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Sample records for als model mice

  1. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice

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    Koval, Erica D.; Shaner, Carey; Zhang, Peter; du Maine, Xavier; Fischer, Kimberlee; Tay, Jia; Chau, B. Nelson; Wu, Gregory F.; Miller, Timothy M.

    2013-01-01

    microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1G93A mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS. PMID:23740943

  2. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS.

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    Svitlana Garbuzova-Davis

    2007-11-01

    Full Text Available The blood-brain barrier (BBB, blood-spinal cord barrier (BSCB, and blood-cerebrospinal fluid barrier (BCSFB control cerebral/spinal cord homeostasis by selective transport of molecules and cells from the systemic compartment. In the spinal cord and brain of both ALS patients and animal models, infiltration of T-cell lymphocytes, monocyte-derived macrophages and dendritic cells, and IgG deposits have been observed that may have a critical role in motor neuron damage. Additionally, increased levels of albumin and IgG have been found in the cerebrospinal fluid in ALS patients. These findings suggest altered barrier permeability in ALS. Recently, we showed disruption of the BBB and BSCB in areas of motor neuron degeneration in the brain and spinal cord in G93A SOD1 mice modeling ALS at both early and late stages of disease using electron microscopy. Examination of capillary ultrastructure revealed endothelial cell degeneration, which, along with astrocyte alteration, compromised the BBB and BSCB. However, the effect of these alterations upon barrier function in ALS is still unclear. The aim of this study was to determine the functional competence of the BSCB in G93A mice at different stages of disease.Evans Blue (EB dye was intravenously injected into ALS mice at early or late stage disease. Vascular leakage and the condition of basement membranes, endothelial cells, and astrocytes were investigated in cervical and lumbar spinal cords using immunohistochemistry. Results showed EB leakage in spinal cord microvessels from all G93A mice, indicating dysfunction in endothelia and basement membranes and confirming our previous ultrastructural findings on BSCB disruption. Additionally, downregulation of Glut-1 and CD146 expressions in the endothelial cells of the BSCB were found which may relate to vascular leakage.Results suggest that the BSCB is compromised in areas of motor neuron degeneration in ALS mice at both early and late stages of the disease.

  3. Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice.

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    Miyazaki, Kazunori; Masamoto, Kazuto; Morimoto, Nobutoshi; Kurata, Tomoko; Mimoto, Takahumi; Obata, Takayuki; Kanno, Iwao; Abe, Koji

    2012-03-01

    The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow-metabolism coupling is disturbed in motor neuron degeneration of ALS model mice. In vivo capillary imaging showed progressive decrease of capillary diameter, capillary density, and red blood cell speed during the disease course. Spinal blood flow was progressively decreased in the anterior gray matter (GM) from presymptomatic stage to 0.80-fold of wild-type (WT) mice, 0.61 at early-symptomatic, and 0.49 at end stage of the disease. Local spinal glucose utilization (LSGU) was transiently increased to 1.19-fold in anterior GM at presymptomatic stage, which in turn progressively decreased to 0.84 and 0.60 at early-symptomatic and end stage of the disease. The LSGU/SBF ratio representing flow-metabolism uncoupling (FMU) preceded the sequential pathological changes in the spinal cord of ALS mice and was preferentially found in the affected region of ALS. The present study suggests that this early and progressive FMU could profoundly involve in the whole disease process as a vascular factor of ALS pathology, and could also be a potential target for therapeutic intervention of ALS.

  4. Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice.

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    Kosuge, Yasuhiro; Miyagishi, Hiroko; Yoneoka, Yuki; Yoneda, Keiko; Nango, Hiroshi; Ishige, Kumiko; Ito, Yoshihisa

    2017-07-04

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice. Copyright © 2017 Elsevier Ltd. All rights

  5. Genetic biomarkers for ALS disease in transgenic SOD1(G93A mice.

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    Ana C Calvo

    Full Text Available The pathophysiological mechanisms of both familial and sporadic Amyotrophic Lateral Sclerosis (ALS are unknown, although growing evidence suggests that skeletal muscle tissue is a primary target of ALS toxicity. Skeletal muscle biopsies were performed on transgenic SOD1(G93A mice, a mouse model of ALS, to determine genetic biomarkers of disease longevity. Mice were anesthetized with isoflurane, and three biopsy samples were obtained per animal at the three main stages of the disease. Transcriptional expression levels of seventeen genes, Ankrd1, Calm1, Col19a1, Fbxo32, Gsr, Impa1, Mef2c, Mt2, Myf5, Myod1, Myog, Nnt, Nogo A, Pax7, Rrad, Sln and Snx10, were tested in each muscle biopsy sample. Total RNA was extracted using TRIzol Reagent according to the manufacturer's protocol, and variations in gene expression were assayed by real-time PCR for all of the samples. The Pearson correlation coefficient was used to determine the linear correlation between transcriptional expression levels throughout disease progression and longevity. Consistent with the results obtained from total skeletal muscle of transgenic SOD1(G93A mice and 74-day-old denervated mice, five genes (Mef2c, Gsr, Col19a1, Calm1 and Snx10 could be considered potential genetic biomarkers of longevity in transgenic SOD1(G93A mice. These results are important because they may lead to the exploration of previously unexamined tissues in the search for new disease biomarkers and even to the application of these findings in human studies.

  6. A novel mouse model with impaired dynein/dynactin function develops amyotrophic lateral sclerosis (ALS)-like features in motor neurons and improves lifespan in SOD1-ALS mice

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    E. Teuling (Eva); V. van Dis (Vera); P. Wulf (Phebe); E.D. Haasdijk (Elize); A.S. Akhmanova (Anna); C.C. Hoogenraad (Casper); D. Jaarsma (Dick)

    2008-01-01

    textabstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by progressive motor neuron degeneration and muscle paralysis. Genetic evidence from man and mouse has indicated that mutations in the dynein/dynactin motor complex are correlated with motor neuron

  7. Craniofacial Statistical Deformation Models of Wild-type mice and Crouzon mice

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    Ólafsdóttir, Hildur; Darvann, Tron Andre; Ersbøll, Bjarne Kjær

    2007-01-01

    Crouzon syndrome is characterised by the premature fusion of cranial sutures and synchondroses leading to craniofacial growth disturbances. The gene causing the syndrome was discovered approximately a decade ago and recently the first mouse model of the syndrome was generated. In this study, a set...... of Micro CT scannings of the heads of wild-type (normal) mice and Crouzon mice were investigated. Statistical deformation models were built to assess the anatomical differences between the groups, as well as the within-group anatomical variation. Following the approach by Rueckert et al. we built an atlas...

  8. Differential autophagy power in the spinal cord and muscle of transgenic ALS mice.

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    Valeria eCrippa

    2013-11-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a motoneuron disease characterized by misfolded proteins aggregation in affected motoneurons. In mutant SOD1 (mutSOD1 ALS models, aggregation correlates to impaired functions of proteasome and/or autophagy, both essential for the intracellular chaperone-mediated protein quality control (PQC, and a reduced mutSOD1 clearance from motoneurons. Skeletal muscle cells are also sensitive to mutSOD1 toxicity, but no mutSOD1 aggregates are formed in these cells, that might better manage mutSOD1 than motoneurons. Thus, we analysed in spinal cord and in muscle of transgenic (tg G93A-SOD1 at presymptomatic (PS, 8 weeks and symptomatic (S, 16 weeks stages, and in age-matched control mice, whether mutSOD1 differentially modulates relevant PQC players, such as HSPB8, BAG3, and BAG1. Possible sex differences were also considered. No changes of HSPB8, BAG3 and BAG1 at PS stage (8 weeks were seen in all tissues examined in tg G93A-SOD1 and control mice. At S stage (16 weeks, HSPB8 dramatically increased in skeletal muscle of tg G93A-SOD1 mice, while a minor increase occurred in spinal cord of male, but not female tg G93A-SOD1 mice. BAG3 expression increased both in muscle and spinal cord of tg G93A-SOD1 mice at S stage, BAG1 expression increased only in muscle of the same mice. Since, HSPB8-BAG3 complex assists mutSOD1 autophagic removal, we analysed two well-known autophagic markers, LC3 and p62. Both LC3 and p62 mRNAs were significantly up-regulated in skeletal muscle of tg G93A-SOD1 mice at S stage (16 weeks. This suggests that mutSOD1 expression induces a robust autophagic response specifically in muscle. Together these results demonstrate that, in muscle mutSOD1-induced autophagic response is much higher than in spinal cords. In addition, if mutSOD1 exerts toxicity in muscle, this may not be mediated by misfolded protein accumulation. It remains unclear whether in muscle mutSOD1 toxicity is related to aberrant autophagy

  9. The lemon balm extract ALS-L1023 inhibits obesity and nonalcoholic fatty liver disease in female ovariectomized mice.

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    Kim, Jeongjun; Lee, Hyunghee; Lim, Jonghoon; Lee, Haerim; Yoon, Seolah; Shin, Soon Shik; Yoon, Michung

    2017-08-01

    Increasing evidence indicates that angiogenesis inhibitors regulate obesity. This study aimed to determine whether the lemon balm extract ALS-L1023 inhibits diet-induced obesity and nonalcoholic fatty liver disease (NAFLD) in female ovariectomized (OVX) mice. OVX mice received a low fat diet (LFD), a high fat diet (HFD) or HFD supplemented with ALS-L1023 (ALS-L1023) for 15 weeks. HFD mice exhibited increases in visceral adipose tissue (VAT) angiogenesis, body weight, VAT mass and VAT inflammation compared with LFD mice. In contrast, all of these effects were reduced in ALS-L1023 mice compared with HFD mice. Serum lipids and liver injury markers were improved in ALS-L1023 mice. Hepatic lipid accumulation, inflammatory cells and collagen levels were lower in ALS-L1023 mice than in HFD mice. ALS-L1023 mice exhibited a tendency to normalize hepatic expression of genes involved in lipid metabolism, inflammation and fibrosis to levels in LFD mice. ALS-L1023 also induced Akt phosphorylation and increased Nrf2 mRNA expression in livers of obese mice. Our results indicate that the angiogenesis inhibitor ALS-L1023 can regulate obesity, hepatic steatosis and fibro-inflammation, in part through improvement of VAT function, in obese OVX mice. These findings suggest that angiogenesis inhibitors may contribute to alleviation of NAFLD in post-menopausal women with obesity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1 Mice

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    Gotkine Marc

    2013-01-01

    Full Text Available Objective. Previous research suggests that acetylcholinesterase (AChE may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101, which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model. Methods. ALS (G93A-SOD1 mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose. Results. mEN101 given at the presymptomatic (but not symptomatic stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters. Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.

  11. Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier

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    Eve, David J.; Steiner, George; Mahendrasah, Ajay; Sanberg, Paul R.; Kurien, Crupa; Thomson, Avery; Borlongan, Cesar V.; Garbuzova-Davis, Svitlana

    2018-01-01

    Blood-spinal cord barrier (BSCB) alterations, including capillary rupture, have been demonstrated in animal models of amyotrophic lateral sclerosis (ALS) and ALS patients. To date, treatment to restore BSCB in ALS is underexplored. Here, we evaluated whether intravenous transplantation of human bone marrow CD34+ (hBM34+) cells into symptomatic ALS mice leads to restoration of capillary integrity in the spinal cord as determined by detection of microhemorrhages. Three different doses of hBM34+ cells (5 × 104, 5 × 105 or 1 × 106) or media were intravenously injected into symptomatic G93A SOD1 mice at 13 weeks of age. Microhemorrhages were determined in the cervical and lumbar spinal cords of mice at 4 weeks post-treatment, as revealed by Perls’ Prussian blue staining for ferric iron. Numerous microhemorrhages were observed in the gray and white matter of the spinal cords in media-treated mice, with a greater number of capillary ruptures within the ventral horn of both segments. In cell-treated mice, microhemorrhage numbers in the cervical and lumbar spinal cords were inversely related to administered cell doses. In particular, the pervasive microvascular ruptures determined in the spinal cords in late symptomatic ALS mice were significantly decreased by the highest cell dose, suggestive of BSCB repair by grafted hBM34+ cells. The study results provide translational outcomes supporting transplantation of hBM34+ cells at an optimal dose as a potential therapeutic strategy for BSCB repair in ALS patients. PMID:29535831

  12. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish.

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    Gros-Louis, Francois; Kriz, Jasna; Kabashi, Edor; McDearmid, Jonathan; Millecamps, Stéphanie; Urushitani, Makoto; Lin, Li; Dion, Patrick; Zhu, Qinzhang; Drapeau, Pierre; Julien, Jean-Pierre; Rouleau, Guy A

    2008-09-01

    Recessive ALS2 mutations are linked to three related but slightly different neurodegenerative disorders: amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. To investigate the function of the ALS2 encoded protein, we generated Als2 knock-out (KO) mice and zAls2 knock-down zebrafish. The Als2(-/-) mice lacking exon 2 and part of exon 3 developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebrafish had severe developmental abnormalities, swimming deficits and motor neuron perturbation. We identified, by RT-PCR, northern and western blotting novel Als2 transcripts in mouse central nervous system. These Als2 transcripts were present in Als2 null mice as well as in wild-type littermates and some rescued the zebrafish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2 KO mice from developing severe neurodegenerative disease and might also regulate the severity of the motor neurons phenotype observed in ALS2 patients.

  13. The wobbler mouse, an ALS animal model

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    Moser, Jakob Maximilian; Bigini, Paolo; Schmitt-John, Thomas

    2013-01-01

    This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking...

  14. Modeling Human Leukemia Immunotherapy in Humanized Mice

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    Jinxing Xia

    2016-08-01

    Full Text Available The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL, which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI, a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.

  15. Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier.

    Science.gov (United States)

    Eve, David J; Steiner, George; Mahendrasah, Ajay; Sanberg, Paul R; Kurien, Crupa; Thomson, Avery; Borlongan, Cesar V; Garbuzova-Davis, Svitlana

    2018-02-13

    Blood-spinal cord barrier (BSCB) alterations, including capillary rupture, have been demonstrated in animal models of amyotrophic lateral sclerosis (ALS) and ALS patients. To date, treatment to restore BSCB in ALS is underexplored. Here, we evaluated whether intravenous transplantation of human bone marrow CD34 + (hBM34 + ) cells into symptomatic ALS mice leads to restoration of capillary integrity in the spinal cord as determined by detection of microhemorrhages. Three different doses of hBM34 + cells (5 × 10 4 , 5 × 10 5 or 1 × 10 6 ) or media were intravenously injected into symptomatic G93A SOD1 mice at 13 weeks of age. Microhemorrhages were determined in the cervical and lumbar spinal cords of mice at 4 weeks post-treatment, as revealed by Perls' Prussian blue staining for ferric iron. Numerous microhemorrhages were observed in the gray and white matter of the spinal cords in media-treated mice, with a greater number of capillary ruptures within the ventral horn of both segments. In cell-treated mice, microhemorrhage numbers in the cervical and lumbar spinal cords were inversely related to administered cell doses. In particular, the pervasive microvascular ruptures determined in the spinal cords in late symptomatic ALS mice were significantly decreased by the highest cell dose, suggestive of BSCB repair by grafted hBM34 + cells. The study results provide translational outcomes supporting transplantation of hBM34 + cells at an optimal dose as a potential therapeutic strategy for BSCB repair in ALS patients.

  16. Dorsal skinfold chamber models in mice

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    Schreiter, Jeannine

    2017-07-01

    Full Text Available Background/purpose: The use of dorsal skinfold chamber models has substantially improved the understanding of micro-vascularisation in pathophysiology over the last eight decades. It allows pathophysiological studies of vascularisation over a continuous period of time. The dorsal skinfold chamber is an attractive technique for monitoring the vascularisation of autologous or allogenic transplants, wound healing, tumorigenesis and compatibility of biomaterial implants. To further reduce the animals’ discomfort while carrying the dorsal skinfold chamber, we developed a smaller chamber (the Leipzig Dorsal Skinfold Chamber and summarized the commercial available chamber models. In addition we compared our model to the common chamber. Methods: The Leipzig Dorsal Skinfold Chamber was applied to female mice with a mean weight of 22 g. Angiogenesis within the dorsal skinfold chamber was evaluated after injection of fluorescein isothiocyanate dextran with an Axio Scope microscope. The mean vessel density within the dorsal skinfold chamber was assessed over a period of 21 days at five different time points. The gained data were compared to previous results using a bigger and heavier dorsal skinfold model in mice. A PubMed and a patent search were performed and all papers related to “dorsal skinfold chamber” from 1 of January 2006 to 31 of December 2015 were evaluated regarding the dorsal skinfold chamber models and their technical improvements. The main models are described and compared to our titanium Leipzig Dorsal Skinfold Chamber model.Results: The Leipzig Dorsal Skinfold Chamber fulfils all requirements of continuous models known from previous chamber models while reducing irritation to the mice. Five different chamber models have been identified showing substantial regional diversity. The newly elaborated titanium dorsal skinfold chamber may replace the pre-existing titanium chamber model used in Germany so far, as it is smaller and lighter

  17. Development of an Allergic Conjunctivitis Model in Mice

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    Tolga Kocatürk

    2012-12-01

    Full Text Available Pur po se: To develop an animal model that simulates human allergic conjunctivitis to understand the physiopathogenesis of allergic diseases and for developing novel therapeutic interventions. Ma te ri al and Met hod: BALB/c mice (12 males were divided into two groups each comprised of six mice. For sensitization, on the 1st and 8th days, a 0.2 ml mixed solution, adjusted to a concentration to 5mg/ml of ovalbumin (OVA and 15mg/ml of aluminium hydroxide, was administered intraperitoneally to the mice in Group 1 and 0.2 ml saline solution to the mice in Group 2. To induce experimental allergic conjunctivitis, an antigen challenge was made on days 15 and 18, using an OVA solution (5mg/ml instilled into both eyes of the mice in Group 1; while the mice in Group 2 received Human Balanced Salt Solution instead of OVA. For the clinical evaluation, the occurrence of conjunctival and palpebral oedema, conjunctival hyperaemia, and lacrimation were observed. For the histological examination, eyeballs, eyelids, and lacrimal glands were removed and prepared according to the routine processing method of the tissue laboratory. Immunohistochemical examination was made with mast cell tryptase using the labeled streptavidin–biotin amplification method and 3.3´-diaminobenzidine, in addition to hematoxylin-eosin (HE, and toluidine blue (TB staining. Re sults: Evident conjunctival oedema, palpebral oedema, conjunctival hyperaemia, and lacrimation were observed in Group 1. Mean mast cell density in cells/mm2, infiltrating the subconjunctival tissue was significantly high in Group 1 (allergy group, 23.17±7.46, p<0.0001 when compared to Group 2 (5.58±3.12. There was no increase in eosinophil and lymphocyte counts as well as vascular intensity in the subconjunctival tissue in any group. Dis cus si on: The murine model developed is similar to the human allergic conjunctivitis both clinically and histopathologically and can be used as a template for future studies

  18. Differential autophagy power in the spinal cord and muscle of transgenic ALS mice

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    Crippa, Valeria; Boncoraglio, Alessandra; Galbiati, Mariarita; Aggarwal, Tanya; Rusmini, Paola; Giorgetti, Elisa; Cristofani, Riccardo; Carra, Serena; Pennuto, Maria; Poletti, Angelo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a motoneuron disease characterized by misfolded proteins aggregation in affected motoneurons. In mutant SOD1 (mutSOD1) ALS models, aggregation correlates to impaired functions of proteasome and/or autophagy, both essential for the intracellular

  19. Riluzole does not improve lifespan or motor function in three ALS mouse models.

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    Hogg, Marion C; Halang, Luise; Woods, Ina; Coughlan, Karen S; Prehn, Jochen H M

    2017-12-08

    Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 G93A model, the TDP-43 A315T model, and the recently developed FUS (1-359) model. Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression. Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1 G93A transgenic mice as assessed by Rotarod and stride length analysis. Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.

  20. Effect of infection by irradiated Trichinella Spirals larvae on mice and assessment the role of Al bendazole in treating them

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    Moawad, M.A.F.; Amin, M.M.

    2005-01-01

    The present study was carried out to investigate the effect of infection with irradiated Trichinella Spiralis larvae on mice and to asses the role of albendazole in treating them. This study included parasitological and histopathological studies on mice infected with irradiated Trichinella Spiralis larvae in comparison with mice infected with non-irradiated Trichinella Spiralis only or with mice treated after infection by albendazole. The obtained data revealed that, in mice infected with irradiated Trichinella Spiralis larvae (50 Krad or 80 Krad), the number and length of worms in the small intestine, as well as, the number of encysted larvae in muscles of mice, especially diaphragm and tongue, were significantly decreased. Also, using al bendazole 24 hours after infection with irradiated larvae lead to high significant decrease in all the previously mentioned parameters

  1. The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice

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    Choi, Jeong A. [Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Chung, Yoo-Ri [Department of Ophthalmology, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Byun, Hyae-Ran [Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Park, Hwangseo [Department of Bioscience and Biotechnology, Sejong University, Seoul (Korea, Republic of); Koh, Jae-Young, E-mail: jkko@amc.seoul.kr [Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Yoon, Young Hee, E-mail: yhyoon@amc.seoul.kr [Department of Ophthalmology, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2017-01-15

    Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC. - Highlights: • The effects of riluzole were examined in streptozotocin-induced diabetic mice. • The diameter of retinal vessels and the number of pericytes were severely reduced. • The levels of MCP1 and PKC were increased, while riluzole reversed all changes. • Riluzole attenuated the level of MCP1 in AGE- or mLDL-treated retinal pericytes. • Riluzole attenuated both MCP1 induction and pericyte loss in diabetic retinopathy.

  2. The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice

    International Nuclear Information System (INIS)

    Choi, Jeong A.; Chung, Yoo-Ri; Byun, Hyae-Ran; Park, Hwangseo; Koh, Jae-Young; Yoon, Young Hee

    2017-01-01

    Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC. - Highlights: • The effects of riluzole were examined in streptozotocin-induced diabetic mice. • The diameter of retinal vessels and the number of pericytes were severely reduced. • The levels of MCP1 and PKC were increased, while riluzole reversed all changes. • Riluzole attenuated the level of MCP1 in AGE- or mLDL-treated retinal pericytes. • Riluzole attenuated both MCP1 induction and pericyte loss in diabetic retinopathy.

  3. SOD1 aggregation in ALS mice shows simplistic test tube behavior.

    Science.gov (United States)

    Lang, Lisa; Zetterström, Per; Brännström, Thomas; Marklund, Stefan L; Danielsson, Jens; Oliveberg, Mikael

    2015-08-11

    A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.

  4. Food anticipation in Bmal1-/- and AAV-Bmal1 rescued mice: a reply to Fuller et al

    Directory of Open Access Journals (Sweden)

    Mistlberger Ralph E

    2009-08-01

    Full Text Available Abstract Evidence that circadian food-anticipatory activity and temperature rhythms are absent in Bmal1 knockout mice and rescued by restoration of Bmal1 expression selectively in the dorsomedial hypothalamus was published in 2008 by Fuller et al and critiqued in 2009 by Mistlberger et al. Fuller et al have responded to the critique with new information. Here we update our critique in the light of this new information. We also identify and correct factual and conceptual errors in the Fuller et al response. We conclude that the original results of Fuller et al remain inconclusive and fail to clarify the role of Bmal1 or the dorsomedial hypothalamus in the generation of food-entrainable rhythms in mice.

  5. Microstructural defects modeling in the Al-Mo system

    International Nuclear Information System (INIS)

    Pascuet, Maria I.; Fernandez, Julian R.; Monti, Ana M.

    2006-01-01

    In this work we have utilized computer simulation techniques to study microstructural defects, such as point defects and interfaces, in the Al-Mo alloy. Such alloy is taken as a model to study the Al(fcc)/U-Mo(bcc) interface. The EAM interatomic potential used has been fitted to the formation energy and lattice constant of the AlMo 3 intermetallic. Formation of vacancies for both components Al and Mo and anti-sites, Al Mo and Mo Al , as well as vacancy migration was studied in this structure. We found that the lowest energy defect complex that preserves stoichiometry is the antisite pair Al Mo +Mo Al , in correspondence with other intermetallics of the same structure. Our results also suggest that the structure of the Al(fcc)/Mo(bcc) interface is unstable, while that of the Al(fcc)/Al 5 Mo interface is stable, as observed experimentally. (author) [es

  6. Halloysite nanotubes-induced Al accumulation and oxidative damage in liver of mice after 30-day repeated oral administration.

    Science.gov (United States)

    Wang, Xue; Gong, Jiachun; Gui, Zongxiang; Hu, Tingting; Xu, Xiaolong

    2018-06-01

    Halloysite (Al 2 Si 2 O 5 (OH) 4 ·nH 2 O) nanotubes (HNTs) are natural clay materials and widely applied in many fields due to their natural hollow tubular structures. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility, however the in vivo toxicity of HNTs remains unclear. The objective of this study was to assess the hepatic toxicity of the purified HNTs in mice via oral route. The purified HNTs were orally administered to mice at 5, 50, and 300 mg/kg body weight (BW) every day for 30 days. Oral administration of HNTs stimulated the growth of the mice at the low dose (5 mg/kg BW) with no liver toxicity, but inhibited the growth of the mice at the middle (50 mg/kg BW) and high (300 mg/kg BW) doses. In addition, oral administration of HNTs at the high dose caused Al accumulation in the liver but had no marked effect on the Si content in the organ. The Al accumulation caused significant oxidative stress in the liver, which induced hepatic dysfunction and histopathologic changes. These findings demonstrated that Al accumulation-induced oxidative stress played an important role in the oral HNTs-caused liver injury. © 2018 Wiley Periodicals, Inc.

  7. A Fruitful Endeavor: Modeling ALS in the Fruit Fly

    Science.gov (United States)

    Casci, Ian; Pandey, Udai Bhan

    2014-01-01

    For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research. PMID:25289585

  8. Modeling of TiAl Alloy Grating by Investment Casting

    OpenAIRE

    Yi Jia; Shulong Xiao; Jing Tian; Lijuan Xu; Yuyong Chen

    2015-01-01

    The investment casting of TiAl alloys has become the most promising cost-effective technique for manufacturing TiAl components. This study aimed to investigate a series of problems associated with the investment casting of TiAl alloys. The mold filling and solidification of this casting model were numerically simulated using ProCAST. Shrinkage porosity was quantitatively predicted by a built-in feeding criterion. The results obtained from the numerical simulations were compared with experimen...

  9. A sensitive venous bleeding model in haemophilia A mice

    DEFF Research Database (Denmark)

    Pastoft, Anne Engedahl; Lykkesfeldt, Jens; Ezban, M.

    2012-01-01

    Haemostatic effect of compounds for treating haemophilia can be evaluated in various bleeding models in haemophilic mice. However, the doses of factor VIII (FVIII) for normalizing bleeding used in some of these models are reported to be relatively high. The aim of this study was to establish a se...

  10. From animal models to human disease: a genetic approach for personalized medicine in ALS.

    Science.gov (United States)

    Picher-Martel, Vincent; Valdmanis, Paul N; Gould, Peter V; Julien, Jean-Pierre; Dupré, Nicolas

    2016-07-11

    Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

  11. Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS mouse model.

    Directory of Open Access Journals (Sweden)

    Csilla Ari

    Full Text Available Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG, the main ingredient of the DP, and the ketogenic diet (KD, would increase motor function and survival in a mouse model of ALS (SOD1-G93A. ALS mice were fed standard rodent diet (SD, KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001 and 4.2% (p = 0.006, respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which

  12. Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.

    Science.gov (United States)

    Ari, Csilla; Poff, Angela M; Held, Heather E; Landon, Carol S; Goldhagen, Craig R; Mavromates, Nicholas; D'Agostino, Dominic P

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong

  13. Firn Model Intercomparison Experiment (FirnMICE)

    DEFF Research Database (Denmark)

    Lundin, Jessica M.D.; Stevens, C. Max; Arthern, Robert

    2017-01-01

    Evolution of cold dry snow and firn plays important roles in glaciology; however, the physical formulation of a densification law is still an active research topic. We forced eight firn-densification models and one seasonal-snow model in six different experiments by imposing step changes in tempe...

  14. Modeling of TiAl Alloy Grating by Investment Casting

    Directory of Open Access Journals (Sweden)

    Yi Jia

    2015-12-01

    Full Text Available The investment casting of TiAl alloys has become the most promising cost-effective technique for manufacturing TiAl components. This study aimed to investigate a series of problems associated with the investment casting of TiAl alloys. The mold filling and solidification of this casting model were numerically simulated using ProCAST. Shrinkage porosity was quantitatively predicted by a built-in feeding criterion. The results obtained from the numerical simulations were compared with experiments, which were carried out on Vacuum Skull Furnace using an investment block mold. The investment casting of TiAl grating was conducted for verifying the correctness and feasibility of the proposed method. The tensile test results indicated that, at room temperature, the tensile strength and elongation were approximately 675 MPa and 1.7%, respectively. The microstructure and mechanical property of the investment cast TiAl alloy were discussed.

  15. 26Al yields from rotating Wolf--Rayet star models

    OpenAIRE

    Vuissoz, C.; Meynet, G.; Knoedlseder, J.; Cervino, M.; Schaerer, D.; Palacios, A.; Mowlavi, N.

    2003-01-01

    We present new $^{26}$Al stellar yields from rotating Wolf--Rayet stellar models which, at solar metallicity, well reproduce the observed properties of the Wolf-Rayet populations. These new yields are enhanced with respect to non--rotating models, even with respect to non--rotating models computed with enhanced mass loss rates. We briefly discuss some implications of the use of these new yields for estimating the global contribution of Wolf-Rayet stars to the quantity of $^{26}$Al now present...

  16. Activation of the Wnt/{beta}-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yanchun [Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong (China); Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong (China); Guan, Yingjun, E-mail: guanyj@wfmc.edu.cn [Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong (China); Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong (China); Liu, Huancai [Department of Orthopedic, Affiliated Hospital, Weifang Medical University, Weifang, Shandong (China); Wu, Xin; Yu, Li; Wang, Shanshan; Zhao, Chunyan; Du, Hongmei [Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong (China); Wang, Xin, E-mail: xwang@rics.bwh.harvard.edu [Department of Neurosurgery, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States)

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer Wnt3a and Cyclin D1 were upregulated in the spinal cord of the ALS mice. Black-Right-Pointing-Pointer {beta}-catenin translocated from the cell membrane to the nucleus in the ALS mice. Black-Right-Pointing-Pointer Wnt3a, {beta}-catenin and Cyclin D1 co-localized for astrocytes were all increased. Black-Right-Pointing-Pointer BrdU/Cyclin D1 double-positive cells were increased in the spinal cord of ALS mice. Black-Right-Pointing-Pointer BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. -- Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however, the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, {beta}-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/{beta}-catenin signaling pathway. We determined the expression of Wnt3a, {beta}-catenin, and Cyclin D1 in the adult spinal cord of SOD1{sup G93A} ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, {beta}-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, {beta}-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, {beta}-catenin or Cyclin D1 in mature GFAP{sup +} astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest that

  17. Activation of the Wnt/β-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice

    International Nuclear Information System (INIS)

    Chen, Yanchun; Guan, Yingjun; Liu, Huancai; Wu, Xin; Yu, Li; Wang, Shanshan; Zhao, Chunyan; Du, Hongmei; Wang, Xin

    2012-01-01

    Highlights: ► Wnt3a and Cyclin D1 were upregulated in the spinal cord of the ALS mice. ► β-catenin translocated from the cell membrane to the nucleus in the ALS mice. ► Wnt3a, β-catenin and Cyclin D1 co-localized for astrocytes were all increased. ► BrdU/Cyclin D1 double-positive cells were increased in the spinal cord of ALS mice. ► BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. -- Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however, the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, β-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/β-catenin signaling pathway. We determined the expression of Wnt3a, β-catenin, and Cyclin D1 in the adult spinal cord of SOD1 G93A ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, β-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, β-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, β-catenin or Cyclin D1 in mature GFAP + astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest that neurodegeneration activates the Wnt/β-catenin signaling pathway, which is associated with glial proliferation in the adult spinal cord of ALS transgenic mice. This

  18. Human reconstructed skin xenografts on mice to model skin physiology.

    Science.gov (United States)

    Salgado, Giorgiana; Ng, Yi Zhen; Koh, Li Fang; Goh, Christabelle S M; Common, John E

    Xenograft models to study skin physiology have been popular for scientific use since the 1970s, with various developments and improvements to the techniques over the decades. Xenograft models are particularly useful and sought after due to the lack of clinically relevant animal models in predicting drug effectiveness in humans. Such predictions could in turn boost the process of drug discovery, since novel drug compounds have an estimated 8% chance of FDA approval despite years of rigorous preclinical testing and evaluation, albeit mostly in non-human models. In the case of skin research, the mouse persists as the most popular animal model of choice, despite its well-known anatomical differences with human skin. Differences in skin biology are especially evident when trying to dissect more complex skin conditions, such as psoriasis and eczema, where interactions between the immune system, epidermis and the environment likely occur. While the use of animal models are still considered the gold standard for systemic toxicity studies under controlled environments, there are now alternative models that have been approved for certain applications. To overcome the biological limitations of the mouse model, research efforts have also focused on "humanizing" the mice model to better recapitulate human skin physiology. In this review, we outline the different approaches undertaken thus far to study skin biology using human tissue xenografts in mice and the technical challenges involved. We also describe more recent developments to generate humanized multi-tissue compartment mice that carry both a functioning human immune system and skin xenografts. Such composite animal models provide promising opportunities to study drugs, disease and differentiation with greater clinical relevance. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  19. Early phenotypical diagnoses in Trembler-J mice model.

    Science.gov (United States)

    Rosso, Gonzalo; Cal, Karina; Canclini, Lucía; Damián, Juan Pablo; Ruiz, Paul; Rodríguez, Héctor; Sotelo, José Roberto; Vazquez, Cristina; Kun, Alejandra

    2010-06-30

    Pmp-22 mutant mice (Trembler-J: B6.D2-Pmp22/J), are used as a model to study Charcot-Marie-Tooth type 1A (CMT1A). The identification of individual genotypes is a routine in the management of the Tr(J) colony. The earliest phenotypic manifestation of the pmp-22 mutation is just about 20th postnatal days, when pups begin to tremble. In this study, a rapid and simple diagnostic method was developed by modifying the Tail Suspension Test (MTST) to determine the difference between the Tr(J) and the wild-type mice phenotype. The animal behavioral phenotypes generated during the test were consistent with the specific genotype of each animal. The MTST allowed us to infer the heterozygous genotype in early postnatal stages, at 11 days after birth. The motor impairment of Tr(J) mice was also analyzed by a Fixed Bar Test (FBT), which revealed the disease evolution according to age. The main advantages of MTST are its objectivity, simplicity, and from the viewpoint of animal welfare, it is a non-invasive technique that combined with his rapidity show its very well applicability for use from an early age in these mice. Copyright 2010 Elsevier B.V. All rights reserved.

  20. Halloysite Nanotubes-Induced Al Accumulation and Fibrotic Response in Lung of Mice after 30-Day Repeated Oral Administration.

    Science.gov (United States)

    Wang, Xue; Gong, Jiachun; Rong, Rui; Gui, Zongxiang; Hu, Tingting; Xu, Xiaolong

    2018-03-21

    Natural halloysite (Al 2 Si 2 O 5 (OH) 4 · nH 2 O) nanotubes (HNT) are clay materials with hollow tubular structure and are widely applied in many fields. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility; however, the in vivo toxicity of HNTs remains unclear. In this study, the biodistribution and pulmonary toxicity of the purified HNTs in mice were investigated after intragastric administration for 30 days. HNTs have high stability in biological conditions. Oral administration of HNTs caused significant Al accumulation predominantly in the lung with relative slight effects on Si biodistribution. Oral administration of HNTs stimulated the growth of the mice at low dose (5 mg/kg BW) with no pulmonary toxicity but inhibited the mouse growth and resulted in oxidative stress and inflammation in lung at high dose (50 mg/kg BW). In addition, oral HNTs at high dose could be absorbed from the gastrointestinal tract and deposited in lung and could also induce pulmonary fibrosis.

  1. An Improved Model for FE Modeling and Simulation of Closed Cell Al-Alloy Foams

    OpenAIRE

    Hasan, MD. Anwarul

    2010-01-01

    Cell wall material properties of Al-alloy foams have been derived by a combination of nanoindentation experiment and numerical simulation. Using the derived material properties in FE (finite element) modeling of foams, the existing constitutive models of closed-cell Al-alloy foams have been evaluated against experimental results. An improved representative model has been proposed for FE analysis of closed-cell Al-alloy foams. The improved model consists of a combination of spherical and cruci...

  2. Modeling the neuroanatomic propagation of ALS in the spinal cord

    Science.gov (United States)

    Drawert, Brian; Thakore, Nimish; Mitchell, Brian; Pioro, Erik; Ravits, John; Petzold, Linda R.

    2017-07-01

    Recent hypotheses of amyotrophic lateral sclerosis (ALS) progression have posited a point-source origin of motor neuron death with neuroanatomic propagation either contiguously to adjacent regions, or along networks via axonal and synaptic connections. Although the molecular mechanisms of propagation are unknown, one leading hypothesis is a "prion-like" spread of misfolded and aggregated proteins, including SOD1 and TDP-43. We have developed a mathematical model representing cellular and molecular spread of ALS in the human spinal cord. Our model is based on the stochastic reaction-diffusion master equation approach using a tetrahedral discretized space to capture the complex geometry of the spinal cord. Domain dimension and shape was obtained by reconstructing human spinal cord from high-resolution magnetic resonance (MR) images and known gross and histological neuroanatomy. Our preliminary results qualitatively recapitulate the clinically observed pattern of spread of ALS thorough the spinal cord.

  3. Bioactivity of Epigallocatechin Gallate Nanoemulsions Evaluated in Mice Model.

    Science.gov (United States)

    Koutelidakis, Antonios E; Argyri, Konstantina; Sevastou, Zoi; Lamprinaki, Dimitra; Panagopoulou, Elli; Paximada, Evi; Sali, Aggeliki; Papalazarou, Vassilis; Mallouchos, Athanasios; Evageliou, Vasiliki; Kostourou, Vasiliki; Mantala, Ioanna; Kapsokefalou, Maria

    2017-09-01

    The hypothesis that incorporation of epigallocatechin gallate (EGCG) into nanoemulsions may increase its bioactivity compared with EGCG aqueous solutions was examined in mice. After an in vitro study in a model system with stimulated gastrointestinal conditions, the following EGCG nanoemulsions were used in a mice experiment: Emulsion I: emulsion water in oil (W/O), which contained 0.23 mg/mL EGCG in aqueous phase; Emulsion II: emulsion oil in water (O/W), which contained 10% olive oil and 0.23 mg/mL esterified EGCG in fatty phase; and Emulsion III: emulsion O/W in water (W1/O/W2; 8:32:60), which contained 32% olive oil and 0.23 mg/mL EGCG in aqueous phase. After 2 h of mice administration by gavage with 0.1 mL of EGCG nanoemulsions, total antioxidant capacity (TAC) of plasma and some tissues (especially colon, jejunum, heart, spleen) was measured with Ferric-Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity (ORAC) assays. No toxic effects were observed after administration of 0.23 mg/mL esterified EGCG in CD1 mouse strain. The study concluded that administration of mice with the three EGCG nanoemulsions did not increase their TAC in specific tissues, compared with an aqueous EGCG solution at the same concentration. Nevertheless, the esterified EGCG emulsion (Emulsion II) exerted an increase in mice plasma compared with aqueous EGCG and showed higher values of TAC in several tissues, compared with Emulsions I and III. EGCG nanoemulsions could be considered a useful method in plethora functional food applications, but further research is required for safer results.

  4. Towards an elastic model of wurtzite AlN nanowires

    International Nuclear Information System (INIS)

    Mitrushchenkov, A; Chambaud, G; Yvonnet, J; He, Q-C

    2010-01-01

    Starting with ab initio calculations of AlN wurtzite [0001] nanowires with diameters up to 4 nm, a finite element method is developed to deal with larger nanostructures/nanoparticles. The ab initio calculations show that the structure of the nanowires can be well represented by an internal part with AlN bulk elastic properties, and one atomic surface layer with its own elastic behavior. The proposed finite element method includes surface elements with their own elastic properties using surface elastic coefficients deduced from the ab initio calculations. The elastic properties obtained with the finite element model compare very well with those obtained with the full ab initio calculations.

  5. Mutant mice: experimental organisms as materialised models in biomedicine.

    Science.gov (United States)

    Huber, Lara; Keuck, Lara K

    2013-09-01

    Animal models have received particular attention as key examples of material models. In this paper, we argue that the specificities of establishing animal models-acknowledging their status as living beings and as epistemological tools-necessitate a more complex account of animal models as materialised models. This becomes particularly evident in animal-based models of diseases that only occur in humans: in these cases, the representational relation between animal model and human patient needs to be generated and validated. The first part of this paper presents an account of how disease-specific animal models are established by drawing on the example of transgenic mice models for Alzheimer's disease. We will introduce an account of validation that involves a three-fold process including (1) from human being to experimental organism; (2) from experimental organism to animal model; and (3) from animal model to human patient. This process draws upon clinical relevance as much as scientific practices and results in disease-specific, yet incomplete, animal models. The second part of this paper argues that the incompleteness of models can be described in terms of multi-level abstractions. We qualify this notion by pointing to different experimental techniques and targets of modelling, which give rise to a plurality of models for a specific disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models.

    Science.gov (United States)

    Hoye, Mariah L; Koval, Erica D; Wegener, Amy J; Hyman, Theodore S; Yang, Chengran; O'Brien, David R; Miller, Rebecca L; Cole, Tracy; Schoch, Kathleen M; Shen, Tao; Kunikata, Tomonori; Richard, Jean-Philippe; Gutmann, David H; Maragakis, Nicholas J; Kordasiewicz, Holly B; Dougherty, Joseph D; Miller, Timothy M

    2017-05-31

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining the in vivo miRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents. SIGNIFICANCE STATEMENT Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease

  7. Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS.

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    Barkha P Patel

    2010-02-01

    Full Text Available Caloric restriction (CR extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS--citrate synthase content and activity, cytochrome c oxidase--COX activity and protein content of COX subunit-I and IV and UCP3-uncoupling protein 3, oxidative damage (MDA--malondialdehyde and PC--protein carbonyls, antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase, inflammation (TNF-alpha, stress response (Hsp70 and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9 in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females or CR (n = 13; 6 females, with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%, despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83% in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62% and white (30% gastrocnemius. TNF-alpha was higher (52% in CR vs. AL mice and Hsp70 was lower (62% in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41% and CR vs. AL females (52%. Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice.

  8. A novel model of human skin pressure ulcers in mice.

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    Andrés A Maldonado

    Full Text Available INTRODUCTION: Pressure ulcers are a prevalent health problem in today's society. The shortage of suitable animal models limits our understanding and our ability to develop new therapies. This study aims to report on the development of a novel and reproducible human skin pressure ulcer model in mice. MATERIAL AND METHODS: Male non-obese, diabetic, severe combined immunodeficiency mice (n = 22 were engrafted with human skin. A full-thickness skin graft was placed onto 4×3 cm wounds created on the dorsal skin of the mice. Two groups with permanent grafts were studied after 60 days. The control group (n = 6 was focused on the process of engraftment. Evaluations were conducted with photographic assessment, histological analysis and fluorescence in situ hybridization (FISH techniques. The pressure ulcer group (n = 12 was created using a compression device. A pressure of 150 mmHg for 8 h, with a total of three cycles of compression-release was exerted. Evaluations were conducted with photographic assessment and histological analysis. RESULTS: Skin grafts in the control group took successfully, as shown by visual assessment, FISH techniques and histological analysis. Pressure ulcers in the second group showed full-thickness skin loss with damage and necrosis of all the epidermal and dermal layers (ulcer stage III in all cases. Complete repair occurred after 40 days. CONCLUSIONS: An inexpensive, reproducible human skin pressure ulcer model has been developed. This novel model will facilitate the development of new clinically relevant therapeutic strategies that can be tested directly on human skin.

  9. Phenylethanoid Glycosides of Cistanche on menopausal syndrome model in mice

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    Shuo Tian

    2017-05-01

    Full Text Available Cistanche is the traditional and precious Chinese herbal, with two thousand years of use history in China. It has the effect on tonifying kidney, strong supplement to the liver and kidney, and replenishing essence and blood, known as the “desert ginseng”. Here, we explored the mechanism of Phenylethanoid Glycosides of Cistanche (PGC to the model mice of menopausal syndrome, as well as the therapeutic effect and characteristics of PGC to the menopausal syndrome. In this study, KM mice were reproduced by the complete resection of the ovaries on both sides of the back to establish the model mice of menopausal syndrome (MPS, and received distilled water or drugs, respectively. Model mice received distilled water. Mice received 200 mg/(kg day high doses of Phenylethanoid Glycosides of Cistanche (HPGC, and 100 mg/(kg day medium doses of Phenylethanoid Glycosides of Cistanche (MPGC, and 50 mg/(kg day low doses of Phenylethanoid Glycosides of Cistanche (LPGC. After 21 days, it could determine the number of independent activities and the number of standing, the latent period of first entering the dark room, and the electric number. It also calculated the viscera index of uterus, thymus, spleen, measured the levels of estradiol (E2, testosterone (T, luteinizing hormone (LH, and follicle-stimulating hormone (FSH in the serum. Furthermore, it observed the pathological changes of uterus, thymus, spleen and pituitary of mice. The results showed that behavioral indicators: Compared with the model group (MG, HPGC, MPGC, LPGC could increase the independent activities (P < 0.01; HPGC, MPGC could increase the number of standing, the latent period of first entering the dark room, and reduce the electric number (P < 0.01; LPGC could increase the number of standing (P < 0.05; Viscera index: Compared with MG, HPGC, MPGC could increase the viscera index of uterus, thymus, spleen (P < 0.01; LPGC could increase the viscera index of uterus (P < 0

  10. Of Men and Mice: Modeling the Fragile X Syndrome

    Science.gov (United States)

    Dahlhaus, Regina

    2018-01-01

    The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research. PMID:29599705

  11. Thermodynamic modeling of the Mg-Al-Ca system

    Energy Technology Data Exchange (ETDEWEB)

    Janz, A.; Groebner, J. [Clausthal University of Technology, Institute of Metallurgy, Robert-Koch-Str. 42, D-38678 Clausthal-Zellerfeld (Germany); Cao, H.; Zhu, J.; Chang, Y.A. [Department of Materials Science and Engineering, University of Wisconsin, 1509 University Ave., Madison, WI 53706 (United States); Schmid-Fetzer, R. [Clausthal University of Technology, Institute of Metallurgy, Robert-Koch-Str. 42, D-38678 Clausthal-Zellerfeld (Germany)], E-mail: schmid-fetzer@tu-clausthal.de

    2009-02-15

    A thermodynamic model has been developed that provides a quantitative description for a wide area of the Mg-Al-Ca system. All available experimental data plus new key experiments using differential scanning calorimetry/differential thermal analysis have been considered to create a dataset which reproduces the primary crystallizing phases, the extensive ternary solubilities of binary phases and the ternary C36 Laves phase. This enables validated thermodynamic calculations in various areas of this ternary system.

  12. Focal Transplantation of Human iPSC-Derived Glial-Rich Neural Progenitors Improves Lifespan of ALS Mice

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    Takayuki Kondo

    2014-08-01

    Full Text Available Transplantation of glial-rich neural progenitors has been demonstrated to attenuate motor neuron degeneration and disease progression in rodent models of mutant superoxide dismutase 1 (SOD1-mediated amyotrophic lateral sclerosis (ALS. However, translation of these results into a clinical setting requires a renewable human cell source. Here, we derived glial-rich neural progenitors from human iPSCs and transplanted them into the lumbar spinal cord of ALS mouse models. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan. Our data suggest a potential therapeutic mechanism via activation of AKT signal. The results demonstrated the efficacy of cell therapy for ALS by the use of human iPSCs as cell source.

  13. Effect of fluoxetine on disease progression in a mouse model of ALS

    Science.gov (United States)

    Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

    2014-01-01

    Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

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

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    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.

  15. Fabrication, Testing and Modeling of the MICE Superconducting Spectrometer Solenoids

    International Nuclear Information System (INIS)

    Virostek, S.P.; Green, M.A.; Trillaud, F.; Zisman, M.S.

    2010-01-01

    The Muon Ionization Cooling Experiment (MICE), an international collaboration sited at Rutherford Appleton Laboratory in the UK, will demonstrate ionization cooling in a section of realistic cooling channel using a muon beam. A five-coil superconducting spectrometer solenoid magnet will provide a 4 tesla uniform field region at each end of the cooling channel. Scintillating fiber trackers within the 400 mm diameter magnet bore tubes measure the emittance of the beam as it enters and exits the cooling channel. Each of the identical 3-meter long magnets incorporates a three-coil spectrometer magnet section and a two-coil section to match the solenoid uniform field into the other magnets of the MICE cooling channel. The cold mass, radiation shield and leads are currently kept cold by means of three two-stage cryocoolers and one single-stage cryocooler. Liquid helium within the cold mass is maintained by means of a re-condensation technique. After incorporating several design changes to improve the magnet cooling and reliability, the fabrication and acceptance testing of the spectrometer solenoids have proceeded. The key features of the spectrometer solenoid magnets, the development of a thermal model, the results of the recently completed tests, and the current status of the project are presented.

  16. Calculation of Gibbs energy of Zr-Al-Ni, Zr-Al-Cu, Al-Ni-Cu and Zr-Al-Ni-Cu liquid alloys based on quasiregular solution model

    International Nuclear Information System (INIS)

    Li, H.Q.; Yang, Y.S.; Tong, W.H.; Wang, Z.Y.

    2007-01-01

    With the effects of electronic structure and atomic size being introduced, the mixing enthalpy as well as the Gibbs energy of the ternary Zr-Al-Cu, Ni-Al-Cu, Zr-Ni-Al and quaternary Zr-Al-Ni-Cu systems are calculated based on quasiregular solution model. The computed results agree well with the experimental data. The sequence of Gibbs energies of different systems is: G Zr-Al-Ni-Cu Zr-Al-Ni Zr-Al-Cu Cu-Al-Ni . To Zr-Al-Cu, Ni-Al-Cu and Zr-Ni-Al, the lowest Gibbs energy locates in the composition range of X Zr 0.39-0.61, X Al = 0.38-0.61; X Ni = 0.39-0.61, X Al = 0.38-0.60 and X Zr = 0.32-0.67, X Al = 0.32-0.66, respectively. And to the Zr-Ni-Al-Cu system with 66.67% Zr, the lowest Gibbs energy is obtained in the region of X Al = 0.63-0.80, X Ni = 0.14-0.24

  17. Radio-sensitivity of the cells from amyotrophic lateral sclerosis model mice transfected with human mutant SOD1

    International Nuclear Information System (INIS)

    Wate, Reika; Ito, Hidefumi; Kusaka, Hirofumi; Takahashi, Sentaro; Kubota, Yoshihisa; Suetomi, Katsutoshi; Sato, Hiroshi; Okayasu, Ryuichi

    2005-01-01

    In order to clarify the possible involvement of oxidative damage induced by ionizing radiation in the onset and/or progression of familial amyotrophic lateral sclerosis (ALS), we studied radio-sensitivity in primary cells derived from ALS model mice expressing human mutant Cu/Zn superoxide dismutase (SOD1). The primary mouse cells expressed both mouse and the mutant human SOD1. The cell survival of the transgenic mice (with mutant SOD1), determined by counting cell numbers at a scheduled time after X-irradiation, is very similar to that of cells from wild type animals. The induction and repair of DNA damage in the transgenic cells, measured by single cell gel electrophoresis and pulsed field gel electrophoresis, are also similar to those of wild type cells. These results indicate that the human mutant SOD1 gene does not seem to contribute to the alteration of radio-sensitivity, at least in the fibroblastic cells used here. Although it is necessary to consider the difference in cell types between fibroblastic and neuronal cells, the present results may suggest that ionizing radiation is not primarily responsible for the onset of familial ALS with the SOD1 mutation, and that the excess risks are probably not a concern for radiation diagnosis and therapy in familial ALS patients. (author)

  18. Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice

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    Chen Xiaoxin

    2009-07-01

    Full Text Available Abstract Background Esophago-gastroduodenal anastomosis with rats mimics the development of human Barrett's esophagus and esophageal adenocarcinoma by introducing mixed reflux of gastric and duodenal contents into the esophagus. However, use of this rat model for mechanistic and chemopreventive studies is limited due to lack of genetically modified rat strains. Therefore, a mouse model of esophageal adenocarcinoma is needed. Methods We performed reflux surgery on wild-type, p53A135V transgenic, and INK4a/Arf+/- mice of A/J strain. Some mice were also treated with omeprazole (1,400 ppm in diet, iron (50 mg/kg/m, i.p., or gastrectomy plus iron. Mouse esophagi were harvested at 20, 40 or 80 weeks after surgery for histopathological analysis. Results At week 20, we observed metaplasia in wild-type mice (5%, 1/20 and p53A135V mice (5.3%, 1/19. At week 40, metaplasia was found in wild-type mice (16.2%, 6/37, p53A135V mice (4.8%, 2/42, and wild-type mice also receiving gastrectomy and iron (6.7%, 1/15. Esophageal squamous cell carcinoma developed in INK4a/Arf+/- mice (7.1%, 1/14, and wild-type mice receiving gastrectomy and iron (21.4%, 3/14. Among 13 wild-type mice which were given iron from week 40 to 80, twelve (92.3% developed squamous cell carcinoma at week 80. None of these mice developed esophageal adenocarcinoma. Conclusion Surgically induced gastroesophageal reflux produced esophageal squamous cell carcinoma, but not esophageal adenocarcinoma, in mice. Dominant negative p53 mutation, heterozygous loss of INK4a/Arf, antacid treatment, iron supplementation, or gastrectomy failed to promote esophageal adenocarcinoma in these mice. Further studies are needed in order to develop a mouse model of esophageal adenocarcinoma.

