalian cells. This study was performed to increase the knowledge on the mutagenic potential of piplartine using the Salmonella/microsome assay, V79 cell micronucleus and chromosome aberration assays, and mouse bone-marrow micronucleus tests. Piplartine was isolated from the roots of Piper tuberculatum. This extracted compound was unable to induce a mutagenic response in any Salmonella typhimurium strain either in the presence or absence of metabolic activation. Piplartine showed mutagenic effects in V79 cells, as there was an increased frequency of aberrant cells and micronuclei formation. In addition, piplartine administered at 50mg/kg did not induce micronucleus formation in vivo, but a dose of 100mg/kg induced an increase in the levels of micronucleus polychromatic erythrocytes (MNPCEs). Overall, these results provide further support that piplartine induces in vivo and in vitro mutagenicity in eukaryotic models.

  1. Modelling nanoparticles formation in the plasma plume induced by nanosecond pulsed lasers

    Energy Technology Data Exchange (ETDEWEB)

    Girault, M. [Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), UMR 6303 CNRS-Universite de Bourgogne, 9 Av. A. Savary, BP 47 870, F-21078 Dijon Cedex (France); Centre Lasers Intenses et Applications (CELIA), Universite de Bordeaux 1, 43 rue Pierre Noailles, Talence (France); Hallo, L., E-mail: hallo@celia.u-bordeaux1.fr [CEA CESTA, 15 Avenue des Sablieres CS 60001, 33116 Le Barp Cedex (France); Centre Lasers Intenses et Applications (CELIA), Universite de Bordeaux 1, 43 rue Pierre Noailles, Talence (France); Lavisse, L.; Lucas, M.C. Marco de [Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), UMR 6303 CNRS-Universite de Bourgogne, 9 Av. A. Savary, BP 47 870, F-21078 Dijon Cedex (France); Hebert, D. [CEA CESTA, 15 Avenue des Sablieres CS 60001, 33116 Le Barp Cedex (France); Potin, V.; Jouvard, J.-M. [Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), UMR 6303 CNRS-Universite de Bourgogne, 9 Av. A. Savary, BP 47 870, F-21078 Dijon Cedex (France)

    2012-09-15

    Highlights: Black-Right-Pointing-Pointer Nanoparticles spatial localization in the plume induced by a pulsed laser. Black-Right-Pointing-Pointer Plasma plume obtained by laser irradiation. Black-Right-Pointing-Pointer Particles and debris formation. Black-Right-Pointing-Pointer Powder generation. Black-Right-Pointing-Pointer Conditions of formation. - Abstract: Nanoparticles formation in a laser-induced plasma plume in the ambient air has been investigated by using numerical simulations and physical models. For high irradiances, or for ultrashort laser pulses, nanoparticles are formed by condensation, as fine powders, in the expanding plasma for very high pairs of temperature and pressure. At lower irradiances, or nanosecond laser pulses, another thermodynamic paths are possible, which cross the liquid-gas transition curve while laser is still heating the target and the induced plasma. In this work, we explore the growth of nanoparticles in the plasma plume induced by nanosecond pulsed lasers as a function of the laser irradiance. Moreover, the influence of the ambient gas has also been investigated.

  2. The cationic amino acid transporter 2 is induced in inflammatory lung models and regulates lung fibrosis

    Directory of Open Access Journals (Sweden)

    Rothenberg Marc E

    2010-06-01

    Full Text Available Abstract Background Arginine is an amino acid that serves as a substrate for the enzymes nitric oxide synthase (NOS and arginase, leading to synthesis of NO and ornithine, respectively. As such, arginine has the potential to influence diverse fundamental processes in the lung. Methods We used mice deficient in cationic amino acid transporter (CAT 2 in models of allergic airway inflammation and pulmonary fibrosis. Results We report that the arginine transport protein CAT2 was over-expressed in the lung during the induction of allergic airway inflammation. Furthermore, CAT2 mRNA was strongly induced by transgenically over-expressed IL-4, and allergen-induced expression was dependent upon signal-transducer-and-activator-of-transcription (STAT 6. In situ mRNA hybridization demonstrated marked staining of CAT2, predominantly in scattered mononuclear cells. Analysis of allergic airway inflammation and bleomycin-induced inflammation in CAT2-deficient mice revealed that while inflammation was independent of CAT2 expression, bleomycin-induced fibrosis was dependent upon CAT2. Mechanistic analysis revealed that arginase activity in macrophages was partly dependent on CAT2. Conclusion Taken together, these results identify CAT2 as a regulator of fibrotic responses in the lung.