  19. Analytical modeling of AlGaN/AlN/GaN heterostructures including effects of distributed surface donor states

    Energy Technology Data Exchange (ETDEWEB)

    Goyal, Nitin, E-mail: nitin@unik.no [Carinthian Tech Research CTR AG, Europastraße 4/1, Technologiepark Villach, A-9524 Villach/St. Magdalen (Austria); Department of Electronics and Telecommunication, Norwegian University of Science and Technology, Trondheim NO7034 (Norway); Fjeldly, Tor A. [Department of Electronics and Telecommunication, Norwegian University of Science and Technology, Trondheim NO7034 (Norway)

    2014-07-14

    In this paper, a physics based analytical model is presented for calculation of the two-dimensional electron gas density and the bare surface barrier height of AlGaN/AlN/GaN material stacks. The presented model is based on the concept of distributed surface donor states and the self-consistent solution of Poisson equation at the different material interfaces. The model shows good agreement with the reported experimental data and can be used for the design and characterization of advanced GaN devices for power and radio frequency applications.

  20. A novel mice model of metabolic syndrome: the high-fat-high-fructose diet-fed ICR mice

    Science.gov (United States)

    Zhuhua, Zhang; Zhiquan, Wang; Zhen, Yang; Yixin, Niu; Weiwei, Zhang; Xiaoyong, Li; Yueming, Liu; Hongmei, Zhang; Li, Qin; Qing, Su

    2015-01-01

    Currently, the metabolic syndrome (MS) is occurring at growing rates worldwide, raising extensive concerns on the mechanisms and therapeutic interventions for this disorder. Herein, we described a novel method of establishing MS model in rodents. Male Institute of Cancer Research (ICR) mice were fed with high-fat-high-fructose (HFHF) diet or normal chow (NC) respectively for 12 weeks. Metabolic phenotypes were assessed by glucose tolerance test, insulin tolerance test and hyperinsulinemic-euglycemic clamp. Blood pressure was measured by a tail-cuff system. At the end of the experiment, mice were sacrificed, and blood and tissues were harvested for subsequent analysis. Serum insulin levels were measured by ELISA, and lipid profiles were determined biochemically. The HFHF diet-fed ICR mice exhibited obvious characteristics of the components of MS, including obvious obesity, severe insulin resistance, hyperinsulinemia, dislipidemia, significant hypertension and hyperuricemia. Our data suggest that HFHF diet-fed ICR mice may be a robust and efficient animal model that could well mimic the basic pathogenesis of human MS. PMID:26134356

  1. A novel mice model of metabolic syndrome: the high-fat-high-fructose diet-fed ICR mice.

    Science.gov (United States)

    Zhuhua, Zhang; Zhiquan, Wang; Zhen, Yang; Yixin, Niu; Weiwei, Zhang; Xiaoyong, Li; Yueming, Liu; Hongmei, Zhang; Li, Qin; Qing, Su

    2015-01-01

    Currently, the metabolic syndrome (MS) is occurring at growing rates worldwide, raising extensive concerns on the mechanisms and therapeutic interventions for this disorder. Herein, we described a novel method of establishing MS model in rodents. Male Institute of Cancer Research (ICR) mice were fed with high-fat-high-fructose (HFHF) diet or normal chow (NC) respectively for 12 weeks. Metabolic phenotypes were assessed by glucose tolerance test, insulin tolerance test and hyperinsulinemic-euglycemic clamp. Blood pressure was measured by a tail-cuff system. At the end of the experiment, mice were sacrificed, and blood and tissues were harvested for subsequent analysis. Serum insulin levels were measured by ELISA, and lipid profiles were determined biochemically. The HFHF diet-fed ICR mice exhibited obvious characteristics of the components of MS, including obvious obesity, severe insulin resistance, hyperinsulinemia, dislipidemia, significant hypertension and hyperuricemia. Our data suggest that HFHF diet-fed ICR mice may be a robust and efficient animal model that could well mimic the basic pathogenesis of human MS.

  2. Alterations of in vivo CA1 network activity in Dp(16)1Yey Down syndrome model mice.

    Science.gov (United States)

    Raveau, Matthieu; Polygalov, Denis; Boehringer, Roman; Amano, Kenji; Yamakawa, Kazuhiro; McHugh, Thomas J

    2018-02-27

    Down syndrome, the leading genetic cause of intellectual disability, results from an extra-copy of chromosome 21. Mice engineered to model this aneuploidy exhibit Down syndrome-like memory deficits in spatial and contextual tasks. While abnormal neuronal function has been identified in these models, most studies have relied on in vitro measures. Here, using in vivo recording in the Dp(16)1Yey model, we find alterations in the organization of spiking of hippocampal CA1 pyramidal neurons, including deficits in the generation of complex spikes. These changes lead to poorer spatial coding during exploration and less coordinated activity during sharp-wave ripples, events involved in memory consolidation. Further, the density of CA1 inhibitory neurons expressing neuropeptide Y, a population key for the generation of pyramidal cell bursts, were significantly increased in Dp(16)1Yey mice. Our data refine the 'over-suppression' theory of Down syndrome pathophysiology and suggest specific neuronal subtypes involved in hippocampal dysfunction in these model mice. © 2018, Raveau et al.

  3. Thermodynamic modeling of the Ti-Al-Cr ternary system

    International Nuclear Information System (INIS)

    Chen Leyi; Qiu Aitao; Liu Lanjie; Jiang Ming; Lu Xionggang; Li Chonghe

    2011-01-01

    Research highlights: → The full experimental results of the Ti-Al-Cr ternary system and its sub-binary systems are reviewed and analysed in detail. → Based on the latest thermodynamic assessments of the Ti-Al, Ti-Cr and Al-Cr systems and the ternary experimental data in literature, the thermodynamic parameters of the Ti-Al-Cr ternary system are fully assessed by the Calphad method. → The transformation of disorder to order (bcc a 2 to B2) and the new ternary compound L 12T i 25 Cr 8 Al 67 are considered in this work. - Abstract: The Ti-Al-Cr ternary system is one of the most important systems to studying the titanium alloys. Some experimental data of this ternary system are available and a few partial thermodynamic assessments are reported. However, no full thermodynamic descriptions were published. In this study, the previous work on the Ti-Al-Cr system and its related binary systems are reviewed. Based on the thermodynamic descriptions of the Ti-Al, Ti-Cr and Al-Cr systems and the ternary experimental data in literature, the Ti-Al-Cr ternary system is assessed by means of the Calphad method. Several isothermal sections from 1073 K to 1573 K and some invariant reactions are calculated, which are in good agreement with the most of the experimental results.

  4. PGC-1 silencing compounds the perturbation of mitochondrial function caused by mutant SOD1 in skeletal muscle of ALS mouse model

    Directory of Open Access Journals (Sweden)

    Yan eQi

    2015-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a lethal neurodegenerative disease causing death of motor neurons. This study investigated the roles of energy metabolism in the pathogenesis of ALS in the SOD1(G93A transgenic mouse model. Control and SOD1(G93A mice were administered with shcontrol or shPGC-1α in combination with PBS or TZD for 8 weeks. Gene expression was analyzed by quantitative real-time PCR and western blot. ROS and fibrosis were assessed with a colorimetric kit and Sirius staining respectively. Inflammatory cytokines were measured using ELISA kits. The levels of tissue ROS and serum inflammatory cytokines were significantly higher in SOD1(G93A mice compared to control mice, and knocking down PGC-1α drastically increased cytokine levels in both control and SOD1(G93A mice. Muscle fibrosis was much severer in SOD1(G93A mice, and worsened by silencing PGC-1α and attenuate d by TZD. The expression levels of PGC-1α, SOD1, UCP2, and cytochrome C were substantially reduced by shPGC-1α and increased by TZD in muscle of both control and SOD1(G93A mice whereas the level of NF-B was significantly elevated in SOD1(G93A mice, which was further increased by PGC-1α silencing. These data indicated that disruption of energy homeostasis would exacerbate the pathological changes caused by SOD1 mutations to promote the pathogenesis of ALS.

  5. Modeling myocardial infarction in mice: methodology, monitoring, pathomorphology.

    Science.gov (United States)

    Ovsepyan, A A; Panchenkov, D N; Prokhortchouk, E B; Telegin, G B; Zhigalova, N A; Golubev, E P; Sviridova, T E; Matskeplishvili, S T; Skryabin, K G; Buziashvili, U I

    2011-01-01

    Myocardial infarction is one of the most serious and widespread diseases in the world. In this work, a minimally invasive method for simulating myocardial infarction in mice is described in the Russian Federation for the very first time; the procedure is carried out by ligation of the coronary heart artery or by controlled electrocoagulation. As a part of the methodology, a series of anesthetic, microsurgical and revival protocols are designed, owing to which a decrease in the postoperational mortality from the initial 94.6 to 13.6% is achieved. ECG confirms the development of large-focal or surface myocardial infarction. Postmortal histological examination confirms the presence of necrosis foci in the heart muscles of 87.5% of animals. Altogether, the medical data allow us to conclude that an adequate mouse model for myocardial infarction was generated. A further study is focused on the standardization of the experimental procedure and the use of genetically modified mouse strains, with the purpose of finding the most efficient therapeutic approaches for this disease.

  6. 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...

  7. Models of anxiety: responses of mice to novelty and open spaces in a 3D maze.

    Science.gov (United States)

    Ennaceur, A; Michalikova, S; van Rensburg, R; Chazot, P L

    2006-11-01

    The present report describes the emotional responses of different strains of mice to exposure to a novel open space model of anxiety using a 3D spatial navigation task. The 3D maze is modification of the radial maze with flexible arms that can be raised above or lowered below the horizontal level of a central platform. To access the arms animals need to cross a bridge linking the arms to the central platform. In this model, mice are exposed to novelty in an unfamiliar open space setting with no safe alternative. Fear from novelty is compounded with the need to explore. The drive to escape and the drive to approach are intermingled making this open space model radically different from the current models of anxiety which provide animals with the choice between safe and anxiogenic spaces. In a series of experiments, we examined the behaviour of different groups of mice from C57, C3H, CD1 and Balb/c strains. In the first experiment, different groups of C57 mice were tested in one of the three arms configurations. In the second experiment, C57 mice were compared to C3H mice. In the third experiment, C57 mice were compared to CD1 and Balb/c mice in the raised arm configuration over three successive sessions. In the fourth experiment, we examined the behaviour of C57 mice in the lowered arm configuration with an open and an enclosed central. In the final experiment, we examined the difference between C57 and C3H mice of both genders. Using several spatio-temporal parameters of the transition responses between central platform, bridges and arms, we have been able to show consistent results demonstrating significant differences between C57 and C3H mice, and between Balb/c and both C57 and CD1 mice. C3H appear more anxious than C57 mice, and Balb/c mice seem more anxious than C57 and CD1 mice. We also observed significant differences between sexes in C3H mice but not in C57 mice. C3H male mice appear more anxious than C3H female mice and than both C57 male and female mice

  8. A mouse model of familial ALS has increased CNS levels of endogenous ubiquinol9/10 and does not benefit from exogenous administration of ubiquinol10.

    Directory of Open Access Journals (Sweden)

    Jacopo Lucchetti

    Full Text Available Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS, a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1(G93A transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0-3.4 µg/mL, no effect was found on the disease progression and survival of SOD1(G93A mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (≤10% than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1(G93A mice, in comparison with age-matched SOD1(WT. Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1(G93A mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to

  9. A multiplicative reinforcement learning model capturing learning dynamics and interindividual variability in mice

    OpenAIRE

    Bathellier, Brice; Tee, Sui Poh; Hrovat, Christina; Rumpel, Simon

    2013-01-01

    Learning speed can strongly differ across individuals. This is seen in humans and animals. Here, we measured learning speed in mice performing a discrimination task and developed a theoretical model based on the reinforcement learning framework to account for differences between individual mice. We found that, when using a multiplicative learning rule, the starting connectivity values of the model strongly determine the shape of learning curves. This is in contrast to current learning models ...

  10. A Novel Iron Chelator-Radical Scavenger Ameliorates Motor Dysfunction and Improves Life Span and Mitochondrial Biogenesis in SOD1G93A ALS Mice.

    Science.gov (United States)

    Golko-Perez, Sagit; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H; Weinreb, Orly

    2017-02-01

    The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multitarget brain permeable monoamine oxidase inhibitor/iron chelating-radical scavenging drug, VAR10303 (VAR), co-administered with high-calorie/energy-supplemented diet (ced) in SOD1 G93A transgenic amyotrophic lateral sclerosis (ALS) mice. Administration of VAR-ced was initiated after the appearance of disease symptoms (at day 88), as this regimen is comparable with the earliest time at which drug therapy could start in ALS patients. Using this rescue protocol, we demonstrated in the current study that VAR-ced treatment provided several beneficial effects in SOD1 G93A mice, including improvement in motor performance, elevation of survival time, and attenuation of iron accumulation and motoneuron loss in the spinal cord. Moreover, VAR-ced treatment attenuated neuromuscular junction denervation and exerted a significant preservation of myofibril regular morphology, associated with a reduction in the expression levels of genes related to denervation and atrophy in the gastrocnemius (GNS) muscle in SOD1 G93A mice. These effects were accompanied by upregulation of mitochondrial DNA and elevated activities of complexes I and II in the GNS muscle. We have also demonstrated that VAR-ced treatment upregulated the mitochondrial biogenesis master regulator, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and increased PGC-1α-targeted metabolic genes and proteins, such as, PPARγ, UCP1/3, NRF1/2, Tfam, and ERRα in GNS muscle. These results provide evidence of therapeutic potential of VAR-ced in SOD1 G93A mice with underlying molecular mechanisms, further supporting the importance role of multitarget iron chelators in ALS treatment.

  11. Multi-tissue computational modeling analyzes pathophysiology of type 2 diabetes in MKR mice.

    Directory of Open Access Journals (Sweden)

    Amit Kumar

    Full Text Available Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective.

  12. Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication.

    Science.gov (United States)

    Dunn, Emily N; Ferrara-Bowens, Teresa M; Chachich, Mark E; Honnold, Cary L; Rothwell, Cristin C; Hoard-Fruchey, Heidi M; Lesyna, Catherine A; Johnson, Erik A; Cerasoli, Douglas M; McDonough, John H; Cadieux, C Linn

    2018-06-07

    Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.

  13. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

    Science.gov (United States)

    Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

    2015-09-01

    The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans.

  14. Gene expression changes in spinal motoneurons of the SOD1G93A transgenic model for ALS after treatment with G-CSF

    Science.gov (United States)

    Henriques, Alexandre; Kastner, Stefan; Chatzikonstantinou, Eva; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Wafzig, Oliver; Krüger, Carola; Spoelgen, Robert; Gonzalez De Aguilar, Jose-Luis; Gretz, Norbert; Schneider, Armin

    2015-01-01

    Background: Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3–5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. Results: Motoneurons from SOD1G93A mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1G93A motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12. Conclusions: Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1G93A motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS. PMID:25653590

  15. Gene expression changes in spinal motoneurons of the SOD1G93A transgenic model for ALS after treatment with G-CSF.

    Directory of Open Access Journals (Sweden)

    Alexandre eHenriques

    2015-01-01

    Full Text Available ABSTRACTBackgroundAmyotrophic lateral sclerosis (ALS is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3-5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. ResultsMotoneurons from SOD1G93A mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age, when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age. Upon G-CSF treatment, transcriptomic deregulations of SOD1G93A motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12.ConclusionsOur data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1G93A motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.

  16. Gene expression changes in spinal motoneurons of the SOD1(G93A) transgenic model for ALS after treatment with G-CSF.

    Science.gov (United States)

    Henriques, Alexandre; Kastner, Stefan; Chatzikonstantinou, Eva; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Wafzig, Oliver; Krüger, Carola; Spoelgen, Robert; Gonzalez De Aguilar, Jose-Luis; Gretz, Norbert; Schneider, Armin

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3-5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1(G93A) mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. Motoneurons from SOD1(G93A) mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1(G93A) motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12. Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1(G93A) motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.

  17. Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models.

    Directory of Open Access Journals (Sweden)

    Marcelo R Vargas

    Full Text Available The nuclear factor erythroid 2-related factor 2 (Nrf2 governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1 cause familial forms of amyotrophic lateral sclerosis (ALS, a fatal disorder characterized by the progressive loss of motor neurons and subsequent muscular atrophy. We have previously shown that Nrf2 activation in astrocytes delays neurodegeneration in ALS mouse models. To further investigate the role of Nrf2 in ALS we determined the effect of absence of Nrf2 or its restricted overexpression in neurons or type II skeletal muscle fibers on symptoms onset and survival in mutant hSOD1 expressing mice. We did not observe any detrimental effect associated with the lack of Nrf2 in two different mutant hSOD1 animal models of ALS. However, restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset but failed to extend survival in hSOD1(G93A mice. These results highlight the concept that not only the pharmacological target but also the cell type targeted may be relevant when considering a Nrf2-mediated therapeutic approach for ALS.

  18. An overview of mice models: a key for understanding subtypes of mania

    Directory of Open Access Journals (Sweden)

    Jorge Mauricio Cuartas Arias

    2016-09-01

    Full Text Available Animal models have been broadly used in the study of pathophysiology and molecular and neurochemical pathways in neuropsychiatric diseases. Different approaches have used both consanguineous and non-consanguineous mice models to model behavioral patterns associated with the maniac spectrum. However, the disadvantages of validating clinical and experimental protocols have hindered the replication of these studies. In this article, the advantages and disadvantages of using consanguineous lines and non-consanguineous stocks in mice animal models for the study of mania and its subtypes are discussed. Additionally, new experimental alternatives to advance the pathogenesis and pharmacogenetics of mania using animal models are proposed and analyzed.

  19. Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

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    Eva Buck

    2017-05-01

    Full Text Available Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS upper and lower motoneurons degenerate whereas in Huntington’s disease (HD medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3, regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A. In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2. Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

  20. Development of sensitisation or tolerance following repeated OVA inhalation in BALB/cJ mice. Dose-dependency and modulation by the Al(OH)3 adjuvant

    DEFF Research Database (Denmark)

    Clausen, Susanne Knoth; Bergqvist, Mette; Poulsen, Lars K.

    2003-01-01

    Anthropogenically induced exposures may, due to their adjuvant effect, promote development of sensitisation to commonly occurring aeroallergens. No generally accepted model exists for determination of adjuvant effect of airborne substances. Therefore, BALB/cJ mice were exposed for 10 consecutive...

  1. Mice overexpressing both non-mutated human SOD1 and mutated SOD1G93A genes: a competent experimental model for studying iron metabolism in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Anna eGajowiak

    2016-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive neurodegenerative disease characterized by degeneration and loss of motor neurons in the spinal cord, brainstem and motor cortex. Up to 10% of ALS cases are inherited (familial, fALS and associated with mutations, frequently in the superoxide dismutase 1 (SOD1 gene. Rodent transgenic models of ALS are often used to elucidate a complex pathogenesis of this disease. Of importance, both ALS patients and animals carrying mutated human SOD1 gene show symptoms of oxidative stress and iron metabolism misregulation. The aim of our study was to characterize changes in iron metabolism in one of the most commonly used models of ALS – transgenic mice overexpressing human mutated SOD1G93A gene. We analyzed the expression of iron-related genes in asymptomatic, 2-month old and symptomatic, 4-month old SOD1G93A mice. In parallel, respective age-matched mice overexpressing human non-mutated SOD1 transgene and control mice were analyzed. We demonstrate that the overexpression of both SOD1 and SOD1G93A genes account for a substantial increase in SOD1 protein levels and activity in selected tissues and that not all the changes in iron metabolism genes expression are specific for the overexpression of the mutated form of SOD1.

  2. Establishment of an animal model of mice with radiation- injured soft tissue blood vessels

    International Nuclear Information System (INIS)

    Wang Daiyou; Yu Dahai; Wu Jiaxiao; Wei Shanliang; Wen Yuming

    2004-01-01

    Objective: The aim of this study was to establish an animal model of mice with radiation-injured soft tissue blood vessels. Methods: Forty male mice were irradiated with 30 Gy on the right leg. After the irradiation was finished each of the 40 male mice was tested with angiography, and its muscle tissues on the bilateral legs were examined with vessel staining assay and electron microscopy. Results: The results showed that the number of vessels on the right leg was less than that on the left leg, the microvessel density, average diameter and average sectional area of the right leg were all lower than those of the left, and the configuration and ultra-structure of vessels were also different between both sides of legs. Conclusion: In the study authors successfully established an animal model of mice with radiation-injured soft tissue blood vessels

  3. Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT.

    Science.gov (United States)

    Liu, Xiang; Liu, Jun; Guan, Yubao; Li, Huiling; Huang, Liyan; Tang, Hailing; He, Jianxing

    2012-04-01

    To establish a simple and highly efficient orthotopic animal model of lung cancer cell line A549 and evaluate the growth pattern of intrathoracic tumors by spiral CT. A549 cells (5×10(6) mL(-1)) were suspended and inoculated into the right lung of BALB/c nude mice via intrathoracic injection. Nude mice were scanned three times each week by spiral CT after inoculation of lung cancer cell line A549. The survival time and body weight of nude mice as well as tumor invasion and metastasis were examined. Tissue was collected for subsequent histological assay after autopsia of mice. The tumor-forming rate of the orthotopic lung cancer model was 90%. The median survival time was 30.7 (range, 20-41) days. The incidence of tumor metastasis was 100%. The mean tumor diameter and the average CT value gradually increased in a time-dependent manner. The method of establishing the orthotopic lung cancer model through transplanting A549 cells into the lung of nude mice is simple and highly successful. Spiral CT can be used to evaluate intrathoracic tumor growth in nude mice vividly and dynamically.

  4. Regulation of an Autoimmune Model for Multiple Sclerosis in Th2-Biased GATA3 Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Viromi Fernando

    2014-01-01

    Full Text Available T helper (Th2 cells have been proposed to play a neuroprotective role in multiple sclerosis (MS. This is mainly based on “loss-of-function” studies in an animal model for MS, experimental autoimmune encephalomyelitis (EAE, using blocking antibodies against Th2 related cytokines, and knockout mice lacking Th2-related molecules. We tested whether an increase of Th2 responses (“gain-of-function” approach could alter EAE, the approach of novel GATA binding protein 3 (GATA3-transgenic (tg mice that overexpress GATA3, a transcription factor required for Th2 differentiation. In EAE induced with myelin oligodendrocyte glycoprotein (MOG35−55 peptide, GATA3-tg mice had a significantly delayed onset of disease and a less severe maximum clinical score, compared with wild-type C57BL/6 mice. Histologically, GATA3-tg mice had decreased levels of meningitis and demyelination in the spinal cord, and anti-inflammatory cytokine profiles immunologically, however both groups developed similar levels of MOG-specific lymphoproliferative responses. During the early stage, we detected higher levels of interleukin (IL-4 and IL-10, with MOG and mitogen stimulation of regional lymph node cells in GATA3-tg mice. During the late stage, only mitogen stimulation induced higher IL-4 and lower interferon-γ and IL-17 production in GATA3-tg mice. These results suggest that a preexisting bias toward a Th2 immune response may reduce the severity of inflammatory demyelinating diseases, including MS.

  5. Modelling of U-Mo/Al Dispersion fuel fission induced swelling and creep

    International Nuclear Information System (INIS)

    Jeong, Gwan Yoon; Sohn, Dong Seong; Kim, Yeon Soo

    2014-01-01

    In a Dispersion fuel which U-Mo particles are dispersed in Al metal matrix, a similar phenomenon forming a bulge region was observed but it is difficult to quantify and construct a model for explaining creep and swelling because of its complex microstructure change during irradiation including interaction layer (IL) and porosity formation. In a Dispersion fuel meat, fission product induces fuel particles swelling and it has to be accommodated by the deformation of the Al matrix and newly formed IL during irradiation. Then, it is reasonable that stress from fuel swelling in the complex structure should be relaxed by local adjustments of particles, Al matrix, and IL. For analysis of U-Mo/Al Dispersion fuel creep, the creep of U-Mo particle, Al matrix, and IL should be considered. Moreover, not only fuel particle swelling and IL growth, but also fuel and Al matrix consumptions due to IL formation are accounted in terms of their volume fraction changes during irradiation. In this work, fuel particles, Al matrix and IL are treated in a way of homogenized constituents: Fuel particles, Al matrix and IL consist of an equivalent meat during irradiation. Meat volume swelling of two representative plates was measured: One (Plate A) was a pure Al matrix with 6g/cc uranium loading, the other (Plate B) a silicon added Al matrix with 8g/cc uranium loading. The meat swelling of calculated as a function of burnup. The meat swelling of calculation and measurement was compared and the creep rate coefficients for Al and IL were estimated by repetitions. Based on assumption that only the continuous phase of Al-IL combined matrix accommodated the stress from fuel particle swelling and it was allowed to have creep deformation, the homogenization modeling was performed. The meat swelling of two U-Mo/Al Dispersion fuel plates was modeled by using homogenization model

  6. Modelling of U-Mo/Al Dispersion fuel fission induced swelling and creep

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Gwan Yoon; Sohn, Dong Seong [Ulsan National Institute of Science and Technology, Ulsan (Korea, Republic of); Kim, Yeon Soo [Argonne National Laboratory, Argonne (United States)

    2014-05-15

    In a Dispersion fuel which U-Mo particles are dispersed in Al metal matrix, a similar phenomenon forming a bulge region was observed but it is difficult to quantify and construct a model for explaining creep and swelling because of its complex microstructure change during irradiation including interaction layer (IL) and porosity formation. In a Dispersion fuel meat, fission product induces fuel particles swelling and it has to be accommodated by the deformation of the Al matrix and newly formed IL during irradiation. Then, it is reasonable that stress from fuel swelling in the complex structure should be relaxed by local adjustments of particles, Al matrix, and IL. For analysis of U-Mo/Al Dispersion fuel creep, the creep of U-Mo particle, Al matrix, and IL should be considered. Moreover, not only fuel particle swelling and IL growth, but also fuel and Al matrix consumptions due to IL formation are accounted in terms of their volume fraction changes during irradiation. In this work, fuel particles, Al matrix and IL are treated in a way of homogenized constituents: Fuel particles, Al matrix and IL consist of an equivalent meat during irradiation. Meat volume swelling of two representative plates was measured: One (Plate A) was a pure Al matrix with 6g/cc uranium loading, the other (Plate B) a silicon added Al matrix with 8g/cc uranium loading. The meat swelling of calculated as a function of burnup. The meat swelling of calculation and measurement was compared and the creep rate coefficients for Al and IL were estimated by repetitions. Based on assumption that only the continuous phase of Al-IL combined matrix accommodated the stress from fuel particle swelling and it was allowed to have creep deformation, the homogenization modeling was performed. The meat swelling of two U-Mo/Al Dispersion fuel plates was modeled by using homogenization model.

  7. Modeling cognition and disease using human glial chimeric mice

    DEFF Research Database (Denmark)

    Goldman, Steven A.; Nedergaard, Maiken; Windrem, Martha S.

    2015-01-01

    , oligodendrocytes as well. As a result, the recipient brains may become inexorably humanized with regards to their resident glial populations, yielding human glial chimeric mouse brains. These brains provide us a fundamentally new tool by which to assess the species-specific attributes of glia in modulating human...... for studying the human-specific contributions of glia to psychopathology, as well as to higher cognition. As such, the assessment of human glial chimeric mice may provide us new insight into the species-specific contributions of glia to human cognitive evolution, as well as to the pathogenesis of human...

  8. Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

    Science.gov (United States)

    Oestreich, A K; Carleton, S M; Yao, X; Gentry, B A; Raw, C E; Brown, M; Pfeiffer, F M; Wang, Y; Phillips, C L

    2016-01-01

    Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

  9. Motivational Disturbances and Effects of L-dopa Administration in Neurofibromatosis-1 Model Mice

    Science.gov (United States)

    Wozniak, David F.; Diggs-Andrews, Kelly A.; Conyers, Sara; Yuede, Carla M.; Dearborn, Joshua T.; Brown, Jacquelyn A.; Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F.; Gutmann, David H.

    2013-01-01

    Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1

  10. Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice.

    Directory of Open Access Journals (Sweden)

    David F Wozniak

    Full Text Available Children with neurofibromatosis type 1 (NF1 frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice. In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at

  11. Protective effect of metformin on D-galactose-induced aging model in mice.

    Science.gov (United States)

    Fatemi, Iman; Khaluoi, Amin; Kaeidi, Ayat; Shamsizadeh, Ali; Heydari, Sara; Allahtavakoli, Mohammad Aa

    2018-01-01

    Metformin (Met), an antidiabetic biguanide, reduces hyperglycemia via improving glucose utilization and reducing the gluconeogenesis. Met has been shown to exert neuroprotective, antioxidant and anti-inflammatory properties. The present study investigated the possible effect of Met on the D-galactose (D-gal)-induced aging in mice. Met (1 and 10 mg/kg/p.o.), was administrated daily in D-gal-received (500 mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behavior, cognitive function, and physical power were evaluated by the elevated plus-maze, novel object recognition task (NORT), and forced swimming capacity test, respectively. The brains were analyzed for the level of superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). Met decreased the anxiety-like behavior in D-gal-treated mice. Also, Met treated mice showed significantly improved learning and memory ability in NORT compared to the D-gal-treated mice. Furthermore, Met increased the physical power as well as the activity of SOD and BDNF level in D-gal-treated mice. Our results suggest that the use of Met can be an effective strategy for prevention and treatment of D-gal-induced aging in animal models. This effect seems to be mediated by attenuation of oxidative stress and enhancement of the neurotrophic factors.

  12. Interaction between Al3+ and acrylic acid and polyacrylic acid in acidic aqueous solution: a model experiment for the behavior of Al3+ in acidified soil solution.

    Science.gov (United States)

    Etou, Mayumi; Masaki, Yuka; Tsuji, Yutaka; Saito, Tomoyuki; Bai, Shuqin; Nishida, Ikuko; Okaue, Yoshihiro; Yokoyama, Takushi

    2011-01-01

    From the viewpoint of the phytotoxicity and mobility of Al(3+) released from soil minerals due to soil acidification, the interaction between Al(3+) and acrylic acid (AA) and polyacrylic acid (PAA) as a model compound of fulvic acid was investigated. The interaction was examined at pH 3 so as to avoid the hydrolysis of Al(3+). The interaction between Al(3+) and AA was weak. However, the interaction between Al(3+) and PAA was strong and depended on the initial (COOH in PAA)/Al molar ratio (R(P)) of the solution. For the range of 1/R(P), the interaction between Al(3+) and PAA can be divided into three categories: (1) 1:1 Al-PAA-complex (an Al(3+) combines to a carboxyl group), (2) intermolecular Al-PAA-complex (an Al(3+) combines to more than 2 carboxyl groups of other Al-PAA-complexes) in addition to the 1:1 Al-PAA-complex and (3) precipitation of intermolecular complexes. In conclusion, R(P) is an important factor affecting the behavior of Al(3+) in acidic soil solution.

  13. Mice with chimeric livers are an improved model for human lipoprotein metabolism.

    Science.gov (United States)

    Ellis, Ewa C S; Naugler, Willscott Edward; Nauglers, Scott; Parini, Paolo; Mörk, Lisa-Mari; Jorns, Carl; Zemack, Helen; Sandblom, Anita Lövgren; Björkhem, Ingemar; Ericzon, Bo-Göran; Wilson, Elizabeth M; Strom, Stephen C; Grompe, Markus

    2013-01-01

    Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism. FRG [ F ah(-/-) R ag2(-/-)Il2r g (-/-)]) mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL) was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR. Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA). Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal. Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.

  14. Simplified 2DEG carrier concentration model for composite barrier AlGaN/GaN HEMT

    International Nuclear Information System (INIS)

    Das, Palash; Biswas, Dhrubes

    2014-01-01

    The self consistent solution of Schrodinger and Poisson equations is used along with the total charge depletion model and applied with a novel approach of composite AlGaN barrier based HEMT heterostructure. The solution leaded to a completely new analytical model for Fermi energy level vs. 2DEG carrier concentration. This was eventually used to demonstrate a new analytical model for the temperature dependent 2DEG carrier concentration in AlGaN/GaN HEMT

  15. An inducer of VGF protects cells against ER stress-induced cell death and prolongs survival in the mutant SOD1 animal models of familial ALS.

    Directory of Open Access Journals (Sweden)

    Masamitsu Shimazawa

    2010-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF: VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS.

  16. Model Research On Synthesis Of Al2O3-C Layers By MOCVD

    Directory of Open Access Journals (Sweden)

    Sawka A.

    2015-06-01

    Full Text Available These are model studies whose aim is to obtain information that would allow development of new technology for synthesizing monolayers of Al2O3-C with adjusted microstructure on cemented carbides. The Al2O3-C layer will constitute an intermediate layer on which the outer layer of Al2O3 without carbon is synthesized. The purpose of the intermediate layer is to block the cobalt diffusion to the synthesized outer layer of Al2O3 and to stop the diffusion of air oxygen to the substrate during the synthesis of the outer layer. This layer should be thin, continuous, dense and uniform in thickness.

  17. Modeling of AlMg Sheet Forming at Elevated Temperatures

    NARCIS (Netherlands)

    van den Boogaard, Antonius H.; Bolt, P.; Werkhoven, R.

    2001-01-01

    The process limits of aluminum sheet forming processes can be improved by control-ling local flow behavior by means of elevated temperatures and temperature gradients. In order to accurately model the deep drawing or stretching of aluminum sheet at elevated temperatures, a model is required that

  18. The influence of stachydrine hydrochloride on the reperfusion model of mice with repetitive cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Mingsan Miao

    2017-03-01

    Full Text Available To study the influence of stachydrine hydrochloride on the inflammatory cytokines and tissue morphology of the re-perfusion model of mice with repetitive cerebral ischemia and probe into the protection mechanism of stachydrine hydrochloride for cerebral ischemia reperfusion impairment. Build a repetitive cerebral ischemia reperfusion model by first blocking the common carotid artery on both sides for 10 min, then resuming perfusion for 10 min and then blocking the common carotid artery on both sides again for 10 min. Before the operation, all the mice in the Nimodipine group, and the big, medium and small stachydrine hydrochloride dose groups were given corresponding gastric perfusion, the mice in the sham operation group and the modeled groups were at the same time given 0.5% sodium carboxymethyl cellulose for gastric perfusion of the same volume. The medicine was fed daily for 7 consecutive days. The model was built 1 h after the last feed and the perfusion continued for 24 h after the operation. Then the death rate of the mice was calculated. The mouse brains were taken out to test the ICAM-1 level and the TNF-α level, and the serum was taken out to test the NSE level and the MPO level. The tissue morphology changes were also observed. All the repetitive cerebral ischemia reperfusion models were successfully duplicated. The stachydrine hydrochloride in all the dose groups significantly reduced the death rates of big and small mice, reduced the level of ICAM-1 and the level of TNF-α in the brain tissues and the NSE level and the MPO level in the serum, significantly alleviating the pathological impairment in the hippocampus. Stachydrine hydrochloride can significantly reduce the death rate of mice, improve the pathological changes in the hippocampus, inhibit inflammatory reactions after ischemia, thus reducing the re-perfusion impairment after cerebral ischemia.

  19. Motor impulsivity in APP-SWE mice: a model of Alzheimer's disease.

    Science.gov (United States)

    Adriani, Walter; Ognibene, Elisa; Heuland, Emilie; Ghirardi, Orlando; Caprioli, Antonio; Laviola, Giovanni

    2006-09-01

    Among transgenic mouse models of Alzheimer's disease, APP-SWE mice have been shown to develop beta-amyloid plaques and to exhibit progressive impairment of cognitive function. Human Alzheimer's disease, however, also includes secondary clinical manifestations, spanning from hyperactivity to agitation. The aim of this study was a better characterization of motor impulsivity in APP-SWE mice, observed at 12 months of age, when levels of soluble beta-amyloid are elevated and beta-amyloid neuritic plaques start to appear. Mice were tested for spatial learning abilities in the Morris water maze (seven daily sessions, four trials per day). The distance traveled to reach the hidden platform showed a learning curve in both groups. This profile, however, was somewhat delayed in APP-SWE mice, thus confirming slightly impaired spatial capacities. To evaluate motor impulsivity, animals were trained to nose-poke for a food reward, which was delivered after a waiting interval that increased over days (15-60 s). Further nose-poking during this signaled waiting interval resulted in food-reward loss and electric-shock punishment. APP-SWE mice received an increased quantity of punishment and were able to earn fewer food rewards, suggesting inability to wait already at the lowest delay. After the animals were killed, prefrontal cortex samples were assessed for neurochemical parameters. Serotonin turnover was elevated in the prefrontal cortex of APP-SWE mice compared with controls. The results clearly confirm cognitive deficits, and are consistent with the hypothesis of reduced behavioral-inhibition abilities. Together with recent findings, APP-SWE mice emerge as a suitable animal model, characterized by a number of specific behavioral alterations, resembling primary and secondary symptoms of human Alzheimer's disease.

  20. A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS.

    Science.gov (United States)

    Hatzipetros, Theo; Kidd, Joshua D; Moreno, Andy J; Thompson, Kenneth; Gill, Alan; Vieira, Fernando G

    2015-10-06

    The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening protocol, demonstrated in video herein, which reliably assesses the neuromuscular function of SOD1-G93A mice in a quick manner. This protocol encompasses a simple neurological scoring system (NeuroScore) designed to assess hindlimb function. NeuroScore is focused on hindlimb function because hindlimb deficits are the earliest reported neurological sign of disease in SOD1-G93A mice. The protocol developed by ALS TDI provides an unbiased assessment of onset of paresis (slight or partial paralysis), progression and severity of paralysis and it is sensitive enough to identify drug-induced changes in disease progression. In this report, the combination of a detailed manuscript with video minimizes scoring ambiguities and inter-experimenter variability thus allowing for the protocol to be adopted by other laboratories and enabling comparisons between studies taking place at different settings. We believe that this video protocol can serve as an excellent training tool for present and future ALS researchers.

  1. Transcriptional profiling reveals progeroid Ercc1(-/Δ) mice as a model system for glomerular aging.

    Science.gov (United States)

    Schermer, Bernhard; Bartels, Valerie; Frommolt, Peter; Habermann, Bianca; Braun, Fabian; Schultze, Joachim L; Roodbergen, Marianne; Hoeijmakers, Jan Hj; Schumacher, Björn; Nürnberg, Peter; Dollé, Martijn Et; Benzing, Thomas; Müller, Roman-Ulrich; Kurschat, Christine E

    2013-08-16

    Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1(-/Δ) progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1(-/Δ) mice showed cluster formation between young WT and Ercc1(-/Δ) as well as old WT and Ercc1(-/Δ) samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1(-/Δ) mice (p aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1(-/Δ) mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies.

  2. Transcriptional profiling reveals progeroid Ercc1-/Δ mice as a model system for glomerular aging

    Science.gov (United States)

    2013-01-01

    Background Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1-/Δ progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. Results In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1-/Δ mice showed cluster formation between young WT and Ercc1-/Δ as well as old WT and Ercc1-/Δ samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1-/Δ mice (p aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1-/Δ mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies. PMID:23947592

  3. Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

    Science.gov (United States)

    Hara, Toshiro; Murakami, Yoshinori; Seiki, Motoharu; Sakamoto, Takeharu

    2017-08-26

    Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV-PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT-derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  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. Toward an animal model for antisocial behavior : parallels between mice and humans

    NARCIS (Netherlands)

    Sluyter, F; Arseneault, L; Moffitt, TE; Veenema, AH; de Boer, S; Koolhaas, JM

    The goal of this article is to examine whether mouse lines genetically selected for short and long attack latencies are good animal models for antisocial behavior in humans. To this end, we compared male Short and Long Attack Latency mice (SAL and LAL, respectively) with the extremes of the Dunedin

  6. Development of a model for marburgvirus based on severe-combined immunodeficiency mice

    Directory of Open Access Journals (Sweden)

    Kalina Warren V

    2007-10-01

    Full Text Available Abstract The filoviruses, Ebola (EBOV and Marburg (MARV, cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by performing 9 sequential passages in progressively older mice (suckling to adult. Evaluation of this model identified many similarities between infection in mice and nonhuman primates, including viral tropism for antigen-presenting cells, high viral titers in the spleen and liver, and an equivalent mean time to death. Existence of the EBOV mouse model has increased our understanding of host responses to filovirus infections and likely has accelerated the development of countermeasures, as it is one of the only hemorrhagic fever viruses that has multiple candidate vaccines and therapeutics. Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid mice was highly successful in reducing the time to death in scid mice from 50–70 days to 7–10 days after MARV-Ci67, -Musoke, or -Ravn challenge. We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains. These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates. Also, as shown here, the scid-adapted MARV mouse models can be used to evaluate the efficacy of candidate antiviral therapeutic molecules, such as phosphorodiamidate morpholino oligomers or antibodies.

  7. Magnetic properties of Fe–Al for quenched diluted spin-1 Ising model

    International Nuclear Information System (INIS)

    Freitas, A.S.; Albuquerque, Douglas F. de; Fittipaldi, I.P.; Moreno, N.O.

    2014-01-01

    We study the phase diagram of Fe 1−q Al q alloys via the quenched site diluted spin-1 ferromagnetic Ising model by employing effective field theory. One suggests a new approach to exchange interaction between nearest neighbors of Fe that depends on the powers of the Al (q) instead of the linear dependence proposed in other papers. In such model we propose the same kind of the exchange interaction in which the iron–nickel alloys obtain an excellent theoretical description of the experimental data of the T–q phase diagram for all Al concentration q. - Highlights: • We apply the quenched Ising model spin-1 to study the properties of Fe–Al. • We employ the EFT and suggest a new approach to ferromagnetic coupling. • The new probability distribution is considered. • The phase diagram is obtained for all values of q in T–q plane

  8. Magnetic properties of Fe–Al for quenched diluted spin-1 Ising model

    Energy Technology Data Exchange (ETDEWEB)

    Freitas, A.S. [Departamento de Física, Universidade Federal de Sergipe, 49100-000, São Cristovão, SE (Brazil); Coordenadoria de Física, Instituto Federal de Sergipe, 49400-000 Lagarto, SE (Brazil); Albuquerque, Douglas F. de, E-mail: douglas@ufs.br [Departamento de Física, Universidade Federal de Sergipe, 49100-000, São Cristovão, SE (Brazil); Departamento de Matemática, Universidade Federal de Sergipe, 49100-000, São Cristovão, SE (Brazil); Fittipaldi, I.P. [Representação Regional do Ministério da Ciência, Tecnologia e Inovação no Nordeste - ReNE, 50740-540 Recife, PE (Brazil); Moreno, N.O. [Departamento de Física, Universidade Federal de Sergipe, 49100-000, São Cristovão, SE (Brazil)

    2014-08-01

    We study the phase diagram of Fe{sub 1−q}Al{sub q} alloys via the quenched site diluted spin-1 ferromagnetic Ising model by employing effective field theory. One suggests a new approach to exchange interaction between nearest neighbors of Fe that depends on the powers of the Al (q) instead of the linear dependence proposed in other papers. In such model we propose the same kind of the exchange interaction in which the iron–nickel alloys obtain an excellent theoretical description of the experimental data of the T–q phase diagram for all Al concentration q. - Highlights: • We apply the quenched Ising model spin-1 to study the properties of Fe–Al. • We employ the EFT and suggest a new approach to ferromagnetic coupling. • The new probability distribution is considered. • The phase diagram is obtained for all values of q in T–q plane.

  9. Experimental pneumococcal meningitis in mice: a model of intranasal infection

    NARCIS (Netherlands)

    Zwijnenburg, P. J.; van der Poll, T.; Florquin, S.; van Deventer, S. J.; Roord, J. J.; van Furth, A. M.

    2001-01-01

    Effective laboratory animal models of bacterial meningitis are needed to unravel the pathophysiology of this disease. Previous models have failed to simulate human meningitis by using a directly intracerebral route of infection. Hyaluronidase is a virulence factor of Streptococcus pneumoniae. In

  10. Modeling of Eutectic Formation in Al-Si Alloy Using A Phase-Field Method

    Directory of Open Access Journals (Sweden)

    Ebrahimi Z.

    2017-12-01

    Full Text Available We have utilized a phase-field model to investigate the evolution of eutectic silicon in Al-Si alloy. The interfacial fluctuations are included into a phase-field model of two-phase solidification, as stochastic noise terms and their dominant role in eutectic silicon formation is discussed. We have observed that silicon spherical particles nucleate on the foundation of primary aluminum phase and their nucleation continues on concentric rings, through the Al matrix. The nucleation of silicon particles is attributed to the inclusion of fluctuations into the phase-field equations. The simulation results have shown needle-like, fish-bone like and flakes of silicon phase by adjusting the noise coefficients to larger values. Moreover, the role of primary Al phase on nucleation of silicon particles in Al-Si alloy is elaborated. We have found that the addition of fluctuations plays the role of modifiers in our simulations and is essential for phase-field modeling of eutectic growth in Al-Si system. The simulated finger-like Al phases and spherical Si particles are very similar to those of experimental eutectic growth in modified Al-Si alloy.

  11. APP transgenic mice for modelling behavioral and psychological symptoms of dementia (BPSD)

    Science.gov (United States)

    Lalonde, R.; Fukuchi, K.; Strazielle, C.

    2012-01-01

    The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioral and psychological symptoms of Alzeimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine. PMID:22373961

  12. A crystallographic constitutive model for Ni3Al (L12) intermetallics

    International Nuclear Information System (INIS)

    Choi, Y.S.; Dimiduk, D.M.; Uchic, M.D.; Parthasarathy, T.A.

    2005-01-01

    A constitutive model was developed in order to capture the unique thermo-mechanical flow behavior of L1 2 -structured Ni 3 (Al, X) alloys. This model utilized a framework for flow-stress partitioning, which was previously proposed by Ezz and Hirsch, and incorporated a model for exhaustion hardening proposed by Caillard. The simulation results well represent the major aspects of the thermo-mechanical flow behavior of Ni 3 (Al, X) alloys, such as a flow-stress anomaly, its strain dependence and a work-hardening rate anomaly. Selected limitations are discussed along with our current efforts toward extending the present model

  13. Modeling bladder cancer in mice: opportunities and challenges

    Science.gov (United States)

    Kobayashi, Takashi; Owczarek, Tomasz B.; McKiernan, James M.; Abate-Shen, Cory

    2015-01-01

    The prognosis and treatment of bladder cancer have hardly improved in the last 20 years. Bladder cancer remains a debilitating and often fatal disease, and among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as impact its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described and particularly few that develop invasive cancer phenotypes. This review focuses on opportunities for improving the landscape of mouse models of bladder cancer. PMID:25533675

  14. Standardization of a spinal cord lesion model and neurologic evaluation using mice

    Science.gov (United States)

    Borges, Paulo Alvim; Cristante, Alexandre Fogaça; de Barros-Filho, Tarcísio Eloy Pessoa; Natalino, Renato Jose Mendonça; dos Santos, Gustavo Bispo; Marcon, Raphael Marcus

    2018-01-01

    OBJECTIVE: To standardize a spinal cord lesion mouse model. METHODS: Thirty BALB/c mice were divided into five groups: four experimental groups and one control group (sham). The experimental groups were subjected to spinal cord lesion by a weight drop from different heights after laminectomy whereas the sham group only underwent laminectomy. Mice were observed for six weeks, and functional behavior scales were applied. The mice were then euthanized, and histological investigations were performed to confirm and score spinal cord lesion. The findings were evaluated to prove whether the method of administering spinal cord lesion was effective and different among the groups. Additionally, we correlated the results of the functional scales with the results from the histology evaluations to identify which scale is more reliable. RESULTS: One mouse presented autophagia, and six mice died during the experiment. Because four of the mice that died were in Group 5, Group 5 was excluded from the study. All the functional scales assessed proved to be significantly different from each other, and mice presented functional evolution during the experiment. Spinal cord lesion was confirmed by histology, and the results showed a high correlation between the Basso, Beattie, Bresnahan Locomotor Rating Scale and the Basso Mouse Scale. The mouse function scale showed a moderate to high correlation with the histological findings, and the horizontal ladder test had a high correlation with neurologic degeneration but no correlation with the other histological parameters evaluated. CONCLUSION: This spinal cord lesion mouse model proved to be effective and reliable with exception of lesions caused by a 10-g drop from 50 mm, which resulted in unacceptable mortality. The Basso, Beattie, Bresnahan Locomotor Rating Scale and Basso Mouse Scale are the most reliable functional assessments, and but the horizontal ladder test is not recommended. PMID:29561931

  15. [Effects of chrysalis oil on learning, memory and oxidative stress in D-galactose-induced ageing model of mice].

    Science.gov (United States)

    Chen, Weiping; Yang, Qiongjie; Wei, Xing

    2013-11-01

    To investigate the effects of chrysalis oil on learning, memory and oxidative stress in D-galactose-induced ageing model of mice. Mice were injected intraperitoneally with D-galactose daily and received chrysalis oil intragastrically simultaneously for 30 d. Then mice underwent space navigation test and spatial probe test, superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) contents in mouse brain were measured. Compared to model group, escape latency in mice treated with 6 ml/kg*d chrysalis oil was significantly shorter (Pchrysalis oil were significantly increased (PChrysalis oil treatment (12ml/kg*d) significantly increased SOD and GSH-PX activity and reduced MDA contents in brain of D-galactose-induced aging mice. Chrysalis oil can improve the ability of learning and memory in D-galactose-induced aging mice, and inhibit peroxidation in brain tissue.

  16. Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

    Directory of Open Access Journals (Sweden)

    Claudia Fuchs

    2018-01-01

    Full Text Available CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/− mouse, has been little characterized. The lack of detailed behavioral profiling of this model remains a crucial gap that must be addressed in order to advance preclinical studies. Here, we provide a behavioral and molecular characterization of heterozygous Cdkl5 +/− mice. We found that Cdkl5 +/− mice reliably recapitulate several aspects of CDKL5 disorder, including autistic-like behaviors, defects in motor coordination and memory performance, and breathing abnormalities. These defects are associated with neuroanatomical alterations, such as reduced dendritic arborization and spine density of hippocampal neurons. Interestingly, Cdkl5 +/− mice show age-related alterations in protein kinase B (AKT and extracellular signal-regulated kinase (ERK signaling, two crucial signaling pathways involved in many neurodevelopmental processes. In conclusion, our study provides a comprehensive overview of neurobehavioral phenotypes of heterozygous female Cdkl5 +/− mice and demonstrates that the heterozygous female might be a valuable animal model in preclinical studies on CDKL5 disorder.

  17. Collagen VI Null Mice as a Model for Early Onset Muscle Decline in Aging

    Directory of Open Access Journals (Sweden)

    Daniele Capitanio

    2017-10-01

    Full Text Available Collagen VI is an extracellular matrix (ECM protein playing a key role in skeletal muscles and whose deficiency leads to connective tissue diseases in humans and in animal models. However, most studies have been focused on skeletal muscle features. We performed an extensive proteomic profiling in two skeletal muscles (diaphragm and gastrocnemius of wild-type and collagen VI null (Col6a1−/− mice at different ages, from 6- (adult to 12- (aged month-old to 24 (old month-old. While in wild-type animals the number of proteins and the level of modification occurring during aging were comparable in the two analyzed muscles, Col6a1−/− mice displayed a number of muscle-type specific variations. In particular, gastrocnemius displayed a limited number of dysregulated proteins in adult mice, while in aged muscles the modifications were more pronounced in terms of number and level. In diaphragm, the differences displayed by 6-month-old Col6a1−/− mice were more pronounced compared to wild-type mice and persisted at 12 months of age. In adult Col6a1−/− mice, the major variations were found in the enzymes belonging to the glycolytic pathway and the tricarboxylic acid (TCA cycle, as well as in autophagy-related proteins. When compared to wild-type animals Col6a1−/− mice displayed a general metabolic rewiring which was particularly prominent the diaphragm at 6 months of age. Comparison of the proteomic features and the molecular analysis of metabolic and autophagic pathways in adult and aged Col6a1−/− diaphragm indicated that the effects of aging, culminating in lipotoxicity and autophagic impairment, were already present at 6 months of age. Conversely, the effects of aging in Col6a1−/− gastrocnemius were similar but delayed becoming apparent at 12 months of age. A similar metabolic rewiring and autophagic impairment was found in the diaphragm of 24-month-old wild-type mice, confirming that fatty acid synthase (FASN increment and

  18. Blood-CNS Barrier Impairment in ALS Patients versus an Animal Model

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    Svitlana eGarbuzova-Davis

    2014-02-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a severe neurodegenerative disease with a compli-cated and poorly understood pathogenesis. Recently, alterations in the blood-Central Nervous System barrier (B-CNS-B have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been deter-mined in mutant SOD1 rodent models, identifying barrier damage during disease develop-ment which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS has been limited. We recently showed structural and functional impairment in postmortem gray and white mat-ter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degenera-tion, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages are indicated in both mutant SOD1 animal models of ALS and SALS pa-tients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnor-malities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood-CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies.

  19. Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

    International Nuclear Information System (INIS)

    Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa Pui Ling; Nakayama, Aki; Morisawa, Shinsuke

    2007-01-01

    Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses

  20. A model of alcohol drinking under an intermittent access schedule using group-housed mice.

    Directory of Open Access Journals (Sweden)

    Magdalena Smutek

    Full Text Available Here, we describe a new model of voluntary alcohol drinking by group-housed mice. The model employs sensor-equipped cages that track the behaviors of the individual animals via implanted radio chips. After the animals were allowed intermittent access to alcohol (three 24 h intervals every week for 4 weeks, the proportions of licks directed toward bottles containing alcohol were 50.9% and 39.6% for the male and female mice, respectively. We used three approaches (i.e., quinine adulteration, a progressive ratio schedule and a schedule involving a risk of punishment to test for symptoms of compulsive alcohol drinking. The addition of 0.01% quinine to the alcohol solution did not significantly affect intake, but 0.03% quinine induced a greater than 5-fold reduction in the number of licks on the alcohol bottles. When the animals were required to perform increasing numbers of instrumental responses to obtain access to the bottle with alcohol (i.e., a progressive ratio schedule, they frequently reached a maximum of 21 responses irrespective of the available reward. Although the mice rarely achieved higher response criteria, the number of attempts was ∼ 10 times greater in case of alcohol than water. We have developed an approach for mapping social interactions among animals that is based on analysis of the sequences of entries into the cage corners. This approach allowed us to identify the mice that followed other animals in non-random fashions. Approximately half of the mice displayed at least one interaction of this type. We have not yet found a clear correlation between imitative behavior and relative alcohol preference. In conclusion, the model we describe avoids the limitations associated with testing isolated animals and reliably leads to stable alcohol drinking. Therefore, this model may be well suited to screening for the effects of genetic mutations or pharmacological treatments on alcohol-induced behaviors.

  1. Rho, a Fraction From Rhodiola crenulate, Ameliorates Hepatic Steatosis in Mice Models

    Directory of Open Access Journals (Sweden)

    Qin Yi

    2018-03-01

    Full Text Available The prevalence of non-alcoholic fatty liver disease (NAFLD, which is developed from hepatic steatosis, is increasing worldwide. However, no specific drugs for NAFLD have been approved yet. To observe the effects of Rho, a fraction from Rhodiola crenulate, on non-alcoholic hepatic steatosis, three mouse models with characteristics of NAFLD were used including high-fat diet (HFD-induced obesity (DIO mice, KKAy mice, and HFD combined with tetracycline stimulated Model-T mice. Hepatic lipid accumulation was determined via histopathological analysis and/or hepatic TG determination. The responses to insulin were evaluated by insulin tolerance test (ITT, glucose tolerance test (GTT, and hyperinsulinemic-euglycemic clamp, respectively. The pathways involved in hepatic lipid metabolism were observed via western-blot. Furthermore, the liver microcirculation was observed by inverted microscopy. The HPLC analysis indicated that the main components of Rho were flavan polymers. The results of histopathological analysis showed that Rho could ameliorate hepatic steatosis in DIO, KKAy, and Model-T hepatic steatosis mouse models, respectively. After Rho treatment in DIO mice, insulin resistance was improved with increasing glucose infusion rate (GIR in hyperinsulinemic-euglycemic clamp, and decreasing areas under the blood glucose-time curve (AUC in both ITT and GTT; the pathways involved in fatty acid uptake and de novo lipogenesis were both down-regulated, respectively. However, the pathways involved in beta-oxidation and VLDL-export on hepatic steatosis were not changed significantly. The liver microcirculation disturbances were also improved by Rho in DIO mice. These results suggest that Rho is a lead nature product for hepatic steatosis treatment. The mechanism is related to enhancing insulin sensitivity, suppressing fatty acid uptake and inhibiting de novo lipogenesis in liver.

  2. [The effect of hypertonic seawater and isotonic seawater for nasal mucosa of allergic rhinitis mice model].

    Science.gov (United States)

    Deng, Zhifeng; Xu, Yu; Ou, Jin; Xiang, Rong; Tao, Zezhang

    2014-12-01

    To study the effect of hypertonic seawater and isotonic seawater for nasal mucosa of allergic rhinitis mice model, and explore the possible mechanism of nasal irrigation with seawater in treatment of allergic rhinitis. We used Der pl to make allergic rhinitis model of BALB/c mice, and divided them into three groups randomly. Nasal irrigation with hypertonic seawater (HS) or isotonic seawater (IS) in the treatment group 1-14 days after modeling, and black control (BC) group was given no treatment after modeling. Normal control (NC) group was given no treatment, the number of rubs and sneezings in each group were counted in 30 min after the last nasal irrigation. Mice were then killed 24 h after the last therapy. The noses of mice from each group were removed and fixed, then the slices were stained with hematoxylin and eosin, the others were observed by transmission electron microscope. Mice with hypertonic seawater and isotonic seawater were significantly improved in rubs and sneezings compared to the black control group (P 0. 05); Ciliated columnar epithelium cells in mucosal tissues of HS group and IS group were arranged trimly, better than that in the black control group. Morphology and microstructure in nasal mucosal of HS group was closer to the normal group than in IS group. The injury of nasal mucosa ciliated epithelium was significantly improved by nasal irrigation with hypertonic seawater and isotonic seawater, and the former is better than the latter, the mechanism of nasal irrigation with seawater in treatment of allergic rhinitis may rely on repairing the injured nasal mucosa ciliated epithelium, thereby the symptoms of nasal was reduced.

  3. Lifetime modelling for MCrAlY coatings in industrial gas turbine blades

    Directory of Open Access Journals (Sweden)

    Krukovsky Pavel

    2004-01-01

    Full Text Available A novel theoretical and experimental approach for lifetime modelling of MCrAlY coatings for stationary gas turbines has been undertaken using the Inverse Problem Solution (IPS technique. With this technique feasible experimental data acquired after a defined experimental time t e are used as input values for the model parameters estimation. In the first stage of the approach a model, based on the oxidation and diffusion processes (Fick's first and second law was assumed, which considers the Al concentration profile across the coating. The measured average Al concentration profiles in the two-phase g+b and g - regions of coating as well as base metal were used as input values for the model parameters estimation and calculational prediction of the long term diffusion and oxidation behavior of the coating was performed. The time, when the b-NiAl phase is completely consumed was assumed as the coating lifetime end. Exposure experiments were carried out with a NiCoCrAlY coating (200 micron thickness with 8% Al in air at 900 °C and 950 °C, currently up to 10000 h. The oxide scale is growing continuously and no other oxides were observed. The average and b-NiAl phase concentration profiles of Al across the coating thickness were determined by electron microprobe and image analysis systems in the initial state after 700 and 10000 h of oxidation. The concentration profile measured after 700 h was used as input values for the model parameters estimation in order to calculate the Al and b-NiAl phase concentration profiles after 10000 h. The computational forecast for 10000 h at 950 °C and 900 °C are in good agreement with the measured data. The approach was applied for NiCoCrAlY (200 micron thickness coating lifetime modelling at 950 °C and 900 °C as well as for different coating thicknesses at 950 °C.

  4. 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.

  5. MODELING OF INTERACTION LAYER GROWTH BETWEEN U-Mo PARTICLES AND AN Al MATRIX

    OpenAIRE

    YEON SOO KIM; G.L. HOFMAN; HO JIN RYU; JONG MAN PARK; A.B. ROBINSON; D.M. WACHS

    2013-01-01

    Interaction layer growth between U-Mo alloy fuel particles and Al in a dispersion fuel is a concern due to the volume expansion and other unfavorable irradiation behavior of the interaction product. To reduce interaction layer (IL) growth, a small amount of Si is added to the Al. As a result, IL growth is affected by the Si content in the Al matrix. In order to predict IL growth during fabrication and irradiation, empirical models were developed. For IL growth prediction during fabrication an...

  6. Development of an experimental model of neutrophilic pulmonary response induction in mice

    Directory of Open Access Journals (Sweden)

    Leonardo Araújo Pinto

    2003-08-01

    Full Text Available BACKGROUND: Several lung diseases are characterized by a predominantly neutrophilic inflammation. A better understanding of the mechanisms of action of some drugs on the airway inflammation of such diseases may bring advances to the treatment. OBJECTIVE: To develop a method to induce pulmonary neutrophilic response in mice, without active infection. METHODS: Eight adult Swiss mice were used. The study group (n = 4 received an intranasal challenge with 1 x 10(12 CFU/ml of Pseudomonas aeruginosa (Psa, frozen to death. The control group (n = 4 received an intranasal challenge with saline solution. Two days after the intranasal challenge, a bron­choalveolar lavage (BAL was performed with total cell and differential cellularity counts. RESULTS: The total cell count was significantly higher in the group with Psa, as compared to the control group (median of 1.17 x 10(6 and 0.08 x 10(6, respectively, p = 0.029. In addition to this, an absolute predominance of neutrophils was found in the differential cellularity of the mice that had received the Psa challenge. CONCLUSIONS: The model of inducing a neutrophilic pulmonary disease using frost-dead bacteria was successfully developed. This neutrophilic inflammatory response induction model in Swiss mice lungs may be an important tool for testing the anti-inflammatory effect of some antimicrobial drugs on the inflammation of the lower airways.

  7. Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice.

    Science.gov (United States)

    Seese, Ronald R; Wang, Kathleen; Yao, Yue Qin; Lynch, Gary; Gall, Christine M

    2014-11-25

    Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.

  8. Of mice and women: rodent models of placental malaria

    DEFF Research Database (Denmark)

    Hviid, Lars; Marinho, Claudio R F; Staalsoe, Trine

    2010-01-01

    Pregnant women are at increased malaria risk. The infections are characterized by placental accumulation of infected erythrocytes (IEs) with adverse consequences for mother and baby. Placental IE sequestration in the intervillous space is mediated by variant surface antigens (VSAs) selectively...... expressed in placental malaria (PM) and specific for chondroitin sulfate A (CSA). In Plasmodium falciparum, these VSA(PM) appear largely synonymous with the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family variant VAR2CSA. As rodent malaria parasites do not possess PfEMP1 homologs......, the usefulness of experimental mouse PM models remains controversial. However, many features of murine and human PM are similar, including involvement of VSAs analogous to PfEMP1. It thus appears that rodent model studies can further the understanding of VSA-dependent malaria pathogenesis and immunity....

  9. Mottled Mice and Non-Mammalian Models of Menkes Disease

    DEFF Research Database (Denmark)

    Lenartowicz, Małgorzata; Krzeptowski, Wojciech; Lipiński, Paweł

    2015-01-01

    Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critica......-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals....

  10. Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice.

    Science.gov (United States)

    Yamaguchi, Hiroshi; Hara, Yuta; Ago, Yukio; Takano, Erika; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2017-08-30

    We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Histone Acetylation in Microglia Contributes to Exercise-Induced Hypoalgesia in Neuropathic Pain Model Mice.

    Science.gov (United States)

    Kami, Katsuya; Taguchi, Satoru; Tajima, Fumihiro; Senba, Emiko

    2016-05-01

    Physical exercise can attenuate neuropathic pain (NPP), but the exact mechanism underlying exercise-induced hypoalgesia (EIH) remains unclear. Recent studies have shown that histone hyperacetylation via pharmacological inhibition of histone deacetylases in the spinal cord attenuates NPP, and that histone acetylation may lead to the production of analgesic factors including interleukin 10. We intended to clarify whether histone acetylation in microglia in the spinal dorsal horn contributes to EIH in NPP model mice. C57BL/6J mice underwent partial sciatic nerve ligation (PSL) and PSL- and sham-runner mice ran on a treadmill at a speed of 7 m/min for 60 min/d, 5 days per week, from 2 days after the surgery. PSL-sedentary mice developed mechanical allodynia and heat hyperalgesia, but such behaviors were significantly attenuated in PSL-runner mice. In immunofluorescence analysis, PSL surgery markedly increased the number of histone deacetylase 1-positive/CD11b-positive microglia in the ipsilateral superficial dorsal horn, and they were significantly decreased by treadmill-running. Moreover, the number of microglia with nuclear expression of acetylated H3K9 in the ipsilateral superficial dorsal horn was maintained at low levels in PSL-sedentary mice, but running exercise significantly increased them. Therefore, we conclude that the epigenetic modification that causes hyperacetylation of H3K9 in activated microglia may play a role in producing EIH. This article presents the importance of epigenetic modification in microglia in producing EIH. The current research is not only helpful for developing novel nonpharmacological therapy for NPP, but will also enhance our understanding of the mechanisms and availability of exercise in our daily life. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

  12. GH dysfunction in Engrailed-2 knockout mice, a model for autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Giovanni eProvenzano

    2014-09-01

    Full Text Available Insulin-like growth factor 1 (IGF-1 signaling promotes brain development and plasticity. Altered IGF-1 expression has been associated to autism spectrum disorders (ASD. IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children. Accordingly, IGF-1 treatment can rescue behavioral deficits in mouse models of ASD, and IGF-1 trials have been proposed for ASD children. IGF-1 is mainly synthesized in the liver, and its synthesis is dependent on growth hormone (GH produced in the pituitary gland. GH also modulates cognitive functions, and altered levels of GH have been detected in ASD patients.Here we analyzed the expression of GH, IGF-1, their receptors and regulatory hormones in the neuroendocrine system of adult male mice lacking the homeobox transcription factor Engrailed-2 (En2-/- mice. En2-/- mice display ASD-like behaviors (social interactions, defective spatial learning, increased seizure susceptibility accompanied by relevant neuropathological changes (loss of cerebellar and forebrain inhibitory neurons. Recent studies showed that En2 modulates IGF-1 activity during postnatal cerebellar development.We found that GH mRNA expression was markedly deregulated throughout the neuroendocrine axis in En2-/- mice, as compared to wild-type (WT controls. In mutant mice, GH mRNA levels were significantly increased in the pituitary gland, blood and liver, whereas decreased levels were detected in the hippocampus. These changes were paralleled by decreased levels of GH protein in the hippocampus but not other tissues of En2-/- mice. IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2-/- hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes. Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.

  13. DETERMINATION OF AGE AND GENDER DIFFERENCES IN BIOCHEMICAL PROCESSES AFFECTING THE DISPOSITION OF 2-BUTOXYETHANOL AND ITS METABOLITES IN MICE AND RATS TO IMPROVE PBPK MODELING

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; Grant, Donna M.; Farris, Elizabeth; Weitz, Karl K.; Soelberg, Jolen J.; Thrall, K D.; Poet, Torka S.

    2005-03-28

    2-Butoxyethanol (BE) is the most widely used glycol ether solvent. BE's major metabolite, butoxyacetic acid (BAA), causes hemolysis with significant species differences in sensitivity. Several PBPK models have been developed over the past two decades to describe the disposition of BE and BAA in male rats and humans to refine health risk assessments. More recent efforts by Lee et al. (1998) to describe the kinetics of BE and BAA in the National Toxicology Program (NTP) chronic inhalation studies required the use of several assumptions to extrapolate model parameters from earlier PBPK models developed for young male rats to include female F344 and both sexes of B6C3F1 mice and the effects of aging. To replace these assumptions, studies were conducted to determine the impact of age, gender and species on the metabolism of BE, and the tissue partitioning, renal acid transport and plasma protein binding of BAA. In the current study, the Lee et al. PBPK model was updated and expanded to include the further metabolism of BAA and the salivary excretion of BE and BAA which may contribute to the forestomach irritation observed in mice in the NTP study. The revised model predicted that peak blood concentrations of BAA achieved following 6-hr inhalation exposures are greatest in young adult female rats at concentrations up to 300 ppm. This is not the case predicted for old (>18 months) animals, where peak blood concentrations of BAA in male and female mice were similar to or greater than female rats. The revised model serves as a quantitative tool for integrating an extensive pharmacokinetic and mechanistic database into a format that can readily be used to compare internal dosimetry across dose, route of exposure and species.

  14. Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta.

    Science.gov (United States)

    Grafe, Ingo; Alexander, Stefanie; Yang, Tao; Lietman, Caressa; Homan, Erica P; Munivez, Elda; Chen, Yuqing; Jiang, Ming Ming; Bertin, Terry; Dawson, Brian; Asuncion, Franklin; Ke, Hua Zhu; Ominsky, Michael S; Lee, Brendan

    2016-05-01

    Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality, and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin-neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage-associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1-week-old and 6-week-old Crtap(-/-) mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of "pediatric" and "young adult" recessive OI. Vehicle-treated Crtap(-/-) and wild-type (WT) mice served as controls. Compared with control Crtap(-/-) mice, micro-computed tomography (μCT) analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab-treated Crtap(-/-) mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole-bone strength in Crtap(-/-) mice, with more robust effects in the week 6 to 12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6 to 12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen posttranslational modification. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.

  15. Functional and muscular adaptations in an experimental model for isometric strength training in mice.

    Directory of Open Access Journals (Sweden)

    Karsten Krüger

    Full Text Available Exercise training induces muscular adaptations that are highly specific to the type of exercise. For a systematic study of the differentiated exercise adaptations on a molecular level mouse models have been used successfully. The aim of the current study was to develop a suitable mouse model of isometric strength exercise training characterized by specific adaptations known from strength training. C57BL/6 mice performed an isometric strength training (ST for 10 weeks 5 days/week. Additionally, either a sedentary control group (CT or a regular endurance training group (ET groups were used as controls. Performance capacity was determined by maximum holding time (MHT and treadmill spirometry, respectively. Furthermore, muscle fiber types and diameter, muscular concentration of phosphofructokinase 1 (PFK, succinate dehydrogenase (SDHa, and glucose transporter type 4 (GLUT4 were determined. In a further approach, the effect of ST on glucose intolerance was tested in diabetic mice. In mice of the ST group we observed an increase of MHT in isometric strength tests, a type II fiber hypertrophy, and an increased GLUT4 protein content in the membrane fraction. In contrast, in mice of the ET group an increase of VO(2max, a shift to oxidative muscle fiber type and an increase of oxidative enzyme content was measured. Furthermore strength training was effective in reducing glucose intolerance in mice fed a high fat diet. An effective murine strength training model was developed and evaluated, which revealed marked differences in adaptations known from endurance training. This approach seems also suitable to test for therapeutical effects of strength training.

  16. “Drinking in the Dark” (DID) Procedures: A Model of Binge-Like Ethanol Drinking in Non-Dependent Mice

    Science.gov (United States)

    Thiele, Todd E.; Navarro, Montserrat

    2013-01-01

    This review provides an overview of an animal model of binge-like ethanol drinking that has come to be called “drinking in the dark” (DID), a procedure that promotes high levels of ethanol drinking and pharmacologically relevant blood ethanol concentrations (BECs) in ethanol-preferring strains of mice. Originally described by Rhodes et al. (2005), the most common variation of the DID procedure, using singly housed mice, involves replacing the water bottle with a bottle containing 20% ethanol for 2 to 4 hours, beginning 3 hours into the dark cycle. Using this procedure, high ethanol drinking strains of mice (e.g., C57BL/6J) typically consume enough ethanol to achieve BECs greater than 100 mg/dL and to exhibit behavioral evidence of intoxication. This limited access procedure takes advantage of the time in the animal’s dark cycle in which the levels of ingestive behaviors are high, yet high ethanol intake does not appear to stem from caloric need. Mice have the choice of drinking or avoiding the ethanol solution, eliminating the stressful conditions that are inherent in other models of binge-like ethanol exposure in which ethanol is administered by the experimenter, and in some cases, potentially painful. The DID procedure is a high throughput approach that does not require extensive training or the inclusion of sweet compounds to motivate high levels of ethanol intake. The high throughput nature of the DID procedure makes it useful for rapid screening of pharmacological targets that are protective against binge-like drinking and for identifying strains of mice that exhibit binge-like drinking behavior. Additionally, the simplicity of DID procedures allows for easy integration into other paradigms, such as prenatal ethanol exposure and adolescent ethanol drinking. It is suggested that the DID model is a useful tool for studying the neurobiology and genetics underlying binge-like ethanol drinking, and may be useful for studying the transition to ethanol

  17. Mathematical modeling of left ventricular dimensional changes in mice during aging

    Directory of Open Access Journals (Sweden)

    Yang Tianyi

    2012-12-01

    Full Text Available Abstract Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV, which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age.

  18. Modeling of interaction layer growth between U-Mo particles and an Al matrix

    International Nuclear Information System (INIS)

    Kim, Yeon Soo; Horman, G. L.; Ryu, Ho Jin; Park, Jong Man; Robinson, A. B.; Wachs, D. M.

    2013-01-01

    Interaction layer growth between U-Mo alloy fuel particles and Al in a dispersion fuel is a concern due to the volume expansion and other unfavorable irradiation behavior of the interaction product. To reduce interaction layer (IL) growth, a small amount of Si is added to the Al. As a result, IL growth is affected by the Si content in the Al matrix. In order to predict IL growth during fabrication and irradiation, empirical models were developed. For IL growth prediction during fabrication and any follow-on heating process before irradiation, out-of-pile heating test data were used to develop kinetic correlations. Two out-of-pile correlations, one for the pure Al matrix and the other for the Al matrix with Si addition, respectively, were developed, which are Arrhenius equations that include temperature and time. For IL growth predictions during irradiation, the out-of-pile correlations were modified to include a fission-rate term to consider fission enhanced diffusion, and multiplication factors to incorporate the Si addition effect and the effect of the Mo content. The in-pile correlation is applicable for a pure Al matrix and an Al matrix with the Si content up to 8 wt%, for fuel temperatures up to 200 .deg. C, and for Mo content in the range of 6 - 10wt%. In order to cover these ranges, in-pile data were included in modeling from various tests, such as the US RERTR-4, -5, -6, -7 and -9 tests and Korea's KOMO-4 test, that were designed to systematically examine the effects of the fission rate, temperature, Si content in Al matrix, and Mo content in U-Mo particles. A model converting the IL thickness to the IL volume fraction in the meat was also developed

  19. MODELING OF INTERACTION LAYER GROWTH BETWEEN U-Mo PARTICLES AND AN Al MATRIX

    Directory of Open Access Journals (Sweden)

    YEON SOO KIM

    2013-12-01

    Full Text Available Interaction layer growth between U-Mo alloy fuel particles and Al in a dispersion fuel is a concern due to the volume expansion and other unfavorable irradiation behavior of the interaction product. To reduce interaction layer (IL growth, a small amount of Si is added to the Al. As a result, IL growth is affected by the Si content in the Al matrix. In order to predict IL growth during fabrication and irradiation, empirical models were developed. For IL growth prediction during fabrication and any follow-on heating process before irradiation, out-of-pile heating test data were used to develop kinetic correlations. Two out-of-pile correlations, one for the pure Al matrix and the other for the Al matrix with Si addition, respectively, were developed, which are Arrhenius equations that include temperature and time. For IL growth predictions during irradiation, the out-of-pile correlations were modified to include a fission-rate term to consider fission enhanced diffusion, and multiplication factors to incorporate the Si addition effect and the effect of the Mo content. The in-pile correlation is applicable for a pure Al matrix and an Al matrix with the Si content up to 8 wt%, for fuel temperatures up to 200 °C, and for Mo content in the range of 6 – 10wt%. In order to cover these ranges, in-pile data were included in modeling from various tests, such as the US RERTR-4, -5, -6, -7 and -9 tests and Korea's KOMO-4 test, that were designed to systematically examine the effects of the fission rate, temperature, Si content in Al matrix, and Mo content in U-Mo particles. A model converting the IL thickness to the IL volume fraction in the meat was also developed.

  20. An alternant method to the traditional NASA hindlimb unloading model in mice.

    Science.gov (United States)

    Ferreira, J Andries; Crissey, Jacqueline M; Brown, Marybeth

    2011-03-10

    The Morey-Holton hindlimb unloading (HU) method is a widely accepted National Aeronautics and Space Administration (NASA) ground-based model for studying disuse-atrophy in rodents. Our study evaluated an alternant method to the gold-standard Morey-Holton HU tail-traction technique in mice. Fifty-four female mice (4-8 mo.) were HU for 14 days (n=34) or 28 days (n=20). Recovery from HU was assessed after 3 days of normal cage ambulation following HU (n=22). Aged matched mice (n=76) served as weight-bearing controls. Prior to HU a tail ring was formed with a 2-0 sterile surgical steel wire that was passed through the 5(th), 6(th), or 7(th) inter-vertebral disc space and shaped into a ring from which the mice were suspended. Vertebral location for the tail-ring was selected to appropriately balance animal body weight without interfering with defecation. We determined the success of this novel HU technique by assessing body weight before and after HU, degree of soleus atrophy, and adrenal mass following HU. Body weight of the mice prior to HU (24.3 ± 2.9g) did not significantly decline immediately after 14d of HU (22.7 ± 1.9g), 28d of HU (21.3 + 2.1g) or after 3 days recovery (24.0 ± 1.8g). Soleus muscle mass significantly declined (-39.1%, and -46.6%) following HU for 14 days and 28 days respectively (p<0.001). Following 3 days of recovery soleus mass significantly increased to 74% of control values. Adrenal weights of HU mice were not different compared to control mice. The success of our novel HU method is evidenced by the maintenance of animal body weight, comparable adrenal gland weights, and soleus atrophy following HU, corresponding to expected literature values. The primary advantages of this HU method include: 1) ease of tail examination during suspension; 2) decreased likelihood of cyanotic, inflamed, and/or necrotic tails frequently observed with tail-taping and HU; 3) no possibility of mice chewing the traction tape and coming out of the suspension

  1. Recovery Effect and Life Prolong Effect of Long Term Low-Dose Rate Irradiation on Type II Diabetes Model Mice

    International Nuclear Information System (INIS)

    Nomura, T.; Makino, N.; Oda, T.; Suzuki, I.; Sakai, K

    2004-01-01

    The effects of low-dose rate gamma-irradiation were investigated on model mice for type II diabetes mellitus, C57BL/KsJ-db/db. The mice develop the type II diabetes by 10 weeks of age due to obesity and are characterized by hyperinsulinemia. Female 10-week old mice, a group of 12 mice, were irradiated at 0.65 mGy/hr from 137-Cs (370 GBq). The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, the decrease in the glucose level was observed in 3 mice. Such recovery from the diabetes was never observed in 12 mice of non-irradiated control group. There is no systematic difference in the change of body weight, food assumption, and amount of drinking water, between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. The survival was better in the irradiated group: the surviving fraction at the age of 90 weeks was 75% in the irradiated group, while 40% in the non-irradiated. Marked difference was also observed in the appearance of the coat hair, skin, and tail; better condition was kept in the irradiated group. In the irradiated mice mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20 ? 30 weeks compared with the non-irradiated mice. These results suggest that the low-dose irradiation modified the condition of the diabetic mice, which lead not only to the recovery of the diabetes, but also to the suppression of the aging process. (Author)

  2. On process model representation and AlF{sub 3} dynamics of aluminium electrolysis cells

    Energy Technology Data Exchange (ETDEWEB)

    Drengstig, Tormod

    1997-12-31

    This thesis develops a formal graphical based process representation scheme for modelling complex, non-standard unit processes. The scheme is based on topological and phenomenological decompositions. The topological decomposition is the modularization of processes into modules representing volumes and boundaries, whereas the phenomenological decomposition focuses on physical phenomena and characteristics inside these topological modules. This defines legal and illegal connections between components at all levels and facilitates a full implementation of the methodology into a computer aided modelling tool that can interpret graphical symbols and guide modelers towards a consistent mathematical model of the process. The thesis also presents new results on the excess AlF{sub 3} and bath temperature dynamics of an aluminium electrolysis cell. A dynamic model of such a cell is developed and validated against known behaviour and real process data. There are dynamics that the model does not capture and this is further discussed. It is hypothesized that long-term prediction of bath temperature and excess AlF{sub 3} is impossible with a current efficiency model considering only bath composition and temperature. A control strategy for excess AlF{sub 3} and bath temperature is proposed based on an almost constant AlF{sub 3} input close to average consumption and energy manipulations to compensate for the disturbances. 96 refs., 135 figs., 22 tabs.

  3. Are Sema5a mutant mice a good model of autism? A behavioral analysis of sensory systems, emotionality and cognition

    Science.gov (United States)

    Gunn, Rhian K.; Huentelman, Matthew J.; Brown, Richard E.

    2011-01-01

    Semaphorin 5A (Sema5A) expression is reduced in the brain of individuals with autism, thus mice with reduced Sema5A levels may serve as a model of this neurodevelopmental disorder. We tested male and female Sema5a knockout mice (B6.129P2SEMA5A/J) and C57BL/6J controls for emotionality, visual ability, prepulse inhibition, motor learning and cognition. Overall, there were only two genotype differences in emotionality: Sema5a mutant mice had more stretch-attend postures in the elevated plus-maze and more defecations in the open field. All mice could see, but Sema5a mice had better visual ability than C57BL/6J mice. There were no genotype differences in sensory-motor gating. Sema5a mice showed higher levels of activity in the elevated plus-maze and light/dark transition box, and there were sex by genotype differences in the Rotarod, suggesting a sex difference in balance and coordination differentially affected by Sema5a. There were no genotype effects on cognition: Sema5a mice did not differ from C57BL/6J in the Morris water maze, set-shifting or cued and contextual fear conditioning. In the social recognition test, all mice preferred social stimuli, but there was no preference for social novelty, thus the Sema5A mice do not have a deficit in social behavior. Overall, there were a number of sex differences, with females showing greater activity and males performing better in tests of spatial learning and memory, but no deficits in the behavior of Sema5A mice. We conclude that the Sema5a mice do not meet the behavioral criteria for a mouse model of autism. PMID:21777623

  4. Generation of a new bioluminescent model for visualisation of mammary tumour development in transgenic mice

    LENUS (Irish Health Repository)

    Zagozdzon, Agnieszka M

    2012-05-30

    AbstractBackgroundNumerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study.ResultsA new mouse strain (MMTV-Luc2 mice) expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal.ConclusionsWe have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and\\/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques.

  5. Generation of a new bioluminescent model for visualisation of mammary tumour development in transgenic mice

    Directory of Open Access Journals (Sweden)

    Zagozdzon Agnieszka M

    2012-05-01

    Full Text Available Abstract Background Numerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study. Results A new mouse strain (MMTV-Luc2 mice expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal. Conclusions We have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques.

  6. Gelam honey attenuates ovalbumin-induced airway inflammation in a mice model of allergic asthma

    Directory of Open Access Journals (Sweden)

    Nur Salme Suhana Shamshuddin

    2018-01-01

    Full Text Available Allergic asthma is a chronic inflammatory disorder of the pulmonary airways. Gelam honey has been proven to possess anti-inflammatory property with great potential to treat an inflammatory condition. However, the effect of ingestion of Gelam honey on allergic asthma has never been studied. This study aimed to investigate the efficacy of Gelam honey on the histopathological changes in the lungs of a mice model of allergic asthma. Forty-two Balb/c mice were divided into seven groups: control, I, II, III, IV, V and VI group. All groups except the control were sensitized and challenged with ovalbumin. Mice in groups I, II, III, IV, and V were given honey at a dose of 10% (v/v, 40% (v/v and 80% (v/v, dexamethasone 3 mg/kg, and phosphate buffered saline (vehicle respectively, orally once a day for 5 days of the challenged period. Mice were sacrificed 24 h after the last OVA challenged and the lungs were evaluated for histopathological changes by light microscopy. All histopathological parameters such as epithelium thickness, the number of mast cell and mucus expression in Group III significantly improved when compared to Group VI except for subepithelial smooth muscle thickness (p < 0.05. In comparing Group III and IV, all the improvements in histopathological parameters were similar. Also, Gelam honey showed a significant (p < 0.05 reduction in inflammatory cell infiltration and beta-hexosaminidase level in bronchoalveolar lavage fluid. In conclusion, we demonstrated that administration of high concentration of Gelam honey alleviates the histopathological changes of mice model of allergic asthma.

  7. Optimization of a Clinically Relevant Model of White Matter Stroke in Mice: Histological and Functional Evidences

    Science.gov (United States)

    Ahmad, Abdullah S.; Satriotomo, Irawan; Fazal, Jawad A.; Nadeau, Stephen E.; Doré, Sylvain

    2015-01-01

    Background and Purpose White matter (WM) injury during stroke increases the risk of disability and gloomy prognosis of post-stroke rehabilitation. However, modeling of WM loss in rodents has proven to be challenging. Methods We report improved WM injury models in male C57BL/6 mice. Mice were given either endothelin-1 (ET-1) or L-N5-(1-iminoethyl)ornitine (L-NIO) into the periventricular white matter (PVWM), in the corpus callosum (CC), or in the posterior limb of internal capsule (PLIC). Anatomical and functional outcomes were quantified on day 7 post injection. Results Injection of ET-1 or L-NIO caused a small focal lesion in the injection site in the PVWM. No significant motor function deficits were observed in the PVWM lesion model. We next targeted the PLIC by using single or double injections of L-NIO and found that this strategy induced small focal infarction. Interestingly, injection of L-NIO in the PLIC also resulted in gliosis, and significant motor function deficits. Conclusions By employing different agents, doses, and locations, this study shows the feasibility of inducing brain WM injury accompanied with functional deficits in mice. Selective targeting of the injury location, behavioral testing, and the agents chosen to induce WM injury are all keys to successfully develop a mouse model and subsequent testing of therapeutic interventions against WM injury. PMID:27512724

  8. Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear.

    Science.gov (United States)

    Xu, Meiyu; Li, Lina; Ohtsu, Hiroshi; Pittenger, Christopher

    2015-05-19

    Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Development of a Murine Model for Aerosolized Ebolavirus Infection Using a Panel of Recombinant Inbred Mice

    Directory of Open Access Journals (Sweden)

    Malak Kotb

    2012-12-01

    Full Text Available Countering aerosolized filovirus infection is a major priority of biodefense research.  Aerosol models of filovirus infection have been developed in knock-out mice, guinea pigs and non-human primates; however, filovirus infection of immunocompetent mice by the aerosol route has not been reported.  A murine model of aerosolized filovirus infection in mice should be useful for screening vaccine candidates and therapies.  In this study, various strains of wild-type and immunocompromised mice were exposed to aerosolized wild-type (WT or mouse-adapted (MA Ebola virus (EBOV.  Upon exposure to aerosolized WT-EBOV, BALB/c, C57BL/6 (B6, and DBA/2 (D2 mice were unaffected, but 100% of severe combined immunodeficiency (SCID and 90% of signal transducers and activators of transcription (Stat1 knock-out (KO mice became moribund between 7–9 days post-exposure (dpe.  Exposure to MA-EBOV caused 15% body weight loss in BALB/c, but all mice recovered.  In contrast, 10–30% lethality was observed in B6 and D2 mice exposed to aerosolized MA-EBOV, and 100% of SCID, Stat1 KO, interferon (IFN-γ KO and Perforin KO mice became moribund between 7–14 dpe. In order to identify wild-type, inbred, mouse strains in which exposure to aerosolized MA-EBOV is uniformly lethal, 60 BXD (C57BL/6 crossed with DBA/2 recombinant inbred (RI and advanced RI (ARI mouse strains were exposed to aerosolized MA-EBOV, and monitored for disease severity. A complete spectrum of disease severity was observed. All BXD strains lost weight but many recovered. However, infection was uniformly lethal within 7 to 12 days post-exposure in five BXD strains.  Aerosol exposure of these five BXD strains to 10-fold less MA-EBOV resulted in lethality ranging from 0% in two strains to 90–100% lethality in two strains.  Analysis of post-mortem tissue from BXD strains that became moribund and were euthanized at the lower dose of MA-EBOV, showed liver damage in all mice as well as lung lesions in

  10. Influence of Asian dust particles on immune adjuvant effects and airway inflammation in asthma model mice.

    Directory of Open Access Journals (Sweden)

    Jun Kurai

    Full Text Available An Asian dust storm (ADS contains airborne particles that affect conditions such as asthma, but the mechanism of exacerbation is unclear. The objective of this study was to compare immune adjuvant effects and airway inflammation induced by airborne particles collected on ADS days and the original ADS soil (CJ-1 soil in asthma model mice.Airborne particles were collected on ADS days in western Japan. NC/Nga mice were co-sensitized by intranasal instillation with ADS airborne particles and/or Dermatophagoides farinae (Df, and with CJ-1 soil and/or Df for 5 consecutive days. Df-sensitized mice were stimulated with Df challenge intranasally at 7 days after the last Df sensitization. At 24 hours after challenge, serum allergen specific antibody, differential leukocyte count and inflammatory cytokines in bronchoalveolar lavage fluid (BALF were measured, and airway inflammation was examined histopathologically.Co-sensitization with ADS airborne particles and Df increased the neutrophil and eosinophil counts in BALF. Augmentation of airway inflammation was also observed in peribronchiolar and perivascular lung areas. Df-specific serum IgE was significantly elevated by ADS airborne particles, but not by CJ-1 soil. Levels of interleukin (IL-5, IL-13, IL-6, and macrophage inflammatory protein-2 were higher in BALF in mice treated with ADS airborne particles.These results suggest that substances attached to ADS airborne particles that are not in the original ADS soil may play important roles in immune adjuvant effects and airway inflammation.

  11. Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

    Directory of Open Access Journals (Sweden)

    Dominic Landgraf

    Full Text Available The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning.

  12. Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.

    Science.gov (United States)

    Landgraf, Dominic; Long, Jaimie; Der-Avakian, Andre; Streets, Margo; Welsh, David K

    2015-01-01

    The state of being helpless is regarded as a central aspect of depression, and therefore the learned helplessness paradigm in rodents is commonly used as an animal model of depression. The term 'learned helplessness' refers to a deficit in escaping from an aversive situation after an animal is exposed to uncontrollable stress specifically, with a control/comparison group having been exposed to an equivalent amount of controllable stress. A key feature of learned helplessness is the transferability of helplessness to different situations, a phenomenon called 'trans-situationality'. However, most studies in mice use learned helplessness protocols in which training and testing occur in the same environment and with the same type of stressor. Consequently, failures to escape may reflect conditioned fear of a particular environment, not a general change of the helpless state of an animal. For mice, there is no established learned helplessness protocol that includes the trans-situationality feature. Here we describe a simple and reliable learned helplessness protocol for mice, in which training and testing are carried out in different environments and with different types of stressors. We show that with our protocol approximately 50% of mice develop learned helplessness that is not attributable to fear conditioning.

  13. Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Bianca De Filippis

    2015-01-01

    Full Text Available Rett syndrome (RTT is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2 cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task. A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

  14. Antipsychotic activity of aqueous ethanolic extract of Tinospora Cordifolia in amphetamine challenged mice model

    Directory of Open Access Journals (Sweden)

    Bindu nee Giri Jain

    2010-01-01

    Full Text Available Tinospora cordifolia is reported to have CNS active principle and is used for the treatment of various neurological disorders. Hence, the effect of aqueous ethanolic extract of Tinospora cordifolia was investigated for its putative antipsychotic activity using amphetamine challenged mice model. Haloperidol (1 mg/kg i.p. was administered acutely to mice as standard drug. Control animals received vehicle (10% DMSO. The in vivo receptor binding studies were carried out to correlate the antipsychotic activity of the extract with its capacity to bind to the DAD2 receptor. The results in SLA showed that the hydro alcoholic extract of the stems of Tinospora cordifolia at a dose level of 250 mg/kg and 500 mg/kg showed no significant antipsychotic activity in amphetamine induced hyperactivity in mice when compared to standard. Extract alone treated group at a dos level of 250 mg/kg and 500 mg/kg showed a decreased in locomotor activity when compared to the control. The plant extract increased the DAD2 receptor binding in a dose dependent manner in treated mice compared to the control group.

  15. Development of an in vivo model of Chlamydia abortus chronic infection in mice overexpressing IL-10.

    Science.gov (United States)

    Del Río, Laura; Murcia, Antonio; Buendía, Antonio J; Álvarez, Daniel; Ortega, Nieves; Navarro, José A; Salinas, Jesús; Caro, María Rosa

    2018-01-01

    Chlamydia abortus, like other members of the family Chlamydiaceae, have a unique intracellular developmental cycle that is characterized by its chronic nature. Infection of a flock can remain undetected for months, until abortion occurs the following reproductive season but, to date, neither the location nor the mechanisms that maintain this latent phase are fully understood. Studies have shown that IL-10 produced as a response to certain micro-organisms sustains the intracellular survival of pathogens and increases host susceptibility to chlamydial infections. In order to induce a sustained infection C. abortus, transgenic mice that constitutively express IL-10 were infected and the immunological mechanisms that maintain infection in these mice were compared with the mechanisms of a resistant wild-type mouse strain. Viable bacteria could be detected in different tissues of transgenic mice up to 28 days after infection, as analysed by bacterial isolation and immunohistochemistry. Chronic infection in these mice was associated with an impaired recruitment of macrophages, decreased iNOS activity at the site of infection and a more diffuse distribution of inflammatory cells in the liver. This murine model can be of great help for understanding the immunological and bacterial mechanisms that lead to chronic chlamydial infections. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. An experimental model for the study of cognitive disorders: the hippocampus and associative learning in mice.

    Science.gov (United States)

    Delgado-García, José M; Gruart, Agnès

    2008-12-01

    The availability of transgenic mice mimicking selective human neurodegenerative and psychiatric disorders calls for new electrophysiological and microstimulation techniques capable of being applied in vivo in this species. In this article, we will concentrate on experiments and techniques developed in our laboratory during the past few years. Thus we have developed different techniques for the study of learning and memory capabilities of wild-type and transgenic mice with deficits in cognitive functions, using classical conditioning procedures. These techniques include different trace (tone/SHOCK and shock/SHOCK) conditioning procedures ? that is, a classical conditioning task involving the cerebral cortex, including the hippocampus. We have also developed implantation and recording techniques for evoking long-term potentiation (LTP) in behaving mice and for recording the evolution of field excitatory postsynaptic potentials (fEPSP) evoked in the hippocampal CA1 area by the electrical stimulation of the commissural/Schaffer collateral pathway across conditioning sessions. Computer programs have also been developed to quantify the appearance and evolution of eyelid conditioned responses and the slope of evoked fEPSPs. According to the present results, the in vivo recording of the electrical activity of selected hippocampal sites during classical conditioning of eyelid responses appears to be a suitable experimental procedure for studying learning capabilities in genetically modified mice, and an excellent model for the study of selected neuropsychiatric disorders compromising cerebral cortex functioning.

  17. Methanol Extract of Euchelus asper Prevents Bone Resorption in Ovariectomised Mice Model

    Directory of Open Access Journals (Sweden)

    Babita Balakrishnan

    2014-01-01

    Full Text Available Marine molluscs are widely distributed throughout the world and many bioactive compounds exhibiting antiviral, antitumor, antileukemic, and antibacterial activity have been reported worldwide. The present study was designed to investigate the beneficial effect of methanol extract of Euchelus asper (EAME on estrogen deficiency induced osteoporosis in ovariectomised mice model. Forty-two female Swiss albino mice were randomly assigned into Sham operated (Sham group and six ovariectomised (OVX subgroups such as OVX with vehicle (OVX; OVX with estradiol (2 mg/kg/day; OVX with EAME of graded doses (25, 50, 100, and 200 mg/kg/day. Bone turnover markers like serum alkaline phosphatase (ALP, serum acid phosphatase (ACP, serum calcium, and histological investigations of tibia and uterus were analysed. Metaphyseal DNA content of the femur bone was also studied. Antiosteoclastogenic activity of EAME was examined. Administration of EAME was able to reduce the increased bone turnover markers in the ovariectomised mice. Histomorphometric analysis revealed an increase in bone trabeculation and restoration of trabecular separation by EAME treatment. Metaphyseal DNA content of the femur of the OVX mice was increased by EAME administration. EAME also showed a potent antiosteoclastogenic behaviour. Thus, the present study reveals that EAME was able to successfully reduce the estrogen deficiency induced bone loss.

  18. Modelling Eutectic Growth in Unmodified and Modified Near-Eutectic Al-Si Alloy

    DEFF Research Database (Denmark)

    Tiedje, Niels Skat; Hattel, Jesper Henri; Taylor, John A.

    2013-01-01

    growth parameters from the literature that depend on the type of modification (unmodified, Na-modified or Sr-modified) are used to describe differences in growth of the alloys. Modelling results are compared with solidification experiments where an Al-12.5wt%Si alloy was cast in unmodified, Na modified......A numerical model that describes solidification of primary aluminium grains and nucleation and growth of eutectic cells is used to analyse the solidification of an Al-12.5wt% Si alloy. Nucleation of eutectic cells is modelled using an Oldfield-type nucleation model where the number of nuclei...... and Sr modified forms. The model confirms experimental observations of how modification and alloy composition influence nucleation, growth and finally the size of eutectic cells in the alloys. Modelling results are used to explain how cooling conditions in the casting act together with the nuclei density...

  19. Effect of harmane on the convulsive threshold in epilepsy models in mice.

    Science.gov (United States)

    Aricioglu, Feyza; Yillar, Okan; Korcegez, Eylem; Berkman, Kemal

    2003-12-01

    The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC(50)) values or MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose-dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.

  20. Nb3Al insert experiment log book. 3rd experiment of CS model coil

    International Nuclear Information System (INIS)

    Sugimoto, Makoto; Koizumi, Norikiyo; Isono, Takaaki

    2002-10-01

    The cool down of CS model coil and Nb 3 Al insert was started on March 4, 2002. It took almost one month and immediately started coil charge since April 3, 2002. The charge test of Nb 3 Al insert and CS model coil was completed on May 2, 2002. All of the experiments including the warm up was also completed on May 30, 2002. In this campaign, total shot numbers were 102 and the size of the data file in the DAS (Data Acquisition System) was about 5.2 GB. This report is a database that consists of the log list and the log sheets of every shot. (author)

  1. A simple localized-itinerant model for PrAl3: crystal field and exchange effects

    International Nuclear Information System (INIS)

    Ranke, P.J. von; Palermo, L.

    1990-01-01

    We present a simple magnetic model for PrAl sub(3). The effects of crystal field are treated using a reduced set of levels and the corresponding wave functions are extracted from the actual crystal field levels of Pr sup(+3) in a hexagonal symmetry. The exchange between 4f- and conduction electrons are dealt within a molecular field approximation. An analytical magnetic state equation is derived and the magnetic behaviour discussed. The parameters of the model are estimated from a fitting of the inverse susceptibility of PrAl sub(3) given in the literature. (author)

  2. Experimental investigation and thermodynamic modeling of the Ni-Al-Ru ternary system

    International Nuclear Information System (INIS)

    Zhu, J.; Zhang, C.; Cao, W.; Yang, Y.; Zhang, F.; Chen, S.; Morgan, D.; Chang, Y.A.

    2009-01-01

    In this study, a thermodynamic description of the Ni-Al-Ru system was obtained in terms of experimental phase equilibrium data as well as first-principles-calculated energetics. The calculated isotherms and liquidus projection using this description are in accord with the experimental data obtained in the present study as well as those previously reported in the literature, and the model-calculated enthalpies of formation agree with subsequent first-principles-calculated values. During the thermodynamic modeling of the Ni-Al-Ru system, we encountered great challenges initially to account for one of the experimentally determined isotherms reported in the literature. To reconcile these discrepancies, additional experiments were carried out and the results obtained supported the phase equilibrium data reported in the literature. The model-calculated enthalpies agree with subsequent first-principles-calculated values. The approach adopted in this study using phase equilibrium data of Ni-Al-Ru and the descriptions of Ni-Al and Ni-Ru to identify errors in the enthalpy of AlRu could be a general tool that could be used for other systems

  3. Data Modeling, Feature Extraction, and Classification of Magnetic and EMI Data, ESTCP Discrimination Study, Camp Sibert, AL. Demonstration Report

    Science.gov (United States)

    2008-09-01

    Figure 19. Misfit versus depth curve for the EM63 Pasion -Oldenburg model fit to anomaly 649. Two cases are considered: (i) using all the data which...selection of optimal models; c) Fitting of 2- and 3-dipole Pasion -Oldenburg models to the EM63 cued- interrogation data and selection of optimal models...Hart et al., 2001; Collins et al., 2001; Pasion & Oldenburg, 2001; Zhang et al., 2003a, 2003b; Billings, 2004). The most promising discrimination

  4. Effect of Qing Nao tablet on blood stasis model of mice

    Science.gov (United States)

    Kong, Xuejun; Hao, Shaojun; Wang, Hongyu; Liu, Xiaobin; Xie, Guoqi; Li, Wenjun; Zhang, Zhengchen

    2018-04-01

    To investigate the effect of Qing Nao tablet on mouse model of blood stasis syndrome, 60 mice, male and female, were randomly divided into 6 groups, were fed with large, small doses of Qing Nao tablet suspension, Naoluotong saline suspension and the same volume (group 2, 0.1ml/10g), administer 1 times daily, orally for 15 days. Intragastric administration for first days, in addition to the 1 group saline group every day in the hind leg intramuscular saline, the other 5 groups each rat day hind leg muscle injection of dexamethasone 0.8mg/kg intramuscular injection every day, 1 times, 15 days. 1 hour continuous intramuscular injection and intramuscular drug perfusion on the sixteenth day after mice. The eyeball blood, heparin after whole blood viscosity test. Compared with the control group, model group, high and low shear viscosity were significantly increased (Pgroup, high dose group and Qing Nao tablet Naoluotong group can significantly reduce the viscosity at high shear and (Pgroup can significantly reduce high shear and shear viscosity (Pgroup can significantly reduce the low shear viscosity (Pgroup can significantly reduce the low shear viscosity (Pgroup were lower high cut, low shear viscosity and trend The potential (P>0.05). The Qing Nao tablet has a good effect on the model of blood stasis in mice.

  5. A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model.

    Directory of Open Access Journals (Sweden)

    Kazunori Tanaka

    Full Text Available Amyotrophic lateral sclerosis (ALS is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methylamino]-N-[4-(pyridin-2-yl-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316 selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP and NF-E2-related factor 2 (Nrf2 which governed glutathione (GSH-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1-100 µg/kg/day WN1316 in ALS(SOD1(H46R and ALS(SOD1(G93A mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1β and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris. Thus, WN1316 would be a novel therapeutic agent for ALS.

  6. High Temperature Mechanical Constitutive Modeling of a High-Nb TiAl Alloy

    Directory of Open Access Journals (Sweden)

    DONG Chengli

    2018-02-01

    Full Text Available Uniaxial tensile, low cycle fatigue, fatigue-creep interaction and creep experiments of a novel high-Nb TiAl alloy (i.e. Ti-45Al-8Nb-0.2W-0.2B-0.02Y (atom fraction/% were conducted at 750℃ to obtain its tested data and curves. Based on Chaboche visco-plasticity unified constitutive model, Ohno-Wang modified non-linear kinematic hardening was introduced in Chaboche constitutive model to describe the cyclic hardening/softening, and Kachanov damage was coupled in Chaboche constitutive model to characterize the accelerated creep stage. The differential equations of the constitutive model discretized by explicit Euler method were compiled in to ABAQUS/UMAT to simulate the mechanical behavior of high-Nb TiAl alloy at different test conditions. The results show that Chaboche visco-plasticity unified constitutive model considering both Ohno-Wang modified non-linear kinematic hardening and Kachanov damage is able to simulate the uniaxial tensile, low cycle fatigue, fatigue-creep interaction and creep behavior of high-Nb TiAl alloy and has high accuracy.

  7. Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression.

    Science.gov (United States)

    Tortarolo, Massimo; Vallarola, Antonio; Lidonnici, Dario; Battaglia, Elisa; Gensano, Francesco; Spaltro, Gabriella; Fiordaliso, Fabio; Corbelli, Alessandro; Garetto, Stefano; Martini, Elisa; Pasetto, Laura; Kallikourdis, Marinos; Bonetto, Valentina; Bendotti, Caterina

    2015-10-01

    Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2-/- mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology. We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co-cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1-G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi-intervention therapies. © 2015 International Society for Neurochemistry.