  3. A Simple Model for Probabilistic Seismic Hazard Analysis of Induced Seismicity Associated With Deep Geothermal Systems

    Science.gov (United States)

    Schlittenhardt, Joerg; Spies, Thomas; Kopera, Juergen; Morales Aviles, Wilhelm

    2014-05-01

    In the research project MAGS (Microseismic activity of geothermal systems) funded by the German Federal Ministry of Environment (BMU) a simple model was developed to determine seismic hazard as the probability of the exceedance of ground motion of a certain size. Such estimates of the annual frequency of exceedance of prescriptive limits of e.g. seismic intensities or ground motions are needed for the planning and licensing, but likewise for the development and operation of deep geothermal systems. For the development of the proposed model well established probabilistic seismic hazard analysis (PSHA) methods for the estimation of the hazard for the case of natural seismicity were adapted to the case of induced seismicity. Important differences between induced and natural seismicity had to be considered. These include significantly smaller magnitudes, depths and source to site distances of the seismic events and, hence, different ground motion prediction equations (GMPE) that had to be incorporated to account for the seismic amplitude attenuation with distance as well as differences in the stationarity of the underlying tectonic and induced processes. Appropriate GMPE's in terms of PGV (peak ground velocity) were tested and selected from the literature. The proposed model and its application to the case of induced seismicity observed during the circulation period (operation phase of the plant) at geothermal sites in Germany will be presented. Using GMPE's for PGV has the advantage to estimate hazard in terms of velocities of ground motion, which can be linked to engineering regulations (e.g. German DIN 4150) which give prescriptive standards for the effects of vibrations on buildings and people. It is thus possible to specify the probability of exceedance of such prescriptive standard values and to decide whether they can be accepted or not. On the other hand hazard curves for induced and natural seismicity can be compared to study the impact at a site. Preliminary

  4. 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.

  5. Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury

    NARCIS (Netherlands)

    Aslami, H.; Heinen, A.; Roelofs, J.J.T.H.; Zuurbier, C.J.; Schultz, M.J.; Juffermans, N.P.

    2010-01-01

    Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended-animation-like state induced by hydrogen sulfide (H2S) protects against

  6. Effect of magnesium supplementation on blood rheology in NOS inhibition-induced hypertension model.

    Science.gov (United States)

    Cengiz, Melike; Ülker, Pinar; Üyüklü, Mehmet; Yaraş, Nazmi; Özen, Nur; Aslan, Mutay; Özyurt, Dilek; Basralı, Filiz

    2016-01-27

    This study investigated the effects of magnesium on blood rheological properties and blood pressure in nitric oxide synthase (NOS) inhibition-induced hypertension model. Hypertension was induced by oral administration of the nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/day) for 6 weeks and systolic blood pressure was measured by the tail-cuff method. The groups receiving magnesium supplementation were fed with rat chow containing 0.8% magnesium oxide during the experiment. At the end of experiment, blood samples were obtained from abdominal aorta, using ether anesthesia. Plasma and erythrocyte magnesium levels were determined by the atomic absorption spectrometer. RBC deformability and aggregation were determined by rotational ektacytometry. Plasma fibrinogen concentration was evaluated by ELISA. Whole blood and plasma viscosities were determined by viscometer and intracellular free Ca++ level was measured by using spectroflurometric method. Blood pressure was elevated in hypertensive groups and suppressed by magnesium therapy. Plasma viscosity and RBC aggregation were found to be higher in hypertensive rats than control animals and these parameters significantly decreased in magnesium supplemented hypertensive animals. Other measurements were not different between experimental groups. These results confirm that blood pressure, plasma viscosity and RBC aggregation increased in NOS inhibition-induced hypertension model and oral magnesium supplementation improved these parameters.

  7. 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.

  8. 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.

  9. Intravenous lipid emulsion in the resuscitation of cocaine-induced cardiovascular arrest in a rat model.

    Science.gov (United States)

    Chai, Peter R; Hack, Jason B

    2016-08-01

    Intravenous lipid emulsion (ILE) is a potential antidote for severe overdose of certain lipophilic drugs. Cocaine overdose is often fatal and has no antidote. The use of ILE after cocaine-induced cardiac arrest has been suggested but is not well characterized. The objective of the study is to determine if ILE would reverse cocaine-induced cardiac arrest in a rat model. Twelve Sprague-Dawley rats with intra-arterial and intravenous access were sedated with isoflurane and split into 2 cocaine dose groups, then given either ILE or normal saline (NS) intravenously (IV)-group A, 7 animals received cocaine (10 mg/kg IV) with 6 of 7 given ILE (15 mg/kg IV) and 1 of 7 given NS (equal volume); group B, 5 animals received cocaine (5 mg/kg IV) with 3 of 5 given ILE (15 mg/kg IV) and 2 of 5 given NS (equal volume). Closed chest compressions were initiated for asystole and continued for 15 minutes with rhythm checks every minute. All 12 rats experienced cardiac arrest after cocaine bolus. Resuscitation was successful in 1 of 7 rats in group A and 0 of 5 in group B. Intravenous lipid emulsion administration did not affect outcome of cocaine-induced cardiac arrest compared with control in this model. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. A novel concurrent pictorial choice model of mood-induced relapse in hazardous drinkers.

    Science.gov (United States)

    Hardy, Lorna; Hogarth, Lee

    2017-12-01

    This study tested whether a novel concurrent pictorial choice procedure, inspired by animal self-administration models, is sensitive to the motivational effect of negative mood induction on alcohol-seeking in hazardous drinkers. Forty-eight hazardous drinkers (scoring ≥7 on the Alcohol Use Disorders Inventory) recruited from the community completed measures of alcohol dependence, depression, and drinking coping motives. Baseline alcohol-seeking was measured by percent choice to enlarge alcohol- versus food-related thumbnail images in two alternative forced-choice trials. Negative and positive mood was then induced in succession by means of self-referential affective statements and music, and percent alcohol choice was measured after each induction in the same way as baseline. Baseline alcohol choice correlated with alcohol dependence severity, r = .42, p = .003, drinking coping motives (in two questionnaires, r = .33, p = .02 and r = .46, p = .001), and depression symptoms, r = .31, p = .03. Alcohol choice was increased by negative mood over baseline (p mood (p = .54, ηp2 = .008). The negative mood-induced increase in alcohol choice was not related to gender, alcohol dependence, drinking to cope, or depression symptoms (ps ≥ .37). The concurrent pictorial choice measure is a sensitive index of the relative value of alcohol, and provides an accessible experimental model to study negative mood-induced relapse mechanisms in hazardous drinkers. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  11. 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.

  12. 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.

  13. The isolated perfused kidney of the pig: new model to evaluate shock wave-induced lesions.

    Science.gov (United States)

    Köhrmann, K U; Back, W; Bensemann, J; Florian, J; Weber, A; Kahmann, F; Rassweiler, J; Alken, P

    1994-04-01

    Little is known about the mechanisms and determining factors of shock wave-induced kidney trauma. After classification of the renal lesion in a canine model, we attempted to establish an ex vivo model using the isolated kidney of the pig perfused by Tyrode's solution under physiologic conditions. After shock wave application on the Modulith SL 20, vessel lesions were evaluated by microangiography to determine the size and frequency of dye extravasation in the different areas of the organ. Variation of the focus localization caused different patterns of lesions that characterized the pathway of the shock wave. In particular, constant petechial extravasation in the cortex was observed. The generator voltage correlated with the diameter and the frequency of the lesion area. The number of shock waves primarily affected the incidence of vessel rupture in the regions adjacent to the focal zone. Light microscopy revealed dose-dependent necrosis of tubular cells up to gap-like parenchymal defects. Even after application of the minimal shock wave doses, electron microscopy demonstrated vacuolization of tubular cells in the shock wave focus. Traumatic junctions between capillaries and the tubulur system can explain clinically observed macrohematuria without renal hematomas. With this model, it was possible to evaluate localization and dose dependence of shock wave-induced kidney trauma with high sensitivity and reproducibility. Further advantages of the model were easy availability and the fact that studies on living animals were not necessary. Therefore, standardization and comparison of different lithotripters becomes possible.