  8. Aerobic Exercise Decreases Lung Inflammation by IgE Decrement in an OVA Mice Model.

    Science.gov (United States)

    Camargo Hizume-Kunzler, Deborah; Greiffo, Flavia R; Fortkamp, Bárbara; Ribeiro Freitas, Gabriel; Keller Nascimento, Juliana; Regina Bruggemann, Thayse; Melo Avila, Leonardo; Perini, Adenir; Bobinski, Franciane; Duarte Silva, Morgana; Rocha Lapa, Fernanda; Paula Vieira, Rodolfo; Vargas Horewicz, Verônica; Soares Dos Santos, Adair Roberto; Cattelan Bonorino, Kelly

    2017-06-01

    Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p<0.05), total IgE, IL-4 and IL-5 lung levels and OVA-specific IgE and IgG1 titers (p<0.05). There was an increase of NOS-2 expression, IL-10 and IL-1ra lung levels in the OVA groups (p<0.05). Our results showed that AE attenuated the acute lung inflammation, suggesting immunomodulatory properties on the sensitization process in the early phases of antigen presentation in asthma. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Immunomodulation Effects of Bryophyllum Pinnatum on Pregnant Pristane-Induced Lupus Mice Model

    Directory of Open Access Journals (Sweden)

    Nurdiana Nurdiana

    2017-03-01

    Full Text Available Objective: To determine the effect of Bryophyllum pinnatum treatment in modulating immune response and the pregnancy outcomes of pregnant pristane-induced lupus mice model. Methods: Sixteen Balb/c mice were intraperitoneally injected with single 0.5 cc pristane to induce lupus manifestations. After 12 weeks of injection, mice were mated and considered as gestational day 0 (GD0. Mice were divided into 4 groups based on the dosages of Bryophyllum pinnatum: control (no treatment, B1 (10.5 mg/kg, B2 (21 mg/kg, and B3 (42 mg/kg. The treatment was given orally every day started from GD9 until 9 days. At the end of the study, blood pressure and fetal size were measured. Serum anti-dsDNA and urine albumin levels were measured by ELISA. Spleen T helper (Th and mature B cells percentages were measured by flow cytometry. Results: Administration of Bryophyllum pinnatum reduced the percentages of Th1 (p=0.006, Th2 (p=0.005, Th17 (p=0.000, and mature B cells (p=0.007 in dose-dependent manner. B1 and B2 had significantly lower of systolic blood pressure compared to control (p=0.026 and p=0.022 respectively. Significantly lower of anti-dsDNA levels were found in B1 group compared to control (p=0.014. However, no significantly different of urine albumin levels were found between groups. Bryophyllum pinnatum also significantly increased the fetus body weight in dose-dependent manner (p=0.000. Conclusion: Treatment of Bryophyllum pinnatum could improve the pregnancy outcome and modulate the immune response in pregnant pristane-induced lupus mice. Therefore, Bryophyllum pinnatum is a potential herb which can be developed as an immunosuppressive agent in the future.

  10. Spdef null mice lack conjunctival goblet cells and provide a model of dry eye.

    Science.gov (United States)

    Marko, Christina K; Menon, Balaraj B; Chen, Gang; Whitsett, Jeffrey A; Clevers, Hans; Gipson, Ilene K

    2013-07-01

    Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef(-/-) mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef(-/-) mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef(-/-) mice revealed down-regulation of goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef(-/-) mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. RECONSTRUCTION OF 3D VECTOR MODELS OF BUILDINGS BY COMBINATION OF ALS, TLS AND VLS DATA

    Directory of Open Access Journals (Sweden)

    H. Boulaassal

    2012-09-01

    Full Text Available Airborne Laser Scanning (ALS, Terrestrial Laser Scanning (TLS and Vehicle based Laser Scanning (VLS are widely used as data acquisition methods for 3D building modelling. ALS data is often used to generate, among others, roof models. TLS data has proven its effectiveness in the geometric reconstruction of building façades. Although the operating algorithms used in the processing chain of these two kinds of data are quite similar, their combination should be more investigated. This study explores the possibility of combining ALS and TLS data for simultaneously producing 3D building models from bird point of view and pedestrian point of view. The geometric accuracy of roofs and façades models is different due to the acquisition techniques. In order to take these differences into account, the surfaces composing roofs and façades are extracted with the same algorithm of segmentation. Nevertheless the segmentation algorithm must be adapted to the properties of the different point clouds. It is based on the RANSAC algorithm, but has been applied in a sequential way in order to extract all potential planar clusters from airborne and terrestrial datasets. Surfaces are fitted to planar clusters, allowing edge detection and reconstruction of vector polygons. Models resulting from TLS data are obviously more accurate than those generated from ALS data. Therefore, the geometry of the roofs is corrected and adapted according to the geometry of the corresponding façades. Finally, the effects of the differences between raw ALS and TLS data on the results of the modeling process are analyzed. It is shown that such combination could be used to produce reliable 3D building models.

  12. Modeling a failure criterion for U-Mo/Al dispersion fuel

    Science.gov (United States)

    Oh, Jae-Yong; Kim, Yeon Soo; Tahk, Young-Wook; Kim, Hyun-Jung; Kong, Eui-Hyun; Yim, Jeong-Sik

    2016-05-01

    The breakaway swelling in U-Mo/Al dispersion fuel is known to be caused by large pore formation enhanced by interaction layer (IL) growth between fuel particles and Al matrix. In this study, a critical IL thickness was defined as a criterion for the formation of a large pore in U-Mo/Al dispersion fuel. Specifically, the critical IL thickness is given when two neighboring fuel particles come into contact with each other in the developed IL. The model was verified using the irradiation data from the RERTR tests and KOMO-4 test. The model application to full-sized sample irradiations such as IRISs, FUTURE, E-FUTURE, and AFIP-1 tests resulted in conservative predictions. The parametric study revealed that the fuel particle size and the homogeneity of the fuel particle distribution are influential for fuel performance.

  13. Thermodynamic modeling of the Al-U and Co-U systems

    International Nuclear Information System (INIS)

    Wang, J.; Liu, X.J.; Wang, C.P.

    2008-01-01

    The thermodynamic assessments of the Al-U and Co-U systems have been carried out by using the CALPHAD (Calculation of Phase Diagrams) method on the basis of the experimental data including thermodynamic properties and phase equilibria. Gibbs free energies of the solution phases were described by the subregular solution models with the Redlich-Kister equation, and those of the intermetallic compounds described by the sublattice models. A consistent set of thermodynamic parameters has been derived for describing the Gibbs free energies of each solution phase and intermetallic compounds in the Al-U and Co-U binary systems. The calculated phase diagrams and thermodynamic properties in the Al-U and Co-U systems are in good agreement with experimental data

  14. Modeling a failure criterion for U–Mo/Al dispersion fuel

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Jae-Yong, E-mail: tylor@kaeri.re.kr [Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon 305-353 (Korea, Republic of); Kim, Yeon Soo [Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439 (United States); Tahk, Young-Wook; Kim, Hyun-Jung; Kong, Eui-Hyun; Yim, Jeong-Sik [Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon 305-353 (Korea, Republic of)

    2016-05-15

    The breakaway swelling in U–Mo/Al dispersion fuel is known to be caused by large pore formation enhanced by interaction layer (IL) growth between fuel particles and Al matrix. In this study, a critical IL thickness was defined as a criterion for the formation of a large pore in U–Mo/Al dispersion fuel. Specifically, the critical IL thickness is given when two neighboring fuel particles come into contact with each other in the developed IL. The model was verified using the irradiation data from the RERTR tests and KOMO-4 test. The model application to full-sized sample irradiations such as IRISs, FUTURE, E-FUTURE, and AFIP-1 tests resulted in conservative predictions. The parametric study revealed that the fuel particle size and the homogeneity of the fuel particle distribution are influential for fuel performance.

  15. Development of a molecular dynamic based cohesive zone model for prediction of an equivalent material behavior for Al/Al2O3 composite

    Energy Technology Data Exchange (ETDEWEB)

    Sazgar, A. [Center of Excellence in Design, Robotics and Automation, Department of Mechanical Engineering, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Movahhedy, M.R., E-mail: movahhed@sharif.edu [Center of Excellence in Design, Robotics and Automation, Department of Mechanical Engineering, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Mahnama, M. [School of Mechanical Engineering, University of Tehran, Tehran (Iran, Islamic Republic of); Sohrabpour, S. [Center of Excellence in Design, Robotics and Automation, Department of Mechanical Engineering, Sharif University of Technology, Tehran (Iran, Islamic Republic of)

    2017-01-02

    The interfacial behavior of composites is often simulated using a cohesive zone model (CZM). In this approach, a traction-separation (T-S) relation between the matrix and reinforcement particles, which is often obtained from experimental results, is employed. However, since the determination of this relation from experimental results is difficult, the molecular dynamics (MD) simulation may be used as a virtual environment to obtain this relation. In this study, MD simulations under the normal and shear loadings are used to obtain the interface behavior of Al/Al2O3 composite material and to derive the T-S relation. For better agreement with Al/Al2O3 interfacial behavior, the exponential form of the T-S relation suggested by Needleman [1] is modified to account for thermal effects. The MD results are employed to develop a parameterized cohesive zone model which is implemented in a finite element model of the matrix-particle interactions. Stress-strain curves obtained from simulations under different loading conditions and volume fractions show a close correlation with experimental results. Finally, by studying the effects of strain rate and volume fraction of particles in Al(6061-T6)/Al2O3 composite, an equivalent homogeneous model is introduced which can predict the overall behavior of the composite.

  16. FEM modeling on the compaction of Fe and Al composite powders

    Directory of Open Access Journals (Sweden)

    Han P.

    2015-01-01

    Full Text Available The compaction process of Fe and Al composite powders subjected to single action die compaction was numerically modeled by FEM method. The relationship between the overall relative density and compaction pressure of the compacts with various Al contents was firstly identified, and the influences of Al content on the local relative density, stress, and their distributions were studied. Then the compaction pressure effects on the above properties with fixed Al content were discussed. Furthermore, detailed flow behaviors of the composite powders during compaction and the relationship between the compaction pressure and the ejection force/spring back of the compact were analyzed. The results show that: (1 With each compaction pressure, higher relative density can be realized with the increase of Al content and the relative density distribution tends to be uniform; (2 When the Al content is fixed, higher compaction pressure can lead to composite compact with higher relative density, and the equivalent Von Mises stress in the central part of the compact increases gradually; (3 Convective flow occurs at the top and bottom parts of the compact close to the die wall, each indicates a different flow behavior; (4 The larger the compaction pressure for each case, the higher the residual elasticity, and the larger the ejection force needed.

  17. Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.

    Directory of Open Access Journals (Sweden)

    Young-Eun Yoo

    Full Text Available Amyotrophic lateral sclerosis (ALS is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT, which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

  18. An improved EEHEMT model for kink effect on AlGaN/GaN HEMT

    International Nuclear Information System (INIS)

    Cao Meng-Yi; Lu Yang; Chen Yong-He; Zheng Jia-Xin; Ma Xiao-Hua; Hao Yue; Wei Jia-Xing; Li Wei-Jun

    2014-01-01

    In this paper, a new current expression based on both the direct currect (DC) characteristics of the AlGaN/GaN high election mobility transistor (HEMT) and the hyperbolic tangent function tanh is proposed, by which we can describe the kink effect of the AlGaN/GaN HEMT well. Then, an improved EEHEMT model including the proposed current expression is presented. The simulated and measured results of I–V, S-parameter, and radio frequency (RF) large-signal characteristics are compared for a self-developed on-wafer AlGaN/GaN HEMT with ten gate fingers each being 0.4-μm long and 125-μm wide (Such an AlGaN/GaN HEMT is denoted as AlGaN/GaN HEMT (10 × 125 μm)). The improved large signal model simulates the I–V characteristic much more accurately than the original one, and its transconductance and RF characteristics are also in excellent agreement with the measured data. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  19. Salivary Gland Dysplasia in Fgf10 Heterozygous Mice: A New Mouse Model of Xerostomia

    Science.gov (United States)

    May, A.J.; Chatzeli, L.; Proctor, G.B.; Tucker, A.S.

    2017-01-01

    Xerostomia, or chronic dry mouth, is a common syndrome caused by a lack of saliva that can lead to severe eating difficulties, dental caries and oral candida infections. The prevalence of xerostomia increases with age and affects approximately 30% of people aged 65 or older. Given the large numbers of sufferers, and the potential increase in incidence given our aging population, it is important to understand the complex mechanisms that drive hyposalivation and the consequences for the dentition and oral mucosa. From this study we propose the Fgf10 +/- mouse as a model to investigate xerostomia. By following embryonic salivary gland development, in vivo and in vitro, we show that a reduction in Fgf10 causes a delay in branching of salivary glands. This leads to hypoplasia of the glands, a phenotype that is not rescued postnatally or by adulthood in both male and female Fgf10 +/- mice. Histological analysis of the glands showed no obvious defect in cellular differentiation or acini/ductal arrangements, however there was a significant reduction in their size and weight. Analysis of saliva secretion showed that hypoplasia of the glands led to a significant reduction in saliva production in Fgf10 +/- adults, giving rise to a reduced saliva pellicle in the oral cavity of these mice. Mature mice were shown to drink more and in many cases had severe tooth wear. The Fgf10 +/- mouse is therefore a useful model to explore the causes and effects of xerostomia. PMID:26321752

  20. Subcutaneous infection model facilitates treatment assessment of secondary Alveolar echinococcosis in mice.

    Directory of Open Access Journals (Sweden)

    Tatiana Küster

    Full Text Available Alveolar echinococcosis (AE in humans is a parasitic disease characterized by severe damage to the liver and occasionally other organs. AE is caused by infection with the metacestode (larval stage of the fox tapeworm Echinococcus multilocularis, usually infecting small rodents as natural intermediate hosts. Conventionally, human AE is chemotherapeutically treated with mebendazole or albendazole. There is, however still the need for improved chemotherapeutical options. Primary in vivo studies on drugs of interest are commonly performed in small laboratory animals such as mice and Mongolian jirds, and in most cases, a secondary infection model is used, whereby E. multilocularis metacestodes are directly injected into the peritoneal cavity or into the liver. Disadvantages of this methodological approach include risk of injury to organs during the inoculation and, most notably, a limitation in the macroscopic (visible assessment of treatment efficacy. Thus, in order to monitor the efficacy of chemotherapeutical treatment, animals have to be euthanized and the parasite tissue dissected. In the present study, mice were infected with E. multilocularis metacestodes through the subcutaneous route and were then subjected to chemotherapy employing albendazole. Serological responses to infection were comparatively assessed in mice infected by the conventional intraperitoneal route. We demonstrate that the subcutaneous infection model for secondary AE facilitates the assessment of the progress of infection and drug treatment in the live animal.

  1. Regulatory T cell activity in immunosuppresive mice model of pseudomonas aeruginosa pneumonia.

    Science.gov (United States)

    Li, Jun-Lu; Chen, Ting-Sang; Yuan, Cong-Cong; Zhao, Guo-Qiang; Xu, Min; Li, Xiao-Yan; Cao, Jie; Xing, Li-Hua

    2017-08-01

    Pseudomonas aeruginosa (PA) pneumonia is a refractory, even lethal complication in immunosuppressive individuals and immune disturbances may promote the pathological process. We aimed to investigate the regulatory T (Treg) cell activity in an immunosuppressive mice model of PA pneumonia by estimating levels of main transcription factor and the main effector of Treg cells, i.e., Forkhead box protein 3 (FOXP3) and interleukine-10 (IL-10). Seventy-two BALB/c mice were divided into four groups randomly: control (A), PA pneumonia (B), immunosuppression (C) and immunosuppression with PA pneumonia (D). Mice were sacrificed at 4, 8 and 24 h after establishing experimental models. The pathological changes of lung tissue were graded, and the FOXP3 mRNA and serum IL-10 levels were detected. Histological analysis of lung tissues showed there were no significantly pathological changes in groups A and C, but significantly pathological changes were found in groups B and D, especially in group D at 8 h (Ppneumonia in immunosuppressive individuals worsens rapidly, which may be associated with Treg cells function disturbance. And Treg cells may be promising as adjuvant therapeutics for PA pneumonia in immunosuppressive individuals.

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

    International Nuclear Information System (INIS)

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

    2004-01-01

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

  3. Salivary Gland Dysplasia in Fgf10 Heterozygous Mice: A New Mouse Model of Xerostomia.

    Science.gov (United States)

    May, A J; Chatzeli, L; Proctor, G B; Tucker, A S

    2015-01-01

    Xerostomia, or chronic dry mouth, is a common syndrome caused by a lack of saliva that can lead to severe eating difficulties, dental caries and oral candida infections. The prevalence of xerostomia increases with age and affects approximately 30% of people aged 65 or older. Given the large numbers of sufferers, and the potential increase in incidence given our aging population, it is important to understand the complex mechanisms that drive hyposalivation and the consequences for the dentition and oral mucosa. From this study we propose the Fgf10 +/- mouse as a model to investigate xerostomia. By following embryonic salivary gland development, in vivo and in vitro, we show that a reduction in Fgf10 causes a delay in branching of salivary glands. This leads to hypoplasia of the glands, a phenotype that is not rescued postnatally or by adulthood in both male and female Fgf10 +/- mice. Histological analysis of the glands showed no obvious defect in cellular differentiation or acini/ductal arrangements, however there was a significant reduction in their size and weight. Analysis of saliva secretion showed that hypoplasia of the glands led to a significant reduction in saliva production in Fgf10 +/- adults, giving rise to a reduced saliva pellicle in the oral cavity of these mice. Mature mice were shown to drink more and in many cases had severe tooth wear. The Fgf10 +/- mouse is therefore a useful model to explore the causes and effects of xerostomia.

  4. FMR1 Knockout mice: A model to study fragile X mental retardation

    Energy Technology Data Exchange (ETDEWEB)

    Oostra, B.A.; Bakker, C.E.; Reyniers, E. [Erasmus Univ., Rotterdam (Netherlands)] [and others

    1994-09-01

    The fragile X syndrome is the most frequent form of inherited mental retardation in humans with an incidence of 1 in 1250 males and 1 in 2500 females. The clinical syndrome includes moderate to severe mental retardation, autistic behavior, macroorchidism, and facial features, such as long face with mandibular prognathism and large, everted ears. The molecular basis for this disease is a large expansion of a triplet repeat (CGG){sub n} in the 5{prime} untranslated region of the FMR1 gene. Due to this large expansion of the CGG repeat, the promoter region becomes methylated and the FMR1 gene is subsequently silenced. Hardly anything is known about the physiologic function of FMR1 and the pathologic mechanisms leading to these symptoms. Since the FMR1 gene is highly conserved in the mouse, we used the mouse to design a knockout model for the fragile X syndrome. These knockout mice lacking Fmrp have normal litter size suggesting that FMR1 is not essential in human gametogenesis and embryonic development. The knockout mice show the abnormalities also seen in the affected organs of human patients. Mutant mice show a gradual development through time of macroorchidism. In the knockout mice we observed cognitive defects in the form of deficits in learning (as shown by the hidden platform Morris water maze task) and behavioral abnormalities such as increased exploratory behavior and hyperactivity. Therefore this knockout mouse may serve as a valuable tool in studying the role of FMR1 in the fragile X syndrome and may serve as a model to elucidate the mechanisms involved in macroorchidism, abnormal behavior, and mental retardation.

  5. eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

    Science.gov (United States)

    Yasvoina, Marina V.

    Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons

  6. Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL.

    Directory of Open Access Journals (Sweden)

    Lu Dai

    Full Text Available Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL, which arises preferentially in the setting of infection with human immunodeficiency virus (HIV. Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.

  7. Dose-response models for the radiation-induction of skin tumours in mice

    International Nuclear Information System (INIS)

    Papworth, D.G.; Hulse, E.V.

    1983-01-01

    Extensive data on radiation-induced skin tumours in mice were examined using 8 models, all based on the concept that incidences of radiation-induced tumours depend on a combination of two radiation effects: a tumour induction process and the loss of reproductive integrity by the potential tumour cells. Models with and without a threshold were used, in spite of theoretical objections to threshold models. No model fitted well both the epidermal and the dermal tumour data and models which proved to be statistically satisfactory for some of the data were rejected for biological reasons. It is concluded that, for skin tumours, dose-response curves depending on a combination of cancer induction and loss of cellular reproductive integrity are distorted by some special, relatively radio-resistant, factor which we have previously postulated as being involved in radiation skin carcinogenesis. (author)

  8. Acute Phase Response and Neutrophils : Lymphocyte Ratio in Response to Astaxanthin in Staphylococcal Mice Mastitis Model

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    Tshering Dolma

    2014-01-01

    Full Text Available The purpose of the study was to determine the immunotherapeutic effect of astaxanthin (AX on total clinical score (TCS, C-reactive protein (CRP, and neutrophil : lymphocyte ratio in mice mastitis model challenged with pathogenic Staphylococcus aureus. Twenty-four lactating mice were divided in 4 equal groups: group I mice served as normal healthy control, group II, positive control, were challenged with pathogenic S. aureus, group III mice were challenged and treated with AX, and group IV were treated with amoxicillin plus sulbactum. The TCS was higher in postchallenged mice; however it was significantly higher in group II untreated mice as compared to group III and group IV mice. The neutrophil was higher and lymphocyte count was lower in group II mice at 120 hrs post challenge (PC. The CRP was positive in all the challenged group at 24 hrs PC, but it remained positive till 120 hrs PC in group II. The parameters are related to enhancement of the mammary defense and reduction of inflammation. Hence AX may be used alone or as an adjunct therapy with antibiotic for amelioration of mastitis. Development of such therapy may be useful to reduce the antibiotic burden in management of intramammary infection.

  9. Effects of Moxibustion Temperature on Blood Cholesterol Level in a Mice Model of Acute Hyperlipidemia: Role of TRPV1

    Directory of Open Access Journals (Sweden)

    Gui-Ying Wang

    2013-01-01

    Full Text Available Objectives. To compare the effects of moxibustion at two different temperatures (38°C and 46°C on the blood cholesterol level in a mice model of acute hyperlipidemia, to detect the different expression levels of transient receptor potential vanilloid subfamily 1 (TRPV1 in the dorsal root ganglions of the wild mice, and to explore the correlation between TRPV1 and moxibustion’s cholesterol-lowering effects. Method. Two different mice models were used: C57BL/6J wild type (WT and TRPV1 gene knockout (TRPV1−/−. Each model was randomly divided into control group and model group with three subgroups after acute hyperlipidemia was established: model control group, 38°C moxibustion group, and 46°C moxibustion group. The mice in 38°C group and 46°C group were subject to moxibustion. After the therapy, the cholesterol concentration in serum was measured, and the expression of TRPV1 was quantified. Results. In WT mice, moxibustion caused a decrease in blood cholesterol level and upregulation of TRPV1 at the mRNA level, which was significantly greater in the 46°C group. In contrast, in TRPV1−/− mice, the differences of cholesterol-lowering effects of moxibustion were lost. Conclusions. Temperature is one of the important factors affecting the effects of moxibustion, and the cholesterol -lowering effect of moxibustion is related to the activation of TRPV1.

  10. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Emond, Claude, E-mail: claude.emond@umontreal.ca [BioSimulation Consulting Inc., Newark, DE (United States); Departments of Environmental and Occupational Health, Medicine Faculty, University of Montreal, Montreal, Quebec (Canada); Sanders, J. Michael, E-mail: sander10@mail.nih.gov [National Cancer Institute, Research Triangle Park, NC (United States); Wikoff, Daniele, E-mail: dwikoff@toxstrategies.com [ToxStrategies, Austin, TX (United States); Birnbaum, Linda S., E-mail: birnbaumls@niehs.nih.gov [National Cancer Institute, Research Triangle Park, NC (United States)

    2013-12-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.

  11. Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model.

    Science.gov (United States)

    Wang, Meng; Yan, Shi-Ju; Zhang, Hong-Tao; Li, Nan; Liu, Tao; Zhang, Ying-Long; Li, Xiao-Xiang; Ma, Qiong; Qiu, Xiu-Chun; Fan, Qing-Yu; Ma, Bao-An

    2017-02-01

    The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma.

  12. A Model of Left Ventricular Dysfunction Complicated by CAWS Arteritis in DBA/2 Mice

    Directory of Open Access Journals (Sweden)

    Naoto Hirata

    2012-01-01

    Full Text Available It was reported previously that a Candida albicans water-soluble fraction (CAWS, including a mannoprotein and β-glucan complex, has strong potency in inducing fatal necrotizing arteritis in DBA/2 mice. In this study, histopathological changes and cardiac function were investigated in this system. One mg/day of CAWS was given to DBA/2 mice via peritoneal injection for five days. The CAWS-treated DBA/2 mice were induced aortitis and died at an incidence of 100% within several weeks. Histological findings included stenosis in the left ventricular outflow tract (LVOT and severe inflammatory changes of the aortic valve with fibrinoid necrosis. Cardiomegaly was observed and heart weight increased 1.62 fold (<0.01. Echocardiography revealed a severe reduction in contractility and dilatation of the cavity in the left ventricle (LV: LV fractional shortening (LVFS decreased from 71% to 38% (<0.01, and the LV end-diastolic diameter (LVDd increased from 2.21 mm to 3.26 mm (<0.01. The titer of BNP mRNA increased in the CAWS-treated group. Severe inflammatory changes resulting from CAWS brought about lethal LV dysfunction by aortic valve deformation with LVOT stenosis. This system is proposed as an easy and useful experimental model of heart failure because CAWS arteritis can be induced by CAWS injection alone.

  13. Comparative study of two models of combined pulmonary fibrosis and emphysema in mice.

    Science.gov (United States)

    Zhang, Wan-Guang; Wu, Si-Si; He, Li; Yang, Qun; Feng, Yi-Kuan; Chen, Yue-Tao; Zhen, Guo-Hua; Xu, Yong-Jian; Zhang, Zhen-Xiang; Zhao, Jian-Ping; Zhang, Hui-Lan

    2017-04-01

    Combined pulmonary fibrosis and emphysema (CPFE) is an "umbrella term" encompassing emphysema and pulmonary fibrosis, but its pathogenesis is not known. We established two models of CPFE in mice using tracheal instillation with bleomycin (BLM) or murine gammaherpesvirus 68 (MHV-68). Experimental mice were divided randomly into four groups: A (normal control, n=6), B (emphysema, n=6), C (emphysema+MHV-68, n=24), D (emphysema+BLM, n=6). Group C was subdivided into four groups: C1 (sacrificed on day 367, 7 days after tracheal instillation of MHV-68); C2 (day 374; 14days); C3 (day 381; 21days); C4 (day 388; 28days). Conspicuous emphysema and interstitial fibrosis were observed in BLM and MHV-68 CPFE mouse models. However, BLM induced diffuse pulmonary interstitial fibrosis with severely diffuse pulmonary inflammation; MHV-68 induced relatively modest inflammation and fibrosis, and the inflammation and fibrosis were not diffuse, but instead around bronchioles. Inflammation and fibrosis were detectable in the day-7 subgroup and reached a peak in the day-28 subgroup in the emphysema + MHV-68 group. Levels of macrophage chemoattractant protein-1, macrophage inflammatory protein-1α, interleukin-13, and transforming growth factor-β1 in bronchoalveolar lavage fluid were increased significantly in both models. Percentage of apoptotic type-2 lung epithelial cells was significantly higher; however, all four types of cytokine and number of macrophages were significantly lower in the emphysema+MHV-68 group compared with the emphysema +BLM group. The different changes in pathology between BLM and MHV-68 mice models demonstrated different pathology subtypes of CPFE: macrophage infiltration and apoptosis of type-II lung epithelial cells increased with increasing pathology score for pulmonary fibrosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

  14. ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.

    Science.gov (United States)

    Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C; Chen, Adam; Tamrazian, Eric; Babaniyi, Olusegun; Selig, Martin; Hynynen, Meri; Woolf, Clifford J; Brown, Robert H

    2014-01-28

    ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

  15. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

    Science.gov (United States)

    Kirman, C R; Suh, M; Proctor, D M; Hays, S M

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Safety Analysis Report for Packaging (SARP): USA/9507/BLF (ERDA--AL), Model AL-M1

    International Nuclear Information System (INIS)

    Watkins, R.A.; Bertram, R.E.; Blauvelt, R.K.; Edling, D.A.; Flanagan, T.M.; Griffin, J.F.; Rhinehammer, T.B.

    1977-01-01

    The SARP includes structural integrity, thermal resistance, radiation shielding and radiological safety, nuclear criticality safety, and quality control of three insulated drum shipping containers identified as USA/9507/BLF (ERDA-AL), also called AL-M1, configurations 1, 3, and 5. Complete physical and technical descriptions of the packages are presented. Each package consists of an inner container centered within an insulated steel drum. The contents are plutonium-239 and uranium-235 in configurations-1 and -3. The configuration-5 package is intended for shipment of up to 100,000 Ci of tritiated water immobilized on a sorbent such as molecular sieve

  17. Protective effect of atorvastatin on d-galactose-induced aging model in mice.

    Science.gov (United States)

    Kaviani, Elham; Rahmani, Mohammadreza; Kaeidi, Ayat; Shamsizadeh, Ali; Allahtavakoli, Mohamad; Mozafari, Nazanin; Fatemi, Iman

    2017-09-15

    Atorvastatin (Ator), competitive inhibitors of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, is a cholesterol lowering drug. Ator has been shown to have neuroprotective, antioxidant and anti-inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. Here we assessed the effect of Ator on the d-galactose (d-gal)-induced aging in mice. For this purpose, Ator (0.1 and 1mg/kg/p.o.), was administrated daily in d-gal-received (500mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behaviors and cognitive functions were evaluated by the elevated plus-maze and novel object recognition tasks, respectively. Physical power was assessed by forced swimming capacity test. Animals brains were analyzed for the superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). We found that Ator decreases the anxiety-like behaviors in d-gal-treated mice. Also, our behavioral tests showed that Ator reverses the d-gal induced learning and memory impairment. Furthermore, we found that Ator increases the physical power of d-gal-treated mice. Our results indicated that the neuroprotective effect of Ator on d-gal induced neurotoxicity is mediated, at least in part, by an increase in the SOD and BDNF levels. The results of present study suggest that Ator could be used as a novel therapeutic strategy for the treatment of age-related conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice.

    Directory of Open Access Journals (Sweden)

    Fuminori Odagiri

    Full Text Available Inherited dilated cardiomyopathy (DCM is characterized by dilatation and dysfunction of the ventricles, and often results in sudden death or heart failure (HF. Although angiotensin receptor blockers (ARBs have been used for the treatment of HF, little is known about the effects on postulated electrical remodeling that occurs in inherited DCM. The aim of this study was to examine the effects of candesartan, one of the ARBs, on cardiac function and electrical remodeling in the hearts of inherited DCM model mice (TNNT2 ΔK210. DCM mice were treated with candesartan in drinking water for 2 months from 1 month of age. Control, non-treated DCM mice showed an enlargement of the heart with prolongation of QRS and QT intervals, and died at t1/2 of 70 days. Candesartan dramatically extended the lifespan of DCM mice, suppressed cardiac dilatation, and improved the functional parameters of the myocardium. It also greatly suppressed prolongation of QRS and QT intervals and action potential duration (APD in the left ventricular myocardium and occurrence of ventricular arrhythmia. Expression analysis revealed that down-regulation of Kv4.2 (Ito channel protein, KChIP2 (auxiliary subunit of Kv4.2, and Kv1.5 (IKur channel protein in DCM was partially reversed by candesartan administration. Interestingly, non-treated DCM heart had both normal-sized myocytes with moderately decreased Ito and IKur and enlarged cells with greatly reduced K+ currents (Ito, IKur IK1 and Iss. Treatment with candesartan completely abrogated the emergence of the enlarged cells but did not reverse the Ito, and IKur in normal-sized cells in DCM hearts. Our results indicate that candesartan treatment suppresses structural remodeling to prevent severe electrical remodeling in inherited DCM.

  19. Animal models of physiologic markers of male reproduction: genetically defined infertile mice

    Energy Technology Data Exchange (ETDEWEB)

    Chubb, C.

    1987-10-01

    The present report focuses on novel animal models of male infertility: genetically defined mice bearing single-gene mutations that induce infertility. The primary goal of the investigations was to identify the reproductive defects in these mutant mice. The phenotypic effects of the gene mutations were deciphered by comparing the mutant mice to their normal siblings. Initially testicular steroidogenesis and spermatogenesis were investigated. The physiologic markers for testicular steroidogenesis were steroid secretion by testes perifused in vitro, seminal vesicle weight, and Leydig cell histology. Spermatogenesis was evaluated by the enumeration of homogenization-resistant sperm/spermatids in testes and by morphometric analyses of germ cells in the seminiferous epithelium. If testicular function appeared normal, the authors investigated the sexual behavior of the mice. The parameters of male sexual behavior that were quantified included mount patency, mount frequency, intromission latency, thrusts per intromission, ejaculation latency, and ejaculation duration. Females of pairs breeding under normal circumstances were monitored for the presence of vaginal plugs and pregnancies. The patency of the ejaculatory process was determined by quantifying sperm in the female reproductive tract after sexual behavior tests. Sperm function was studied by quantitatively determining sperm motility during videomicroscopic observation. Also, the ability of epididymal sperm to function within the uterine environment was analyzed by determining sperm capacity to initiate pregnancy after artificial insemination. Together, the experimental results permitted the grouping of the gene mutations into three general categories. They propose that the same biological markers used in the reported studies can be implemented in the assessment of the impact that environmental toxins may have on male reproduction.

  20. Protective Effect of Anthocyanins Extract from Blueberry on TNBS-Induced IBD Model of Mice

    Directory of Open Access Journals (Sweden)

    Lin-Hua Wu

    2011-01-01

    Full Text Available This study was carried out to evaluate the protective effect of anthocyanins extract of blueberry on trinitrobenzene sulfonic acid (TNBS-induced inflammatory bowel disease (IBD model of mice. The study employed female C57BL/6 mice (n = 50, and colitis was induced by intracolonic injection of 0.5 mg of TNBS dissolved in 50% ethanol–phosphate buffered solution. The mice were divided into five groups (n = 10: vehicle, TNBS control and anthocyanins groups that received different doses of anthocyanins extract (10, 20 and 40 mg kg-1 daily for 6 days. Both increase in body weight and diarrhea symptoms were monitored each day. After 6 days, the animals were killed, and the following parameters were assessed: colon length, morphological score, histological score and biochemical assay (NO, myeloperoxidase (MPO, interleukin (IL-12, IL-10, tumor necrosis factor (TNF-α and interferon (IFN-γ. The results showed that the anthocyanins extract of blueberry rendered strong protection against TNBS-induced colonic damage at a dosage of 40 mg kg-1. When compared with the control, anthocyanins extract significantly prevented loss of body weight and ameliorated the scores of diarrhea, morphology and histology. Treatment with anthocyanins extract restored IL-10 excretion, as well as caused reduction in the levels of NO, MPO, IL-12, TNF-α and IFN-γ. Our research revealed the protective effect of anthocyanins extract from blueberry on TNBS-induced experimental colitis in mice, as well as examined whether high levels of dietary blueberries would lower the risk or have protective effects on human IBD, which may require further investigation.

  1. Mucuna pruriens reduces inducible nitric oxide synthase expression in Parkinsonian mice model.

    Science.gov (United States)

    Yadav, Satyndra Kumar; Rai, Sachchida Nand; Singh, Surya Pratap

    2017-03-01

    Parkinson's disease is one of the most common neurodegenerative disease found in aged peoples. Plentiful studies are being conducted to find a suitable and effective cure for this disease giving special impetus on use of herbal plants. The study aimed at investigating the effect of ethanolic extract of Mucuna pruriens (Mp) on level of nitric oxide (NO) in paraquat (PQ) induced Parkinson's disease (PD) mouse model and its subsequent contribution to lipid peroxidation. Twenty four Swiss albino mice were divided into three groups; Control, PQ and PQ+Mp. PQ doses were given intraperitoneally, twice in a week and oral dose of ethanolic extract of Mp seed was given for 9 weeks. Nitrite content and lipid peroxidation was measured in all treated groups along with respective controls. RNA was isolated from the nigrostriatal tissue of control and the treated mice and was reverse transcribed into cDNA. PCR was performed to amplify iNOS mRNA and western blot analysis was performed to check its protein level. We had also perfused the mice in all treated group and performed Tyrosine hydroxylase (TH) and iNOS immunoreactivity in substantia nigra region of mice brain. PQ-treatment increased nitrite content, expression of iNOS and lipid peroxidation compared to respective controls. Mp treatment resulted in a significant attenuation of iNOS expression, nitrite content and lipid peroxidation demonstrating that it reduces nitric oxide in PQ-induced Parkinson's disease. Interestingly; we also observed that mRNA, protein expression and immunoreactivity of iNOS was significantly decreased after Mp treatment and TH immunoreactivity was significantly improved after the treatment of Mp. Our results demonstrated that Mp protects the dopaminergic neurons from the NO injury in substantia nigra. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. 125I-β-CIT imaging study of striatal dopamine transporters in mice model of parkinsonism

    International Nuclear Information System (INIS)

    Liu Zhenguo; Sun Wenshan; Weng Zhongfang; Chen Shengdi; Shen Minghua; Zhu Chengmo

    2001-01-01

    Objective: To detect the activity of striatal dopamine transporters (DAT) in lesions of different order of severity of MPTP-induced mice model of parkinsonism by autoradiography with 125 I-β-CIT and to evaluate the clinical use of the β-CIT imaging for DAT detection. Methods: With regard to the different duration (days) of MPTP treatment, the C57BL mice were randomly divided into 5 groups, that is MPTP 1, 3, 5 and 7 day groups and control group treated with normal saline instead of MPTP. Two hours after intravenous administration with 125 I-β-CIT of 148 kBq, the brain tissue sections were imaged by autoradiography. The levels of dopamine (DA) and its metabolites were measured by high performance liquid chromatography and electrochemical detection (HPLC-ECD). The tyrosine hydroxylase (TH)-positive cells and fibres in the substantia nigra and striatum of the mice were observed by means of immunohistochemical technique. Results: As compared with control group, the radioactivity ratios of striatum to cortex (ST/CX) in 4 MPTP-treated groups were significantly reduced, by 20%, 42%, 45% and 52%, respectively. The concentrations of DA in the striatum of 4 MPTP-treated groups were remarkably decreased, by 47%, 75%, 95% and 95%, respectively. The gradual loss of DA neurons and fibres in the substantia nigra and striatum in 4 MPTP-treated groups was observed under microscopy. Conclusions: The functional abnormality of DAT paralleled the changes observed in neurochemistry and neuropathology studies in the lesions of different order of injury of the MPTP-treated mice. The β-CIT scanning for the activity of DAT may be useful for diagnosing PD at earlier phase and for monitoring the progression of the disease

  3. A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice.

    Science.gov (United States)

    Schirm, Sibylle; Ahnert, Peter; Wienhold, Sandra; Mueller-Redetzky, Holger; Nouailles-Kursar, Geraldine; Loeffler, Markus; Witzenrath, Martin; Scholz, Markus

    2016-01-01

    Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future.

  4. Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions.

    Science.gov (United States)

    Pittenger, Christopher

    2017-01-01

    While the normal functions of histamine (HA) in the central nervous system have gradually come into focus over the past 30 years, the relationship of abnormalities in neurotransmitter HA to human disease has been slower to emerge. New insight came with the 2010 description of a rare nonsense mutation in the biosynthetic enzyme histidine decarboxylase (Hdc) that was associated with Tourette syndrome (TS) and related conditions in a single family pedigree. Subsequent genetic work has provided further support for abnormalities of HA signaling in sporadic TS. As a result of this genetic work, Hdc knockout mice, which were generated more than 15 years ago, have been reexamined as a model of the pathophysiology of TS and related conditions. Parallel work in these KO mice and in human carriers of the Hdc mutation has revealed abnormalities in the basal ganglia system and its modulation by dopamine (DA) and has confirmed the etiologic, face, and predictive validity of the model. The Hdc-KO model thus serves as a unique platform to probe the pathophysiology of TS and related conditions, and to generate specific hypotheses for subsequent testing in humans. This chapter summarizes the development and validation of this model and recent and ongoing work using it to further investigate pathophysiological changes that may contribute to these disorders.

  5. Specificity of anti-tau antibodies when analyzing mice models of Alzheimer's disease: problems and solutions.

    Directory of Open Access Journals (Sweden)

    Franck R Petry

    Full Text Available Aggregates of hyperphosphorylated tau protein are found in a group of diseases called tauopathies, which includes Alzheimer's disease. The causes and consequences of tau hyperphosphorylation are routinely investigated in laboratory animals. Mice are the models of choice as they are easily amenable to transgenic technology; consequently, their tau phosphorylation levels are frequently monitored by Western blotting using a panel of monoclonal/polyclonal anti-tau antibodies. Given that mouse secondary antibodies can recognize endogenous mouse immunoglobulins (Igs and the possible lack of specificity with some polyclonal antibodies, non-specific signals are commonly observed. Here, we characterized the profiles of commonly used anti-tau antibodies in four different mouse models: non-transgenic mice, tau knock-out (TKO mice, 3xTg-AD mice, and hypothermic mice, the latter a positive control for tau hyperphosphorylation. We identified 3 tau monoclonal antibody categories: type 1, characterized by high non-specificity (AT8, AT180, MC1, MC6, TG-3, type 2, demonstrating low non-specificity (AT270, CP13, CP27, Tau12, TG5, and type 3, with no non-specific signal (DA9, PHF-1, Tau1, Tau46. For polyclonal anti-tau antibodies, some displayed non-specificity (pS262, pS409 while others did not (pS199, pT205, pS396, pS404, pS422, A0024. With monoclonal antibodies, most of the interfering signal was due to endogenous Igs and could be eliminated by different techniques: i using secondary antibodies designed to bind only non-denatured Igs, ii preparation of a heat-stable fraction, iii clearing Igs from the homogenates, and iv using secondary antibodies that only bind the light chain of Igs. All of these techniques removed the non-specific signal; however, the first and the last methods were easier and more reliable. Overall, our study demonstrates a high risk of artefactual signal when performing Western blotting with routinely used anti-tau antibodies, and proposes

  6. Multiscale modeling of θ' precipitation in Al-Cu binary alloys

    International Nuclear Information System (INIS)

    Vaithyanathan, V.; Wolverton, C.; Chen, L.Q.

    2004-01-01

    We present a multiscale model for studying the growth and coarsening of θ' precipitates in Al-Cu alloys. Our approach utilizes a novel combination of the mesoscale phase-field method with atomistic approaches such as first-principles total energy and linear response calculations, as well as a mixed-space cluster expansion coupled with Monte Carlo simulations. We give quantitative first-principles predictions of: (i) bulk energetics of the Al-Cu solid solution and θ ' precipitate phases, (ii) interfacial energies of the coherent and semi-coherent θ ' /Al interfaces, and (iii) stress-free misfit strains and coherency strain energies of the θ ' /Al system. These first-principles data comprise all the necessary energetic information to construct our phase-field model of microstructural evolution. Using our multiscale approach, we elucidate the effects of various energetic contributions on the equilibrium shape of θ ' precipitates, finding that both the elastic energy and interfacial energy anisotropy contributions play critical roles in determining the aspect ratio of θ ' precipitates. Additionally, we have performed a quantitative study of the morphology of two-dimensional multi-precipitate microstructures during growth and coarsening, and compared the calculated results with experimentally observed morphologies. Our multiscale first-principles/phase-field method is completely general and should therefore be applicable to a wide variety of problems in microstructural evolution

  7. Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS

    Science.gov (United States)

    De Rose, Francescaelena; Marotta, Roberto; Talani, Giuseppe; Catelani, Tiziano; Solari, Paolo; Poddighe, Simone; Borghero, Giuseppe; Marrosu, Francesco; Sanna, Enrico; Kasture, Sanjay; Acquas, Elio; Liscia, Anna

    2017-01-01

    The present study was aimed at characterizing the effects of Withania somnifera (Wse) and Mucuna pruriens (Mpe) on a Drosophila melanogaster model for Amyotrophic Lateral Sclerosis (ALS). In particular, the effects of Wse and Mpe were assessed following feeding the flies selectively overexpressing the wild human copper, zinc-superoxide dismutase (hSOD1-gain-of-function) in Drosophila motoneurons. Although ALS-hSOD1 mutants showed no impairment in life span, with respect to GAL4 controls, the results revealed impairment of climbing behaviour, muscle electrophysiological parameters (latency and amplitude of ePSPs) as well as thoracic ganglia mitochondrial functions. Interestingly, Wse treatment significantly increased lifespan of hSDO1 while Mpe had not effect. Conversely, both Wse and Mpe significantly rescued climbing impairment, and also latency and amplitude of ePSPs as well as failure responses to high frequency DLM stimulation. Finally, mitochondrial alterations were any more present in Wse- but not in Mpe-treated hSOD1 mutants. Hence, given the role of inflammation in the development of ALS, the high translational impact of the model, the known anti-inflammatory properties of these extracts, and the viability of their clinical use, these results suggest that the application of Wse and Mpe might represent a valuable pharmacological strategy to counteract the progression of ALS and related symptoms. PMID:28102336

  8. High performance W-AlN cermet solar coatings designed by modelling calculations and deposited by DC magnetron sputtering

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qi-Chu [School of Physics, The University of Sydney, Sydney, NSW 2006 (Australia); Shen, Y.G. [Department of Manufacturing Engineering and Engineering Management, City University of Hong Kong (Hong Kong)

    2004-01-25

    High solar performance W-AlN cermet solar coatings were designed using a numerical computer model and deposited experimentally. In the numerical calculations aluminium oxynitride (AlON) was used as ceramic component. The dielectric function and then complex refractive index of W-AlON cermet materials were calculated using the Sheng's approximation. The layer thickness and W metal volume fraction were optimised to achieve maximum photo-thermal conversion efficiency for W-AlON cermet solar coatings on an Al reflector with a surface AlON ceramic anti-reflection layer. Optimisation calculations show that the W-AlON cermet solar coatings with two and three cermet layers have nearly identical solar absorptance, emittance and photo-thermal conversion efficiency that are much better than those for films with one cermet layer. The optimised calculated AlON/W-AlON/Al solar coating film with two cermet layers has a high solar absorptance of 0.953 and a low hemispherical emittance of 0.051 at 80C for a concentration factor of 2. The AlN/W-AlN/Al solar selective coatings with two cermet layers were deposited using two metal target direct current magnetron sputtering technology. During the deposition of W-AlN cermet layer, both Al and W targets were run simultaneously in a gas mixture of argon and nitrogen. By substrate rotation a multi-sub-layer system consisting of alternating AlN ceramic and W metallic sub-layers was deposited that can be considered as a macro-homogeneous W-AlN cermet layer. A solar absorptance of 0.955 and nearly normal emittance of 0.056 at 80C have been achieved for deposited W-AlN cermet solar coatings.

  9. Role of green tea on nicotine toxicity on liver and lung of mice ...

    African Journals Online (AJOL)

    DR_Mohsen

    2012-01-26

    Jan 26, 2012 ... formation of lipid peroxidative products (Zhen et al.,. 2007). Antioxidant .... mg/kg green tea for three weeks showing normal lung structure with ..... injury in experimental model of carrageenan induced pleurisy in mice. Resp.

  10. Postactivation depression of the Ia EPSP in motoneurons is reduced in both the G127X SOD1 model of amyotrophic lateral sclerosis and in aged mice

    DEFF Research Database (Denmark)

    Hedegaard, Anne; Lehnhoff, Janna; Moldovan, Mihai

    2015-01-01

    Post Activation Depression (PActD) of Ia afferent EPSPs in spinal motoneurons results in a long lasting depression of the stretch reflex. PActD is of clinical interest as it has been shown to be reduced in a number of spastic disorders. Using in vivo intracellular recordings of Ia EPSPs in adult...... mice, we demonstrate that PActD in adult (100-220 days) C57BL/6J mice is both qualitatively and quantitatively similar to that which has been observed in larger animals with respect to both magnitude (approximately 20% depression of EPSPs at 0.5 ms after a stimuli train) and time course (returning...... Sclerosis (ALS). Using the G127X SOD1 mutant mouse, an ALS model with a prolonged asymptomatic phase and fulminant symptom onset, we observed that PActD is significantly reduced at both pre-symptomatic (16% depression) and symptomatic (17.3% depression) time points compared to aged-matched controls (22...

  11. Assessment of antidiarrhoeal activity of the methanol extract of Xylocarpus granatum bark in mice model.

    Science.gov (United States)

    Rouf, Razina; Uddin, Shaikh Jamal; Shilpi, Jamil Ahmad; Alamgir, Mahiuddin

    2007-02-12

    The methanol extract of Xylocarpus granatum bark was studied for its antidiarrhoeal properties in experimental diarrhoea, induced by castor oil and magnesium sulphate in mice. At the doses of 250 and 500 mg/kg per oral, the methanol extract showed significant and dose-dependent antidiarrhoeal activity in both models. The extracts also significantly reduced the intestinal transit in charcoal meal test when compared to atropine sulphate (5 mg/kg; i.m.). The results showed that the extracts of Xylocarpus granatum bark have a significant antidiarrhoeal activity and supports its traditional uses in herbal medicine.

  12. Derivation of potential model for LiAlO2 by simple and effective optimization of model parameters

    International Nuclear Information System (INIS)

    Tsuchihira, H.; Oda, T.; Tanaka, S.

    2009-01-01

    Interatomic potentials of LiAlO 2 were constructed by a simple and effective method. In this method, the model function consists of multiple inverse polynomial functions with an exponential truncation function, and parameters in the potential model can be optimized as a solution of simultaneous linear equations. Potential energies obtained by ab initio calculation are used as fitting targets for model parameter optimization. Lattice constants, elastic properties, defect-formation energy, thermal expansions and the melting point were calculated under the constructed potential models. The results showed good agreement with experimental values and ab initio calculation results, which underscores the validity of the presented method.

  13. A bone metastases model of anaplastic thyroid carcinoma in athymic nude mice

    International Nuclear Information System (INIS)

    Zhang, L.; Wang, H.; Liang, S.; Ma, C.

    2015-01-01

    Anaplastic thyroid carcinoma (ATC), an aggressive form of thyroid cancer, represents less than 2% of all thyroid cancers. The survival of patients with ATC remains low especially when accompanied with bone metastasis. This study aims to establish a reproducible animal model of bone metastasis of ATC which may be useful for further research on novel treatment strategy. Eight 6-8 week old female athymic nude mice were randomly selected. ATC cell line ARO cells were injected into the left ventricular cavity of each mouse respectively. Each mouse was imaged using a dedicated small-animal PET/CT scanner after successful injection of [18F]-FDG under deep anesthesia. Pathological examination was carried out to confirm the bone metastases of ATC. Histopathology established ATC bone metastases in five nude mice’s tibia. Similarly, PET image displayed significantly increased radioactivity (P<0.01) in the established bone metastasis compared with the control normal tibia. Both micro-PET/CT and histomorphometric measurement confirmed the bone metastases model of ATC in nude mice by left ventricular cavity injection of ARO cell line. The bone metastases model of ATC will thus facilitate the understanding of its pathogenesis and aid in the development of novel therapies.

  14. Modeling and measurement of the ALS U5 undulator end magnetic structures

    International Nuclear Information System (INIS)

    Humphries, D.; Halbach, K.; Hoyer, E.; Kincaid, B.; Marks, S.; Schlueter, R.

    1993-05-01

    The end structures for the ALS U5.0 undulators utilize a system of dual permanent magnet rotors intended to establish gap independent field performance. They may also be used for tuning of the first and second magnetic field integrals of these devices. The behavior of these structures has been studied by means of a two dimensional modeling with the POISSON Group of computer codes. A parametric study of the magnetic field distribution and first and second integrals of the fields has been conducted. In parallel, magnetic measurements of the final completed structures have been performed using an automated Hall probe measurement system. Results of the modeling and measurements are compared. Implications for tuning of the ends of the devices within the context of the electron beam parameters of the ALS are discussed

  15. Incorporating imperfect detection into joint models of communites: A response to Warton et al.

    Science.gov (United States)

    Beissinger, Steven R.; Iknayan, Kelly J.; Guillera-Arroita, Gurutzeta; Zipkin, Elise; Dorazio, Robert; Royle, Andy; Kery, Marc

    2016-01-01

    Warton et al. [1] advance community ecology by describing a statistical framework that can jointly model abundances (or distributions) across many taxa to quantify how community properties respond to environmental variables. This framework specifies the effects of both measured and unmeasured (latent) variables on the abundance (or occurrence) of each species. Latent variables are random effects that capture the effects of both missing environmental predictors and correlations in parameter values among different species. As presented in Warton et al., however, the joint modeling framework fails to account for the common problem of detection or measurement errors that always accompany field sampling of abundance or occupancy, and are well known to obscure species- and community-level inferences.

  16. Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics.

    Science.gov (United States)

    Sanoh, Seigo; Ohta, Shigeru

    2014-03-01

    Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics (PK) between animals and humans have to be taken into account in interpreting the results. Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P450 (P450) and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver (h-chimeric mice), generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans, using both in vitro and in vivo approaches. The expression of human-specific metabolic enzymes and metabolic activities was confirmed in humanized liver of h-chimeric mice with high replacement ratios, and several reports indicate that the profiles of P450 and non-P450 metabolism in these mice adequately reflect those in humans. Further, the combined use of h-chimeric mice and r-chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism. Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans, although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice. In addition, fresh h-hepatocytes can be isolated reproducibly from h-chimeric mice for metabolic studies. Copyright © 2013 John Wiley & Sons, Ltd.

  17. Of Mice and Men: Empirical Support for the Population-Based Social Epistasis Amplification Model (a Comment on ).

    Science.gov (United States)

    Sarraf, Matthew Alexandar; Woodley Of Menie, Michael Anthony

    2017-01-01

    This commentary article offers new perspective on recent research investigating the behavioral and social ecological effects of a mutation related to autism spectrum disorders in mice. The authors explain the consistency of this research on mice with predictions advanced by a theory of the role of mutations in altering interorganismal gene-gene interactions (social epistasis) in social species including humans, known as the social epistasis amplification model. The potential significance of the mouse research for understanding contemporary human behavioral trends is explored.