  14. A new murine model of stress-induced complex atherosclerotic lesions

    Directory of Open Access Journals (Sweden)

    Amir H. Najafi

    2013-03-01

    The primary purpose of this investigation was to determine whether ApoE−/− mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE−/− mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability.

  15. 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.

  16. A mathematical model for the effects of radiation to the induced cancer in mice

    Science.gov (United States)

    Wada, Takahiro; Manabe, Yuichiro; Bando, Masako

    We have been studying biological effects of radiation in terms of mathematical models. There are two main objects that we need to study: mutation and cancer. We proposed the Whack-A-Mole (WAM) model which takes account of the repair effects to study radiation induced mutations. We applied it to the mutation of several species including Drosophila and mice, and succeeded to reproduce the dose and dose-rate dependence of the mutation rates. Here, as a next step, we study the effects of low dose-rate radiation to an induced cancer in mice. In the experiment, they divided their mice in four groups and kept them under constant gamma-ray radiations with different dose rate for each group since the birth. On the 35th day, chemical carcinogen was given to each mouse and they observed the occurrence and the growth of cancer for one year. Our mathematical model consists of two stages. The first stage describes a multiple-step carcinogenesis and the second stage describes its growth. We assume that the carcinogenesis starts with the chemical carcinogen and that the rate of the following processes depends on the dose rate as it does in the WAM model. We found some irregularities in the data, however, the overall fit is satisfactory. This work was supported by JSPS KAKENHI Grant Number JP16H04637.

  17. Anisotropic Constitutive Model of Strain-Induced Phenomena in Stainless Steels at Cryogenic Temperatures

    International Nuclear Information System (INIS)

    Garion, C.; Skoczen, B.

    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, axisymmetric shells called bellows expansion joints. The stainless steels show three main phenomena induced by plastic strains at cryogenic temperatures: serrated (discontinuous) yielding, γ→α' phase transformation and anisotropic ductile damage. In the present paper, a coupled constitutive model of γ→α' 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 anisotropy. For such a model the shape of the yield surface in the stress space varies as a function of the plastic strains. The constitutive model creates a bridge between material science (experiments) and structural analysis. It has been used to predict the response of beam vacuum and cryogenic bellows to monotonic and cyclic loads developed in the interconnections of the Large Hadron Collider at CERN

  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. Evaluation of the ability of an experimental model to induce bacterial rhinosinusitis in rabbits.

    Science.gov (United States)

    Dolci, Eduardo Landini Lutaif; Campos, Carlos Augusto Correia de; Silva, Leonardo da; Dolci, Ricardo Landini Lutaif; Dolci, José Eduardo Lutaif

    2014-01-01

    For decades, animals have been used in sinonasal experimental models, and the practice has increased substantially in the last few years. This study aimed to assess the pathogenesis of infectious process and medication efficiency to treat rhinosinusitis. To evaluate the efficiency of the proposed experimental model to induce an acute bacterial sinonasal infectious process through histological analysis and sinus secretion cultures. This was an experimental study with 22 New Zealand rabbits, divided into: group A (six rabbits), group B (seven rabbits), group C (seven rabbits), and group D (control group with two rabbits). Rhinosinusitis was induced by the insertion of a synthetic sponge into the right nasal cavity of 20 animals (study groups), followed by the instillation of bacterial strains (50% Staphylococcus sp. and 50% Streptococcus sp.). The groups were euthanized within 10 days (group A), 17 days (group B), and 30 days (groups C and D). All the rabbits of the study group developed acute bacterial rhinosinusitis, which was diagnosed through macroscopic evaluation, histological analysis, and sinus secretion culture. The proposed model is technically simple to perform, it is similar to the rhinogenic model in human beings, and it is highly efficient to reproduce an acute bacterial sinus infection. Copyright © 2014 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. A Versatile New Model of Chemically Induced Chronic Colitis Using an Outbred Murine Strain

    Directory of Open Access Journals (Sweden)

    Monica Barone

    2018-03-01

    Full Text Available Murine colitis models are crucial tools for understanding intestinal homeostasis and inflammation. However, most current models utilize a highly inbred strain of mice, and often only one sex is employed to limit bias. This targeted approach, which in itself is biased, means that murine genetic diversity and sex-related differences are ignored, making it even more difficult to extend findings to humans, who are highly heterogeneous. Furthermore, most models do not examine the chronic form of colitis, an important fact taking into account the chronic nature of the inflammatory bowel diseases (IBD. Here, we attempted to create a more realistic murine colitis model by addressing these three issues. Using chemically induced chronic colon inflammation in an outbred strain of mice (RjOrl:SWISS [CD-1], we (i mimicked the relapsing nature of the disease, (ii better represented normal genetic variability, and (iii employed both female and male mice. Colitis was induced by intrarectal administration of dinitrobenzene sulfonic acid (DNBS. After a recovery period and 3 days before the mice were euthanized, colitis was reactivated by a second administration of DNBS. Protocol length was 24 days. Colitis severity was assessed using body mass, macroscopic scores, and histological scores. Myeloperoxidase (MPO activity, cytokine levels, and lymphocyte populations were also characterized. Our results show that the intrarectal administration of DNBS effectively causes colitis in both female and male CD-1 mice in a dose-dependent manner, as reflected by loss of body mass, macroscopic scores and histological scores. Furthermore, colon cytokine levels and mesenteric lymph node characteristics indicate that this model involves immune system activation. Although some variables were sex-specific, most of the results support including both females and males in the model. Our ultimate goal is to make this model available to researchers for testing candidate anti

  5. Nanodosimetric Simulation of Direct Ion-Induced DNA Damage Using Different Chromatin Geometry Models.

    Science.gov (United States)

    Henthorn, N T; Warmenhoven, J W; Sotiropoulos, M; Mackay, R I; Kirkby, K J; Merchant, M J

    2017-12-01

    Monte Carlo based simulation has proven useful in investigating the effect of proton-induced DNA damage and the processes through which this damage occurs. Clustering of ionizations within a small volume can be related to DNA damage through the principles of nanodosimetry. For simulation, it is standard to construct a small volume of water and determine spatial clusters. More recently, realistic DNA geometries have been used, tracking energy depositions within DNA backbone volumes. Traditionally a chromatin fiber is built within the simulation and identically replicated throughout a cell nucleus, representing the cell in interphase. However, the in vivo geometry of the chromatin fiber is still unknown within the literature, with many proposed models. In this work, the Geant4-DNA toolkit was used to build three chromatin models: the solenoid, zig-zag and cross-linked geometries. All fibers were built to the same chromatin density of 4.2 nucleosomes/11 nm. The fibers were then irradiated with protons (LET 5-80 keV/μm) or alpha particles (LET 63-226 keV/μm). Nanodosimetric parameters were scored for each fiber after each LET and used as a comparator among the models. Statistically significant differences were observed in the double-strand break backbone size distributions among the models, although nonsignificant differences were noted among the nanodosimetric parameters. From the data presented in this article, we conclude that selection of the solenoid, zig-zag or cross-linked chromatin model does not significantly affect the calculated nanodosimetric parameters. This allows for a simulation-based cell model to make use of any of these chromatin models for the scoring of direct ion-induced DNA damage.