  18. A shorter and more specific oral sensitization-based experimental model of food allergy in mice.

    Science.gov (United States)

    Bailón, Elvira; Cueto-Sola, Margarita; Utrilla, Pilar; Rodríguez-Ruiz, Judith; Garrido-Mesa, Natividad; Zarzuelo, Antonio; Xaus, Jordi; Gálvez, Julio; Comalada, Mònica

    2012-07-31

    Cow's milk protein allergy (CMPA) is one of the most prevalent human food-borne allergies, particularly in children. Experimental animal models have become critical tools with which to perform research on new therapeutic approaches and on the molecular mechanisms involved. However, oral food allergen sensitization in mice requires several weeks and is usually associated with unspecific immune responses. To overcome these inconveniences, we have developed a new food allergy model that takes only two weeks while retaining the main characters of allergic response to food antigens. The new model is characterized by oral sensitization of weaned Balb/c mice with 5 doses of purified cow's milk protein (CMP) plus cholera toxin (CT) for only two weeks and posterior challenge with an intraperitoneal administration of the allergen at the end of the sensitization period. In parallel, we studied a conventional protocol that lasts for seven weeks, and also the non-specific effects exerted by CT in both protocols. The shorter protocol achieves a similar clinical score as the original food allergy model without macroscopically affecting gut morphology or physiology. Moreover, the shorter protocol caused an increased IL-4 production and a more selective antigen-specific IgG1 response. Finally, the extended CT administration during the sensitization period of the conventional protocol is responsible for the exacerbated immune response observed in that model. Therefore, the new model presented here allows a reduction not only in experimental time but also in the number of animals required per experiment while maintaining the features of conventional allergy models. We propose that the new protocol reported will contribute to advancing allergy research. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. A simple magnetic model for intermetallics of rare earths: application to PrAl2

    International Nuclear Information System (INIS)

    Ranke, P.J. von; Palermo, L.; Silva, X.A. da.

    1990-01-01

    A simplified description of crystal field for rare earth ion systems, taking in account the first two energy levels is presented. The Hamiltonian is constructed using wave functions of these levels and, the equation of magnetic state is derived. The model is applied to PrAl 2 using experimental data of magnetization versus temperature. The parameters of magnetic behaviour at T = OK and T = T c are analysed. (M.C.K.)

  20. Topological model of austenite-martensite interfaces in Cu-Al-Ni alloy

    Czech Academy of Sciences Publication Activity Database

    Ostapovets, Andriy; Zárubová, Niva; Paidar, Václav

    2012-01-01

    Roč. 122, č. 3 (2012), s. 493-496 ISSN 0587-4246. [International Symposium on Physics of Materials, ISPMA /12./. Praha, 04.09.2011-08.09.2011] R&D Projects: GA AV ČR IAA100100920 Institutional research plan: CEZ:AV0Z10100520 Keywords : CuAlNi * alloy * experimental data * in-situ * topological models * transmission electron microscopy Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 0.531, year: 2012

  1. Analysis of mice tumor models using dynamic MRI data and a dedicated software platform

    Energy Technology Data Exchange (ETDEWEB)

    Alfke, H.; Maurer, E.; Klose, K.J. [Philipps Univ. Marburg (Germany). Dept. of Radiology; Kohle, S.; Rascher-Friesenhausen, R.; Behrens, S.; Peitgen, H.O. [MeVis - Center for Medical Diagnostic Systems and Visualization, Bremen (Germany); Celik, I. [Philipps Univ. Marburg (Germany). Inst. for Theoretical Surgery; Heverhagen, J.T. [Philipps Univ. Marburg (Germany). Dept. of Radiology; Ohio State Univ., Columbus (United States). Dept. of Radiology

    2004-09-01

    Purpose: To implement a software platform (DynaVision) dedicated to analyze data from functional imaging of tumors with different mathematical approaches, and to test the software platform in pancreatic carcinoma xenografts in mice with severe combined immunodeficiency disease (SCID). Materials and Methods: A software program was developed for extraction and visualization of tissue perfusion parameters from dynamic contrast-enhanced images. This includes regional parameter calculation from enhancement curves, parametric images (e.g., blood flow), animation, 3D visualization, two-compartment modeling a mode for comparing different datasets (e.g., therapy monitoring), and motion correction. We analyzed xenograft tumors from two pancreatic carcinoma cell lines (B x PC3 and ASPC1) implanted in 14 SCID mice after injection of Gd-DTPA into the tail vein. These data were correlated with histopathological findings. Results: Image analysis was completed in approximately 15 minutes per data set. The possibility of drawing and editing ROIs within the whole data set makes it easy to obtain quantitative data from the intensity-time curves. In one animal, motion artifacts reduced the image quality to a greater extent but data analysis was still possible after motion correction. Dynamic MRI of mice tumor models revealed a highly heterogeneous distribution of the contrast-enhancement curves and derived parameters, which correlated with differences in histopathology. ASPc1 tumors showed a more hypervascular type of curves with faster and higher signal enhancement rate (wash-in) and a faster signal decrease (wash-out). BXPC3 tumors showed a more hypovascular type with slower wash-in and wash-out. This correlated with the biological properties of the tumors. (orig.)

  2. Analysis of mice tumor models using dynamic MRI data and a dedicated software platform

    International Nuclear Information System (INIS)

    Alfke, H.; Maurer, E.; Klose, K.J.; Celik, I.; Heverhagen, J.T.; Ohio State Univ., Columbus

    2004-01-01

    Purpose: To implement a software platform (DynaVision) dedicated to analyze data from functional imaging of tumors with different mathematical approaches, and to test the software platform in pancreatic carcinoma xenografts in mice with severe combined immunodeficiency disease (SCID). Materials and Methods: A software program was developed for extraction and visualization of tissue perfusion parameters from dynamic contrast-enhanced images. This includes regional parameter calculation from enhancement curves, parametric images (e.g., blood flow), animation, 3D visualization, two-compartment modeling a mode for comparing different datasets (e.g., therapy monitoring), and motion correction. We analyzed xenograft tumors from two pancreatic carcinoma cell lines (B x PC3 and ASPC1) implanted in 14 SCID mice after injection of Gd-DTPA into the tail vein. These data were correlated with histopathological findings. Results: Image analysis was completed in approximately 15 minutes per data set. The possibility of drawing and editing ROIs within the whole data set makes it easy to obtain quantitative data from the intensity-time curves. In one animal, motion artifacts reduced the image quality to a greater extent but data analysis was still possible after motion correction. Dynamic MRI of mice tumor models revealed a highly heterogeneous distribution of the contrast-enhancement curves and derived parameters, which correlated with differences in histopathology. ASPc1 tumors showed a more hypervascular type of curves with faster and higher signal enhancement rate (wash-in) and a faster signal decrease (wash-out). BXPC3 tumors showed a more hypovascular type with slower wash-in and wash-out. This correlated with the biological properties of the tumors. (orig.)

  3. Novel model of a AlGaN/GaN high electron mobility transistor based on an artificial neural network

    Science.gov (United States)

    Cheng, Zhi-Qun; Hu, Sha; Liu, Jun; Zhang, Qi-Jun

    2011-03-01

    In this paper we present a novel approach to modeling AlGaN/GaN high electron mobility transistor (HEMT) with an artificial neural network (ANN). The AlGaN/GaN HEMT device structure and its fabrication process are described. The circuit-based Neuro-space mapping (neuro-SM) technique is studied in detail. The EEHEMT model is implemented according to the measurement results of the designed device, which serves as a coarse model. An ANN is proposed to model AlGaN/GaN HEMT based on the coarse model. Its optimization is performed. The simulation results from the model are compared with the measurement results. It is shown that the simulation results obtained from the ANN model of AlGaN/GaN HEMT are more accurate than those obtained from the EEHEMT model. Project supported by the National Natural Science Foundation of China (Grant No. 60776052).

  4. Novel model of a AlGaN/GaN high electron mobility transistor based on an artificial neural network

    International Nuclear Information System (INIS)

    Cheng Zhi-Qun; Hu Sha; Liu Jun; Zhang Qi-Jun

    2011-01-01

    In this paper we present a novel approach to modeling AlGaN/GaN high electron mobility transistor (HEMT) with an artificial neural network (ANN). The AlGaN/GaN HEMT device structure and its fabrication process are described. The circuit-based Neuro-space mapping (neuro-SM) technique is studied in detail. The EEHEMT model is implemented according to the measurement results of the designed device, which serves as a coarse model. An ANN is proposed to model AlGaN/GaN HEMT based on the coarse model. Its optimization is performed. The simulation results from the model are compared with the measurement results. It is shown that the simulation results obtained from the ANN model of AlGaN/GaN HEMT are more accurate than those obtained from the EEHEMT model. (condensed matter: structural, mechanical, and thermal properties)

  5. Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation.

    Science.gov (United States)

    Ciezka, Magdalena; Acosta, Milena; Herranz, Cristina; Canals, Josep M; Pumarola, Martí; Candiota, Ana Paula; Arús, Carles

    2016-08-01

    The initial aim of this study was to generate a transplantable glial tumour model of low-intermediate grade by disaggregation of a spontaneous tumour mass from genetically engineered models (GEM). This should result in an increased tumour incidence in comparison to GEM animals. An anaplastic oligoastrocytoma (OA) tumour of World Health Organization (WHO) grade III was obtained from a female GEM mouse with the S100β-v-erbB/inK4a-Arf (+/-) genotype maintained in the C57BL/6 background. The tumour tissue was disaggregated; tumour cells from it were grown in aggregates and stereotactically injected into C57BL/6 mice. Tumour development was followed using Magnetic Resonance Imaging (MRI), while changes in the metabolomics pattern of the masses were evaluated by Magnetic Resonance Spectroscopy/Spectroscopic Imaging (MRS/MRSI). Final tumour grade was evaluated by histopathological analysis. The total number of tumours generated from GEM cells from disaggregated tumour (CDT) was 67 with up to 100 % penetrance, as compared to 16 % in the local GEM model, with an average survival time of 66 ± 55 days, up to 4.3-fold significantly higher than the standard GL261 glioblastoma (GBM) tumour model. Tumours produced by transplantation of cells freshly obtained from disaggregated GEM tumour were diagnosed as WHO grade III anaplastic oligodendroglioma (ODG) and OA, while tumours produced from a previously frozen sample were diagnosed as WHO grade IV GBM. We successfully grew CDT and generated tumours from a grade III GEM glial tumour. Freezing and cell culture protocols produced progression to grade IV GBM, which makes the developed transplantable model qualify as potential secondary GBM model in mice.

  6. Nuclear Energy Advanced Modeling and Simulation (NEAMS) Accident Tolerant Fuels High Impact Problem: Coordinate Multiscale FeCrAl Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Gamble, K. A. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Hales, J. D. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Zhang, Y. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Andersson, D. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Capolungo, L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wirth, B. D. [Univ. of Tennessee, Knoxville, TN (United States)

    2017-07-26

    Since the events at the Fukushima-Daiichi nuclear power plant in March 2011 significant research has unfolded at national laboratories, universities and other institutions into alternative materials that have potential enhanced ac- cident tolerance when compared to traditional UO2 fuel zircaloy clad fuel rods. One of the potential replacement claddings are iron-chromium-alunimum (FeCrAl) alloys due to their increased oxidation resistance [1–4] and higher strength [1, 2]. While the oxidation characteristics of FeCrAl are a benefit for accident tolerance, the thermal neu- tron absorption cross section of FeCrAl is about ten times that of Zircaloy. This neutronic penalty necessitates thinner cladding. This allows for slightly larger pellets to give the same cold gap width in the rod. However, the slight increase in pellet diameter is not sufficient to compensate for the neutronic penalty and enriching the fuel beyond the current 5% limit appears to be necessary [5]. Current estimates indicate that this neutronic penalty will impose an increase in fuel cost of 15-35% [1, 2]. In addition to the neutronic disadvantage, it is anticipated that tritium release to the coolant will be larger because the permeability of hydrogen in FeCrAl is about 100 times higher than in Zircaloy [6]. Also, radiation-induced hardening and embrittlement of FeCrAl need to be fully characterized experimentally [7]. Due to the aggressive development schedule for inserting some of the potential materials into lead test assemblies or rods by 2022 [8] multiscale multiphysics modeling approaches have been used to provide insight into these the use of FeCrAl as a cladding material. The purpose of this letter report is to highlight the multiscale modeling effort for iron-chromium-alunimum (FeCrAl) cladding alloys as part of the Nuclear Energy Advanced Modeling and Simulation (NEAMS) program through its Accident Tolerant Fuel (ATF) High Impact Problem (HIP). The approach taken throughout the HIP is to

  7. [Establishment and comparison of stoma and stoma-free heterotopic small intestine transplantation models in mice].

    Science.gov (United States)

    Meng, Ning; Pan, Zhijian; Liu, Yadong; Xu, Xin; Shen, Jiliang; Shen, Bo

    2016-03-01

    To establish stoma and stoma-free murine models of heterotopic small intestine transplantation in order to choose a more effective and reliable model. A total of 140 male 8-10 weeks age C57BL/6(B6) mice weighted 25-30 g were enrolled in the experiment. Syngeneic heterotopic small intestine transplantation was performed between C57BL/6 mice, and recipient mice were divided into either stoma or stoma-free group. Heterotopic small intestine transplantation was performed in 70 mice, with 35 mice in each group. After closing the proximal end of the graft by ligation, the distal end of graft was exteriorized as a stoma then secured to the skin of the abdominal wall in stoma group. In stoma-free group, the distal end of graft was anastomosed end-to-side to the recipient ileum. Successful rate of operation, two-week survival rate, operation time, associated complications, postoperative care time and body weight change were recorded and compared between two groups. The successful rate of stoma group was 65.7%, while it was 80.0% of stoma-free group (χ(2)=1.806, P=0.179). The operation time of donor in stoma group was (48.1±6.6) minutes, while it was (47.2±5.9) minutes in stoma-free group (t=0.598, P=0.552). The operation time of recipient in stoma group was (77.9±9.1) minutes, while it was (76.4±8.3) minutes in stoma-free group (t=0.683, P=0.497). The cold ischemic time of graft in stoma group was (34.7±4.0) minutes, while it was (33.9±4.6) minutes in stoma-free group(t=0.667, P=0.507). The two-week survival rate of stoma group was 45.7%, and it was 77.1% of stoma-free group(χ(2)=7.295, P=0.007). The stoma group had more complications[54.3%(19/35) vs. 22.9%(8/35), χ(2)=7.295, P=0.007], which needed more postoperative care time(191 min vs. 35 min). The weight loss in stoma group in the third day after operation was more significant [(81.52±5.20)% vs. (85.46±4.65)%, t=2.856, P=0.006]. By 2 weeks after operation, the weight of mice in both groups retruned to 95% of

  8. [Establishment of β-aminopropionitrile-induced aortic dissection model in C57Bl/6J mice].

    Science.gov (United States)

    Gao, Y X; Liu, Y T; Zhang, Y Y; Qiu, J J; Zhao, T T; Yu, C A; Zheng, J G

    2018-02-24

    Objective: To establish the mouse aorta dissection (AD) model through drinking water containing β-aminopropionitrile (BAPN). Methods: Forty 3-week-old C57B1/6J male mice were divided into four groups according to randomized block design: control, 0.2, 0.4 and 0.8 g·kg(-1)·d(-1) BAPN groups (dissolving respective dose of BAPN in the drinking water, n= 10 each group). Arterial systolic blood pressure and heart rate were measured weekly in conscious, restrained mice using a noninvasive computerized tail-cuff system. Mice those died of rupture of aortic dissecting aneurysm during the study were autopsied and the aorta was examined. After 4 weeks, survived mice were sacrificed by an overdose of sodium pentobarbital and the whole aorta was harvested and analyzed. Results: The incidence of AD and the mortality of ruptured AD was 0 and 0 in control group, 30% (3/10) and 20% (2/10) in 0.2 g·kg(-1)·d(-1) BAPN group, 50% (5/10) and 40% (4/10) in 0.4 g·kg(-1)·d(-1) BAPN group, 90% (9/10) and 70% (7/10) in 0.8 g·kg(-1)·d(-1) BAPN group (both Pmice died of dissecting aneurysm rupture during the experiment, among which 5 dissecting aneurysms were mainly located in the thoracic aorta and 2 dissecting aneurysms in abdominal aorta. The diameters of thoracic aorta and abdominal aorta were (1.38±0.19) and (1.23±0.13) mm in control group, (2.43±1.56) and (1.30±0.26) mm in 0.2 g·kg(-1)·d(-1) BAPN group, (2.45±1.28) and (1.30±0.31) mm in 0.4 g·kg(-1)·d(-1) BAPN group, (2.87±0.57) and (1.95±0.81) mm in 0.8 g·kg(-1)·d(-1) BAPN group (both Pmice also increased in proportion with BAPN concentration increase. Furthermore, blood-filled false lumen formation and elastic fibers fragmentation were evidenced in hematoxylin-eosin stained and Vitoria blue-Sirius red stained aortic cross-sections of mice in the 0.8 g·kg(-1)·d(-1) BAPN group. Conclusion: BAPN treatment induced aortic dissection model in C57Bl/6J mice can serve as a useful wild-type mouse model for the

  9. ALS and TLS data fusion in cultural heritage documentation and modeling

    Directory of Open Access Journals (Sweden)

    A. Fryskowska

    2015-08-01

    Full Text Available One of the most important aspects of documenting cultural heritage sites is acquiring detailed and accurate data. A popular method of storing 3D information about historical structures is using 3D models. These models are built based on terrestrial or aerial laser scanning data. These methods are seldom used together. Historical buildings usually have a very complex design, therefore the input data, on the basis of which their 3D models are being built, must provide a high enough accuracy to model these complexities. The data processing methods used, as well as the modeling algorithms implemented, should be highly automated and universal. The main of the presented research was to analyze and compare various methods for extracting matching points. The article presents the results of combining data from ALS and TLS using reference points extracted both manually and automatically. Finally, the publication also includes an analysis of the accuracy of the data merging process.

  10. Correction of Flow Curves and Constitutive Modelling of a Ti-6Al-4V Alloy

    Directory of Open Access Journals (Sweden)

    Ming Hu

    2018-04-01

    Full Text Available Isothermal uniaxial compressions of a Ti-6Al-4V alloy were carried out in the temperature range of 800–1050 °C and strain rate range of 0.001–1 s−1. The effects of friction between the specimen and anvils as well as the increase in temperature caused by the high strain rate deformation were considered, and flow curves were corrected as a result. Constitutive models were discussed based on the corrected flow curves. The correlation coefficient and average absolute relative error for the strain compensated Arrhenius-type constitutive model are 0.986 and 9.168%, respectively, while the values for a modified Johnson-Cook constitutive model are 0.924 and 22.673%, respectively. Therefore, the strain compensated Arrhenius-type constitutive model has a better prediction capability than a modified Johnson-Cook constitutive model.

  11. ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease.

    Directory of Open Access Journals (Sweden)

    Daniel Komnig

    Full Text Available Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC. Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride.

  12. Morphological studies in a model for dengue-2 virus infection in mice

    Directory of Open Access Journals (Sweden)

    Ortrud Monika Barth

    2006-12-01

    Full Text Available One of the main difficulties in studying dengue virus infection in humans and in developing a vaccine is the absence of a suitable animal model which develops the full spectrum of dengue fever, dengue haemorrhagic fever, and dengue shock syndrome. It is our proposal to present morphological aspects of an animal model which shows many similarities with the dengue infection in humans. BALB/c mice were intraperitoneally infected with non-neuroadapted dengue virus serotype 2 (DENV-2. Histopathological and morphometrical analyses of liver tissue revealed focal alterations along the infection, reaching wide-ranging portal and centrolobular veins congestion and sinusoidal cell death. Additional ultrastructural observations demonstrated multifocal endothelial injury, platelet recruitment, and alterated hepatocytes. Dengue virus antigen was detected in hepatocytes and in the capillar endothelium of the central lobular vein area. Liver function tests showed high levels of aspartate transaminase and alanine transaminase enzyme activity. Lung tissue showed interstitial pneumonia and mononuclear cells, interseptal oedema, hyperplasia, and hypertrophy of the bronchiolar epithelial cells. DENV-2 led to a transient inflammatory process, but caused focal alterations of the blood-exchange barrier. Viremia was observed from 2nd to 11th day p.i. by isolation of DENV-2 in C6/36 mosquito cell line inoculated with the supernatant of macerated liver, lung, kidney, and cerebellum tissues of the infected mice.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-11-15

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

  14. Oral Modeling of an Adenovirus-Based Quadrivalent Influenza Vaccine in Ferrets and Mice.

    Science.gov (United States)

    Scallan, Ciaran D; Lindbloom, Jonathan D; Tucker, Sean N

    2016-06-01

    Oral vaccines delivered as tablets offer a number of advantages over traditional parenteral-based vaccines including the ease of delivery, lack of needles, no need for trained medical personnel, and the ability to formulate into temperature-stable tablets. We have been evaluating an oral vaccine platform based on recombinant adenoviral vectors for the purpose of creating a prophylactic vaccine to prevent influenza, and have demonstrated vaccine efficacy in animal models and substantial immunogenicity in humans. These studies have evaluated monovalent vaccines to date. To protect against the major circulating A and B influenza strains, a multivalent influenza vaccine will be required. In this study, the immunogenicity of orally delivered monovalent, bivalent, trivalent, and quadrivalent vaccines was tested in ferrets and mice. The various vaccine combinations were tested by blending monovalent recombinant adenovirus vaccines, each expressing hemagglutinin from a single strain. Human tablet delivery was modeled in animals by oral gavage in mice and by endoscopic delivery in ferrets. We demonstrated minimal interference between the various vaccine vectors when used in combination and that the oral quadrivalent vaccine compared favorably to an approved trivalent inactivated vaccine. The quadrivalent vaccine presented here produced immune responses that we predict should be capable of providing protection against multiple influenza strains, and the platform should have applications to other multivalent vaccines. Vaxart, Inc.

  15. Synergistic anticonvulsant effects of pregabalin and amlodipine on acute seizure model of epilepsy in mice.

    Science.gov (United States)

    Qureshi, Itefaq Hussain; Riaz, Azra; Khan, Rafeeq Alam; Siddiqui, Afaq Ahmed

    2017-08-01

    Status epilepticus is a life threatening neurological medical emergency. It may cause serious damage to the brain and even death in many cases if not treated properly. There is limited choice of drugs for the short term and long term management of status epilepticus and the dugs recommended for status epilepticus possess various side effects. The present study was designed to investigate synergistic anticonvulsant effects of pregabalin with amlodipine on acute seizure model of epilepsy in mice. Pentylenetetrazole was used to induce acute seizures which mimic status epilepticus. Pregabalin and amlodipine were used in combination to evaluate synergistic anti-seizure effects on acute seizure model of epilepsy in mice. Diazepam and valproate were used as reference dugs. The acute anti-convulsive activity of pregabalin with amlodipine was evaluated in vivo by the chemical induced seizures and their anti-seizure effects were compared with pentylenetetrazole, reference drugs and to their individual effects. The anti-seizure effects of tested drugs were recorded in seconds on seizure characteristics such as latency of onset of threshold seizures, rearing and fallings and Hind limbs tonic extensions. The seizure protection and mortality to the animals exhibited by the drugs were recorded in percentage. Combination regimen of pregabalin with amlodipine exhibited dose dependent significant synergistic anticonvulsant effects on acute seizures which were superior to their individual effects and equivalent to reference drugs.

  16. Efficacy of SCH27899 in an Animal Model of Legionnaires' Disease Using Immunocompromised A/J Mice

    Science.gov (United States)

    Brieland, Joan K.; Loebenberg, David; Menzel, Fred; Hare, Roberta S.

    2000-01-01

    The efficacy of SCH27899, a new everninomicin antibiotic, against replicative Legionella pneumophila lung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally with L. pneumophila serogroup 1 (105 CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila were assessed. In the absence of SCH27899, there was 100% mortality in L. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of ≥30 MPK resulted in ≥90% survival of infected mice, which was associated with inhibition of intrapulmonary growth of L. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of ≥30 MPK once daily for 5 days resulted in ≥85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicative L. pneumophila lung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic. PMID:10770771

  17. Modelling of the Effectiveness of Al-Ti-B Refiners in Commercial Purity Aluminium

    Science.gov (United States)

    Bunn, A. M.; Evans, P. V.; Bristow, D. J.; Greer, A. L.

    Al-5Ti-1B (wt.%) alloys are effective grain refiners for DC-cast aluminium although as few as 1% of the TiB2 particles added to the melt nucleate grains. The aim of this work is to develop quantitative modelling for prediction of grain sizes in commercial purity aluminium. In this way the low efficiency of refiners can be understood, ultimately to clarify the design rules for a more effective refiner. The modelling focuses on the role of particle size distribution. This is in conjunction with measurements (by scanning electron microscopy and image analysis) of the particle size distributions in commercial Al-5Ti-1B refiners known to have differing performances. The undercooling required for heterogeneous nucleation of oc-Al on the surface of potent TiB2 particles is extremely low. Accordingly, the modelling is based on the assumption that the critical step for a particle to behave as an active growth centre is that required to initiate free growth from the particle surface, rather than the initial heterogeneous nucleation event. It is considered that further initiation of free growth of crystals is stopped by the onset of recalescence in the melt during solidification. Only those particles which are active growth centres at the point of recalescence will contribute towards the final grain size. Negligible interference between particles and spherical growth up to the point of recalescence are assumed; these assumptions are rigorously tested. The model tests the effect of varying the particle size distribution by using measured distributions from `good' and `poor' refiners. The variation of grain size with addition rate of refiner is examined. The model predicts an effective saturation, beyond which further addition has little effect. In general, good agreement is found between the grain-size predictions and conventional grain-refining tests.

  18. Hidden Markov model analysis of maternal behavior patterns in inbred and reciprocal hybrid mice.

    Directory of Open Access Journals (Sweden)

    Valeria Carola

    Full Text Available Individual variation in maternal care in mammals shows a significant heritable component, with the maternal behavior of daughters resembling that of their mothers. In laboratory mice, genetically distinct inbred strains show stable differences in maternal care during the first postnatal week. Moreover, cross fostering and reciprocal breeding studies demonstrate that differences in maternal care between inbred strains persist in the absence of genetic differences, demonstrating a non-genetic or epigenetic contribution to maternal behavior. In this study we applied a mathematical tool, called hidden Markov model (HMM, to analyze the behavior of female mice in the presence of their young. The frequency of several maternal behaviors in mice has been previously described, including nursing/grooming pups and tending to the nest. However, the ordering, clustering, and transitions between these behaviors have not been systematically described and thus a global description of maternal behavior is lacking. Here we used HMM to describe maternal behavior patterns in two genetically distinct mouse strains, C57BL/6 and BALB/c, and their genetically identical reciprocal hybrid female offspring. HMM analysis is a powerful tool to identify patterns of events that cluster in time and to determine transitions between these clusters, or hidden states. For the HMM analysis we defined seven states: arched-backed nursing, blanket nursing, licking/grooming pups, grooming, activity, eating, and sleeping. By quantifying the frequency, duration, composition, and transition probabilities of these states we were able to describe the pattern of maternal behavior in mouse and identify aspects of these patterns that are under genetic and nongenetic inheritance. Differences in these patterns observed in the experimental groups (inbred and hybrid females were detected only after the application of HMM analysis whereas classical statistical methods and analyses were not able to

  19. Ballistic Impact Testing of Aluminum 2024 and Titanium 6Al-4V for Material Model Development

    Science.gov (United States)

    Pereira, J. Michael; Revilock, Duane M.; Ruggeri, Charles R.; Emmerling, William C.; Altobelli, Donald J.

    2012-01-01

    An experimental program is underway to develop a consistent set of material property and impact test data, and failure analysis, for a variety of materials that can be used to develop improved impact failure and deformation models. Unique features of this set of data are that all material property information and impact test results are obtained using identical materials, the test methods and procedures are extensively documented and all of the raw data is available. This report describes ballistic impact testing which has been conducted on aluminum (Al) 2024 and titanium (Ti) 6Al-4vanadium (V) sheet and plate samples of different thicknesses and with different types of projectiles, one a regular cylinder and one with a more complex geometry incorporating features representative of a jet engine fan blade.

  20. Modeling of wear behavior of Al/B_4C composites produced by powder metallurgy

    International Nuclear Information System (INIS)

    Sahin, Ismail; Bektas, Asli; Guel, Ferhat; Cinci, Hanifi

    2017-01-01

    Wear characteristics of composites, Al matrix reinforced with B_4C particles percentages of 5, 10,15 and 20 produced by the powder metallurgy method were studied in this study. For this purpose, a mixture of Al and B_4C powders were pressed under 650 MPa pressure and then sintered at 635 C. The analysis of hardness, density and microstructure was performed. The produced samples were worn using a pin-on-disk abrasion device under 10, 20 and 30 N load through 500, 800 and 1200 mesh SiC abrasive papers. The obtained wear values were implemented in an artificial neural network (ANN) model having three inputs and one output using feed forward backpropagation Levenberg-Marquardt algorithm. Thus, the optimum wear conditions and hardness values were determined.

  1. Modeling of wear behavior of Al/B{sub 4}C composites produced by powder metallurgy

    Energy Technology Data Exchange (ETDEWEB)

    Sahin, Ismail; Bektas, Asli [Gazi Univ., Ankara (Turkey). Dept. of Industrial Design Engineering; Guel, Ferhat; Cinci, Hanifi [Gazi Univ., Ankara (Turkey). Dept. of Materials and Metallurgy Engineering

    2017-06-01

    Wear characteristics of composites, Al matrix reinforced with B{sub 4}C particles percentages of 5, 10,15 and 20 produced by the powder metallurgy method were studied in this study. For this purpose, a mixture of Al and B{sub 4}C powders were pressed under 650 MPa pressure and then sintered at 635 C. The analysis of hardness, density and microstructure was performed. The produced samples were worn using a pin-on-disk abrasion device under 10, 20 and 30 N load through 500, 800 and 1200 mesh SiC abrasive papers. The obtained wear values were implemented in an artificial neural network (ANN) model having three inputs and one output using feed forward backpropagation Levenberg-Marquardt algorithm. Thus, the optimum wear conditions and hardness values were determined.

  2. Understanding H isotope adsorption and absorption of Al-alloys using modeling and experiments (LDRD: #165724)

    Energy Technology Data Exchange (ETDEWEB)

    Ward, Donald K. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Zhou, Xiaowang [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Karnesky, Richard A. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Kolasinski, Robert [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Foster, Michael E. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Thurmer, Konrad [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Chao, Paul [Carnegie Mellon University, Pittsburgh, PA (United States); Epperly, Ethan Nicholas [Livermore Valley Charter Preparatory High School, Livermore, CA (United States); Zimmerman, Jonathan A. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States); Wong, Bryan M. [Univ. of California, Riverside, CA (United States); Sills, Ryan B. [Sandia National Laboratories (SNL-CA), Livermore, CA (United States)

    2015-09-01

    Current austenitic stainless steel storage reservoirs for hydrogen isotopes (e.g. deuterium and tritium) have performance and operational life-limiting interactions (e.g. embrittlement) with H-isotopes. Aluminum alloys (e.g.AA2219), alternatively, have very low H-isotope solubilities, suggesting high resistance towards aging vulnerabilities. This report summarizes the work performed during the life of the Lab Directed Research and Development in the Nuclear Weapons investment area (165724), and provides invaluable modeling and experimental insights into the interactions of H isotopes with surfaces and bulk AlCu-alloys. The modeling work establishes and builds a multi-scale framework which includes: a density functional theory informed bond-order potential for classical molecular dynamics (MD), and subsequent use of MD simulations to inform defect level dislocation dynamics models. Furthermore, low energy ion scattering and thermal desorption spectroscopy experiments are performed to validate these models and add greater physical understanding to them.

  3. Ube3a loss increases excitability and blunts orientation tuning in the visual cortex of Angelman syndrome model mice.

    Science.gov (United States)

    Wallace, Michael L; van Woerden, Geeske M; Elgersma, Ype; Smith, Spencer L; Philpot, Benjamin D

    2017-07-01

    Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A Ube3a STOP/p+ mice recapitulate major features of AS in humans and allow conditional reinstatement of maternal Ube3a with the expression of Cre recombinase. We have recently shown that AS model mice exhibit reduced inhibitory drive onto layer (L)2/3 pyramidal neurons of visual cortex, which contributes to a synaptic excitatory/inhibitory imbalance. However, it remains unclear how this loss of inhibitory drive affects neural circuits in vivo. Here we examined visual cortical response properties in individual neurons to explore the consequences of Ube3a loss on intact cortical circuits and processing. Using in vivo patch-clamp electrophysiology, we measured the visually evoked responses to square-wave drifting gratings in L2/3 regular-spiking (RS) neurons in control mice, Ube3a -deficient mice, and mice in which Ube3a was conditionally reinstated in GABAergic neurons. We found that Ube3a -deficient mice exhibited enhanced pyramidal neuron excitability in vivo as well as weaker orientation tuning. These observations are the first to show alterations in cortical computation in an AS model, and they suggest a basis for cortical dysfunction in AS. NEW & NOTEWORTHY Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of the gene UBE3A Using electrophysiological recording in vivo, we describe visual cortical dysfunctions in a mouse model of AS. Aberrant cellular properties in AS model mice could be improved by reinstating Ube3a in inhibitory neurons. These findings suggest that inhibitory neurons play a substantial role in the pathogenesis of AS. Copyright © 2017 the American Physiological Society.

  4. A novel model for rapid induction of apoptosis in spiral ganglions of mice.

    Science.gov (United States)

    Lee, Ji Eun; Nakagawa, Takayuki; Kim, Tae Soo; Iguchi, Fukuichiro; Endo, Tsuyoshi; Dong, Youyi; Yuki, Kazuo; Naito, Yasushi; Lee, Sang Heun; Ito, Juichi

    2003-06-01

    The survival of the spiral ganglion (SG) is a critical issue in preservation of hearing. Research on topics related to this issue requires a mouse experimental model because such a model has advantages including use of genetic information and knockout or "knockin" mice. Thus, the aim of the study was to establish a mouse model for induction of apoptosis of SG neurons with a definite time course. Laboratory study using experimental animals. C57BL/6 mice were used as experimental animals and were subjected to direct application of cisplatin into the inner ear. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and immunostaining for Neurofilament 200-kD (NF) and peripherin were used for analysis of SG degeneration. In addition, generation of peroxynitrite in affected spiral ganglions was examined by immunostaining for nitrotyrosine. Cellular location of activated caspase-9 and cytochrome-c in dying SG neurons were examined for analysis of cell death pathway. The TUNEL assay and immunohistochemical analysis for NF and peripherin indicated that type I neurons in spiral ganglions were deleted through the apoptotic pathway over time. Spiral ganglion neurons treated with cisplatin exhibited expression of nitrotyrosine, indicating induction of peroxynitrite by cisplatin. In dying SG neurons, expression of activated caspase-9 and translocation of cytochrome-c from mitochondria to cytoplasm were observed, indicating the mitochondrial pathway of apoptosis. The predictable fashion of induction of apoptosis in SG neurons over a well-defined time course in the model in the study will aid studies of the molecular mechanism of cell death and elucidation of a strategy for prevention of SG degeneration.

  5. Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice

    Directory of Open Access Journals (Sweden)

    Andrea Marzi

    2018-04-01

    Full Text Available The common small animal disease models for Zika virus (ZIKV are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR−/− mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR−/− mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR−/− mice (10–12-weeks old. In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

  6. Effects of low dose rate irradiation on life span prolongation of human premature-aging syndrome model mice

    International Nuclear Information System (INIS)

    Nomura, Takaharu

    2006-01-01

    We previously showed that Type II diabetes model mice prolonged of their life span by life long low dose rate irradiation. We also found that antioxidant function in variety tissues of some strain of mice were enhancement after low dose/low dose rate irradiation. The prolongation of life span might depend on certain damaged level of reactive oxygen species. We thought the effect of the prolongation was due to the enhancement of the antioxidant activities after irradiation. We investigated whether the enhancement of antioxidant activities after low dose rate irradiation had an effect on life span prolongation. Four-week-old female human premature-aging syndrome model mice, kl/kl (klotho) mice, which the life span of this model mouse is about 65 days, were irradiated with gamma rays at 0.35, 0.70 or 1.2 mGy/hr. The 0.70 mGy/hr-irradiated group remarkably effected on the prolongation of their life span. Some mice of the group were extremely survived for about and more 100 days. Antioxidant activities in the irradiated groups were enhancement by low dose rate irradiation, however the dependence of the dose rates were not clearly difference. These results suggest that the antioxidant activities in this model mouse were enhanced by the low dose rate irradiation, and may make it possible to prolong the life span of this mouse. (author)

  7. Modeling creep deformation of a two-phase TiAI/Ti3Al alloy with a lamellar microstructure

    Science.gov (United States)

    Bartholomeusz, Michael F.; Wert, John A.

    1994-10-01

    A two-phase TiAl/Ti3Al alloy with a lamellar microstructure has been previously shown to exhibit a lower minimum creep rate than the minimum creep rates of the constituent TiAl and Ti3Al single-phase alloys. Fiducial-line experiments described in the present article demonstrate that the creep rates of the constituent phases within the two-phase TiAl/Ti3Al lamellar alloy tested in compression are more than an order of magnitude lower than the creep rates of single-phase TiAl and Ti3Al alloys tested in compression at the same stress and temperature. Additionally, the fiducial-line experiments show that no interfacial sliding of the phases in the TiAl/Ti3Al lamellar alloy occurs during creep. The lower creep rate of the lamellar alloy is attributed to enhanced hardening of the constituent phases within the lamellar microstructure. A composite-strength model has been formulated to predict the creep rate of the lamellar alloy, taking into account the lower creep rates of the constituent phases within the lamellar micro-structure. Application of the model yields a very good correlation between predicted and experimentally observed minimum creep rates over moderate stress and temperature ranges.

  8. Characterization of the hierarchical microstructure of a Ni-Al-Ti model alloy; Charakterisierung der hierarchischen Mikrostruktur einer Ni-Al-Ti Modell-Legierung

    Energy Technology Data Exchange (ETDEWEB)

    Vogel, Florian

    2014-02-28

    Phase separation of γ{sup '} precipitates determines the microstructure and mechanical properties of nickel-based superalloys. Upon ageing, γ spheres form inside ordered (L1{sub 2}) γ{sup '} precipitates, undergo a morphological change to plates and finally split the γ{sup '} precipitates. To clarify the identity of the insufficiently characterized γ particles and to elucidate their influence on the evolution of the microstructure and the mechanical properties, differently heat treated samples of a Ni-Al-Ti modell alloy were investigated from the micrometer to the atomic scale. The single crystalline cast material was broadly characterized by means of light and scanning electron microscopy, the laue method (back-reflection), differential scanning calorimetry as well as electron probe microanalysis. Dendritic segregations were found, whereas the dendrite cores show an enrichment in nickel and aluminum and in turn the interdendritic regions show an enrichment in titanium. An adequate combination of temperature and time was determined on the basis of quantitative analyses after different homogenization treatments. The evolution of the hierarchical microstructure was investigated on the nanometer scale by means of transmission electron microscopy and on the atomic scale with atom probe tomography. The combined analyses reveal that Ni-rich clusters form within the γ{sup '} precipitates during the early stages of phase separation. These Ni-rich clusters coalesce and thereby form γ spheres which undergo a morphological change to plates accompanied by a chemical evolution. In the beginning the γ spheres are located well within the metastable γ + γ{sup '} two-phase region and later, after the morphological change, achieve the equilibrium composition of the γ phase. Furthermore the involved energies were considered in order to elucidate the driving forces for the phase separation of γ{sup '} precipitates. A correlation between the

  9. Compact modelling of InAlN/GaN HEMT for low noise applications

    International Nuclear Information System (INIS)

    Sakalas, P; Šimukovič, A; Matulionis, A; Piotrowicz, S; Jardel, O; Delage, S L; Mukherjee, A

    2014-01-01

    This paper presents results of high-frequency noise modelling of InAlN/GaN high electron mobility transistors (HEMTs) with different formulations of the minimum noise figure NF min . Current–voltage characteristics and s-parameters of 0.15 μm gate length and 2 × 75 μm gate width InAlN/GaN HEMTs were measured at room temperature in a wide frequency range (300 MHz to 50 GHz) and bias range (V GS from −4.8 to 1 V and V DS from 0 to 21 V). Both the EEHEMT1 and Angelov GaN compact models yielded excellent agreement for transfer and output characteristics, transconductance g m , and f T , f max. High-frequency noise parameters NF min , R n , Γ OPT of InAlN/GaN HEMT were measured in 8–50 GHz frequency band. Noise formulation within the EEHEMT1 model underestimates the measured NF min and R n . The well known three-parameter PRC noise model is in a better agreement with the measured data but neglects the shot noise resulting from the gate leakage. The inductive degenerated source matching method and EEHEMT1 were used to design a single stage LNA operated at 8 GHz frequency. A 10 dB gain with an input reflection of −12 dB with a 2.5 dB of noise factor were obtained at 8 GHz. (paper)

  10. The Effects of Melatonin with Memantin on MPTP-Induced Parkinson Model in Male Mice

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    Reza Talebi

    2015-09-01

    Full Text Available Abstract Background: Oxidative stress and severe neuro-excitation have significant effects on pathogenesis of Parkinson’s disease and agents with antioxidant property can potentially prevent these effects. Herein we examined potential protective effects of melatonin as an antioxidant agent and memantine as an uncompetitive receptor of NMDA, on a model of Parkinson’s disease induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP. Materials and Methods: Male mice were divided into 8 groups with 7 mice in each group: saline, ethanol, melatonin, memantin, MPTP, melatonin+MPTP, memantin+ MPTP, melatonin+ memantin+ MPTP. All of agents were injected intraperitoneally once a day for 14 days before beam traversal test. Dopaminergic neurons of the Substantia Nigra Pars compacta (SNPC were determined by immunohistochemical and were counted. Results: Melatonin improved notably movement dysfunction resulted of MPTP such as the number of errors, paces and the time of movement during behavioral test and also the counting of neurons of Substantia Nigra Pars Compacta. Memantin had a synergic effect on the most of improvements. However, the level of improvement and retrieval of signs was not as in saline and ethanol groups. Conclusion: Melatonin especially together with memantine is able to prevent some of the MPTP-induced dysfunctions. However, the protective effects were not enogh, probably because of the amount of dose and the time of injection.

  11. Inhibition of Asthma in OVA Sensitized Mice Model by a Traditional Uygur Herb Nepeta bracteata Benth.

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    Jing Wang

    2016-01-01

    Full Text Available Asthma is a chronic lung inflammation which affects many people. As current therapies for asthma mainly rely on administration of glucocorticoids and have many side effects, new therapy is needed. In this study, we investigated Nepeta bracteata Benth., a traditional Uygur Herb, for its therapeutics effect in OVA induced asthmatic mice model. Treatment of OVA sensitized asthma mice with extract from Nepeta bracteata Benth. demonstrated improved lung pathology, as well as reduced infiltration of eosinophil and neutrophil. Nepeta bracteata Benth. extract also contributed to the rebalance of Th17/Treg cell via decreasing the Th17 cell and increasing the Treg, which was corresponding with the inhibited Th17 cytokine response and increased IL-10 level. Moreover, the reduced TGF-β level and Smad2/3 protein level also suggested that Nepeta bracteata Benth. extract could inhibit TGF-β mediated airway remodelling as well. Taken together, these data suggested that Nepeta bracteata Benth. may be a novel candidate for future antiasthma drug development.

  12. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

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    Timothy W Lefever

    2017-03-01

    Full Text Available Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana” in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018 in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia, regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  13. Antinociceptive Effect of Ondansetron in Albino Mice Using Acetic Acid Induced Writhing Model

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    Abhay Purohit

    2016-10-01

    Full Text Available Background: Pain is an unpleasant sensory and emotional experience. Pain is a protective mechanism. Pain occurs whenever any tissues are being damaged, and it causes the individual to react and to remove the pain stimulus. Aim and Objectives: To evaluate the antinociceptive effect of ondansetron in comparison with the standard diclofenac. Material and Methods: The antinociceptive effect was tested by using the acetic acid induced writhing model in Swiss Albino mice. Animals were divided into 4 groups of 6 animals each. Animals were received distilled water (control, diclofenac (standard, ondansetron 0.5mg/kg (test I and ondansetron 1mg/kg (test II. After 30 minutes of drug administration, 0.1 ml of 1% acetic acid was injected. Mice were placed individually into glass beakers and five minutes were allowed to elapse. They were then observed for a period of ten minutes and the numbers of writhes were recorded in each animal. The results were expressed as mean ± SEM. One way ANOVA with post-test was used for statistical calculation. Results: The numbers of writhes were 1.33±0.494 for diclofenac; 6.33±1.872 and 9.33±1.706 for ondansetron 0.5 and 1mg/kg respectively. Conclusion: Ondansetron demonstrated statistical significant antinociceptive activity at both doses (0.5mg/kg and 1mg/kg and statistically similar effect as diclofenac

  14. Localization of 131I-chTNT in a nude mice model with human hepatoma

    International Nuclear Information System (INIS)

    Chen Shaoliang; Sun Xiaoguang; Xiu Yan; Zhong Gaoren; Qiao Weiwei; Xu Lanwen; Li Wenzheng

    1998-01-01

    Purpose: In order to evaluate the targeting activity in the animal model with human hepatoma, the 131 I-chTNT radioimmunoimaging was explored. Methods: Radioimmunoimages were taken on different intervals after injection of 131 I-chTNT 5.55 MBq to the nude mice, and tissue distribution was measured. The results of 131 I-chTNT monoclonal antibody group were compared with that of 131 I control group. Results: The experimental group developed tumor positive images after one day of radio-labelled monoclonal antibodies injection and held on until the end of the experiment. The radioactivity in tumor mass was stable, and the half life of 131 I-chTNT in hepatoma mass was 6.0 +- 1.6 days. there was no special radioactivity accumulation in normal liver tissue in the nude mice and the radioactivity in it disappeared rapidly. Statistics indicated the tumor/liver ratio in 1, 2, 3, 5, 7 days were 1.03, 2.43, 5.71, 7.96, 10.67, respectively. Conclusions: The results suggest that 131 I-chTNT monoclonal antibody has a considerable targeting activity, and provide an evidence for that it can be used as a new radiopharmaceutical agent for the imaging and radio therapy of hepatoma

  15. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

    Science.gov (United States)

    Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

    2017-01-01

    Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  16. Effect of curcumin in mice model of vincristine-induced neuropathy.

    Science.gov (United States)

    Babu, Anand; Prasanth, K G; Balaji, Bhaskar

    2015-06-01

    Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p Curcumin at 30 and 60 mg/kg exhibited significant changes (p Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.

  17. Modeling and optimization of a double-well double-barrier GaN/AlGaN/GaN/AlGaN resonant tunneling diode

    Science.gov (United States)

    Liu, Yang; Gao, Bo; Gong, Min; Shi, Ruiying

    2017-06-01

    The influence of a GaN layer as a sub-quantum well for an AlGaN/GaN/AlGaN double barrier resonant tunneling diode (RTD) on device performance has been investigated by means of numerical simulation. The introduction of the GaN layer as the sub-quantum well turns the dominant transport mechanism of RTD from the 3D-2D model to the 2D-2D model and increases the energy difference between tunneling energy levels. It can also lower the effective height of the emitter barrier. Consequently, the peak current and peak-to-valley current difference of RTD have been increased. The optimal GaN sub-quantum well parameters are found through analyzing the electrical performance, energy band, and transmission coefficient of RTD with different widths and depths of the GaN sub-quantum well. The most pronounced electrical parameters, a peak current density of 5800 KA/cm2, a peak-to-valley current difference of 1.466 A, and a peak-to-valley current ratio of 6.35, could be achieved by designing RTD with the active region structure of GaN/Al0.2Ga0.8 N/GaN/Al0.2Ga0.8 N (3 nm/1.5 nm/1.5 nm/1.5 nm).

  18. Optimised and rapid pre-clinical screening in the SOD1(G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS.

    Directory of Open Access Journals (Sweden)

    Richard J Mead

    Full Text Available The human SOD1(G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS. In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6 SOD1(G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

  19. Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS).

    Science.gov (United States)

    Mead, Richard J; Bennett, Ellen J; Kennerley, Aneurin J; Sharp, Paul; Sunyach, Claire; Kasher, Paul; Berwick, Jason; Pettmann, Brigitte; Battaglia, Guiseppe; Azzouz, Mimoun; Grierson, Andrew; Shaw, Pamela J

    2011-01-01

    The human SOD1(G93A) transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6) SOD1(G93A) transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

  20. Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis.

    Science.gov (United States)

    Tian, Cong; Harris, Belinda S; Johnson, Kenneth R

    2016-01-01

    Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory-evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets.

  1. Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System.

    Directory of Open Access Journals (Sweden)

    Miguel Marigil

    Full Text Available In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG model based in the implantation of a guide-screw system.It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies.The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model.Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.

  2. A gate current 1/f noise model for GaN/AlGaN HEMTs

    International Nuclear Information System (INIS)

    Liu Yu'an; Zhuang Yiqi

    2014-01-01

    This work presents a theoretical and experimental study on the gate current 1/f noise in AlGaN/GaN HEMTs. Based on the carrier number fluctuation in the two-dimensional electron gas channel of AlGaN/GaN HEMTs, a gate current 1/f noise model containing a trap-assisted tunneling current and a space charge limited current is built. The simulation results are in good agreement with the experiment. Experiments show that, if V g < V x (critical gate voltage of dielectric relaxation), gate current 1/f noise comes from the superimposition of trap-assisted tunneling RTS (random telegraph noise), while V g > V x , gate current 1/f noise comes from not only the trap-assisted tunneling RTS, but also the space charge limited current RTS. This indicates that the gate current 1/f noise of the GaN-based HEMTs device is sensitive to the interaction of defects and the piezoelectric relaxation. It provides a useful characterization tool for deeper information about the defects and their evolution in AlGaN/GaN HEMTs. (semiconductor devices)

  3. Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures.

    Science.gov (United States)

    Töllner, Kathrin; Twele, Friederike; Löscher, Wolfgang

    2016-04-01

    Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but because testing of antiseizure drug efficacy is extremely laborious in such models, they are only rarely used in the development of novel AEDs. Recently, the use of acute seizure tests in epileptic rats or mice has been proposed as a novel strategy for evaluating novel AEDs for increased antiseizure efficacy. In the present study, we compared the effects of five AEDs (valproate, phenobarbital, diazepam, lamotrigine, levetiracetam) on the pentylenetetrazole (PTZ) seizure threshold in mice that were made epileptic by pilocarpine. Experiments were started 6 weeks after a pilocarpine-induced status epilepticus. At this time, control seizure threshold was significantly lower in epileptic than in nonepileptic animals. Unexpectedly, only one AED (valproate) was less effective to increase seizure threshold in epileptic vs. nonepileptic mice, and this difference was restricted to doses of 200 and 300 mg/kg, whereas the difference disappeared at 400mg/kg. All other AEDs exerted similar seizure threshold increases in epileptic and nonepileptic mice. Thus, induction of acute seizures with PTZ in mice pretreated with pilocarpine does not provide an effective and valuable surrogate method to screen drugs for antiseizure efficacy in a model of difficult-to-treat chronic epilepsy as previously suggested from experiments with this approach in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. A new model mimicking persistent HBV e antigen-negative infection using covalently closed circular DNA in immunocompetent mice.

    Directory of Open Access Journals (Sweden)

    Lei Wang

    Full Text Available Despite the availability of an effective vaccine, hepatitis B virus (HBV infection remains a major health problem. HBV e antigen (HBeAg-negative strains have become prevalent. Previously, no animal model mimicked the clinical course of HBeAg-negative HBV infection. To establish an HBeAg-negative HBV infection model, the 3.2-kb full-length genome of HBeAg-negative HBV was cloned from a clinical sample and then circularized to form covalently closed circular (cccDNA. The resulting cccDNA was introduced into the liver of C57BL/6J mice through hydrodynamic injection. Persistence of the HBeAg-negative infection was monitored at predetermined time points using HBV-specific markers including HBV surface antigen (HBsAg, HBeAg, and HBV core antigen (HBcAg as well as DNA copies. Throughout the study, pAAV-HBV1.2 was used as a control. In mice injected with HBeAg-negative cccDNA, the HBV infection rate was 100% at the initial stage. HBsAg levels increased up to 1 week, at which point levels peaked and dropped quickly thereafter. In 60% of injected mice, HBsAg and HBcAg persisted for more than 10 weeks. High numbers of HBV DNA copies were detected in the serum and liver. Moreover, cccDNA persisted in the liver tissue of HBeAg-negative mice. In contrast to the pAAV-HBV 1.2 injected mice, no HBeAg was found in mice injected with HBeAg-negative HBV throughout the study period. These results demonstrate the first successful establishment of a model of HBeAg-negative HBV-persistent infection in immunocompetent mice. Compared to pAAV-HBV1.2-injected mice, the infection persistence and levels of serum virological and biochemical markers were approximately equal in the model mice. This model will be useful for mechanistic studies on HBeAg-negative HBV infection and will facilitate the evaluation of new antiviral drugs.