  6. 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

  7. 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

  8. A Novel Large Animal Model of Acute Respiratory Distress Syndrome Induced by Mitochondrial Products.

    Science.gov (United States)

    Sanchez, Pablo G; Pasrija, Chetan; Mulligan, Matthew J; Wadhwa, Mandheer; Pratt, Diana L; Li, Tieluo; Gammie, James S; Kon, Zachary N; Pham, Si M; Griffith, Bartley P

    2017-12-01

    We aimed to create a reproducible lung injury model utilizing injection of mitochondrial damage-associated molecular products. Our goal was to characterize the pathophysiologic response to damage-associated molecular pattern mediated organ injury. There remain significant gaps in our understanding of acute respiratory distress syndrome, in part due to the lack of clinically applicable animal models of this disease. Animal models of noninfectious, tissue damage-induced lung injury are needed to understand the signals and responses associated with this injury. Ten pigs (35-45 kg) received an intravenous dose of disrupted mitochondrial products and were followed for 6 hours under general anesthesia. These animals were compared to a control group (n = 5) and a model of lung injury induced by bacterial products (lipopolysaccharide n = 5). Heart rate and temperature were significantly elevated in the mitochondrial product (204 ± 12 and 41 ± 1) and lipopolysaccharide groups (178 ± 18 and 42 ± 0.5) compared with controls (100 ± 13 and 38 ± 0.5) (P products and lipopolysaccharide groups compared with controls (170 ± 39, 196 ± 27, and 564 ± 75 mm Hg respectively, P = 0.001). Lung injury scoring of histological sections was significantly worse in mitochondrial and lipopolysaccharide groups compared with controls (mitochondrial-64 ± 6, lipopolysaccharide-54 ± 8, control-14 ± 1.5, P= 0.002). Our data demonstrated that the presence of mitochondrial products in the circulation leads to systemic inflammatory response and lung injury. In its acute phase lung injury induced by tissue or bacterial products is clinically indistinguishable.

  9. 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

  10. Stochastic Response of Energy Balanced Model for Vortex-Induced Vibration

    DEFF Research Database (Denmark)

    Nielsen, Søren R.K.; Krenk, S.

    A double oscillator model for vortex-induced oscillations of structural elements based on exact power exchange between fluid and structure, recently proposed by authors, is extended to include the effect of the turbulent component of the wind. In non-turbulent flow vortex-induced vibrations...... of lightly damped structures are found on two branches, with the highest amplification branch on the low-frequency branch. The effect free wind turbulence is to destabilize the vibrations on the high amplification branch, thereby reducing the oscillation amplitude. The effect is most pronounced for very...... lightly damped structures. The character of the structural vibrations changes with increasing turbulence and damping from nearly regular harmonic oscillation to typical narrow-banded stochastic response, closely resembling observed behaviour in experiments and full-scale structures....

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. An approach for modelling CANDU Fuel string vibration induced by unsteady flow

    Energy Technology Data Exchange (ETDEWEB)

    Fadaee, M.; Yu, S.D., E-mail: mofadaee@ryerson.ca, E-mail: syu@ryerson.ca [Ryerson Univ., Dept. of Mechanical and Industrial Engineering, Toronto, ON (Canada)

    2015-07-01

    A comprehensive dynamical model is presented in this paper to handle vibration a string of 12 CANDU6 fuel bundles inside a pressure tube under operating conditions. A finite element based computer program is developed at Ryerson University in collaboration with Candu Energy Inc. to simulate fuel string vibration and vibration induced wear in the pressure tube. The focus of this paper is dynamic frictional contact among fuel elements via spacer pads, between fuel elements and the pressure tube via bearing pads, and between neighboring fuel bundles via endplates. The types of deformations are bending, torsion and axial for the fuel elements, and in-plane and out-of-plane bending for the endplates. The system equations of motion are discretized in the time-domain by means of the Bozzak-Newmark scheme; the contact problem is handled using an iterative LCP algorithm. The unsteady flow and flow induced excitations are obtained using the FLUENT-LES. (author)

  16. 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

  17. 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

  18. 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

  19. 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...

  20. 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.

  1. 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.

  2. 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

  3. Effects of magma-induced stress within a cellular automaton model of volcanism

    Science.gov (United States)

    Butters, Olivia J.; Sarson, Graeme R.; Bushby, Paul J.

    2017-07-01

    The cellular automaton model of Piegari, Di Maio, Scandone and Milano, J. Volc. Geoth. Res., 202, 22-28 (2011) is extended to include magma-induced stress (i.e. a local magma-related augmentation of the stress field). This constitutes a nonlinear coupling between the magma and stress fields considered by this model, which affects the statistical distributions of eruptions obtained. The extended model retains a power law relation between eruption size and frequency for most events, as expected from the self-organised criticality inspiring this model; but the power law now applies for a reduced range of size, and there are new peaks of relatively more frequent eruptions of intermediate and large size. The cumulative frequency of repose time between events remains well modelled by a stretched exponential function of repose time (approaching a pure exponential distribution only for the longest repose times), but the time scales of this behaviour are slightly longer, reflecting the increased preference for larger events. The eruptions are relatively more likely to have high volatile (water) content, so would generally be more explosive. The new model also naturally favours a central 'axial' transport conduit, as found in many volcano systems, but which otherwise must be artificially imposed within such models.

  4. 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

  5. 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.

  6. 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.

  7. IL-10-inducing adjuvants enhance sublingual immunotherapy efficacy in a murine asthma model.

    Science.gov (United States)

    Van Overtvelt, Laurence; Lombardi, Vincent; Razafindratsita, Alain; Saint-Lu, Nathalie; Horiot, Stéphane; Moussu, Hélène; Mascarell, Laurent; Moingeon, Philippe

    2008-01-01

    IL-10-inducing adjuvants could enhance the efficacy of allergy vaccines in establishing allergen-specific tolerance. The aim of this study was to identify such adjuvants using in vitro cultures of human and murine cells and to evaluate them in a therapeutic murine model of sublingual immunotherapy (SLIT). Adjuvants stimulating IL-10 gene expression by human or murine immune cells were tested sublingually in BALB/c mice sensitized to ovalbumin (OVA), assessing the reduction in airway hyperresponsiveness (AHR) by whole-body plethysmography. The induction of regulatory T cells (T(reg)) was evaluated using phenotypic and functional assays. T-cell proliferation in cervical lymph nodes (LNs) was assessed following intravenous transfer of CFSE-labelled OVA-specific T cells and FACS analysis. A combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3/Dex) as well as Lactobacillus plantarum were found to induce IL-10 production by human and murine dendritic cells (DCs). The former inhibits LPS-induced DC maturation, whereas L. plantarum induces DC maturation. Following stimulation with VitD3/Dex-pretreated DCs, CD4+ naïve T cells exhibit a T(reg) profile. In contrast, a Th1/T(reg) pattern of differentiation is observed in the presence of DCs treated with L. plantarum. Both adjuvants significantly enhance SLIT efficacy in mice, in association with either induction of Foxp3+ T(reg) cells (for VitD3/Dex) or proliferation of OVA-specific T cells in cervical LNs (for L. plantarum). Both VitD3/Dex and L. plantarum polarize naïve T cells towards IL-10-expressing T cells, through distinct mechanisms. As adjuvants, they both enhance SLIT efficacy in a murine asthma model. 2007 S. Karger AG, Basel

  8. 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.

  9. 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.

  10. 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

  11. 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

    The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model......, 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...... including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia...

  12. Parallelization of the TRIGRS model for rainfall-induced landslides using the message passing interface

    Science.gov (United States)

    Alvioli, M.; Baum, R.L.

    2016-01-01

    We describe a parallel implementation of TRIGRS, the Transient Rainfall Infiltration and Grid-Based Regional Slope-Stability Model for the timing and distribution of rainfall-induced shallow landslides. We have parallelized the four time-demanding execution modes of TRIGRS, namely both the saturated and unsaturated model with finite and infinite soil depth options, within the Message Passing Interface framework. In addition to new features of the code, we outline details of the parallel implementation and show the performance gain with respect to the serial code. Results are obtained both on commercial hardware and on a high-performance multi-node machine, showing the different limits of applicability of the new code. We also discuss the implications for the application of the model on large-scale areas and as a tool for real-time landslide hazard monitoring.

  13. 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...

  14. 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 mechanica