  5. Modeling the anomalous flow behavior of Ni3Al intermetallic single crystals

    International Nuclear Information System (INIS)

    Choi, Y.S.; Parthasarathy, T.A.; Dimiduk, D.M.; Uchic, M.D.

    2004-01-01

    In this study we present a new constitutive model for Ni3Al and Ni3(Al, X) alloys that was developed to represent many of the unusual plastic flow behavior found in L12 intermetallics while maintaining consistency with the experimentally-observed evolution of dislocation substructure. In particular, we sought to develop a model that would not only predict the anomalous increase of the yield strength with increasing temperature, but would also capture other important flow characteristics such as extremely high work-hardening rates that change anomalously with temperature, and a flow stress that is partially to fully reversible with temperature. For this model, we have treated work-hardening as arising from two different sources. Thermally-reversible work hardening is accounted for using the description of screw dislocation motion proposed by Caillard, which involves exhaustion of mobile dislocations by cross-slip locking of the dislocation core and athermal unlocking. Thermally-irreversible work hardening is accounted for using an approach consistent with the theoretical framework proposed by Ezz and Hirsch, which involves both the multiplication of Frank-Reed sources and the interaction of edge-dislocation segments with cross-slip locking events and the dislocation forest. Both work-hardening contributions were incorporated into the rate formulation for thermally-activated plastic flow proposed by Kocks, Argon and Ashby. We will show simulation results for the flow response of Ni3(Al, X) crystals over a wide range of temperatures in the anomalous flow regime, and we will compare these findings with experimental data

  6. Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

    Science.gov (United States)

    Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

    2010-10-20

    In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

  7. Mice selected for high versus low stress reactivity: a new animal model for affective disorders.

    Science.gov (United States)

    Touma, Chadi; Bunck, Mirjam; Glasl, Lisa; Nussbaumer, Markus; Palme, Rupert; Stein, Hendrik; Wolferstätter, Michael; Zeh, Ramona; Zimbelmann, Marina; Holsboer, Florian; Landgraf, Rainer

    2008-07-01

    Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety

  8. Understanding Experimental LCMV Infection of Mice: The Role of Mathematical Models

    Directory of Open Access Journals (Sweden)

    Gennady Bocharov

    2015-01-01

    Full Text Available Virus infections represent complex biological systems governed by multiple-level regulatory processes of virus replication and host immune responses. Understanding of the infection means an ability to predict the systems behaviour under various conditions. Such predictions can only rely upon quantitative mathematical models. The model formulations should be tightly linked to a fundamental step called “coordinatization” (Hermann Weyl, that is, the definition of observables, parameters, and structures that enable the link with a biological phenotype. In this review, we analyse the mathematical modelling approaches to LCMV infection in mice that resulted in quantification of some fundamental parameters of the CTL-mediated virus control including the rates of T cell turnover, infected target cell elimination, and precursor frequencies. We show how the modelling approaches can be implemented to address diverse aspects of immune system functioning under normal conditions and in response to LCMV and, importantly, make quantitative predictions of the outcomes of immune system perturbations. This may highlight the notion that data-driven applications of meaningful mathematical models in infection biology remain a challenge.

  9. Investigation and modeling of Al3(Sc, Zr) precipitation strengthening in the presence of enhanced supersaturation and within Al-Cu binary alloys

    Science.gov (United States)

    Deane, Kyle

    Diffuse Al-Sc and Al-Zr alloys have been demonstrated in literature to be relatively coarsening resistant at higher temperatures when compared with commonly used precipitation strengthening alloys (e.g. 2000 series, 6000 series). However, because of a limited strengthening due to the low solubility of scandium and zirconium in aluminum, and owing to the scarcity and therefore sizeable price tag attached to scandium, little research has been done in the way of optimizing these alloys for commercial applications. With this in mind, this dissertation describes research which aims to tackle several important areas of Al-Sc-Zr research that have been yet unresolved. In Chapter 4, rapid solidification was utilized to enhance the achievable supersaturation of the alloy in an effort to increase the achievable precipitate strengthening. In Chapter 5, Additive Friction Stir processing (AFS), a novel method of mechanically combining materials without melting, was employed in an attempt to pass the benefits of supersaturation from melt spun ribbon into a more structurally useful bulk material. In Chapter 6, a Matlab program written to predict precipitate nucleation, growth, and coarsening with a modified Kampmann and Wagner Numerical (KWN) model, was used to predict heat treatment regimens for more efficient strengthening. Those predictions were then tested experimentally to test the validity of the results. And lastly, in Chapter 7, the effect of zirconium on Al-Cu secondary precipitates was studied in an attempt to increase their thermal stability, as much higher phase fractions of Al-Cu precipitates are achievable than Al-Zr precipitates.

  10. Diffusion model analyses of the experimental data of 12C+27Al, 40Ca dissipative collisions

    International Nuclear Information System (INIS)

    SHEN Wen-qing; QIAO Wei-min; ZHU Yong-tai; ZHAN Wen-long

    1985-01-01

    Assuming that the intermediate system decays with a statistical lifetime, the general behavior of the threefold differential cross section d 3 tau/dZdEdtheta in the dissipative collisions of 68 MeV 12 C+ 27 Al and 68.6 MeV 12 C+ 40 Ca system is analyzed in the diffusion model framework. The lifetime of the intermediate system and the separation distance for the completely damped deep-inelastic component are obtained. The calculated results and the experimental data of the angular distributions and Wilczynski plots are compared. The probable reasons for the differences between them are briefly discussed

  11. Impact Testing of Aluminum 2024 and Titanium 6Al-4V for Material Model Development

    Science.gov (United States)

    Pereira, J. Michael; Revilock, Duane M.; Lerch, Bradley A.; Ruggeri, Charles R.

    2013-01-01

    One of the difficulties with developing and verifying accurate impact models is that parameters such as high strain rate material properties, failure modes, static properties, and impact test measurements are often obtained from a variety of different sources using different materials, with little control over consistency among the different sources. In addition there is often a lack of quantitative measurements in impact tests to which the models can be compared. To alleviate some of these problems, a project is underway to develop a consistent set of material property, impact test data and failure analysis for a variety of aircraft materials that can be used to develop improved impact failure and deformation models. This project is jointly funded by the NASA Glenn Research Center and the FAA William J. Hughes Technical Center. Unique features of this set of data are that all material property data and impact test data are obtained using identical material, the test methods and procedures are extensively documented and all of the raw data is available. Four parallel efforts are currently underway: Measurement of material deformation and failure response over a wide range of strain rates and temperatures and failure analysis of material property specimens and impact test articles conducted by The Ohio State University; development of improved numerical modeling techniques for deformation and failure conducted by The George Washington University; impact testing of flat panels and substructures conducted by NASA Glenn Research Center. This report describes impact testing which has been done on aluminum (Al) 2024 and titanium (Ti) 6Al-4vanadium (V) sheet and plate samples of different thicknesses and with different types of projectiles, one a regular cylinder and one with a more complex geometry incorporating features representative of a jet engine fan blade. Data from this testing will be used in validating material models developed under this program. The material

  12. Lattice stability of metastable AlN and wurtzite-to-rock-salt structural transformation by CALPHAD modeling

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yanhui, E-mail: yanhui.z@hotmail.com [Karlsruhe Institute of Technology (KIT), Institute for Applied Materials-Applied Materials Physics (IAM-AWP), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen (Germany); High-performance Ceramics Division, Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences, 110016, Shenyang (China); Franke, Peter; Li, Dajian; Seifert, Hans Jürgen [Karlsruhe Institute of Technology (KIT), Institute for Applied Materials-Applied Materials Physics (IAM-AWP), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen (Germany)

    2016-12-01

    Reliable lattice stability of cubic AlN with rock-salt structure (rs-AlN) is the prerequisite of accurate thermodynamic modeling of cubic (M, Al)N solid solutions (M = Ti, Zr, Cr etc.). In order to derive the Gibbs energy of metastable rs-AlN, and then its lattice stability, we did the pressure-temperature (P-T) assessment of AlN phases by equations-of-state modeling. Meanwhile, the molar volumes and the heat capacities of wurtzite and rock-salt AlN, as well as the wurtzite-to-rock-salt structural transition at high P&T were successfully incorporated in CALPHAD-type database by integrating thermodynamic data from experiments and ab-initio calculations. These results promise subsequent investigations on phase stabilities and transitions of solid solutions with AlN component and the development of novel multicomponent coatings. - Highlights: • Phase stability investigation for novel multi-component metastable coatings. • Structural transition at high temperature and high pressure. • Integrating thermodynamic data from ab-initio calculations and experiments. • Thermal expansion, isothermal compressibility and heat capacity of w-AlN and rs-AlN.

  13. Genetic background and 227Thorium as risk factors in biologically based models for induction of bone cancer in mice

    International Nuclear Information System (INIS)

    Heidenreich, W.F.; Rosemann, M.

    2012-01-01

    We explore the potential for the biologically based two-stage clonal expansion model to make statements about the influence of genetic factors on the steps in the model. We find evidence that the different susceptibility of BALB/C and CBA/Ca mice to bone cancer after 227 Thorium injection may be mostly due to different promotional responses to radiation. In BALB/C x CBA/Ca back-crossed mice, we analyzed the specific contribution of two individual loci in the carcinogenic process. This analysis suggests that the two high- or low-risk alleles are acting on promotion or on the background parameters, but not on radiation-induced initiation. Taken together with the comparison of CBA/Ca and BALB/C mice, this hints at the possibility that the two loci are candidates for modifying radiation-induced promotion. (orig.)

  14. ApoB100/LDLR-/- hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage.

    Directory of Open Access Journals (Sweden)

    Carlos Ramírez

    Full Text Available Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD. Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR] of human familial hypercholesterolaemia (FH. From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100 levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing and impairment of the episodic-like memory (determined by the integrated memory test. This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.

  15. Modeling the ferrochelatase c.315-48C modifier mutation for erythropoietic protoporphyria (EPP in mice

    Directory of Open Access Journals (Sweden)

    Jasmin Barman-Aksözen

    2017-03-01

    Full Text Available Erythropoietic protoporphyria (EPP is caused by deficiency of ferrochelatase (FECH, which incorporates iron into protoporphyrin IX (PPIX to form heme. Excitation of accumulated PPIX by light generates oxygen radicals that evoke excessive pain and, after longer light exposure, cause ulcerations in exposed skin areas of individuals with EPP. Moreover, ∼5% of the patients develop a liver dysfunction as a result of PPIX accumulation. Most patients (∼97% have a severe FECH mutation (Mut in trans to an intronic polymorphism (c.315-48C, which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3′ splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas show a very strong EPP phenotype that includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after a short period of light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing.

  16. Anticonvulsant activity of Aloe vera leaf extract in acute and chronic models of epilepsy in mice.

    Science.gov (United States)

    Rathor, Naveen; Arora, Tarun; Manocha, Sachin; Patil, Amol N; Mediratta, Pramod K; Sharma, Krishna K

    2014-03-01

    The effect of Aloe vera in epilepsy has not yet been explored. This study was done to explore the effect of aqueous extract of Aloe vera leaf powder on three acute and one chronic model of epilepsy. In acute study, aqueous extract of Aloe vera leaf (extract) powder was administered in doses 100, 200 and 400 mg/kg p.o. Dose of 400 mg/kg of Aloe vera leaf extract was chosen for chronic administration. Oxidative stress parameters viz. malondialdehyde (MDA) and reduced glutathione (GSH) were also estimated in brain of kindled animals. In acute study, Aloe vera leaf (extract) powder in a dose-dependent manner significantly decreased duration of tonic hind limb extension in maximal electroshock seizure model, increased seizure threshold current in increasing current electroshock seizure model, and increased latency to onset and decreased duration of clonic convulsion in pentylenetetrazole (PTZ) model as compared with control group. In chronic study, Aloe vera leaf (extract) powder prevented progression of kindling in PTZ-kindled mice. Aloe vera leaf (extract) powder 400 mg/kg p.o. also reduced brain levels of MDA and increased GSH levels as compared to the PTZ-kindled non-treated group. The results of study showed that Aloe vera leaf (extract) powder possessed significant anticonvulsant and anti-oxidant activity. © 2013 Royal Pharmaceutical Society.

  17. Chronic subordination stress induces hyperphagia and disrupts eating behavior in mice modeling binge-eating-like disorder

    Directory of Open Access Journals (Sweden)

    Maria eRazzoli

    2015-01-01

    Full Text Available Background: Eating disorders are associated with physical morbidity and appear to have causal factors like stressful life events and negative affect. Binge eating disorder (BED is characterized by eating in a discrete period of time a larger than normal amount of food, a sense of lack of control over eating, and marked distress. There are still unmet needs for the identification of mechanisms regulating excessive eating, which is in part due to the lack of appropriate animal models. We developed a naturalistic murine model of subordination stress induced hyperphagia associated with the development of obesity. Here we tested the hypotheses that the eating responses of subordinate mice recapitulate the BED and that limiting hyperphagia could prevent stress-associated metabolic changes. Methods: Adult male mice were exposed to a model of chronic subordination stress associated with the automated acquisition of food intake and we performed a detailed meal pattern analysis. Additionally, using a pair-feeding protocol was test the hypothesis that the manifestation of obesity and the metabolic syndrome could be prevented by limiting hyperphagia. Results: The architecture of feeding of subordinate mice was disrupted during the stress protocol due to disproportionate amount of food ingested at higher rate and with shorter satiety ratio than control mice. Subordinate mice hyperphagia was further exacerbated in response to either hunger or to the acute application of a social defeat. Notably, the obese phenotype but not the fasting hyperglycemia of subordinate mice was abrogated by preventing hyperphagia in a pair feeding paradigm. Conclusion: Overall these results support the validity of our chronic subordination stress to model binge eating disorder allowing for the determination of the underlying molecular mechanisms and the generation of testable predictions for innovative therapies, based on the understanding of the regulation and the control of food

  18. Effect of deformation on structure and reaction of Al isotopes using relativistic mean field densities in Glauber model

    Science.gov (United States)

    Panda, R. N.; Sharma, Mahesh K.; Panigrahi, M.; Patra, S. K.

    2018-06-01

    We have examined the ground state properties of Al isotopes towards the proton rich side from A = 22 to 28 using the well known relativistic mean field (RMF) formalism with NLSH parameter set. The calculated results are compared with the predictions of finite range droplet model and experimental data. The calculation is extended to estimate the reaction cross section for ^{22-28}Al as projectiles with ^{12}C as target. The incident energy of the projectiles are taken as 950 MeV/nucleon, for both spherical and deformed RMF densities as inputs in the Glauber model approximation. Further investigation of enhanced values of total reaction cross section for ^{23}Al and ^{24}Al in comparison to rest of the isotopes indicates the proton skin structure of these isotopes. Specifically, the large value of root mean square radius and total reaction cross section of ^{23}Al could not be ruled out the formation of proton halo.

  19. Population sensitivities of animals to chronic ionizing radiation-model predictions from mice to elephant.

    Science.gov (United States)

    Sazykina, Tatiana G

    2018-02-01

    Model predictions of population response to chronic ionizing radiation (endpoint 'morbidity') were made for 11 species of warm-blooded animals, differing in body mass and lifespan - from mice to elephant. Predictions were made also for 3 bird species (duck, pigeon, and house sparrow). Calculations were based on analytical solutions of the mathematical model, simulating a population response to low-LET ionizing radiation in an ecosystem with a limiting resource (Sazykina, Kryshev, 2016). Model parameters for different species were taken from biological and radioecological databases; allometric relationships were employed for estimating some parameter values. As a threshold of decreased health status in exposed populations ('health threshold'), a 10% reduction in self-repairing capacity of organisms was suggested, associated with a decline in ability to sustain environmental stresses. Results of the modeling demonstrate a general increase of population vulnerability to ionizing radiation in animal species of larger size and longevity. Populations of small widespread species (mice, house sparrow; body mass 20-50 g), which are characterized by intensive metabolism and short lifespan, have calculated 'health thresholds' at dose rates about 6.5-7.5 mGy day -1 . Widespread animals with body mass 200-500 g (rat, common pigeon) - demonstrate 'health threshold' values at 4-5 mGy day -1 . For populations of animals with body mass 2-5 kg (rabbit, fox, raccoon), the indicators of 10% health decrease are in the range 2-3.4 mGy day -1 . For animals with body mass 40-100 kg (wolf, sheep, wild boar), thresholds are within 0.5-0.8 mGy day -1 ; for herbivorous animals with body mass 200-300 kg (deer, horse) - 0.5-0.6 mGy day -1 . The lowest health threshold was estimated for elephant (body mass around 5000 kg) - 0.1 mGy day -1 . According to the model results, the differences in population sensitivities of warm-blooded animal species to ionizing radiation are generally

  20. Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS

    DEFF Research Database (Denmark)

    Nieto-Gonzalez, Jose Luis; Moser, Jakob; Lauritzen, Martin

    2011-01-01

    mice. Also, miniature inhibitory postsynaptic currents recorded under blockade of action potentials were decreased by 64%. Tonic inhibition mediated by extrasynaptic GABA(A) receptors was reduced by 87%. In agreement, we found a decreased density of parvalbumin- and somatostatin-positive inhibitory...... inhibition, which might explain the cortical hyperexcitability in wobbler mice....

  1. Exploring the influence of constitutive models and associated parameters for the orthogonal machining of Ti6Al4V

    Science.gov (United States)

    Pervaiz, S.; Anwar, S.; Kannan, S.; Almarfadi, A.

    2018-04-01

    Ti6Al4V is known as difficult-to-cut material due to its inherent properties such as high hot hardness, low thermal conductivity and high chemical reactivity. Though, Ti6Al4V is utilized by industrial sectors such as aeronautics, energy generation, petrochemical and bio-medical etc. For the metal cutting community, competent and cost-effective machining of Ti6Al4V is a challenging task. To optimize cost and machining performance for the machining of Ti6Al4V, finite element based cutting simulation can be a very useful tool. The aim of this paper is to develop a finite element machining model for the simulation of Ti6Al4V machining process. The study incorporates material constitutive models namely Power Law (PL) and Johnson – Cook (JC) material models to mimic the mechanical behaviour of Ti6Al4V. The study investigates cutting temperatures, cutting forces, stresses, and plastic strains with respect to different PL and JC material models with associated parameters. In addition, the numerical study also integrates different cutting tool rake angles in the machining simulations. The simulated results will be beneficial to draw conclusions for improving the overall machining performance of Ti6Al4V.

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

    OpenAIRE

    FOGAP, Njinju Tongwa

    2007-01-01

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

  3. Synaptic conditions for auto-associative memory storage and pattern completion in Jensen et al.'s model of hippocampal area CA3.

    Science.gov (United States)

    Cheu, Eng Yeow; Yu, Jiali; Tan, Chin Hiong; Tang, Huajin

    2012-12-01

    Jensen et al. (Learn Memory 3(2-3):243-256, 1996b) proposed an auto-associative memory model using an integrated short-term memory (STM) and long-term memory (LTM) spiking neural network. Their model requires that distinct pyramidal cells encoding different STM patterns are fired in different high-frequency gamma subcycles within each low-frequency theta oscillation. Auto-associative LTM is formed by modifying the recurrent synaptic efficacy between pyramidal cells. In order to store auto-associative LTM correctly, the recurrent synaptic efficacy must be bounded. The synaptic efficacy must be upper bounded to prevent re-firing of pyramidal cells in subsequent gamma subcycles. If cells encoding one memory item were to re-fire synchronously with other cells encoding another item in subsequent gamma subcycle, LTM stored via modifiable recurrent synapses would be corrupted. The synaptic efficacy must also be lower bounded so that memory pattern completion can be performed correctly. This paper uses the original model by Jensen et al. as the basis to illustrate the following points. Firstly, the importance of coordinated long-term memory (LTM) synaptic modification. Secondly, the use of a generic mathematical formulation (spiking response model) that can theoretically extend the results to other spiking network utilizing threshold-fire spiking neuron model. Thirdly, the interaction of long-term and short-term memory networks that possibly explains the asymmetric distribution of spike density in theta cycle through the merger of STM patterns with interaction of LTM network.

  4. Ameliorative Effect and Its Mechanism of Forsythiaside on Learning and Memory of Composite Alzheimer’s Disease Model Mice

    Institute of Scientific and Technical Information of China (English)

    XIONG Yu-ping; TIAN Ya-jie

    2016-01-01

    Objective: To explore the ameliorative effect of forsythiaside and its mechanism on learning and memory of composite Alzheimer’s disease (AD) model mice. Methods: Fifty SAMP8 mice of 8 months old were randomly divided into negative control group (gavage of distilled water), positive control group (gavage of donepezil), low-, middle-, and high-dose groups (gavage of forsythiaside 60, 120, and 240 mg/kg, respectively), 10 cases for each group. Another 10 SAMR1 male mice of 8-month old were designed as blank control group (gavage of distilled water). After gavage for 30 consecutive days, Morris water maze test was used to conduct behavioral test 1 h after gavage everyday. 24 h after completing behavior test, the vitality of superoxide dismutase (SOD), acetylcholine esterase (AchE), choline acetyl transferase (ChAT), monoamine oxidase (MAO), and glutathion peroxidase (GSH-PX) as well as the content of malondialdehyde (MDA) and nitric oxide (NO) in brain tissue of mice in each group were tested. Results:In water maze test, forsythiaside could improve the learning and memory ability of composite AD model mice. After being given different doses of forsythiaside for a long term, the activity of SOD, ChAT, and GSH-PX increased inordinately and the content of MDA and NO reduced in varying degrees in a dose-dependent manner. Of all, the high-dose forsythiaside group was the best in therapeutic effect. Conclusion: Forsythiaside has a therapeutic effect on the learning and memory impairment of composite AD model mice probably by regulating the mechanism of the cholinergic system and antioxygenation.

  5. C3H/He Mice as an Incompatible Cholangiocarcinoma Model by Clonorchis sinensis, Dicyclanil and N-Nitrosodimethylamine

    Science.gov (United States)

    Uddin, Md. Hafiz; Li, Shunyu; Jin, Yan; Choi, Min-Ho; Jang, Ja June; Hong, Sung-Tae

    2016-01-01

    Clonorchis sinensis is a Group-I bio-carcinogen, associated with cholangiocarcinoma (CCA). The hamster is the only experimental model of C. sinensis-mediated CCA, but we oblige another animal model. The present study intended to develop a C. sinensis (Cs) mediated CCA model using C3H/He mice, co-stimulated with N-nitrosodimethyl-amine (NDMA) and dicyclanil (DC). The mice were divided into 8 groups with different combinations of Cs, NDMA, and DC. Six months later the mice were sacrificed and subjected to gross and histopathological examination. The body weights were significantly reduced among the groups treated with 2 or more agents (eg. Cs+NDMA, Cs+DC, NDMA+DC, and Cs+NDMA+DC). In contrast, liver weight percentages to body weight were increased in above groups by 4.1% to 4.7%. A Change of the spleen weight was observed only in Cs+NDMA group. Though C. sinensis infection is evident from hyperplastic changes, only 1 worm was recovered. T wo mice, 1 from Cs and the other from Cs+DC group, showed mass forming lesions; 1 (281.2 mm3) from the Cs group was a hepatocellular adenoma and the other (280.6 mm3) from the Cs+DC group was a cystic mass (peliosis). Higher prevalence of gray-white nodules was observed in Cs group (42.9%) followed by Cs+NDMA+DC group (21.4%). The mice of the Cs+NDMA+DC group showed hyper-proliferation of the bile duct with fibrotic changes. No characteristic change for CCA was recognized in any of the groups. In conclusion, C3H/He mice produce no CCA but extensive fibrosis when they are challenged by Cs, NDMA, and DC together. PMID:27417082

  6. C3H/He Mice as an Incompatible Cholangiocarcinoma Model by Clonorchis sinensis, Dicyclanil and N-Nitrosodimethylamine.

    Science.gov (United States)

    Uddin, Md Hafiz; Li, Shunyu; Jin, Yan; Choi, Min-Ho; Jang, Ja June; Hong, Sung-Tae

    2016-06-01

    Clonorchis sinensis is a Group-I bio-carcinogen, associated with cholangiocarcinoma (CCA). The hamster is the only experimental model of C. sinensis-mediated CCA, but we oblige another animal model. The present study intended to develop a C. sinensis (Cs) mediated CCA model using C3H/He mice, co-stimulated with N-nitrosodimethyl-amine (NDMA) and dicyclanil (DC). The mice were divided into 8 groups with different combinations of Cs, NDMA, and DC. Six months later the mice were sacrificed and subjected to gross and histopathological examination. The body weights were significantly reduced among the groups treated with 2 or more agents (eg. Cs+NDMA, Cs+DC, NDMA+DC, and Cs+NDMA+DC). In contrast, liver weight percentages to body weight were increased in above groups by 4.1% to 4.7%. A Change of the spleen weight was observed only in Cs+NDMA group. Though C. sinensis infection is evident from hyperplastic changes, only 1 worm was recovered. T wo mice, 1 from Cs and the other from Cs+DC group, showed mass forming lesions; 1 (281.2 mm(3)) from the Cs group was a hepatocellular adenoma and the other (280.6 mm(3)) from the Cs+DC group was a cystic mass (peliosis). Higher prevalence of gray-white nodules was observed in Cs group (42.9%) followed by Cs+NDMA+DC group (21.4%). The mice of the Cs+NDMA+DC group showed hyper-proliferation of the bile duct with fibrotic changes. No characteristic change for CCA was recognized in any of the groups. In conclusion, C3H/He mice produce no CCA but extensive fibrosis when they are challenged by Cs, NDMA, and DC together.

  7. An herbal medicine, Go-sha-jinki-gan (GJG, increases muscle weight in severe muscle dystrophy model mice

    Directory of Open Access Journals (Sweden)

    Yusei Takemoto

    2017-12-01

    Full Text Available Go-sha-jinki-gan (GJG, a traditional Japanese herbal medicine has a clinical implication to alleviate age-related symptoms, especially in some motor disorders. However, the scientific evidence is limited, and there is a possibility to expand the medical application range of GJG. Using senescence-accelerated mice, our group showed that GJG exerted an effect to prevent sarcopenia, the aged-related loss of skeletal muscle. Because muscular dystrophy is characterized by a progressive loss of skeletal muscle, we examined the effects of GJG on a mouse model of muscular dystrophy. Using a newly established mouse model for Duchenne muscular dystrophy (DMD, DBA/2-mdx, we showed that GJG significantly increased the body and skeletal muscle weights in comparison to the control DBA/2-mdx mice, regardless of gender. The increased skeletal muscle mass resulted from an increment in the myofiber size, but not from the myofiber number. Both the skeletal muscle regenerative ability and the accumulation of fibrosis (the dystrophic pathology in GJG-fed DBA/2-mdx mice were comparable to those in control DBA/2-mdx mice, suggesting that the cellular target of GJG is myofibers, with no contribution from the muscle satellite cells neither in an direct nor in an indirect manner. Taken together, GJG increased the skeletal muscle mass in a mouse model of muscular dystrophy, in addition to our previously tested sarcopenia mouse model.

  8. Effects of Chimonanthus nitens Oliv. Leaf Extract on Glycolipid Metabolism and Antioxidant Capacity in Diabetic Model Mice

    Directory of Open Access Journals (Sweden)

    Hui Chen

    2017-01-01

    Full Text Available The paper investigated the antihyperglycemic and antihyperlipidemic efficacy and antioxidant capacity of Chimonanthus nitens Oliv. leaf extract (COE in combination of high-glucose-fat diet-fed and streptozotocin-induced diabetic model mice. Various physiological indexes in diabetic model mice were well improved especially by oral administration of high dose of COE; the results were listed as follows. Fast blood glucose (FBG level and serum triglyceride (TC, total cholesterol (TG, low-density lipoprotein cholesterol (LDLC, and malondialdehyde (MDA as well as MDA in liver were significantly reduced; fasting serum insulin (FINS and insulin sensitivity index (ISI were both increased; high-density lipoprotein cholesterol (HDLC in serum was significantly increased; total antioxidant capacity (T-AOC, activities of superoxide dismutase (SOD, glutathione peroxidase (GSH-Px, and catalase (CAT in serum and liver were apparently enhanced; liver coefficient (LC, liver transaminase, and alkaline phosphatase (ALP were decreased. Furthermore, pancreas islets and liver in diabetic model mice showed some extend of improvement in morphology and function after 4 weeks of COE treatment. In consequence, COE was advantageous to regulate glycolipid metabolism and elevate antioxidant capacity in diabetic model mice. Thus, the present study will provide a scientific evidence for the use of COE in the management of diabetes and its related complications.

  9. Neuropsychiatric Symptom Modeling in Male and Female C57BL/6J Mice after Experimental Traumatic Brain Injury

    Science.gov (United States)

    Tucker, Laura B.; Burke, John F.; Fu, Amanda H.

    2017-01-01

    Abstract Psychiatric symptoms such as anxiety and depression are frequent and persistent complaints following traumatic brain injury (TBI). Modeling these symptoms in animal models of TBI affords the opportunity to determine mechanisms underlying behavioral pathologies and to test potential therapeutic agents. However, testing these symptoms in animal models of TBI has yielded inconsistent results. The goal of the current study was to employ a battery of tests to measure multiple anxiety- and depressive-like symptoms following TBI in C57BL/6J mice, and to determine if male and female mice are differentially affected by the injury. Following controlled cortical impact (CCI) at a parietal location, neither male nor female mice showed depressive-like symptoms as measured by the Porsolt forced-swim test and sucrose preference test. Conclusions regarding anxiety-like behaviors were dependent upon the assay employed; CCI-induced thigmotaxis in the open field suggested an anxiogenic effect of the injury; however, results from the elevated zero maze, light-dark box, and marble-burying tests indicated that CCI reduced anxiety-like behaviors. Fewer anxiety-like behaviors were also associated with the female sex. Increased levels of activity were also measured in female mice and injured mice in these tests, and conclusions regarding anxiety should be taken with caution when experimental manipulations induce changes in baseline activity. These results underscore the irreconcilability of results from studies attempting to model TBI-induced neuropsychiatric symptoms. Changes in injury models or better attempts to replicate the clinical syndrome may improve the translational applicability of rodent models of TBI-induced anxiety and depression. PMID:27149139

  10. Effects of low-dose rate irradiation on two types of type II diabetes model mice

    International Nuclear Information System (INIS)

    Nomura, Takaji; Sakai, Kazuo

    2004-01-01

    The effects of low-dose rate gamma-irradiation were investigated in two mouse strains - C57BL/KsJ-db/db (db mouse) and AKITA (AKITA mouse)-for type II diabetes mellitus. Both strains develop the developed type II diabetes by about 8 weeks of age due to dysfunction of the insulin/insulin receptor. The db Mouse' shows obese and exhibits hyperinsulinism, and the onset of Type II diabetes like resembles that for Westerners. On the other hand, the AKITA mouse has exhibits disordered insulin secretion, and the diabetes such as resembles that of Asians. Ten-week old female mice, in groups of 8 or 12, were irradiated at 0.65 mGy/hr in the low-dose rate irradiation facility in the Low Dose Radiation Research Center. The level of urine glucose was measured with test slips. The urine glucose levels of all of the mice were highly elevated the beginning of the irradiation. In the irradiated group of db mice, three mice showed decrease in glucose level compare to the level of non-irradiated diabetes mice after 35, 52 or 80 weeks of irradiation. All had maintained a normal level thereafter. No such improvement in diabetes was ever observed in the 12 mice of in the non-irradiated control group. The AKITA mice, however, did not decrease the glucose level regardless of the irradiation. Both the db mice and AKITA mice had their lives prolonged their life by the irradiation. The survival rate of db mice at the age of 90 weeks was 75% in the irradiated group, but 50% in the non-irradiated group. The average life span was 104 weeks in the irradiated group and 87 weeks in the control group. Furthermore, a marked difference was furthermore observed in the appearance of the coat hair, skin, and tail; appearances were well preserved in the irradiated group. The average life span in the irradiated AKITA mice was also longer than that for the non-irradiated mice, 51 weeks and 41 weeks in the irradiated and non-irradiated group respectively. These results suggest that the low-dose irradiation

  11. Mathematical Modeling of Tuberculosis Bacillary Counts and Cellular Populations in the Organs of Infected Mice

    Science.gov (United States)

    Bru, Antonio; Cardona, Pere-Joan

    2010-01-01

    Background Mycobacterium tuberculosis is a particularly aggressive microorganism and the host's defense is based on the induction of cellular immunity, in which the creation of a granulomatous structure has an important role. Methodology We present here a new 2D cellular automata model based on the concept of a multifunctional process that includes key factors such as the chemokine attraction of the cells; the role of innate immunity triggered by natural killers; the presence of neutrophils; apoptosis and necrosis of infected macrophages; the removal of dead cells by macrophages, which induces the production of foamy macrophages (FMs); the life cycle of the bacilli as a determinant for the evolution of infected macrophages; and the immune response. Results The results obtained after the inclusion of two degrees of tolerance to the inflammatory response triggered by the infection shows that the model can cover a wide spectrum, ranging from highly-tolerant (i.e. mice) to poorly-tolerant hosts (i.e. mini-pigs or humans). Conclusions This model suggest that stopping bacillary growth at the onset of the infection might be difficult and the important role played by FMs in bacillary drainage in poorly-tolerant hosts together with apoptosis and innate lymphocytes. It also shows the poor ability of the cellular immunity to control the infection, provides a clear protective character to the granuloma, due its ability to attract a sufficient number of cells, and explains why an already infected host can be constantly reinfected. PMID:20886087

  12. Deletion of the App-Runx1 region in mice models human partial monosomy 21

    Directory of Open Access Journals (Sweden)

    Thomas Arbogast

    2015-06-01

    Full Text Available Partial monosomy 21 (PM21 is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21. The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage-sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf. Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21.

  13. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations

    Energy Technology Data Exchange (ETDEWEB)

    Kirman, C.R., E-mail: ckirman@summittoxicology.com [Summit Toxicology, PO Box 3209, Bozeman, MT 59715 (United States); Suh, M.; Proctor, D.M. [ToxStrategies, Mission Viejo, CA (United States); Hays, S.M. [Summit Toxicology, PO Box 3209, Bozeman, MT 59715 (United States)

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. - Highlights: • An improved version of the PBPK model for Cr(VI) toxicokinetics was developed. • The model incorporates data collected to fill important data gaps. • Model predictions for specific age groups and sensitive subpopulations are provided. • Implications to human health risk assessment are discussed.

  14. Forecasting Models for Some Water Quality Parameters of Shatt Al-Hilla River, Iraq

    Directory of Open Access Journals (Sweden)

    Rafa H. Al-Suhili

    2017-07-01

    Full Text Available This paper provides Artificial Neural Networks model versions for forecasting the monthly averages of some chemical water quality parameters of Shatt Al-Hilla River, which is located at Hilla City, south of Iraq. The water quality parameters investigated were Sulphate, Magnesium, Calcium, Alkalinity, and Total Hardness. Results indicate that for Sulphate and Calcium high correlation coefficients models were observed to be (0.9 and 0.88, while for Magnesium, Alkalinity and Hardness low correlation coefficients model were observed to be (0.48,0.58, and 0.51 respectively. Serial correlation behavior of these variables indicate at that high lag time correlations sequences are observed for the first two variables and low ones for the last three water quality parameters. A serial correlation coefficient analysis was done and indicates that as the variable exhibited weak lag correlation structure, then a successful ANN forecasting model could not be obtained even if many trials were done to enhance it's performance, such as increasing the number of nodes, the lagged input variables, and/or changing the learning rate and the momentum term values, or the use of different types of activation functions. On the other hand, those variables that have a strong lag correlation structure can easily fit successful ANN forecasting models

  15. Protective effects of Scrophularia striata in Ovalbumin-induced mice asthma model

    Science.gov (United States)

    2013-01-01

    Background Scrophularia striata Boiss. (Scrophulariaceae) is a plant growing in the northeastern part of Iran and being used as a traditional herb for various inflammatory disorders. This study was designed to investigate the protective effects of the Scrophularia striata extract in Ovalbumin (OVA) induced-asthma mice model. Methods OVA-sensitized mice were intrapritonealy treated with two doses (100 and 200 mg/kg) of the extract on days 8 to 14 separately. Broncoalveolar lavage fluids (BALF) was collected 48 h after the final OVA challenge and then the number of eosinophils and other inflammatory cells were assessed by direct microscopic counting. In addition, total immunoglubolin (Ig) E and OVA-specific IgE levels in serum, IL-4 and IL-5 cytokines in BALF were determined by Enzyme-Linked Immunosorbent Assay. Moreover, phytochemical assay by thin layer chromatography (TLC) and the 2, 2 diphenyl-1-picrylhydrazyl (DPPH) were used to evaluate the main compounds and the antioxidant capacity of the plant extract, respectively. Results The results showed that the main components; including flavonoids, phenolic compounds and phenyl propanoids were presented in the S. striata extract. In addition, the treatment with extract significantly reduced the number of inflammatory cells and suppressed T-helper 2 (Th2) cytokines including IL-4 and IL-5 in BALF. Also, total IgE and OVA-specific IgE levels in the serum decreased. Conclusion Collectively, it is concluded that the extract has the potential to modulate the Th2 cytokines and could be used as immunomodulatory agent in the treatment of allergic asthma. PMID:23837463

  16. Recombinant lambda-phage nanobioparticles for tumor therapy in mice models.

    Science.gov (United States)

    Ghaemi, Amir; Soleimanjahi, Hoorieh; Gill, Pooria; Hassan, Zuhair; Jahromi, Soodeh Razeghi M; Roohvand, Farzin

    2010-05-12

    Lambda phages have considerable potential as gene delivery vehicles due to their genetic tractability, low cost, safety and physical characteristics in comparison to other nanocarriers and gene porters. Little is known concerning lambda phage-mediated gene transfer and expression in mammalian hosts. We therefore performed experiments to evaluate lambda-ZAP bacteriophage-mediated gene transfer and expression in vitro. For this purpose, we constructed recombinant lambda-phage nanobioparticles containing a mammalian expression cassette encoding enhanced green fluorescent protein (EGFP) and E7 gene of human papillomavirus type 16 (lambda-HPV-16 E7) using Lambda ZAP- CMV XR vector. Four cell lines (COS-7, CHO, TC-1 and HEK-239) were transduced with the nanobioparticles. We also characterized the therapeutic anti-tumor effects of the recombinant lambda-HPV-16 E7 phage in C57BL/6 tumor mice model as a cancer vaccine. Obtained results showed that delivery and expression of these genes in fibroblastic cells (COS-7 and CHO) are more efficient than epithelial cells (TC-1 and HEK-239) using these nanobioparticles. Despite the same phage M.O.I entry, the internalizing titers of COS-7 and CHO cells were more than TC-1 and HEK-293 cells, respectively. Mice vaccinated with lambda-HPV-16 E7 are able to generate potent therapeutic antitumor effects against challenge with E7- expressing tumor cell line, TC-1 compared to group treated with the wild phage. The results demonstrated that the recombinant lambda-phages, due to their capabilities in transducing mammalian cells, can also be considered in design and construction of novel and safe phage-based nanomedicines.

  17. Detection of oral early cancerous lesion by using polarization-sensitive optical coherence tomography: mice model

    Science.gov (United States)

    Lee, Hong-Yi; Chen, Ping-Hsien; Lee, Tzu-Han; Chang, Kuo-Wei; Kuo, Wen-Chuan

    2018-02-01

    Oral cancer is the 11th most common cancer worldwide, especially in a male adult. The median age of death in oral cancer was 55 years, 10-20 years earlier than other cancers. Presently, oral cancer is often found in late stage, because the lesion is often flat in early stage and is difficult to diagnose under traditional white light imaging. The only definitive method for determining cancer is an invasive biopsy and then using histology examination. How to detect precancerous lesions or early malignant lesions is an important issue for improving prognosis of oral cancer. Optical coherence tomography (OCT) is a new optical tool for diagnosing early malignant lesions in the skin or gastrointestinal tract recently. Here we report a new method for detecting precancerous or early malignant oral lesions by using swept source polarization-sensitive optical coherence tomography (PS-OCT) with center-wavelength 1310 nm, bandwidth 110 nm and 100 kHz swept rate. We used all single-mode fiber design to detect the change of birefringence information in the epithelium structure. This system has an advantage that enables measurement of backscattered intensity and birefringence simultaneously with only one A-scan per transverse location. In preliminary result, we computed the slope of the every A-scan signal in tissue part using a linear-curve fitting in backscattered intensity and birefringence on the enface. In this research, we used an oral cancer mice model for observing the change of structure and birefringence properties in different stages of oral cancer mice. We presented the parametric enface imaging that can detect the early oral malignant lesions.

  18. Antidepressant-like effect of aqueous extract of Channa striatus fillet in mice models of depression.

    Science.gov (United States)

    Saleem, A M; Taufik Hidayat, M; Mat Jais, A M; Fakurazi, S; Moklas, Mohamad; Sulaiman, M R; Amom, Z

    2011-07-01

    Channa (C.) striatus (Malay-Haruan), is a fresh water snakehead fish, consumed as a rejuvenating diet in post-parturition period in local Malay population. The aqueous extract of C. striatus fillet (AECSF) was reported to act through serotonergic receptor system in a previous study. There is no scientific report on neuropharmacological effects of C. striatus. Based on these data, the antidepressant-like effect of C. striatus was evaluated in mice models of depression. AECSF was prepared by steaming the fillets as described previously. Antidepressant activity was studied in male ICR mice using forced swimming test (FST) and tail suspension test (TST). Open-field test was used to evaluate any psychomotor stimulant activity. AECSF was administered intraperitoneally at the concentrations of 30%, 40% and 50% w/v at the dosage of 10 ml/kg. Amitriptyline (10 mg/kg) was used as positive control. All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly reduced the immobility time (p open-field test. AECSF produced significant reduction of immobility time in both FST and TST. Amitriptyline produced a significant reduction of immobility time in both FST and TST similar to previous findings. The AECSF produced a dose-dependent decrease in locomotor activity in the open-field test. This hypolocomotion effect indicated the absence of any psychomotor stimulant activity thereby supporting the antidepressant-like effect of the AECSF. The pharmacological mechanisms of the observed antidepressant-like effect and hypolocomotion effect are not understood from our study. Hence, further studies are required.

  19. Preparation and biodistribution of 99Tcm-lomefloxacin in inflammatory model mice

    International Nuclear Information System (INIS)

    Liu Jianfeng; Han Jiankui; Zhang Chao; Hou Guihua

    2009-01-01

    Objective: The study of 99 TC m -ciprofloxacin, a fluoroquinolones antibiotic, as a tracer for infection and inflammation imaging has been reported. The aim of this study was to investigate the radio-labeling and biodistribution of lomefloxacin (fluoroquinolones analogue) as an inflammatory imaging agent. Methods: 99 TC m -lomefloxacin was prepared and it underwent quality control with thin layer chromatography (TLC). The different labeling conditions were compared. The radiochemical purity, labeling efficiency, stability and lipid/water partition coefficient of 99 TC m -lomefloxacin were measured. The binding activities of 99 TC m -lomefloxacin with Staphylococci aureus (S. aureus)in vitro were tested. 99 TC m -lomefloxacin was in-ieeted through tail vein in the S. aureus-induced inflammatory model mice. The mice were sacrificed and their blood. inflammatory muscles. major organs were taken out at different time after tracer inieetion. Then the radioactivity count of these samples was measured to observe biodistribution. Whole-body radioauto-graphic images were obtained with storage phosphor screen system. Variance analysis using Concise Statis-tics 10.3 software was performed. Results: 99 TC m -lomefloxacin was lipid-soluble with labeling efficiency of 97.5%. The radiochemieal purity was more than 95% at 6 h after storing in room temperature. In vitro test 99 TC m -lomefloxacin showed good binding characteristic with S. auaresu and was positively correlated with the colony number of S. aureus. The highest binding appeared at 1 h. In vivo 99 TC 5 m-lomefloxacin apparently accumulated in inflammatory tissues at 2 h after tracer injection with the uptake ratio of 4.07 ± 1.05 in inflammatory muscles to control muscles. Whole-body autoradiography showed that all inflammation foci were visualized. Conclusion: 99 TC m -lomefloxacin may be a novel potential agent for inflammatory imaging. (authors)

  20. Analytical models for the 2DEG concentration and gate leakage current in AlGaN/GaN HEMTs

    Science.gov (United States)

    Ahmed, Nadim; Dutta, Aloke K.

    2017-06-01

    In this paper, we present a completely analytical model for the 2DEG concentration in AlGaN/GaN HEMTs as a function of gate bias, considering the donor-like trap states present at the metal/AlGaN interface to be the primary source of 2DEG carriers. To the best of our knowledge, this is a completely new contribution of this work. The electric field in the AlGaN layer is calculated using this model, which is further used to model the gate leakage current under reverse bias. We have modified the existing TTT (Thermionic Trap-Assisted Tunneling) current model, taking into account the effect of both metal/AlGaN interface traps as well as AlGaN bulk traps. The gate current under forward bias is also modeled using the existing thermionic emission model, approximating it by its Taylor series expansion. To take into account the effect of non-zero drain-source bias (VDS), an empirical fitting parameter is introduced in order to model the channel voltage in terms of VDS. The results of our models have been compared with the experimental data reported in the literature for three different devices, and the match is found to be excellent for both forward and reverse bias as well as for zero and non-zero VDS.

  1. Current collapse modeling in AlGaN/GaN HEMT using small signal equivalent circuit for high power application

    Science.gov (United States)

    Nirmal, D.; Arivazhagan, L.; Fletcher, A. S. Augustine; Ajayan, J.; Prajoon, P.

    2018-01-01

    In this paper, the drain current collapse in AlGaN/GaN High Electron Mobility Transistor (HEMT) with field plate engineering is investigated. A small signal equivalent circuit of AlGaN/GaN HEMT is developed and a new drain current model is derived. This model is useful to correlate the impact of intrinsic capacitance and conductance on drain current collapse. The proposed device suppressed the current collapse phenomena by 10% compared with the conventional AlGaN/GaN HEMT. Moreover, the DC characteristics of the simulated device shows a drain current of 900 mA/mm, breakdown voltage of 291 V and transconductance of 175 mS/mm. Besides, the intrinsic capacitance and conductance parameters are extracted and its impact on drain current is analysed. Finally, the simulation results obtained were in compliance with the derived mathematical model of AlGaN/GaN HEMT.

  2. Pseudomonas aeruginosa biofilm aggravates skin inflammatory response in BALB/c mice in a novel chronic wound model

    DEFF Research Database (Denmark)

    Trøstrup, Hannah; Thomsen, Kim; Christophersen, Lars J

    2013-01-01

    model in C3H/HeN and BALB/c mice. The chronic wound was established by an injection of seaweed alginate-embedded P. aeruginosa PAO1 beneath a third-degree thermal lesion providing full thickness skin necrosis, as in human chronic wounds. Cultures revealed growth of PA, and both alginate with or without......Chronic wounds are presumed to persist in the inflammatory state, preventing healing. Emerging evidence indicates a clinical impact of bacterial biofilms in soft tissues, including Pseudomonas aeruginosa (PA) biofilms. To further investigate this, we developed a chronic PA biofilm wound infection...... bacteria organized in clusters, resembling biofilms, and inflammation located adjacent to the PA. The chronic wound infection showed a higher number of PAO1 in the BALB/c mice at day 4 after infection as compared to C3H/HeN mice (p

  3. Gamma aminobutyric acid transporter subtype 1 gene knockout mice: a new model for attention deficit/hyperactivity disorder

    Institute of Scientific and Technical Information of China (English)

    Ping Yang; Guoqiang Cai; Youqing Cai; Jian Fei; Guoxiang Liu

    2013-01-01

    Attention deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity,impaired sustained attention,impulsivity,and is usually accompanied by varying degrees of learning difficulties and lack of motor coordination.However,the pathophysiology and etiology of ADHD remain inconclusive so far.Our previous studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1-/-)is hyperactive and exhibited impaired memory performance in the Morris water maze.In the current study,we found that the gat1-/-mice showed low levels of attentional focusing and increased impulsivity.In addition,the gat1-/-mice displayed ataxia characterized by defects in motor coordination and balance skills.The hyperactivity in the ko mice was reduced by both methylphenidate and amphetamine.Collectively,these results suggest that GAT1 ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD.

  4. Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease

    Directory of Open Access Journals (Sweden)

    Bissada Nagat

    2011-08-01

    Full Text Available Abstract Background Huntington Disease (HD is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2 activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/- to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest. Results YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2. Conclusions The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.

  5. Kaempferol attenuates acute lung injury in caecal ligation and puncture model of sepsis in mice.

    Science.gov (United States)

    Rabha, Dipankar Jyoti; Singh, Thakur Uttam; Rungsung, Soya; Kumar, Tarun; Parida, Subhashree; Lingaraju, Madhu Cholenahalli; Paul, Avishek; Sahoo, Monalisa; Kumar, Dinesh

    2018-03-01

    Kaempferol is a flavonoid and important part of the diet. Kaempferol has shown antioxidant, antiinflammatory and antidiabetic activities in various studies. However, protective potential of kaempferol in acute lung injury induced by sepsis and its mechanism remains unclear. The present study was undertaken to evaluate the effect of kaempferol in sepsis-induced acute lung injury in mice and its possible mechanism of action. Acute lung injury was induced by CLP surgery in mice. Kaempferol (100 mg/kg bw) was administered orally one hour before caecal ligation and puncture surgery in mice. Mice were divided into four groups sham, KEM+sham, sepsis (CLP), and KEM+sepsis. Assessment of lung injury was done by estimation of protein content in lung tissue, lung edema, proinflammatory cytokines in plasma and lung tissue, oxidative stress, antioxidant enzymes, nitrite production, and histopathology. Kaempferol pretreated mice showed significant (P Kaempferol pretreatment showed reduction in cytokines IL-6, IL-1β, and TNF-α in plasma as well as in lung tissue in comparison with septic mice without pretreatment. Pretreatment with kaempferol did not show any reduction in MDA level in comparison with septic mice. Antioxidant enzymes SOD and catalase and nonenzymatic antioxidant GSH activities were also increased with kaempferol pretreatment in septic mice. Further, kaempferol pretreatment reduced the lung tissue nitrite level (P Kaempferol pretreatment did not decrease bacterial load in septic mice. Mice pretreated with kaempferol followed by sepsis showed lesser infiltration of cells and more arranged alveolar structure in histopathological analysis. The study suggests that kaempferol showed attenuation in sepsis-induced acute lung injury in mice through suppression of oxidative stress, iNOS, and ICAM-1 pathways.

  6. RT-PCR detection of Candida albicans ALS gene expression in the reconstituted human epithelium (RHE) model of oral candidiasis and in model biofilms.

    Science.gov (United States)

    Green, Clayton B; Cheng, Georgina; Chandra, Jyotsna; Mukherjee, Pranab; Ghannoum, Mahmoud A; Hoyer, Lois L

    2004-02-01

    An RT-PCR assay was developed to analyse expression patterns of genes in the Candida albicans ALS (agglutinin-like sequence) family. Inoculation of a reconstituted human buccal epithelium (RHE) model of mucocutaneous candidiasis with strain SC5314 showed destruction of the epithelial layer by C. albicans and also formation of an upper fungal layer that had characteristics similar to a biofilm. RT-PCR analysis of total RNA samples extracted from C. albicans-inoculated buccal RHE showed that ALS1, ALS2, ALS3, ALS4, ALS5 and ALS9 were consistently detected over time as destruction of the RHE progressed. Detection of transcripts from ALS7, and particularly from ALS6, was more sporadic, but not associated with a strictly temporal pattern. The expression pattern of ALS genes in C. albicans cultures used to inoculate the RHE was similar to that observed in the RHE model, suggesting that contact of C. albicans with buccal RHE does little to alter ALS gene expression. RT-PCR analysis of RNA samples extracted from model denture and catheter biofilms showed similar gene expression patterns to the buccal RHE specimens. Results from the RT-PCR analysis of biofilm RNA specimens were consistent between various C. albicans strains during biofilm development and were comparable to gene expression patterns in planktonic cells. The RT-PCR assay described here will be useful for analysis of human clinical specimens and samples from other disease models. The method will provide further insight into the role of ALS genes and their encoded proteins in the diverse interactions between C. albicans and its host.

  7. An Animal Model of Trichloroethylene-Induced Skin Sensitization in BALB/c Mice.

    Science.gov (United States)

    Wang, Hui; Zhang, Jia-xiang; Li, Shu-long; Wang, Feng; Zha, Wan-sheng; Shen, Tong; Wu, Changhao; Zhu, Qi-xing

    2015-01-01

    Trichloroethylene (TCE) is a major occupational hazard and environmental contaminant that can cause multisystem disorders in the form of occupational medicamentosa-like dermatitis. Development of dermatitis involves several proinflammatory cytokines, but their role in TCE-mediated dermatitis has not been examined in a well-defined experimental model. In addition, few animal models of TCE sensitization are available, and the current guinea pig model has apparent limitations. This study aimed to establish a model of TCE-induced skin sensitization in BALB/c mice and to examine the role of several key inflammatory cytokines on TCE sensitization. The sensitization rate of dorsal painted group was 38.3%. Skin edema and erythema occurred in TCE-sensitized groups, as seen in 2,4-dinitrochlorobenzene (DNCB) positive control. Trichloroethylene sensitization-positive (dermatitis [+]) group exhibited increased thickness of epidermis, inflammatory cell infiltration, swelling, and necrosis in dermis and around hair follicle, but ear painted group did not show these histological changes. The concentrations of serum proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 were significantly increased in 24, 48, and 72 hours dermatitis [+] groups treated with TCE and peaked at 72 hours. Deposition of TNF-α, IFN-γ, and IL-2 into the skin tissue was also revealed by immunohistochemistry. We have established a new animal model of skin sensitization induced by repeated TCE stimulations, and we provide the first evidence that key proinflammatory cytokines including TNF-α, IFN-γ, and IL-2 play an important role in the process of TCE sensitization. © The Author(s) 2015.

  8. Interpolation Routines Assessment in ALS-Derived Digital Elevation Models for Forestry Applications

    Directory of Open Access Journals (Sweden)

    Antonio Luis Montealegre

    2015-07-01

    Full Text Available Airborne Laser Scanning (ALS is capable of estimating a variety of forest parameters using different metrics extracted from the normalized heights of the point cloud using a Digital Elevation Model (DEM. In this study, six interpolation routines were tested over a range of land cover and terrain roughness in order to generate a collection of DEMs with spatial resolution of 1 and 2 m. The accuracy of the DEMs was assessed twice, first using a test sample extracted from the ALS point cloud, second using a set of 55 ground control points collected with a high precision Global Positioning System (GPS. The effects of terrain slope, land cover, ground point density and pulse penetration on the interpolation error were examined stratifying the study area with these variables. In addition, a Classification and Regression Tree (CART analysis allowed the development of a prediction uncertainty map to identify in which areas DEMs and Airborne Light Detection and Ranging (LiDAR derived products may be of low quality. The Triangulated Irregular Network (TIN to raster interpolation method produced the best result in the validation process with the training data set while the Inverse Distance Weighted (IDW routine was the best in the validation with GPS (RMSE of 2.68 cm and RMSE of 37.10 cm, respectively.

  9. Modeling and Analysis of CNC Milling Process Parameters on Al3030 based Composite

    Science.gov (United States)

    Gupta, Anand; Soni, P. K.; Krishna, C. M.

    2018-04-01

    The machining of Al3030 based composites on Computer Numerical Control (CNC) high speed milling machine have assumed importance because of their wide application in aerospace industries, marine industries and automotive industries etc. Industries mainly focus on surface irregularities; material removal rate (MRR) and tool wear rate (TWR) which usually depends on input process parameters namely cutting speed, feed in mm/min, depth of cut and step over ratio. Many researchers have carried out researches in this area but very few have taken step over ratio or radial depth of cut also as one of the input variables. In this research work, the study of characteristics of Al3030 is carried out at high speed CNC milling machine over the speed range of 3000 to 5000 r.p.m. Step over ratio, depth of cut and feed rate are other input variables taken into consideration in this research work. A total nine experiments are conducted according to Taguchi L9 orthogonal array. The machining is carried out on high speed CNC milling machine using flat end mill of diameter 10mm. Flatness, MRR and TWR are taken as output parameters. Flatness has been measured using portable Coordinate Measuring Machine (CMM). Linear regression models have been developed using Minitab 18 software and result are validated by conducting selected additional set of experiments. Selection of input process parameters in order to get best machining outputs is the key contributions of this research work.

  10. Continuum modeling of {10Ῑ2} twinning in a Mg-3%Al-1%Zn rolled sheet

    Directory of Open Access Journals (Sweden)

    Pérez-Prado, M. T.

    2010-12-01

    Full Text Available Acrystal plasticity continuum model with differentiated self- and cross- hardeningmechanisms for twin and slip systems has been utilized to predict the slip/twin activities and texture evolution in a rolled and annealed Mg-3%Al-1%Zn sheet compressed along the rolling direction (RD and tensile tested along the normal direction (ND. The contribution of twinning is significantly larger during tension along ND, leading to a significant texture change with strain. A good correlation is found between simulations and recent experimental results.

    Un modelo continuo de plasticidad cristalina, que contempla los mecanismos de auto-endurecimiento y endurecimiento cruzado para los sistemas de maclado y deslizamiento, se ha utilizado para predecir las actividades de deslizamiento y del maclado, así como la evolución de la textura, de una chapa laminada y recocida de la aleación de magnesio Mg-3%Al-1%Zn ensayada en compresión, a lo largo de la dirección de laminación (DL y en tensión, a lo largo de la dirección normal (DN. Se encontró que la contribución del maclado es mucho más importante cuando la muestra se tensiona a lo lago de DN, lo que da lugar a un cambio fuerte de textura. Se observó una buena correspondencia entre las simulaciones y resultados experimentales recientes.

  11. Persistent Coxiella burnetii infection in mice overexpressing IL-10: an efficient model for chronic Q fever pathogenesis.

    Directory of Open Access Journals (Sweden)

    Soraya Meghari

    2008-02-01

    Full Text Available Interleukin (IL-10 increases host susceptibility to microorganisms and is involved in intracellular persistence of bacterial pathogens. IL-10 is associated with chronic Q fever, an infectious disease due to the intracellular bacterium Coxiella burnetii. Nevertheless, accurate animal models of chronic C. burnetii infection are lacking. Transgenic mice constitutively expressing IL-10 in macrophages were infected with C. burnetti by intraperitoneal and intratracheal routes and infection was analyzed through real-time PCR and antibody production. Transgenic mice exhibited sustained tissue infection and strong antibody response in contrast to wild-type mice; thus, bacterial persistence was IL-10-dependent as in chronic Q fever. The number of granulomas was low in spleen and liver of transgenic mice infected through the intraperitoneal route, as in patients with chronic Q fever. Macrophages from transgenic mice were unable to kill C. burnetii. C. burnetii-stimulated macrophages were characterized by non-microbicidal transcriptional program consisting of increased expression of arginase-1, mannose receptor, and Ym1/2, in contrast to wild-type macrophages in which expression of inducible NO synthase and inflammatory cytokines was increased. In vivo results emphasized macrophage data. In spleen and liver of transgenic mice infected with C. burnetii by the intraperitoneal route, the expression of arginase-1 was increased while microbicidal pathway consisting of IL-12p40, IL-23p19, and inducible NO synthase was depressed. The overexpression of IL-10 in macrophages prevents anti-infectious competence of host, including the ability to mount granulomatous response and microbicidal pathway in tissues. To our knowledge, this is the first efficient model for chronic Q fever pathogenesis.

  12. Protective effects of white button mushroom (Agaricus bisporus against hepatic steatosis in ovariectomized mice as a model of postmenopausal women.

    Directory of Open Access Journals (Sweden)

    Noriko Kanaya

    Full Text Available Nonalcoholic fatty liver disease (NAFLD includes various hepatic pathologies ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH, fibrosis and cirrhosis. Estrogen provides a protective effect on the development of NAFLD in women. Therefore, postmenopausal women have a higher risk of developing NAFLD. Hepatic steatosis is an early stage of fatty liver disease. Steatosis can develop to the aggressive stages (nonalcoholic steatohepatitis, fibrosis and cirrhosis. Currently, there is no specific drug to prevent/treat these liver diseases. In this study, we found that white button mushroom (WBM, Agaricus Bisporus, has protective effects against liver steatosis in ovariectomized (OVX mice (a model of postmenopausal women. OVX mice were fed a high fat diet supplemented with WBM powder. We found that dietary WBM intake significantly lowered liver weight and hepatic injury markers in OVX mice. Pathological examination of liver tissue showed less fat accumulation in the livers of mice on WBM diet; moreover, these animals had improved glucose clearance ability. Microarray analysis revealed that genes related to the fatty acid biosynthesis pathway, particularly the genes for fatty acid synthetase (Fas and fatty acid elongase 6 (Elovl6, were down-regulated in the liver of mushroom-fed mice. In vitro mechanistic studies using the HepG2 cell line showed that down-regulation of the expression of FAS and ELOVL6 by WBM extract was through inhibition of Liver X receptor (LXR signaling and its downstream transcriptional factor SREBP1c. These results suggest that WBM is protective against hepatic steatosis and NAFLD in OVX mice as a model for postmenopausal women.

  13. Inhibitory effects on bone resorption in postmenopausal osteoporosis model mice by delivery of serum calcium decreasing factor (caldecrin) gene

    International Nuclear Information System (INIS)

    Oi, Michi; Kido, Seisui; Hasegawa, Hiroya; Fujimoto, Kengo; Tomomura, Mineko; Kanegae, Haruhide; Suda, Naoto; Tomomura, Akito

    2011-01-01

    Osteoporosis is a common condition in which decrease in the bone volume and strength occurs due to increased bone resorption. Caldecrin is a serine protease, with a molecular weight of 28kDa, and it is the causative factor of hypocalcemia frequently seen in acute pancreatitis. Recent reports have shown that caldecrin also acts to inhibit both differentiation of the osteoclasts and function of the mature osteoclasts. In this study, the osteoporosis model mice were used and bilateral ovariectomy was conducted in these mice. Effect of bone absorption was estimated after introducing genetically the pCaldecrin-IRES-hrGFP expressing vector into the femoral muscle by use of the hemagglutinating virus of Japan (HVJ)-liposomes. After the bilateral ovariectomy, serum calcium levels were raised and the bone mass of the femur was decreased. However, in the genetically introduced groups of the model mice, serum calcium levels were significantly lowered. Concomitantly, significant increase in bone density, trabecular width and number of trabecular was observed. Moreover, based on the histological findings, inhibition of bone resorption in the caldecrin-introduced osteoporosis model mice was confirmed. The present study indicates that caldecrin can be expected to become a novel cure for osteoporosis. (author)

  14. A Unified Physical Model for Creep and Hot Working of Al-Mg Solid Solution Alloys

    Directory of Open Access Journals (Sweden)

    Stefano Spigarelli

    2017-12-01

    Full Text Available The description of the dependence of steady-state creep rate on applied stress and temperature is almost invariably based on the Norton equation or on derived power-law relationships. In hot working, the Norton equation does not work, and is therefore usually replaced with the Garofalo (sinh equation. Both of these equations are phenomenological in nature and can be seldom unambiguously related to microstructural parameters, such as dislocation density, although early efforts in this sense led to the introduction of the “natural power law” with exponent 3. In an attempt to overcome this deficiency, a recent model with sound physical basis has been successfully used to describe the creep response of fcc metals, such as copper. The main advantage of this model is that it does not require any data fitting to predict the strain rate dependence on applied stress and temperature, which is a particularly attractive peculiarity when studying the hot workability of metals. Thus, the model, properly modified to take into account solid solution strengthening effects, has been here applied to the study of the creep and hot-working of simple Al-Mg single phase alloys. The model demonstrated an excellent accuracy in describing both creep and hot working regimes, still maintaining its most important feature, that is, it does not require any fitting of the experimental data.

  15. Phase constitution and interface structure of nano-sized Ag-Cu/AlN multilayers: Experiment and ab initio modeling

    Energy Technology Data Exchange (ETDEWEB)

    Pigozzi, Giancarlo; Janczak-Rusch, Jolanta; Passerone, Daniele; Antonio Pignedoli, Carlo; Patscheider, Joerg; Jeurgens, Lars P. H. [Empa, Swiss Federal Laboratories for Materials Science and Technology, Ueberlandstrasse 129, CH-8600 Duebendorf (Switzerland); Antusek, Andrej [Empa, Swiss Federal Laboratories for Materials Science and Technology, Ueberlandstrasse 129, CH-8600 Duebendorf (Switzerland); Faculty of Materials Science and Technology, Slovak University of Technology in Bratislava, Paulinska 16, 917 24 Trnava (Slovakia); Parlinska-Wojtan, Magdalena [Empa, Swiss Federal Laboratories for Materials Science and Technology, Ueberlandstrasse 129, CH-8600 Duebendorf (Switzerland); University of Rzeszow, Institute of Physics, ul. Rejtana 16a, 35-959 Rzeszow (Poland); Bissig, Vinzenz [Kirsten Soldering AG, Hinterbergstrasse 32, CH-6330 Cham (Switzerland)

    2012-10-29

    Nano-sized Ag-Cu{sub 8nm}/AlN{sub 10nm} multilayers were deposited by reactive DC sputtering on {alpha}-Al{sub 2}O{sub 3}(0001) substrates. Investigation of the phase constitution and interface structure of the multilayers evidences a phase separation of the alloy sublayers into nanosized grains of Ag and Cu. The interfaces between the Ag grains and the quasi-single-crystalline AlN sublayers are semi-coherent, whereas the corresponding Cu/AlN interfaces are incoherent. The orientation relationship between Ag and AlN is constant throughout the entire multilayer stack. These observations are consistent with atomistic models of the interfaces as obtained by ab initio calculations.

  16. Compensatory mechanisms in genetic models of neurodegeneration: are the mice better than humans?

    Directory of Open Access Journals (Sweden)

    Grzegorz eKreiner

    2015-03-01

    Full Text Available Neurodegenerative diseases are one of the main causes of mental and physical disabilities. Neurodegeneration has been estimated to begin many years before the first clinical symptoms manifest, and even a prompt diagnosis at this stage provides very little advantage for a more effective treatment as the currently available pharmacotherapies are based on disease symptomatology. The etiology of the majority of neurodegenerative diseases remains unknown, and even for those diseases caused by identified genetic mutations, the direct pathways from gene alteration to final cell death have not yet been fully elucidated. Advancements in genetic engineering have provided many transgenic mice that are used as an alternative to pharmacological models of neurodegenerative diseases. Surprisingly, even the models reiterating the same causative mutations do not fully recapitulate the inevitable neuronal loss, and some fail to even show phenotypic alterations, which suggests the possible existence of compensatory mechanisms. A better evaluation of these mechanisms may not only help us to explain why neurodegenerative diseases are mostly late-onset disorders in humans but may also provide new markers and targets for novel strategies designed to extend neuronal function and survival. The aim of this mini-review is to draw attention to this under-explored field in which investigations may reasonably contribute to unveiling hidden reserves in the organism.

  17. Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice

    Science.gov (United States)

    Sherman, Maxwell A.; Lee, Shane; Law, Robert; Haegens, Saskia; Thorn, Catherine A.; Hämäläinen, Matti S.; Moore, Christopher I.; Jones, Stephanie R.

    2016-01-01

    Human neocortical 15–29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (∼50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. PMID:27469163

  18. Atomistic modelling of the interdiffusion of Al in the UMo based fuel

    International Nuclear Information System (INIS)

    Garces, Jorge E.; Marino, Armando C.; Bozzolo, Guillermo

    2002-01-01

    The analysis of the initial stages and trends in the process of interdiffusion of Al in the UMo solid solution as a function of Mo concentration is made using the BFS method for alloys. The approach presented in this work helps to understand the exchange mechanism between adatoms and substrate atoms in the binary systems, leading to the behavior observed in the ternary Al-U-Mo system. While in Al/U Al atoms show a noticeable tendency to interdiffusion in the bulk, in Al/Mo the same atoms show a tendency to layer-by-layer growth and the formation of structures in the overlayer. In the case of Al/U-Mo, the two competing behaviors observed for Al/Mo and Al/U, translate into the role of regions rich in Mo acting as interdiffusion barriers, in excellent agreement with experimental evidence. (author)

  19. Stochastic modeling of columnar dendritic grain growth in weld pool of Al-Cu alloy

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Z.B.; Tian, N. [The State Key Laboratory of Advanced Welding Production Technology, Harbin Institute of Technology, Harbin (China); Wei, Y.H. [College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing (China); The State Key Laboratory of Advanced Welding Production Technology, Harbin Institute of Technology, Harbin (China); Zhan, X.H.

    2009-04-15

    A multi-scale model is used to simulate columnar dendritic growth in TIG (tungsten inert-gas) weld molten pool of Al-Cu alloy. The grain morphologies at the edge of the weld pool are studied. The simulated results indicate that the average primary dendrite spacing changes during the solidification process in the weld pool because of the complicated thermal field, solute diffusion field and competitive growth. And it is shown that the secondary dendrite arms grow insufficiently in the space between dendrite trunks if the primary dendrite spacing is small. And the phenomenon has been explained by analyzing the influence of the solute accumulation on the constitutional undercooling and undercooling gradient when there are two different opposite solute diffusion fields. (copyright 2009 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  20. Modelling of anisotropy for Al-Li 2099 T83 extrusions and effect of precipitate density

    International Nuclear Information System (INIS)

    Bois-Brochu, Alexandre; Blais, Carl; Tchitembo Goma, Franck Armel; Larouche, Daniel

    2016-01-01

    The development of aluminum-lithium alloys for aerospace applications requires a thorough understanding of how processing and product geometry impact their microstructure, texture and mechanical properties. The anisotropy of the mechanical properties is in part related to the deformation texture formed during thermo-mechanical processing. In this study, two different extrusions of Al-Li 2099 T83 were characterized, a cylindrical extrusion and an integrally stiffened panel (ISP). A model is proposed to predict mechanical properties and their anisotropy as a function of the <111> fiber texture. Furthermore, the volume fraction of precipitates was measured in zones of high anisotropy (cylindrical extrusion) and low anisotropy (ISP). Results show that there is no significant difference between the two parts concerning volume fraction of precipitates.

  1. Modelling of anisotropy for Al-Li 2099 T83 extrusions and effect of precipitate density

    Energy Technology Data Exchange (ETDEWEB)

    Bois-Brochu, Alexandre, E-mail: Alexandre.Bois-Brochu.1@ulaval.ca; Blais, Carl, E-mail: Carl.Blais@gmn.ulaval.ca; Tchitembo Goma, Franck Armel, E-mail: Franck-Armel.Tchitembo-Goma.1@ulaval.ca; Larouche, Daniel, E-mail: Daniel.Larouche@gmn.ulaval.ca

    2016-09-15

    The development of aluminum-lithium alloys for aerospace applications requires a thorough understanding of how processing and product geometry impact their microstructure, texture and mechanical properties. The anisotropy of the mechanical properties is in part related to the deformation texture formed during thermo-mechanical processing. In this study, two different extrusions of Al-Li 2099 T83 were characterized, a cylindrical extrusion and an integrally stiffened panel (ISP). A model is proposed to predict mechanical properties and their anisotropy as a function of the <111> fiber texture. Furthermore, the volume fraction of precipitates was measured in zones of high anisotropy (cylindrical extrusion) and low anisotropy (ISP). Results show that there is no significant difference between the two parts concerning volume fraction of precipitates.

  2. Computational Study of Ethanol Conversion on Al 8 O 12 as a Model for γ-Al 2 O 3

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Zongtang; Wang, Yong; Dixon, David A.

    2015-10-15

    Correlated molecular orbital theory at the coupled cluster CCSD(T) level with density functional theory geometries is used to study ethanol dehydration, dehydrogenation, and condensation reactions on an the Al8O12 cluster which is a model for γ-Al2O3. The Al in the active site on the cluster is a strong Lewis acid. The reactions begin with formation of a very stable Lewis acid–base ethanol–cluster adduct. Dehydration proceeds by β-H transfer to a bicoordinate oxygen leading to the direct formation of ethylene and two OH groups following an E2 mechanism. Dehydrogenation proceeds directly by α-H transfer to the active metal center and a proton transfer to a bicoordinate bridge O to form acetaldehyde plus a metal hydride and a hydroxyl, again an E2 mechanism. After addition of a second ethanol, diethyl ether is generated by an α-C transfer from the first to the second ethanol, an acid-driven SN2 mechanism. Condensation and dehydration with two alcohols have comparable energy barriers. The addition of a second ethanol or a water molecule raises the energy barriers. Condensation and dehydration are predicted to be more likely than dehydrogenation. The computational results for the mechanism and the energetics agree well with the available experimental data.

  3. Thermodynamic modelling and Gulliver-Scheil simulation of multi-component Al alloys

    International Nuclear Information System (INIS)

    Du Yong; Liu Shuhong; Chang, Keke; Hu Biao; Bu Mengjie; Jie Wanqi; Huang Weidong; Wang Jincheng

    2012-01-01

    Based on critical review for the available experimental phase diagram data of the Al-Cu-Fe-Mn, Al-Cu-Fe-Ni, Al-Cu-Fe-Si, Al-Fe-Mg-Si, Al-Fe-Mn-Si, and Al-Mg-Mn-Zn systems, a set of self-consistent thermodynamic parameters for these systems has been established using CALPHAD approach. In combination with the constituent binary, ternary, and quaternary systems, a thermodynamic database for the Al-Cu-Fe-Mg-Mn-Ni-Si-Zn system is developed. The calculated phase diagrams and invariant reactions agree well with the experimental data. The obtained database has been used to describe the solidification behaviour of Al alloys: Al365.1(91.95Al-0.46Fe-0.3Mg-0.32Mn-6.97Si, in wt.%) and Al365.2 (92.77Al-0.08Fe-0.35Mg-6.8Si, in wt.%) under both equilibrium and Gulliver-Scheil non-equilibrium conditions. The reliability of the present thermodynamic database is verified by the good agreement between calculation and measurement for both equilibrium and Gulliver–Scheil non-equilibrium solidification.

  4. Biodistribution dosimetric study of radiopharmaceutical 99mTc Ixolaris in mice for melanoma diagnosis by molecular image and translational model for human beings

    International Nuclear Information System (INIS)

    Soriano, Sarah Canuto Silva

    2015-01-01

    The labeling of Ixolaris with 99m Tc was developed by Barboza et.al. (2013) aiming its use primarily in glioblastoma and after in melanoma diagnosis, a less common but very aggressive cancer and with high mortality rate. Preliminary tests on animals have proven its effectiveness of labeling but a dosimetric study to human clinical trials should be performed. This study aimed to: (1) determine the biokinetic model for the radiotracer 99m Tc-Ixolaris in mice by imaging dosimetry method; and (2) estimate the absorbed and effective dose resulting from the use of a new radiopharmaceutical for melanoma and metastases diagnosis in human beings, since a dosimetric study of new radiopharmaceuticals in animals is necessary to test them subsequently in humans and apply for registration in ANVISA. According to SPECT images, was found a latency period of 15 to 21 days for the development of lung metastasis in mice. Three C57BL6 mice, one control animal, and two animals with induced cell line B16-F10 murine melanoma were tested. The 99m Tc-Ixolaris radiopharmaceutical was administered intravenously in a caudal vein, and SPECT images were acquired 0.5 h, 1.5 h, 2.5 h, 3.5 h and 24 h post-administration for analysis and biodistribution quantification. The biokinetic model was determined and thus, obtained cumulative activity in order to estimate the absorbed dose in each organ. The mass and metabolic differences between mice and humans were considered and used to extrapolate the data acquired at different scales. Based on dose factors provided by the software MIRDOSE and Olinda (S factor), absorbed doses in irradiated target organs were calculated for the source organs, and finally the effective dose was estimated. The results indicate that for diagnostic exams conducted in human melanoma patients by administering approximately 25.7 MBq the estimated effective dose was 4.3 mSv. Comparing with effective doses obtained in other diagnostic techniques with 99m Tc, a range of effective

  5. Atomistic modeling and simulation of the role of Be and Bi in Al diffusion in U-Mo fuel

    Science.gov (United States)

    Hofman, G. L.; Bozzolo, G.; Mosca, H. O.; Yacout, A. M.

    2011-07-01

    Within the RERTR program, previous experimental and modeling studies identified Si as the alloying addition to the Al cladding responsible for inhibiting Al interdiffusion in the UMo fuel. However, difficulties with reprocessing have rendered this choice inappropriate, leading to the need to study alternative elements. In this work, we discuss the results of an atomistic modeling effort which allows for the systematic study of several possible alloying additions. Based on the behavior observed in the phase diagrams, beryllium or bismuth additions suggest themselves as possible options to replace Si. The results of temperature-dependent simulations using the Bozzolo-Ferrante-Smith (BFS) method for the energetics for varying concentrations of either element are shown, indicating that Be could have a substantial effect in stopping Al interdiffusion, while Bi does not. Details of the calculations and the dependence of the role of each alloying addition as a function of temperature and concentration (of beryllium or bismuth in Al) are shown.

  6. Atomistic modeling and simulation of the role of Be and Bi in Al diffusion in U-Mo fuel

    Energy Technology Data Exchange (ETDEWEB)

    Hofman, G.L. [Argonne National Laboratory, 9700 S. Cass Ave., Argonne, IL 60439 (United States); Bozzolo, G., E-mail: guille_bozzolo@yahoo.com [Argonne National Laboratory, 9700 S. Cass Ave., Argonne, IL 60439 (United States); Mosca, H.O. [Gerencia de Investigaciones y Aplicaciones, CNEA, Av. Gral Paz 1499, B165KNA, San Martin, Buenos Aires (Argentina); Yacout, A.M. [Argonne National Laboratory, 9700 S. Cass Ave., Argonne, IL 60439 (United States)

    2011-07-15

    Within the RERTR program, previous experimental and modeling studies identified Si as the alloying addition to the Al cladding responsible for inhibiting Al interdiffusion in the UMo fuel. However, difficulties with reprocessing have rendered this choice inappropriate, leading to the need to study alternative elements. In this work, we discuss the results of an atomistic modeling effort which allows for the systematic study of several possible alloying additions. Based on the behavior observed in the phase diagrams, beryllium or bismuth additions suggest themselves as possible options to replace Si. The results of temperature-dependent simulations using the Bozzolo-Ferrante-Smith (BFS) method for the energetics for varying concentrations of either element are shown, indicating that Be could have a substantial effect in stopping Al interdiffusion, while Bi does not. Details of the calculations and the dependence of the role of each alloying addition as a function of temperature and concentration (of beryllium or bismuth in Al) are shown.

  7. First-principles calculations, experimental study, and thermodynamic modeling of the Al-Co-Cr system.

    Directory of Open Access Journals (Sweden)

    Xuan L Liu

    Full Text Available The phase relations and thermodynamic properties of the condensed Al-Co-Cr ternary alloy system are investigated using first-principles calculations based on density functional theory (DFT and phase-equilibria experiments that led to X-ray diffraction (XRD and electron probe micro-analysis (EPMA measurements. A thermodynamic description is developed by means of the calculations of phase diagrams (CALPHAD method using experimental and computational data from the present work and the literature. Emphasis is placed on modeling the bcc-A2, B2, fcc-γ, and tetragonal-σ phases in the temperature range of 1173 to 1623 K. Liquid, bcc-A2 and fcc-γ phases are modeled using substitutional solution descriptions. First-principles special quasirandom structures (SQS calculations predict a large bcc-A2 (disordered/B2 (ordered miscibility gap, in agreement with experiments. A partitioning model is then used for the A2/B2 phase to effectively describe the order-disorder transitions. The critically assessed thermodynamic description describes all phase equilibria data well. A2/B2 transitions are also shown to agree well with previous experimental findings.

  8. On modeling the CNC end milling characteristics of Al-7075/WC powder metallurgy composites

    Science.gov (United States)

    Hanuman, N. S. V. N.; Rao, P. Gangadhara; Kumar, B. Sudheer; Karthik, N.

    2017-07-01

    Surface finish and material removal rate are two important factors in the manufacturing which affect acceptability of the product which in turn reflects on the profitability of the organization. The worth of the production setup to produce the components with high material removal rate (MRR) without sacrificing the surface requirements can play vital role in sustainability and profitability of the organization. In this paper, the effect of process parameters on metal removal rate and surface roughness has been investigated in milling of Al7075-MMC with WC as reinforcement element. Cutting speed, feed and depth of cut have been taken as input factors in three level response surface methodologies used for experimentation. Mathematical models have been developed using response surface methodology to predict surface finish, and metal removal rate in term of machining parameters. Depth of cut and feed rate are found to be a dominant parameter for surface roughness; whereas feed rate mainly affects the metal removal rate. The results of mathematical models have been compared with the experimental and found to be in good agreement. The results of predicted model can be used in selection of process parameters to insure desired quality and improved productivity.

  9. D Model of AL Zubarah Fortress in Qatar - Terrestrial Laser Scanning VS. Dense Image Matching

    Science.gov (United States)

    Kersten, T.; Mechelke, K.; Maziull, L.

    2015-02-01

    In September 2011 the fortress Al Zubarah, built in 1938 as a typical Arabic fortress and restored in 1987 as a museum, was recorded by the HafenCity University Hamburg using terrestrial laser scanning with the IMAGER 5006h and digital photogrammetry for the Qatar Museum Authority within the framework of the Qatar Islamic Archaeology and Heritage Project. One goal of the object recording was to provide detailed 2D/3D documentation of the fortress. This was used to complete specific detailed restoration work in the recent years. From the registered laser scanning point clouds several cuttings and 2D plans were generated as well as a 3D surface model by triangle meshing. Additionally, point clouds and surface models were automatically generated from digital imagery from a Nikon D70 using the open-source software Bundler/PMVS2, free software VisualSFM, Autodesk Web Service 123D Catch beta, and low-cost software Agisoft PhotoScan. These outputs were compared with the results from terrestrial laser scanning. The point clouds and surface models derived from imagery could not achieve the same quality of geometrical accuracy as laser scanning (i.e. 1-2 cm).

  10. Modeling on oxide dependent 2DEG sheet charge density and threshold voltage in AlGaN/GaN MOSHEMT

    Science.gov (United States)

    Panda, J.; Jena, K.; Swain, R.; Lenka, T. R.

    2016-04-01

    We have developed a physics based analytical model for the calculation of threshold voltage, two dimensional electron gas (2DEG) density and surface potential for AlGaN/GaN metal oxide semiconductor high electron mobility transistors (MOSHEMT). The developed model includes important parameters like polarization charge density at oxide/AlGaN and AlGaN/GaN interfaces, interfacial defect oxide charges and donor charges at the surface of the AlGaN barrier. The effects of two different gate oxides (Al2O3 and HfO2) are compared for the performance evaluation of the proposed MOSHEMT. The MOSHEMTs with Al2O3 dielectric have an advantage of significant increase in 2DEG up to 1.2 × 1013 cm-2 with an increase in oxide thickness up to 10 nm as compared to HfO2 dielectric MOSHEMT. The surface potential for HfO2 based device decreases from 2 to -1.6 eV within 10 nm of oxide thickness whereas for the Al2O3 based device a sharp transition of surface potential occurs from 2.8 to -8.3 eV. The variation in oxide thickness and gate metal work function of the proposed MOSHEMT shifts the threshold voltage from negative to positive realizing the enhanced mode operation. Further to validate the model, the device is simulated in Silvaco Technology Computer Aided Design (TCAD) showing good agreement with the proposed model results. The accuracy of the developed calculations of the proposed model can be used to develop a complete physics based 2DEG sheet charge density and threshold voltage model for GaN MOSHEMT devices for performance analysis.

  11. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model

    Science.gov (United States)

    Canelles, Sandra; Argente, Jesús; Barrios, Vicente

    2016-01-01

    ABSTRACT Insulin receptor substrate-2-deficient (IRS2−/−) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2−/− mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2−/− mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2−/− mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2−/− mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. PMID:27013528

  12. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

    Science.gov (United States)

    Avraham, Y; Grigoriadis, Nc; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, Em

    2011-04-01

    Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  13. Sclerostin antibody treatment improves the bone phenotype of Crtap−/− mice, a model of recessive Osteogenesis Imperfecta

    Science.gov (United States)

    Grafe, Ingo; Alexander, Stefanie; Yang, Tao; Lietman, Caressa; Homan, Erica P; Munivez, Elda; Chen, Yuqing; Jiang, Ming Ming; Bertin, Terry; Dawson, Brian; Asuncion, Franklin; Ke, Hua Zhu; Ominsky, Michael S; Lee, Brendan

    2016-01-01

    Osteogenesis Imperfecta (OI) is characterized by low bone mass, poor bone quality and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1 and 6 week old Crtap−/− mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of “pediatric” and “young adult” recessive OI. Vehicle treated Crtap−/− and wildtype (WT) mice served as controls. Compared with control Crtap−/− mice, microCT analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab treated Crtap−/− mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole bone strength in Crtap−/− mice, with more robust effects in the week 6–12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6–12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen post-translational modification. PMID:26716893

  14. YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17

    Directory of Open Access Journals (Sweden)

    K. Saidas Nair

    2016-08-01

    Full Text Available A variety of inherited animal models with different genetic causes and distinct genetic backgrounds are needed to help dissect the complex genetic etiology of glaucoma. The scarcity of such animal models has hampered progress in glaucoma research. Here, we introduce a new inherited glaucoma model: the inbred mouse strain YBR/EiJ (YBR. YBR mice develop a form of pigmentary glaucoma. They exhibit a progressive age-related pigment-dispersing iris disease characterized by iris stromal atrophy. Subsequently, these mice develop elevated intraocular pressure (IOP and glaucoma. Genetic mapping studies utilizing YBR as a glaucoma-susceptible strain and C57BL/6J as a glaucoma-resistant strain were performed to identify genetic loci responsible for the iris disease and high IOP. A recessive locus linked to Tyrp1b on chromosome 4 contributes to iris stromal atrophy and high IOP. However, this is not the only important locus. A recessive locus on YBR chromosome 17 causes high IOP independent of the iris stromal atrophy. In specific eyes with high IOP caused by YBR chromosome 17, the drainage angle (through which ocular fluid leaves the eye is largely open. The YBR alleles of genes on chromosomes 4 and 17 underlie the development of high IOP and glaucoma but do so through independent mechanisms. Together, these two loci act in an additive manner to increase the susceptibility of YBR mice to the development of high IOP. The chromosome 17 locus is important not only because it causes IOP elevation in mice with largely open drainage angles but also because it exacerbates IOP elevation and glaucoma induced by pigment dispersion. Therefore, YBR mice are a valuable resource for studying the genetic etiology of IOP elevation and glaucoma, as well as for testing new treatments.

  15. 3D visualization and quantification of bone and teeth mineralization for the study of osteo/dentinogenesis in mice models

    Science.gov (United States)

    Marchadier, A.; Vidal, C.; Ordureau, S.; Lédée, R.; Léger, C.; Young, M.; Goldberg, M.

    2011-03-01

    Research on bone and teeth mineralization in animal models is critical for understanding human pathologies. Genetically modified mice represent highly valuable models for the study of osteo/dentinogenesis defects and osteoporosis. Current investigations on mice dental and skeletal phenotype use destructive and time consuming methods such as histology and scanning microscopy. Micro-CT imaging is quicker and provides high resolution qualitative phenotypic description. However reliable quantification of mineralization processes in mouse bone and teeth are still lacking. We have established novel CT imaging-based software for accurate qualitative and quantitative analysis of mouse mandibular bone and molars. Data were obtained from mandibles of mice lacking the Fibromodulin gene which is involved in mineralization processes. Mandibles were imaged with a micro-CT originally devoted to industrial applications (Viscom, X8060 NDT). 3D advanced visualization was performed using the VoxBox software (UsefulProgress) with ray casting algorithms. Comparison between control and defective mice mandibles was made by applying the same transfer function for each 3D data, thus allowing to detect shape, colour and density discrepencies. The 2D images of transverse slices of mandible and teeth were similar and even more accurate than those obtained with scanning electron microscopy. Image processing of the molars allowed the 3D reconstruction of the pulp chamber, providing a unique tool for the quantitative evaluation of dentinogenesis. This new method is highly powerful for the study of oro-facial mineralizations defects in mice models, complementary and even competitive to current histological and scanning microscopy appoaches.

  16. Deletion of the App-Runx1 region in mice models human partial monosomy 21.

    Science.gov (United States)

    Arbogast, Thomas; Raveau, Matthieu; Chevalier, Claire; Nalesso, Valérie; Dembele, Doulaye; Jacobs, Hugues; Wendling, Olivia; Roux, Michel; Duchon, Arnaud; Herault, Yann

    2015-06-01

    Partial monosomy 21 (PM21) is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21). The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage-sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf). Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21. © 2015. Published by The Company of Biologists Ltd.

  17. Buddleja thyrsoides Lam. crude extract presents antinociceptive effect on an arthritic pain model in mice.

    Science.gov (United States)

    Fialho, Maria Fernanda Pessano; Brusco, Indiara; da Silva Brum, Evelyne; Piana, Mariana; Boligon, Aline Augusti; Trevisan, Gabriela; Oliveira, Sara Marchesan

    2017-08-17

    Arthritis is a chronic inflammatory disease which reduces the life quality of affected individuals. Therapeutic tools used for treating inflammatory pain are associated with several undesirable effects. Buddleja thyrsoides Lam., known as 'Barbasco' or 'Cambara', is mostly used in several disorders and possesses antirheumatic, anti-inflammatory, and analgesic properties. Here, we investigated the antinociceptive and anti-inflammatory effects of the B. thyrsoides crude extract applied orally and topically in acute pain models and an arthritic pain model induced by complete Freund's adjuvant (CFA) paw injection in male mice (25-30 g). The high-performance liquid chromatography (HPLC) of the B. thyrsoides extract crude revealed the presence of the lupeol, stigmasterol, and β-sitosterol. The stability study of the B. thyrsoides gel did not show relevant changes at low temperatures. The oral treatment with the B. thrysoides extract prevented the capsaicin-induced spontaneous nociception and the acetic acid-induced abdominal writhing, but did not alter the thermal threshold in the tail immersion test. The B. thyrsoides antinociceptive effect was not reversed by naloxone in the capsaicin test. The B. thyrsoides oral or topical treatment reversed the CFA-induced mechanical allodynia and thermal hyperalgesia with maximum inhibition ( I max ) of 69 ± 6 and 68 ± 5% as well as 78 ± 15 and 87 ± 12%, respectively. Moreover, the topical but not oral treatment inhibited the CFA-induced cell infiltration, but did not reduce the paw edema significantly. The oral treatment with B. thyrsoides did not cause adverse effects. These findings suggest that the oral or topical treatment with B. thyrsoides presents antinociceptive actions in an arthritic pain model without causing adverse effects. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  18. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways.

    Science.gov (United States)

    Guerenne, Laura; Beurlet, Stéphanie; Said, Mohamed; Gorombei, Petra; Le Pogam, Carole; Guidez, Fabien; de la Grange, Pierre; Omidvar, Nader; Vanneaux, Valérie; Mills, Ken; Mufti, Ghulam J; Sarda-Mantel, Laure; Noguera, Maria Elena; Pla, Marika; Fenaux, Pierre; Padua, Rose Ann; Chomienne, Christine; Krief, Patricia

    2016-01-27

    In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  19. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

    Directory of Open Access Journals (Sweden)

    Laura Guerenne

    2016-01-01

    Full Text Available Abstract Background In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. Methods We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS and acute myeloid leukemia (AML post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Results Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. Conclusions These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  20. Modeling of mechanical properties of as-cast Mg-Li-Al alloys based on PSO-BP algorithm

    Directory of Open Access Journals (Sweden)

    Li Ming

    2012-05-01

    Full Text Available Artificial neural networks have been widely used to predict the mechanical properties of alloys in material research. This study aims to investigate the implicit relationship between the compositions and mechanical properties of as-cast Mg-Li-Al alloys. Based on the experimental collection of the tensile strength and the elongation of representative Mg-Li-Al alloys, a momentum back-propagation (BP neural network with a single hidden layer was established. Particle swarm optimization (PSO was applied to optimize the BP model. In the neural network, the input variables were the contents of Mg, Li and Al, and the output variables were the tensile strength and the elongation. The results show that the proposed PSO-BP model can describe the quantitative relationship between the Mg-Li-Al alloy’s composition and its mechanical properties. It is possible that the mechanical properties to be predicted without experiment by inputting the alloy composition into the trained network model. The prediction of the influence of Al addition on the mechanical properties of as-cast Mg-Li-Al alloys is consistent with the related research results.

  1. Effect of phase interaction on catalytic CO oxidation over the SnO_2/Al_2O_3 model catalyst

    International Nuclear Information System (INIS)

    Chai, Shujing; Bai, Xueqin; Li, Jing; Liu, Cheng; Ding, Tong; Tian, Ye; Liu, Chang; Xian, Hui; Mi, Wenbo; Li, Xingang

    2017-01-01

    Highlights: • Activity for CO oxidation is greatly enhanced by interaction between SnO_2 and Al_2O_3. • Interaction between SnO_2 and Al_2O_3 phases can generate oxygen vacancies. • Oxygen vacancies play an import role for catalytic CO oxidation. • Sn"4"+ cations are the effective sites for catalytic CO oxidation. • Langmuir-Hinshelwood model is preferred for catalytic CO oxidation. - Abstract: We investigated the catalytic CO oxidation over the SnO_2/Al_2O_3 model catalysts. Our results show that interaction between the Al_2O_3 and SnO_2 phases results in the significantly improved catalytic activity because of the formation of the oxygen vacancies. The oxygen storage capacity of the SnO_2/Al_2O_3 catalyst prepared by the physically mixed method is nearly two times higher than that of the SnO_2, which probably results from the change of electron concentration on the interface of the SnO_2 and Al_2O_3 phases. Introducing water vapor to the feeding gas would a little decrease the activity of the catalysts, but the reaction rate could completely recover after removal of water vapor. The kinetics results suggest that the surface Sn"4"+ cations are effective CO adsorptive sites, and the surface adsorbed oxygen plays an important role upon CO oxidation. The reaction pathways upon the SnO_2-based catalysts for CO oxidation follow the Langmuir-Hinshelwood model.

  2. Systemic synergism between codeine and morphine in three pain models in mice.

    Science.gov (United States)

    Miranda, Hugo F; Noriega, Viviana; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

    2013-01-01

    The combination of two analgesic agents offers advantages in pain treatment. Codeine and morphine analgesia is due to activation of opioid receptor subtypes. This study, performed in mice using isobolographic analysis, evaluated the type of interaction in intraperitoneal (ip) or intrathecal (it) coadministration of codeine and morphine, in three nociceptive behavioral models. Intrathecal morphine resulted to be 7.5 times more potent than ip morphine in the writhing test, 55.6 times in the tail flick test and 1.7 times in phase II of the orofacial formalin test; however, in phase I of the same test ip was 1.2 times more potent than it morphine. Intrathecal codeine resulted being 3.4 times more potent than ip codeine in the writhing test, 1.6 times in the tail flick test, 2.5 times in phase I and 6.7 times in phase II of the orofacial formalin test. Opioid coadministration had a synergistic effect in the acute tonic pain (acetic acid writhing test), acute phasic pain (tail flick test) and inflammatory pain (orofacial formalin test). The interaction index ranged between 0.284 (writhing ip) and 0.440 (orofacial formalin phase II ip). This synergy may relate to the different pathways of pain transmission and to the different intracellular signal transduction. The present findings also raise the possibility of potential clinical advantages in combining opioids in pain management.

  3. Altered aquaporins in the brains of mice submitted to intermittent hypoxia model of sleep apnea.

    Science.gov (United States)

    Baronio, Diego; Martinez, Denis; Fiori, Cintia Zappe; Bambini-Junior, Victorio; Forgiarini, Luiz Felipe; Pase da Rosa, Darlan; Kim, Lenise Jihe; Cerski, Marcelle Reesink

    2013-01-15

    Rostral fluid displacement has been proposed as a pathophysiologic mechanism of both central and obstructive sleep apnea. Aquaporins are membrane proteins that regulate water transport across the cell membrane and are involved in brain edema formation and resolution. The present study investigated the effect of intermittent hypoxia (IH), a model of sleep apnea, on brain aquaporins. Mice were exposed to intermittent hypoxia to a nadir of 7% oxygen fraction. Brain water content, Aquaporin-1 and Aquaporin-3 were measured in the cerebellum and hippocampus. Hematoxylin-eosin and immunohistochemistry stainings were performed to evaluate cell damage. Compared to the sham group, the hypoxia group presented higher brain water content, lower levels of Aquaporin-1 and similar levels of Aquaporin-3. Immunoreactivity to GFAP and S100B was stronger in the hypoxia group in areas of extensive gliosis, compatible with cytotoxic edema. These findings, although preliminary, indicate an effect of IH on aquaporins levels. Further investigation about the relevance of these data on the pathophysiology of OSA is warranted. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Oxidative stress may be involved in distant organ failure in tourniquet shock model mice.

    Science.gov (United States)

    Nishikata, Rie; Kato, Naho; Hiraiwa, Kouichi

    2014-03-01

    Crush syndrome is characterized by prolonged shock resulting from extensive muscle damage and multiple organ failure. However, the pathogenesis of multiple organ failure has not yet been completely elucidated. Therefore, we investigated the molecular biological and histopathological aspects of distant organ injury in crush syndrome by using tourniquet shock model mice. DNA microarray analysis of the soleus muscle showed an increase in the mRNA levels of Cox-2, Hsp70, c-fos, and IL-6, at 3h after ischemia/reperfusion injury at the lower extremity. In vivo staining with hematoxylin and eosin (HE) showed edema and degeneration in the soleus muscle, but no change in the distant organs. Immunohistological staining of the HSP70 protein revealed nuclear translocation in the soleus muscle, kidney, liver, and lung. The c-fos mRNA levels were elevated in the soleus muscle, kidney, and liver, displaying nuclear translocation of c-FOS protein. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) analysis suggested the involvement of apoptosis in ischemia/reperfusion injury in the soleus muscle. Apoptotic cells were not found in greater quantities in the kidney. Oxidative stress, as determined using a free radical elective evaluator (d-ROM test), markedly increased after ischemia/reperfusion injury. Therefore, examination of immunohistological changes and determination of oxidative stress are proposed to be useful in evaluating the extent of tourniquet shock, even before changes are observed by HE staining. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Periosteal PTHrP regulates cortical bone modeling during linear growth in mice.

    Science.gov (United States)

    Wang, Meina; VanHouten, Joshua N; Nasiri, Ali R; Tommasini, Steven M; Broadus, Arthur E

    2014-07-01

    The modeling of long bone surfaces during linear growth is a key developmental process, but its regulation is poorly understood. We report here that parathyroid hormone-related peptide (PTHrP) expressed in the fibrous layer of the periosteum (PO) drives the osteoclastic (OC) resorption that models the metaphyseal-diaphyseal junction (MDJ) in the proximal tibia and fibula during linear growth. PTHrP was conditionally deleted (cKO) in the PO via Scleraxis gene targeting (Scx-Cre). In the lateral tibia, cKO of PTHrP led to a failure of modeling, such that the normal concave MDJ was replaced by a mound-like deformity. This was accompanied by a failure to induce receptor activator of NF-kB ligand (RANKL) and a 75% reduction in OC number (P ≤ 0.001) on the cortical surface. The MDJ also displayed a curious threefold increase in endocortical osteoblast mineral apposition rate (P ≤ 0.001) and a thickened cortex, suggesting some form of coupling of endocortical bone formation to events on the PO surface. Because it fuses distally, the fibula is modeled only proximally and does so at an extraordinary rate, with an anteromedial cortex in CD-1 mice that was so moth-eaten that a clear PO surface could not be identified. The cKO fibula displayed a remarkable phenotype, with a misshapen club-like metaphysis and an enlargement in the 3D size of the entire bone, manifest as a 40-45% increase in the PO circumference at the MDJ (P ≤ 0.001) as well as the mid-diaphysis (P ≤ 0.001). These tibial and fibular phenotypes were reproduced in a Scx-Cre-driven RANKL cKO mouse. We conclude that PTHrP in the fibrous PO mediates the modeling of the MDJ of long bones during linear growth, and that in a highly susceptible system such as the fibula this surface modeling defines the size and shape of the entire bone. © 2014 Anatomical Society.

  6. Equine H7N7 influenza A viruses are highly pathogenic in mice without adaptation: potential use as an animal model.

    OpenAIRE

    Kawaoka, Y

    1991-01-01

    Equine H7N7 influenza A viruses, representing a broad range of isolates, were lethal in mice without adaptation. After repeated passages, A/Equine/London/1416/73 acquired neurotropism upon intranasal infection. Thus, mice infected with equine influenza A viruses provide a model system for the study of highly virulent mammalian influenza viruses.

  7. Dendritic solidification in undercooled Ni-Zr-Al melts: Experiments and modeling

    Energy Technology Data Exchange (ETDEWEB)

    Galenko, P.K., E-mail: Peter.Galenko@dlr.de [Institut fuer Materialsphysik im Weltraum, Deutsches Zentrum fuer Luft- und Raumfahrt (DLR), D-51170 Koeln (Germany); Reutzel, S.; Herlach, D.M. [Institut fuer Materialsphysik im Weltraum, Deutsches Zentrum fuer Luft- und Raumfahrt (DLR), D-51170 Koeln (Germany); Fries, S.G. [ICAMS, Ruhr-Universitaet Bochum, Stiepeler Strasse 129, D-44780 Bochum (Germany)] [SGF Scientific Consultancy, Arndtstr 9, D-52064 Aachen (Germany); Steinbach, I. [ICAMS, Ruhr-Universitaet Bochum, Stiepeler Strasse 129, D-44780 Bochum (Germany); Apel, M. [ACCESS eV, Intzestrasse 5, D-52072 Aachen (Germany)

    2009-12-15

    The kinetics of dendritic solidification in a ternary Ni{sub 98}Zr{sub 1}Al{sub 1} alloy is investigated experimentally in a range of melt undercoolings 40K{<=}{Delta}T{<=}320K. The growth velocity is measured for samples processed by the electromagnetic levitation technique using a high-speed video camera. With {Delta}T{<=}220K the measured growth rates are the same as those of a binary Ni{sub 99}Zr{sub 1} alloy. In the regime of rapid solidification, especially within the regime of thermal dendritic growth at {Delta}T{>=}220K, growth rates are decreased. Sharp-interface modeling predicts growth rates over the whole range of undercooling. Phase-field simulations give quantitative predictions for the dendritic growth velocity in the solute-controlled growth regime. Results show that the composition and temperature dependency of the thermodynamic data, e.g. liquidus slope and solute partition coefficient, are important for describing the alloys. Our findings give improved sharp-interface model predictions compared to calculations based on an approximation of the thermodynamic data derived from binary phase diagrams.

  8. Evaluation of properties and FEM Model of the Friction welded mild Steel-Al6061-Alumina

    Directory of Open Access Journals (Sweden)

    Hazman Seli

    2013-04-01

    Full Text Available Evaluation of mechanical and interfacial properties of friction welded alumina-mild steel rods with the use of Al6061 sheet are presented in this work. SEM, EDX analysis, hardness and bending strength tests were conducted. The bonds were attained through interfacial interlocking and intermetalllic phase formation with average bending strengths in the range of 40 to 200 MPa and insignificant hardness change in the parent alumina and mild steel. A preliminary simulation was made to predict the deformation, stress, strain and temperature distribution during the joining operation using a fully coupled thermo-mechanical FE model. The aluminum alloy metal being rubbed was simulated using a phenomenological Johnson-Cook viscoplasticity material model, which suited for materials subjected to large strains, high strain rates and high temperatures. The highest stress, strain and deformation are found to be within the heat affected zone of the weld close to the periphery rubbing surface region and correspond to the highest temperature profiles observed.

  9. Evaluation of properties and FEM Model of the Friction welded mild Steel-Al6061-Alumina

    Directory of Open Access Journals (Sweden)

    Hazman Seli

    2012-01-01

    Full Text Available Evaluation of mechanical and interfacial properties of friction welded alumina-mild steel rods with the use of Al6061 sheet are presented in this work. SEM, EDX analysis, hardness and bending strength tests were conducted. The bonds were attained through interfacial interlocking and intermetalllic phase formation with average bending strengths in the range of 40 to 200 MPa and insignificant hardness change in the parent alumina and mild steel. A preliminary simulation was made to predict the deformation, stress, strain and temperature distribution during the joining operation using a fully coupled thermo-mechanical FE model. The aluminum alloy metal being rubbed was simulated using a phenomenological Johnson-Cook viscoplasticity material model, which suited for materials subjected to large strains, high strain rates and high temperatures. The highest stress, strain and deformation are found to be within the heat affected zone of the weld close to the periphery rubbing surface region and correspond to the highest temperature profiles observed.

  10. A Novel Antihepatitis Drug, Bicyclol, Prevents Liver Carcinogenesis in Diethylnitrosamine-Initiated and Phenobarbital-Promoted Mice Tumor Model

    Directory of Open Access Journals (Sweden)

    Hua Sun

    2012-01-01

    Full Text Available Bicyclol, an antihepatitis drug developed by Chinese scientists, has been shown to prevent the malignant transformation induced by 3-methylcholanthrene and 12-O-tetradecanoylphorbol-13-acetate in WB-F344 rat liver epithelial cells. This study provides further evidence on its role as a chemopreventive agent in experimental mice with diethylnitrosamine- (DEN- initiated and phenobarbital- (PB- promoted liver carcinoma. Liver tissue and serum were collected. In the two-stage model of hepatocarcinogenesis in mice, oral administration of bicyclol (100, 200 mg/kg before DEN injection showed significant reduction in the incidence of hepatocellular foci, nodules, or carcinoma. Histopathological examination revealed that there was no hepatocellular carcinoma (HCC and hepatoma formation in the mice pretreated with bicyclol (200 mg/kg at week 20, while the mice treated with DEN/PB developed 33.3% HCC and 55.6% hepatoma. Furthermore, the serum levels of alanine aminotransferase (ALT, alkaline phosphatase (ALP, and α-fetal protein (AFP in serum significantly increased in the DEN/PB model group in comparison with the control group. Pretreatment with bicyclol showed a marked reduction in the above condition. Bicyclol also decreased the expression of AFP and proliferating cell nuclear antigen level in the liver tissue and attenuated the decrease in body weight. In this study, we also found that 10 weeks after stopping the administration of PB and drugs, the control and bicyclol-treated (200 mg/kg animals showed no HCC and hepatoma formation at the time of termination whereas DEN/PB-induced mice developed 100% hepatoma and 50% HCC. These results further indicate that bicyclol has the chemopreventive potential for liver carcinogenesis induced by carcinogens.

  11. Spdef Null Mice Lack Conjunctival Goblet Cells and Provide a Model of Dry Eye

    OpenAIRE

    Marko, Christina K.; Menon, Balaraj B.; Chen, Gang; Whitsett, Jeffrey A.; Clevers, Hans; Gipson, Ilene K.

    2013-01-01

    Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef−/− mice, we determined that Spdef is required for conjunct...

  12. Treatment of mice with fenbendazole attenuates allergic airways inflammation and Th2 cytokine production in a model of asthma.

    Science.gov (United States)

    Cai, Yeping; Zhou, Jiansheng; Webb, Dianne C

    2009-01-01

    Mouse models have provided a significant insight into the role of T-helper (Th) 2 cytokines such as IL-5 and IL-13 in regulating eosinophilia and other key features of asthma. However, the validity of these models can be compromised by inadvertent infection of experimental mouse colonies with pathogens such as oxyurid parasites (pinworms). While the benzimidazole derivative, fenbendazole (FBZ), is commonly used to treat such outbreaks, the effects of FBZ on mouse models of Th2 disease are largely unknown. In this investigation, we show that mice fed FBZ-supplemented food during the in utero and post-weaning period developed attenuated lung eosinophilia, antigen-specific IgG1 and Th2 cytokine responses in a model of asthma. Treatment of the mediastinal lymph node cells from allergic mice with FBZ in vitro attenuated cell proliferation, IL-5 and IL-13 production and expression of the early lymphocyte activation marker, CD69 on CD4(+) T cells and CD19(+) B cells. In addition, eosinophilia and Th2 responses remained attenuated after a 4-week withholding period in allergic mice treated preweaning with FBZ. Thus, FBZ modulates the amplitude of Th2 responses both in vivo and in vitro.

  13. Human anti-plague monoclonal antibodies protect mice from Yersinia pestis in a bubonic plague model.

    Directory of Open Access Journals (Sweden)

    Xiaodong Xiao

    2010-10-01

    Full Text Available Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs against the F1- and V-antigens that can passively protect mice in a murine model of plague; however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252 and two anti-V-specific human mAb (m253, m254 by panning a naïve phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope; m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans.

  14. Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer.

    Directory of Open Access Journals (Sweden)

    Emily L Lowe

    2010-09-01

    Full Text Available Inflammatory bowel disease (IBD is a disorder of chronic inflammation with increased susceptibility to colorectal cancer. The etiology of IBD is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host. Toll-like receptor (TLR signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis, innate immunity and the enhancement of intestinal epithelial cell (IEC integrity. However, the role of TLR2 in the development of colorectal cancer has not been studied. We utilized the AOM-DSS model for colitis-associated colorectal cancer (CAC in wild type (WT and TLR2(-/- mice. Colons harvested from WT and TLR2(-/- mice were used for histopathology, immunohistochemistry, immunofluorescence and cytokine analysis. Mice deficient in TLR2 developed significantly more and larger colorectal tumors than their WT controls. We provide evidence that colonic epithelium of TLR2(-/- mice have altered immune responses and dysregulated proliferation under steady-state conditions and during colitis, which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth. At the earliest time-points assessed, TLR2(-/- colons exhibited a significant increase in aberrant crypt foci (ACF, resulting in tumors that developed earlier and grew larger. In addition, the intestinal microenvironment revealed significantly higher levels of IL-6 and IL-17A concomitant with increased phospho-STAT3 within ACF. These observations indicate that in colitis, TLR2 plays a protective role against the development of CAC.

  15. The Neuroprotective Mechanism of Low-Frequency rTMS on Nigral Dopaminergic Neurons of Parkinson's Disease Model Mice.

    Science.gov (United States)

    Dong, Qiaoyun; Wang, Yanyong; Gu, Ping; Shao, Rusheng; Zhao, Li; Liu, Xiqi; Wang, Zhanqiang; Wang, Mingwei

    2015-01-01

    Background. Parkinson's disease is a neurodegenerative disease in elder people, pathophysiologic basis of which is the severe deficiency of dopamine in the striatum. The purpose of the present study was to evaluate the neuroprotective effect of low-frequency rTMS on Parkinson's disease in model mice. Methods. The effects of low-frequency rTMS on the motor function, cortex excitability, neurochemistry, and neurohistopathology of MPTP-induced Parkinson's disease mice were investigated through behavioral detection, electrophysiologic technique, high performance liquid chromatography-electrochemical detection, immunohistochemical staining, and western blot. Results. Low-frequency rTMS could improve the motor coordination impairment of Parkinson's disease mice: the resting motor threshold significantly decreased in the Parkinson's disease mice; the degeneration of nigral dopaminergic neuron and the expression of tyrosine hydroxylase were significantly improved by low-frequency rTMS; moreover, the expressions of brain derived neurotrophic factor and glial cell line derived neurotrophic factor were also improved by low-frequency rTMS. Conclusions. Low-frequency rTMS had a neuroprotective effect on the nigral dopaminergic neuron which might be due to the improved expressions of brain derived neurotrophic factor and glial cell line-derived neurotrophic factor. The present study provided a theoretical basis for the application of low-frequency rTMS in the clinical treatment and recovery of Parkinson's disease.

  16. Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice

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    Kyung-Hyun Kim

    2015-08-01

    Full Text Available Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

  17. The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice

    Directory of Open Access Journals (Sweden)

    David Harrison

    2011-06-01

    Full Text Available Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata, and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.

  18. The effects of Re addition to the nanostructure of a Ni-Cr-Al model superalloy

    International Nuclear Information System (INIS)

    Yoon, K.E.; Seidman, D.N.; Noebe, R.D.

    2004-01-01

    Full text: The refractory elements, such as W, Mo, Ta, and Re, have been at the center of focus since the late 1970s for the development of single-crystal turbine-blades, and they have improved significantly the high-temperature properties of Ni-based superalloys. The optimum mechanical properties and operating temperature of single-crystal blades are achieved by increasing the total amounts of refractory elements. In spite of the improvement of mechanical properties of Ni-based superalloys utilizing the addition of refractory elements, their effects on the microstructure of superalloys are mostly unidentified at the subnano- to nanoscale. Rhenium (2 at.%) was added to a model ternary Ni-8.5 at.% Cr-10 at.% Al superalloy to study its effects on the temporal evolution. The temporal evolution of γ' (L1 2 ) precipitates in a Ni-Cr-AI-Re FCC alloy, aged at 1073 K from 0.25 to 264 h, is investigated by transmission-electron and three-dimensional atom-probe (3DAP) microscopies. The coarsening kinetics of γ' precipitates is investigated by measuring the mean radius, number density of precipitates and matrix supersaturation, and compared with Umantsev-Olson's (UO) coarsening theory for multicomponent alloys. The coarsening experiments do not agree with the time dependencies prediction of UO theory. The cluster-diffusion-coagulation mechanism is involved in coarsening, as well as evaporation-condenzation mechanism, and is suggested to generate discrepancy between the experiments and theory. The addition of Re reduces the lattices parameter misfit between the matrix and precipitates. Therefore, unlike other Ni-based superalloys, this Ni-Cr-AI-Re alloy does not undergo the sphere-to-cube morphological transition and maintains the spheroidal morphology of the γ' precipitates for extended aging times. In addition, the γ' precipitates do not align along [100] direction, even at the longest aging time of 264 h. Contrary to a commercial superalloy Rene N6, significant Re

  19. [Establishment of Social Stress Induced Depression-like Animal Model in Mice of C57BL/6 Strain and Behavioral Assessments].

    Science.gov (United States)

    Li, Mi-hui; Wu, Xiao; Wei Ying; Dong, Jing-cheng

    2016-02-01

    To establish social stress induced depression-like model in mice of C57BL/6 strain, and to assess its reliability using differenf behavioral methods. Totally 20 male mice of C57BL/6 strain were divided into the normal group and the stress model group by random digit table,10 in each group. Another 10 CD1 mice were subjected to social stress. Mice in the normal control group received no stress, while those in the model group received social stress for 10 successive days. Behavioral assessment was performed using social interaction test (SIT), the elevated plus-maze (EPM) test, tail suspension test (TST), respectively. Serum cortisol level was detected by ELISA to assess the reliability of the model. In the social interaction test when the social target (CDI mice) was inexistent, mice in the normal control group spent longer time in the social interaction zone and less time in the corner zone (P stress induced depression-like animal model in mice of C57BL/6 straineasquite reliable and possibly suitable to be used in integrative medicine research of combination of disease and syndrome model.

  20. Organotypic brain slice cultures of adult transgenic P301S mice--a model for tauopathy studies.

    Directory of Open Access Journals (Sweden)

    Agneta Mewes

    Full Text Available BACKGROUND: Organotypic brain slice cultures represent an excellent compromise between single cell cultures and complete animal studies, in this way replacing and reducing the number of animal experiments. Organotypic brain slices are widely applied to model neuronal development and regeneration as well as neuronal pathology concerning stroke, epilepsy and Alzheimer's disease (AD. AD is characterized by two protein alterations, namely tau hyperphosphorylation and excessive amyloid β deposition, both causing microglia and astrocyte activation. Deposits of hyperphosphorylated tau, called neurofibrillary tangles (NFTs, surrounded by activated glia are modeled in transgenic mice, e.g. the tauopathy model P301S. METHODOLOGY/PRINCIPAL FINDINGS: In this study we explore the benefits and limitations of organotypic brain slice cultures made of mature adult transgenic mice as a potential model system for the multifactorial phenotype of AD. First, neonatal (P1 and adult organotypic brain slice cultures from 7- to 10-month-old transgenic P301S mice have been compared with regard to vitality, which was monitored with the lactate dehydrogenase (LDH- and the MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assays over 15 days. Neonatal slices displayed a constant high vitality level, while the vitality of adult slice cultures decreased significantly upon cultivation. Various preparation and cultivation conditions were tested to augment the vitality of adult slices and improvements were achieved with a reduced slice thickness, a mild hypothermic cultivation temperature and a cultivation CO(2 concentration of 5%. Furthermore, we present a substantial immunohistochemical characterization analyzing the morphology of neurons, astrocytes and microglia in comparison to neonatal tissue. CONCLUSION/SIGNIFICANCE: Until now only adolescent animals with a maximum age of two months have been used to prepare organotypic brain slices. The current study

  1. A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice.

    Science.gov (United States)

    Clopath, Claudia; Badura, Aleksandra; De Zeeuw, Chris I; Brunel, Nicolas

    2014-05-21

    Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions. Copyright © 2014 the authors 0270-6474/14/347203-13$15.00/0.

  2. A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1

    Science.gov (United States)

    Kauffman, Alexander S.; Thackray, Varykina G.; Ryan, Genevieve E.; Tolson, Kristen P.; Glidewell-Kenney, Christine A.; Semaan, Sheila J.; Poling, Matthew C.; Iwata, Nahoko; Breen, Kellie M.; Duleba, Antoni J.; Stener-Victorin, Elisabet; Shimasaki, Shunichi; Webster, Nicholas J.; Mellon, Pamela L.

    2015-01-01

    Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition. PMID:26203175

  3. Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5.

    Science.gov (United States)

    Burrows, Emma L; McOmish, Caitlin E; Buret, Laetitia S; Van den Buuse, Maarten; Hannan, Anthony J

    2015-07-01

    Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

  4. Nonradiative Transitions in Media of Different Polarities and Their Modeling for 12'-Apo-β-Caroten-12'-Al and 8'-Apo-β-Caroten-8'-Al

    Science.gov (United States)

    Pavlovich, V. S.

    2014-09-01

    The theory of nonradiative transitions, based on the model of orientational broadening of electronic levels, is used to interpret known data on the effect of the polarity of the medium and temperature on the lifetime of the S 1( A {/g -}) state for 12'-apo-β-caroten-12'-al and 8'-apo-β-caroten-8'-al. The effect of promoting vibrations on the rate constant for nonradiative transitions is considered. The results make it possible to hypothesize that the internal electric field created by the environment strongly perturbs the pigment molecules. Consequently, in the excited S 1( A {/g -}) state, both pigments exist as different conformers I and II. Their structures differ by a 180° rotation of the cyclohexene ring relative to the polyene chain. Conformer II predominates in polar media, and is found in an intramolecular charge-transfer state S 1( A {/g -}/ ICT). In addition, as a result of fluctuations in the internal electric field, it can also be found in a charge-separated state S 1( A {/g -}/ CS).

  5. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

    Science.gov (United States)

    Konuma, Kuniha; Itoh, Michiko; Suganami, Takayoshi; Kanai, Sayaka; Nakagawa, Nobutaka; Sakai, Takeru; Kawano, Hiroyuki; Hara, Mitsuko; Kojima, Soichi; Izumi, Yuichi; Ogawa, Yoshihiro

    2015-01-01

    Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

  6. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

    Directory of Open Access Journals (Sweden)

    Kuniha Konuma

    Full Text Available Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH, while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS, where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA, a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

  7. Biological effects of CCS in the absence of SOD1 enzyme activation: implications for disease in a mouse model for ALS.

    Science.gov (United States)

    Proescher, Jody B; Son, Marjatta; Elliott, Jeffrey L; Culotta, Valeria C

    2008-06-15

    The CCS copper chaperone is critical for maturation of Cu, Zn-superoxide dismutase (SOD1) through insertion of the copper co-factor and oxidization of an intra-subunit disulfide. The disulfide helps stabilize the SOD1 polypeptide, which can be particularly important in cases of amyotrophic lateral sclerosis (ALS) linked to misfolding of mutant SOD1. Surprisingly, however, over-expressed CCS was recently shown to greatly accelerate disease in a G93A SOD1 mouse model for ALS. Herein we show that disease in these G93A/CCS mice correlates with incomplete oxidation of the SOD1 disulfide. In the brain and spinal cord, CCS over-expression failed to enhance oxidation of the G93A SOD1 disulfide and if anything, effected some accumulation of disulfide-reduced SOD1. This effect was mirrored in culture with a C244,246S mutant of CCS that has the capacity to interact with SOD1 but can neither insert copper nor oxidize the disulfide. In spite of disulfide effects, there was no evidence for increased SOD1 aggregation. If anything, CCS over-expression prevented SOD1 misfolding in culture as monitored by detergent insolubility. This protection against SOD1 misfolding does not require SOD1 enzyme activation as the same effect was obtained with the C244,246S allele of CCS. In the G93A SOD1 mouse, CCS over-expression was likewise associated with a lack of obvious SOD1 misfolding marked by detergent insolubility. CCS over-expression accelerates SOD1-linked disease without the hallmarks of misfolding and aggregation seen in other mutant SOD1 models. These studies are the first to indicate biological effects of CCS in the absence of SOD1 enzymatic activation.

  8. Data mining of Ti-Al semi-empirical parameters for developing reduced order models

    Energy Technology Data Exchange (ETDEWEB)

    Broderick, Scott R [Department of Materials Science and Engineering and Institute for Combinatorial Discovery, Iowa State University, Ames, IA 50011 (United States); Aourag, Hafid [Department of Physics, University Abou Bakr Belkaid, Tlemcen 13000 (Algeria); Rajan, Krishna [Department of Materials Science and Engineering and Institute for Combinatorial Discovery, Iowa State University, Ames, IA 50011 (United States)

    2011-05-15

    A focus of materials design is determining the minimum amount of information necessary to fully describe a system, thus reducing the number of empirical results required and simplifying the data analysis. Screening descriptors calculated through a semi-empirical model, we demonstrate how an informatics-based analysis can be used to address this issue with no prior assumptions. We have developed a unique approach for identifying the minimum number of descriptors necessary to capture all the information of a system. Using Ti-Al alloys of varying compositions and crystal chemistries as the test bed, 5 of the 21 original descriptors from electronic structure calculations are found to capture all the information from the calculation, thereby reducing the structure-chemistry-property search space. Additionally, by combining electronic structure calculations with data mining, we classify the systems by chemistries and structures, based on the electronic structure inputs, and thereby rank the impact of change in chemistry and crystal structure on the electronic structure. -- Research Highlights: {yields} We developed an informatics-based methodology to minimize the necessary information. {yields} We applied this methodology to descriptors from semi-empirical calculations. {yields} We developed a validation approach for maintaining information from screening. {yields} We classified intermetallics and identified patterns of composition and structure.

  9. Development of a reduced model of formation reactions in Zr-Al nanolaminates

    KAUST Repository

    Vohra, Manav

    2014-12-15

    A computational model of anaerobic reactions in metallic multilayered systems with an equimolar composition of zirconium and aluminum is developed. The reduced reaction formalism of M. Salloum and O. M. Knio, Combust. Flame 157(2): 288–295 (2010) is adopted. Attention is focused on quantifying intermixing rates based on experimental measurements of uniform ignition as well as measurements of self-propagating front velocities. Estimates of atomic diffusivity are first obtained based on a regression analysis. A more elaborate Bayesian inference formalism is then applied in order to assess the impact of uncertainties in the measurements, potential discrepancies between predictions and observations, as well as the sensitivity of predictions to inferred parameters. Intermixing rates are correlated in terms of a composite Arrhenius law, which exhibits a discontinuity around the Al melting temperature. Analysis of the predictions indicates that Arrhenius parameters inferred for the low-temperature branch lie within a tight range, whereas the parameters of the high-temperature branch are characterized by higher uncertainty. The latter is affected by scatter in the experimental measurements, and the limited range of bilayers where observations are available. For both branches, the predictions exhibit higher sensitivity to the activation energy than the pre-exponent, whose posteriors are highly correlated.

  10. AC magnetic measurements of the ALS Booster Synchrotron Dipole Magnet engineering model

    International Nuclear Information System (INIS)

    Green, M.I.; Hoyer, E.; Keller, R.; Nelson, D.H.

    1988-09-01

    We made a minimal set of AC magnetic measurements of the engineering model of the ALS Booster Dipole Magnet as part of the process of qualifying its design for production. Magnetic induction integrals over paths approximating electron-beam trajectories were measured with long curved coils connected to an electronic integrator. Magnetic induction was measured with point coils and an integrator and independently with a Hall-effect Gaussmeter. These quantities, and magnet current, were displayed on a commercial digital storage oscilloscope as parametric functions of time. The displayed waveforms were stored, processed and redisplayed as representations of selected magnet parameters. A waveform representing the magnet's effective-length was created by dividing the integral waveform by the magnetic induction waveform. Waveforms of the transfer functions were produced by dividing both the integral waveform and the magnetic induction waveform by the current waveform. Pairs of matched coils, connected in series opposition, provided differential measurements of field uniformity. Quadrupole and sextupole coefficients were derived from the uniformity data. These magnet parameters were measured at 2 and 10 Hz frequencies. Together with measurements of the magnetic field at selected dc levels, the ac measurements demonstrated that the magnet design met specifications and qualified it for production. 7 refs., 7 figs., 3 tabs

  11. Data mining of Ti-Al semi-empirical parameters for developing reduced order models

    International Nuclear Information System (INIS)

    Broderick, Scott R.; Aourag, Hafid; Rajan, Krishna

    2011-01-01

    A focus of materials design is determining the minimum amount of information necessary to fully describe a system, thus reducing the number of empirical results required and simplifying the data analysis. Screening descriptors calculated through a semi-empirical model, we demonstrate how an informatics-based analysis can be used to address this issue with no prior assumptions. We have developed a unique approach for identifying the minimum number of descriptors necessary to capture all the information of a system. Using Ti-Al alloys of varying compositions and crystal chemistries as the test bed, 5 of the 21 original descriptors from electronic structure calculations are found to capture all the information from the calculation, thereby reducing the structure-chemistry-property search space. Additionally, by combining electronic structure calculations with data mining, we classify the systems by chemistries and structures, based on the electronic structure inputs, and thereby rank the impact of change in chemistry and crystal structure on the electronic structure. -- Research Highlights: → We developed an informatics-based methodology to minimize the necessary information. → We applied this methodology to descriptors from semi-empirical calculations. → We developed a validation approach for maintaining information from screening. → We classified intermetallics and identified patterns of composition and structure.

  12. Development of a reduced model of formation reactions in Zr-Al nanolaminates

    KAUST Repository

    Vohra, Manav; Winokur, Justin; Overdeep, Kyle R.; Marcello, Paul; Weihs, Timothy P.; Knio, Omar

    2014-01-01

    A computational model of anaerobic reactions in metallic multilayered systems with an equimolar composition of zirconium and aluminum is developed. The reduced reaction formalism of M. Salloum and O. M. Knio, Combust. Flame 157(2): 288–295 (2010) is adopted. Attention is focused on quantifying intermixing rates based on experimental measurements of uniform ignition as well as measurements of self-propagating front velocities. Estimates of atomic diffusivity are first obtained based on a regression analysis. A more elaborate Bayesian inference formalism is then applied in order to assess the impact of uncertainties in the measurements, potential discrepancies between predictions and observations, as well as the sensitivity of predictions to inferred parameters. Intermixing rates are correlated in terms of a composite Arrhenius law, which exhibits a discontinuity around the Al melting temperature. Analysis of the predictions indicates that Arrhenius parameters inferred for the low-temperature branch lie within a tight range, whereas the parameters of the high-temperature branch are characterized by higher uncertainty. The latter is affected by scatter in the experimental measurements, and the limited range of bilayers where observations are available. For both branches, the predictions exhibit higher sensitivity to the activation energy than the pre-exponent, whose posteriors are highly correlated.

  13. Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet

    Directory of Open Access Journals (Sweden)

    Yang Ching-Hsiu

    2008-09-01

    Full Text Available Abstract Background Pioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2 and DNA glycosylase (Ogg1, MutY. Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression. Results Our results show that hepatic steatosis was induced by a high-fat diet and improved by adding pioglitazone. Malondialdehyde concentration and 8-oxoG staining were strongly increased in the high-fat diet group, but attenuated by pioglitazone. Gene expressions of antioxidant defense mechanism: Sod1, Sod2, Ogg1 and MutY significantly decreased in the high-fat diet group but reversed by pioglitazone co-administration. Conclusion The attenuation of hepatic oxidative DNA damage by pioglitazone in a high-fat diet may be mediated by up-regulation of the antioxidant defense mechanism and oxidative DNA repair activity. The diminution of oxidative damage may explain the clinical benefit of pioglitazone treatment in patients with non-alcoholic fatty liver disease.

  14. Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet

    Science.gov (United States)

    Hsiao, Pi-Jung; Hsieh, Tusty-Jiuan; Kuo, Kung-Kai; Hung, Wei-Wen; Tsai, Kun-Bow; Yang, Ching-Hsiu; Yu, Ming-Lung; Shin, Shyi-Jang

    2008-01-01

    Background Pioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2) and DNA glycosylase (Ogg1, MutY). Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression. Results Our results show that hepatic steatosis was induced by a high-fat diet and improved by adding pioglitazone. Malondialdehyde concentration and 8-oxoG staining were strongly increased in the high-fat diet group, but attenuated by pioglitazone. Gene expressions of antioxidant defense mechanism: Sod1, Sod2, Ogg1 and MutY significantly decreased in the high-fat diet group but reversed by pioglitazone co-administration. Conclusion The attenuation of hepatic oxidative DNA damage by pioglitazone in a high-fat diet may be mediated by up-regulation of the antioxidant defense mechanism and oxidative DNA repair activity. The diminution of oxidative damage may explain the clinical benefit of pioglitazone treatment in patients with non-alcoholic fatty liver disease. PMID:18822121

  15. Steam reforming of different biomass tar model compounds over Ni/Al_2O_3 catalysts

    International Nuclear Information System (INIS)

    Artetxe, Maite; Alvarez, Jon; Nahil, Mohamad A.; Olazar, Martin; Williams, Paul T.

    2017-01-01

    Highlights: • Order of reactivity: anisole > furfural > indene > phenol > toluene > methyl naphthalene. • Higher coke deposition for oxygenates (1.5–2.8%) than for aromatics (0.5–0.8%). • Amorphous coke is deposited for oxygenates and filamentous carbon for aromatics. • Ni content of 20 wt.% shows the higher conversion (90%) and H_2 potential (63%). - Abstract: This work focuses on the removal of the tar derived from biomass gasification by catalytic steam reforming on Ni/Al_2O_3 catalysts. Different tar model compounds (phenol, toluene, methyl naphthalene, indene, anisole and furfural) were individually steam reformed (after dissolving each one in methanol), as well as a mixture of all of them, at 700 °C under a steam/carbon (S/C) ratio of 3 and 60 min on stream. The highest conversions and H_2 potential were attained for anisole and furfural, while methyl naphthalene presented the lowest reactivity. Nevertheless, the higher reactivity of oxygenates compared to aromatic hydrocarbons promoted carbon deposition on the catalyst (in the 1.5–2.8 wt.% range). When the concentration of methanol is decreased in the feedstock and that of toluene or anisole is increased, the selectivity to CO is favoured in the gaseous products, thus increasing coke deposition on the catalyst and decreasing catalyst activity for the steam reforming reaction. Moreover, an increase in Ni loading in the catalyst from 5 to 20% enhances carbon conversion and H_2 formation in the steam reforming of a mixture of all the model compounds studied, but these values decrease for a Ni content of 40%. Coke formation also increased by increasing Ni loading, attaining its maximum value for 40% Ni (6.5 wt.%).

  16. Experimental Parametric Model for Indirect Adhesion Wear Measurement in the Dry Turning of UNS A97075 (Al-Zn Alloy

    Directory of Open Access Journals (Sweden)

    Francisco Javier Trujillo

    2017-02-01

    Full Text Available In this work, the study of the influence of cutting parameters (cutting speed, feed, and depth of cut on the tool wear used in in the dry turning of cylindrical bars of the UNS A97075 (Al-Zn alloy, has been analyzed. In addition, a study of the physicochemical mechanisms of the secondary adhesion wear has been carried out. The behavior of this alloy, from the point of view of tool wear, has been compared to similar aeronautical aluminum alloys, such as the UNS A92024 (Al-Cu alloy and UNS A97050 (Al-Zn alloy. Furthermore, a first approach to the measurement of the 2D surface of the adhered material on the rake face of the tool has been conducted. Finally, a parametric model has been developed from the experimental results. This model allows predicting the intensity of the secondary adhesion wear as a function of the cutting parameters applied.

  17. An Analysis on the Constitutive Models for Forging of Ti6Al4V Alloy Considering the Softening Behavior

    Science.gov (United States)

    Souza, Paul M.; Beladi, Hossein; Singh, Rajkumar P.; Hodgson, Peter D.; Rolfe, Bernard

    2018-05-01

    This paper developed high-temperature deformation constitutive models for a Ti6Al4V alloy using an empirical-based Arrhenius equation and an enhanced version of the authors' physical-based EM + Avrami equations. The initial microstructure was a partially equiaxed α + β grain structure. A wide range of experimental data was obtained from hot compression of the Ti6Al4 V alloy at deformation temperatures ranging from 720 to 970 °C, and at strain rates varying from 0.01 to 10 s-1. The friction- and adiabatic-corrected flow curves were used to identify the parameter values of the constitutive models. Both models provided good overall accuracy of the flow stress. The generalized modified Arrhenius model was better at predicting the flow stress at lower strain rates. However, the model was inaccurate in predicting the peak strain. In contrast, the enhanced physical-based EM + Avrami model revealed very good accuracy at intermediate and high strain rates, but it was also better at predicting the peak strain. Blind sample tests revealed that the EM + Avrami maintained good predictions on new (unseen) data. Thus, the enhanced EM + Avrami model may be preferred over the Arrhenius model to predict the flow behavior of Ti6Al4V alloy during industrial forgings, when the initial microstructure is partially equiaxed.

  18. Flood analysis using HEC-RAS model: a case study for Hafr Al-Batin, Saudi Arabia

    Directory of Open Access Journals (Sweden)

    Al-Zahrani Muhammad

    2016-01-01

    Full Text Available Hafr Al-Batin is a Saudi Arabian city located in the northeastern part of the kingdom. The city lies in the dry valley of Wadi Al-Batin, part of Wadi Al-Rummah, which leads inland towards Medina and formerly emptied into the Arabian Gulf. Hafr Al-Batin is located in an area where three valleys meet, which makes the city under high risk of flooding, especially when intense rain occurs during short duration as in the case of arid and semi-arid regions. The yearly average rainfall intensity of Hafr Al-Baten is estimated to be 125 mm. Recently, extreme rainfall events occurred, generating flood water to flow from all valleys towards the city, causing serious damage to public and private properties. In this study, HEC-HMS and HEC-RAS models are used to simulate flood occurrence in the city. The results indicate that the average flow depths within the part of the main channel passing through Hafr Al-Batin city were 3.02 m, 3.26 m, 3.45 m, 3.76 m, 4.04 m and 4.34 m for the simulated 2, 5, 10, 25, 50 and 100-year design floods, respectively. Flood hazard maps are also generated to identify the areas within the city with high risk of flooding.

  19. Performance evaluation of Al-Zahra academic medical center based on Iran balanced scorecard model.

    Science.gov (United States)

    Raeisi, Ahmad Reza; Yarmohammadian, Mohammad Hossein; Bakhsh, Roghayeh Mohammadi; Gangi, Hamid

    2012-01-01

    Growth and development in any country's national health system, without an efficient evaluation system, lacks the basic concepts and tools necessary for fulfilling the system's goals. The balanced scorecard (BSC) is a technique widely used to measure the performance of an organization. The basic core of the BSC is guided by the organization's vision and strategies, which are the bases for the formation of four perspectives of BSC. The goal of this research is the performance evaluation of Al-Zahra Academic Medical Center in Isfahan University of Medical Sciences, based on Iran BSC model. This is a combination (quantitative-qualitative) research which was done at Al-Zahra Academic Medical Center in Isfahan University of Medical Sciences in 2011. The research populations were hospital managers at different levels. Sampling method was purposive sampling in which the key informed personnel participated in determining the performance indicators of hospital as the BSC team members in focused discussion groups. After determining the conceptual elements in focused discussion groups, the performance objectives (targets) and indicators of hospital were determined and sorted in perspectives by the group discussion participants. Following that, the performance indicators were calculated by the experts according to the predetermined objectives; then, the score of each indicator and the mean score of each perspective were calculated. Research findings included development of the organizational mission, vision, values, objectives, and strategies. The strategies agreed upon by the participants in the focus discussion group included five strategies, which were customer satisfaction, continuous quality improvement, development of human resources, supporting innovation, expansion of services and improving the productivity. Research participants also agreed upon four perspectives for the Al-Zahra hospital BSC. In the patients and community perspective (customer), two objectives and

  20. Mice housed on coal dust-contaminated sand: A model to evaluate the impacts of coal mining on health

    Energy Technology Data Exchange (ETDEWEB)

    Caballero-Gallardo, Karina, E-mail: kcaballerog@unicartagena.edu.co; Olivero-Verbel, Jesus, E-mail: joliverov@unicartagena.edu.co

    2016-03-01

    Coal dust is the most important air pollutant in coal mining in regards to producing deleterious health effects. It permeates the surrounding environment threatening public health. The aim of this study was to evaluate the toxic effects associated with exposure to sand contaminated with coal dust particles below 38 μm in diameter, obtained from a mineral sample collected in the largest coal mine in South America, La Loma, Cesar, Colombia. Sterilized sand was spiked with coal dust to obtain concentrations ranging from zero to 4% coal dust. To model natural exposure, mice were housed for eight weeks in boxes containing this mixture as bedding after which, they were euthanized and blood and tissue samples were collected. Real time PCR analysis revealed an increase in Cyp1A1 mRNA for living on sand with coal dust concentrations greater than 2% compared to mice living on sand without coal dust. Unexpectedly, for mice on coal dust-polluted sand, Sod1, Scd1 and Nqo1 hepatic mRNA were downregulated. The Comet assay in peripheral blood cells and the micronucleus test in blood smears, showed a significant potential genotoxic effect only at the highest coal dust concentration. Histopathological analysis revealed vascular congestion and peribronchial inflammation in the lungs. A dose–response relationship for the presence of hepatic steatosis, vacuolization and nuclei enlargements was observed in the exposed animals. The data suggest living on a soil polluted with coal dust induces molecular, cellular and histopathological changes in mice. Accordingly, the proposed model can be used to identify deleterious effects of exposure to coal dust deposited in soils that may pose health risks for surrounding wildlife populations. - Highlights: • Mice were exposed to coal dust-contaminated sand. • mRNA Markers for PAH exposure, lipid metabolism and oxidative stress increased. • ALT activity in plasma increased at the highest exposure to coal dust. • Liver tissues of exposed

  1. Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

    International Nuclear Information System (INIS)

    Askmyr, M; Ågerstam, H; Lilljebjörn, H; Hansen, N; Karlsson, C; Palffy, S von; Landberg, N; Högberg, C; Lassen, C; Rissler, M; Richter, J; Ehinger, M; Järås, M; Fioretos, T

    2014-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34 + cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML

  2. Validity of leptin receptor-deficiency (db/db) type 2 diabetes mellitus mice as a model of secondary osteoporosis

    Science.gov (United States)

    Huang, Le; You, Yong-Ke; Zhu, Tracy Y.; Zheng, Li-Zhen; Huang, Xiao-Ru; Chen, Hai-Yong; Yao, Dong; Lan, Hui-Yao; Qin, Ling

    2016-06-01

    This study aimed to evaluate the validation of the leptin receptor-deficient mice model for secondary osteoporosis associated with type 2 diabetes mellitus (T2DM) at bone micro-architectural level. Thirty three 36-week old male mice were divided into four groups: normal control (db/m) (n = 7), leptin receptor-deficient T2DM (db/db) (n = 8), human C-reactive protein (CRP) transgenic normal control (crp/db/m) (n = 7), and human CRP transgenic T2DM (crp/db/db) (n = 11). Lumber vertebrae (L5) and bilateral lower limbs were scanned by micro-CT to analyze trabecular and cortical bone quality. Right femora were used for three-point bending to analyze the mechanical properties. Trabecular bone quality at L5 was better in db/db or crp/db/db group in terms of bone mineral density (BMD), bone volume fraction, connectivity density, trabecular number and separation (all p  0.05). Maximum loading and energy yield in mechanical test were similar among groups while the elastic modulus in db/db and crp/db/db significantly lower than db/m. The leptin-receptor mice is not a proper model for secondary osteoporosis associated with T2DM.

  3. Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss.

    Science.gov (United States)

    Iwaniec, U T; Philbrick, K A; Wong, C P; Gordon, J L; Kahler-Quesada, A M; Olson, D A; Branscum, A J; Sargent, J L; DeMambro, V E; Rosen, C J; Turner, R T

    2016-10-01

    Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18-23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies

  4. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    Science.gov (United States)

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-07

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

  5. Evidence of Antidepressive Effects of a Wakan-yaku, Hochuekkito, in Depression Model Mice with Learned-Helplessness Behavior

    Science.gov (United States)

    Tohda, Michihisa; Mingmalairak, Salin

    2013-01-01

    Wakan-yaku is a type of Japanese and Sino traditional, systematized medical care that has been practiced for hundreds of years. This medicinal system includes many antidepressive prescriptions. One of the candidates is Hochuekkito, although experimental evidence has not yet been established clearly. To obtain evidence, a depression model of learned-helplessness (LH) mice was used. Based on the score of escape failure, an index of the depression degree, mice with a depressive condition were selected to assess Hochuekkito's effects. This selection was significant and effective in the following two points: evaluation of the drug effect under disease conditions and minimization of the number of animals. Treatment with Hochuekkito (1 and 5 g/kg p.o.; estimated galenical amount) for 14 days significantly decreased the depression index, the number of escape failures, and desipramine (10 mg/kg p.o.) suggesting that Hochuekkito has an antidepressive effect. PMID:24454491

  6. Evidence of Antidepressive Effects of a Wakan-yaku, Hochuekkito, in Depression Model Mice with Learned-Helplessness Behavior

    Directory of Open Access Journals (Sweden)

    Michihisa Tohda

    2013-01-01

    Full Text Available Wakan-yaku is a type of Japanese and Sino traditional, systematized medical care that has been practiced for hundreds of years. This medicinal system includes many antidepressive prescriptions. One of the candidates is Hochuekkito, although experimental evidence has not yet been established clearly. To obtain evidence, a depression model of learned-helplessness (LH mice was used. Based on the score of escape failure, an index of the depression degree, mice with a depressive condition were selected to assess Hochuekkito’s effects. This selection was significant and effective in the following two points: evaluation of the drug effect under disease conditions and minimization of the number of animals. Treatment with Hochuekkito (1 and 5 g/kg p.o.; estimated galenical amount for 14 days significantly decreased the depression index, the number of escape failures, and desipramine (10 mg/kg p.o. suggesting that Hochuekkito has an antidepressive effect.

  7. Voluntary exercise confers protection against age-related deficits in brain oxygenation in awake mice model of Alzheimer's disease

    Science.gov (United States)

    Lu, Xuecong; Moeini, Mohammad; Li, Baoqiang; Sakadžić, Sava; Lesage, Frédéric

    2018-02-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by short-term memory loss and cognitive inabilities. This work seeks to study the effects of voluntary exercise on the change in oxygen delivery in awake mice models of Alzheimer's disease by monitoring brain tissue oxygenation. Experiments were performed on Young (AD_Y, 3-4 months, n=8), Old (AD_O, 6-7 months, n=8), and Old with exercise (AD_OEX, 6-7 months, n=8) transgenic APPPS1 mice and their controls. Brain tissue oxygenation was measured by two photon phosphorescence lifetime microscopy on the left sensory motor cortex. We found that the average tissue PO2 decreased with age but were regulated by exercise. The results suggest a potential for exercise to improve brain function with age and AD.

  8. Modelling of AlAs/GaAs interfacial structures using high-angle annular dark field (HAADF) image simulations.

    Science.gov (United States)

    Robb, Paul D; Finnie, Michael; Craven, Alan J

    2012-07-01

    High angle annular dark field (HAADF) image simulations were performed on a series of AlAs/GaAs interfacial models using the frozen-phonon multislice method. Three general types of models were considered-perfect, vicinal/sawtooth and diffusion. These were chosen to demonstrate how HAADF image measurements are influenced by different interfacial structures in the technologically important III-V semiconductor system. For each model, interfacial sharpness was calculated as a function of depth and compared to aberration-corrected HAADF experiments of two types of AlAs/GaAs interfaces. The results show that the sharpness measured from HAADF imaging changes in a complicated manner with thickness for complex interfacial structures. For vicinal structures, it was revealed that the type of material that the probe projects through first of all has a significant effect on the measured sharpness. An increase in the vicinal angle was also shown to generate a wider interface in the random step model. The Moison diffusion model produced an increase in the interface width with depth which closely matched the experimental results of the AlAs-on-GaAs interface. In contrast, the interface width decreased as a function of depth in the linear diffusion model. Only in the case of the perfect model was it possible to ascertain the underlying structure directly from HAADF image analysis. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration

    International Nuclear Information System (INIS)

    Ding, Ying; Adachi, Hiroaki; Katsuno, Masahisa; Huang, Zhe; Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki; Funakoshi, Hiroshi; Nakamura, Toshikazu; Sobue, Gen

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. - Highlights: • HGF overexpression ameliorates the motor phenotypes of the SBMA mouse model. • HGF overexpression induces Akt phosphorylation in the SBMA mouse model. • This is the first report of combination therapy in a mouse model of polyQ diseases.

  10. Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Ying [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Adachi, Hiroaki, E-mail: hadachi-ns@umin.org [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555 (Japan); Katsuno, Masahisa [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Huang, Zhe [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555 (Japan); Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Funakoshi, Hiroshi [Center for Advanced Research and Education, Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510 (Japan); Nakamura, Toshikazu [Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034 (Japan); Sobue, Gen, E-mail: sobueg@med.nagoya-u.ac.jp [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

    2015-12-25

    Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. - Highlights: • HGF overexpression ameliorates the motor phenotypes of the SBMA mouse model. • HGF overexpression induces Akt phosphorylation in the SBMA mouse model. • This is the first report of combination therapy in a mouse model of polyQ diseases.

  11. Impaired behavioural pain responses in hph-1 mice with inherited deficiency in GTP cyclohydrolase 1 in models of inflammatory pain

    Science.gov (United States)

    2013-01-01

    Background GTP cyclohydrolase 1 (GTP-CH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4), encoded by the GCH1 gene, has been implicated in the development and maintenance of inflammatory pain in rats. In humans, homozygous carriers of a “pain-protective” (PP) haplotype of the GCH1 gene have been identified exhibiting lower pain sensitivity, but only following pain sensitisation. Ex vivo, the PP GCH1 haplotype is associated with decreased induction of GCH1 after stimulation, whereas the baseline BH4 production is not affected. Contrary, loss of function mutations in the GCH1 gene results in decreased basal GCH1 expression, and is associated with DOPA-responsive dystonia (DRD). So far it is unknown if such mutations affect acute and inflammatory pain. Results In the current study, we examined the involvement of the GCH1 gene in pain models using the hyperphenylalaninemia 1 (hph-1) mouse, a genetic model for DRD, with only 10% basal GTP-CH1 activity compared to wild type mice. The study included assays for determination of acute nociception as well as models for pain after sensitisation. Pain behavioural analysis of the hph-1 mice showed reduced pain-like responses following intraplantar injection of CFA, formalin and capsaicin; whereas decreased basal level of GTP-CH1 activity had no influence in naïve hph-1 mice on acute mechanical and heat pain thresholds. Moreover, the hph-1 mice showed no signs of motor impairment or dystonia-like symptoms. Conclusions In this study, we demonstrate novel evidence that genetic mutations in the GCH1 gene modulate pain-like hypersensitivity. Together, the present data suggest that BH4 is not important for basal heat and mechanical pain, but they support the hypothesis that BH4 plays a role in inflammation-induced hypersensitivity. Our studies suggest that the BH4 pathway could be a therapeutic target for the treatment of inflammatory pain conditions. Moreover, the hph-1 mice provide a valid model to

  12. The antioxidant effect of Asparagus cochinchinensis (Lour.) Merr. shoot in D-galactose induced mice aging model and in vitro.

    Science.gov (United States)

    Lei, Linghua; Ou, Lijun; Yu, Xiaoying

    2016-04-01

    An increasing number of plant components and their extracts have been shown to have beneficial health effects in humans. We aimed to explore the antioxidant effects of the aqueous extract of Asparagus cochinchinensis (Lour.) Merr. shoot in vivo and in vitro. A total of 80 Kun Ming mice were randomly divided into four groups (20/group). The mice in the control group received a daily subcutaneous injection of saline. A daily injection of D-galactose was administered to the aging model group, the vitamin C (Vc) group (positive control group), and the extract treatment group. Regular measurement of blood cells, nitric oxide synthase (NOS), catalase (CAT) activities, superoxide dismutase (SOD) activities, nitric oxide (NO), and malondialdehyde (MDA) concentration, and the expressions of NOS, SOD, and glutathione peroxidase (GPX) in serum levels were obtained. Furthermore, the microstructure of mice viscera was observed using hematoxylin and eosin staining. The aqueous extract of A. cochinchinensis (Lour.) Merr. had similar 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH·) [or 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+)] and higher hydroxyl radicals (or superoxide anion; p < 0.05) radical scavenging capabilities to Vc. Moreover, compared with the aging model group, the aqueous extract of A. cochinchinensis (Lour.) Merr. shoot could obviously increase NOS, CAT, and SOD activities and the NO content, and reduce the MDA content (p < 0.05). Additionally, the microstructure of mice viscera was obviously improved and the expressions of NOS, SOD and GPX were also manifestly increased in the treatment group (p < 0.05). The aqueous extract of A. cochinchinensis (Lour.) Merr. shoot had a strong radical scavenging capability in vivo and in vitro, and might be used to diminish radicals in the body and consequently prevent aging. Copyright © 2016. Published by Elsevier Taiwan LLC.

  13. Mice housed on coal dust-contaminated sand: A model to evaluate the impacts of coal mining on health.

    Science.gov (United States)

    Caballero-Gallardo, Karina; Olivero-Verbel, Jesus

    2016-03-01

    Coal dust is the most important air pollutant in coal mining in regards to producing deleterious health effects. It permeates the surrounding environment threatening public health. The aim of this study was to evaluate the toxic effects associated with exposure to sand contaminated with coal dust particles below 38 μm in diameter, obtained from a mineral sample collected in the largest coal mine in South America, La Loma, Cesar, Colombia. Sterilized sand was spiked with coal dust to obtain concentrations ranging from zero to 4% coal dust. To model natural exposure, mice were housed for eight weeks in boxes containing this mixture as bedding after which, they were euthanized and blood and tissue samples were collected. Real time PCR analysis revealed an increase in Cyp1A1 mRNA for living on sand with coal dust concentrations greater than 2% compared to mice living on sand without coal dust. Unexpectedly, for mice on coal dust-polluted sand, Sod1, Scd1 and Nqo1 hepatic mRNA were downregulated. The Comet assay in peripheral blood cells and the micronucleus test in blood smears, showed a significant potential genotoxic effect only at the highest coal dust concentration. Histopathological analysis revealed vascular congestion and peribronchial inflammation in the lungs. A dose-response relationship for the presence of hepatic steatosis, vacuolization and nuclei enlargements was observed in the exposed animals. The data suggest living on a soil polluted with coal dust induces molecular, cellular and histopathological changes in mice. Accordingly, the proposed model can be used to identify deleterious effects of exposure to coal dust deposited in soils that may pose health risks for surrounding wildlife populations. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Ab initio modeling of Al adsorption on CaF2 surfaces

    International Nuclear Information System (INIS)

    Barzilai, S.; Argaman, N.; Froumin, N.; Fuks, D.; Frage, N.

    2008-01-01

    Ab initio simulations of the adsorption of Al atoms on CaF 2 (0 0 1) and (1 1 1) surfaces have been performed for supercells with 7 different atomic configurations, using density functional theory. For (1 1 1) surfaces, a repulsive interaction was observed for most configurations, while a weak attraction was obtained when the Al atom was placed above F atoms. For the Ca-terminated (0 0 1) surface, the adsorption energy was about 5 times larger, whereas for the F-terminated (0 0 1) surface it was about 20 times greater. The comparative analysis indicates that the (0 0 1) surfaces are reactive and have a strong Al adatom bonding (chemisorption), especially for the F-terminated substrate. On the contrary, the (1 1 1) plane may be considered as non-reactive (physisorption), having a weak bonding of the Al adatom above the F site

  15. Modeling and Simulation of Monolithic AlGaAs/InGaAs Tandem Solar Cell

    Directory of Open Access Journals (Sweden)

    Samia SLIMANI

    2015-06-01

    Full Text Available Employing conventional III-V junctions we report a classical calculation of conduction and valence band edge and the electron and hole densities. It is shown that the optimum performance can be achieved by employing AlGaAs /AlGaAs/InGaAs monolithic cascade solar cells, we have established these calculations by solving the Poisson equation within the framework of the Nextnano.

  16. Modeling of Processing-Induced Pore Morphology in an Additively-Manufactured Ti-6Al-4V Alloy.

    Science.gov (United States)

    Kabir, Mohammad Rizviul; Richter, Henning

    2017-02-08

    A selective laser melting (SLM)-based, additively-manufactured Ti-6Al-4V alloy is prone to the accumulation of undesirable defects during layer-by-layer material build-up. Defects in the form of complex-shaped pores are one of the critical issues that need to be considered during the processing of this alloy. Depending on the process parameters, pores with concave or convex boundaries may occur. To exploit the full potential of additively-manufactured Ti-6Al-4V, the interdependency between the process parameters, pore morphology, and resultant mechanical properties, needs to be understood. By incorporating morphological details into numerical models for micromechanical analyses, an in-depth understanding of how these pores interact with the Ti-6Al-4V microstructure can be gained. However, available models for pore analysis lack a realistic description of both the Ti-6Al-4V grain microstructure, and the pore geometry. To overcome this, we propose a comprehensive approach for modeling and discretizing pores with complex geometry, situated in a polycrystalline microstructure. In this approach, the polycrystalline microstructure is modeled by means of Voronoi tessellations, and the complex pore geometry is approximated by strategically combining overlapping spheres of varied sizes. The proposed approach provides an elegant way to model the microstructure of SLM-processed Ti-6Al-4V containing pores or crack-like voids, and makes it possible to investigate the relationship between process parameters, pore morphology, and resultant mechanical properties in a finite-element-based simulation framework.

  17. Modeling of Processing-Induced Pore Morphology in an Additively-Manufactured Ti-6Al-4V Alloy

    Directory of Open Access Journals (Sweden)

    Mohammad Rizviul Kabir

    2017-02-01

    Full Text Available A selective laser melting (SLM-based, additively-manufactured Ti-6Al-4V alloy is prone to the accumulation of undesirable defects during layer-by-layer material build-up. Defects in the form of complex-shaped pores are one of the critical issues that need to be considered during the processing of this alloy. Depending on the process parameters, pores with concave or convex boundaries may occur. To exploit the full potential of additively-manufactured Ti-6Al-4V, the interdependency between the process parameters, pore morphology, and resultant mechanical properties, needs to be understood. By incorporating morphological details into numerical models for micromechanical analyses, an in-depth understanding of how these pores interact with the Ti-6Al-4V microstructure can be gained. However, available models for pore analysis lack a realistic description of both the Ti-6Al-4V grain microstructure, and the pore geometry. To overcome this, we propose a comprehensive approach for modeling and discretizing pores with complex geometry, situated in a polycrystalline microstructure. In this approach, the polycrystalline microstructure is modeled by means of Voronoi tessellations, and the complex pore geometry is approximated by strategically combining overlapping spheres of varied sizes. The proposed approach provides an elegant way to model the microstructure of SLM-processed Ti-6Al-4V containing pores or crack-like voids, and makes it possible to investigate the relationship between process parameters, pore morphology, and resultant mechanical properties in a finite-element-based simulation framework.

  18. Early thymic T cell development in young transgenic mice overexpressing human Cu/Zn superoxide dismutase, a model of Down syndrome.

    Science.gov (United States)

    Laurent, Julien; Paly, Evelyne; Marche, Patrice N; London, Jacqueline

    2006-06-01

    Previous studies have shown that transgenic mice overexpressing Cu/Zn superoxide dismutase, a model of Down syndrome, exhibit premature thymic involution. We have performed a flow cytometry analysis of the developing thymus in these homozygous transgenic mice (hSOD1/hSOD1: Tg-SOD). Longitudinal follow-up analysis from day 3 to day 280 showed an early thymic development in Tg-SOD mice compared with controls. This early thymic development was associated with an increased migration of mature T cells to peripheral lymphoid organs. BrdU labeling showed no difference between Tg-SOD and control mice, confirming that the greater number of peripheral T cells in Tg-SOD mice was not due to extensive proliferation of these cells but rather to a greater pool of emigrant T cells in Tg-SOD.

  19. Analysis of the main dosimetric peak of Al2O3:C compounds with a model of interacting traps

    International Nuclear Information System (INIS)

    Ortega, F.; Marcazzó, J.; Molina, P.; Santiago, M.; Lester, M.; Henniger, J.; Caselli, E.

    2013-01-01

    The glow curve of Al 2 O 3 :C compounds has been analyzed by employing a model consisting of two active traps, thermally disconnected traps and one recombination centre. The analysis takes into account interaction among traps and the thermal quenching of the thermoluminescent emission. - Highlights: • Glow curves of Al 2 O 3 :C for two doses have been analysed taking into account interactions among traps. • The system of differential equations describing the kinetics has been uncoupled. • The new system of equations takes into account equations without derivatives. • The algorithm used will not become stiff. • The kinetics parameters obtained do not depend on the dose

  20. Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

    NARCIS (Netherlands)

    Simeonova, I.; Jaber, S.; Draskovic, I.; Bardot, B.; Fang, M.; Bouarich-Bourimi, R.; Lejour, V.; Charbonnier, L.; Soudais, C.; Bourdon, J.C.; Huerre, M.; Londono-Vallejo, A.; Toledo, F.

    2013-01-01

    Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53(Delta31), a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis,

  1. Motor, emotional and cognitive deficits in adult BACHD mice : A model for Huntington's disease

    NARCIS (Netherlands)

    Abada, Yah-se K.; Schreiber, Rudy; Ellenbroek, Bart

    2013-01-01

    Rationale: Huntington's disease (HD) is characterized by progressive motor dysfunction, emotional disturbances and cognitive deficits. It is a genetic disease caused by an elongation of the polyglutamine repeats in the huntingtin gene. Whereas HD is a complex disorder, previous studies in mice

  2. Of mice and men: how animal models advance our understanding of T-cell function in RA.

    Science.gov (United States)

    Kobezda, Tamás; Ghassemi-Nejad, Sheida; Mikecz, Katalin; Glant, Tibor T; Szekanecz, Zoltán

    2014-03-01

    The involvement of autoreactive T cells in the pathogenesis of rheumatoid arthritis (RA) as well as in autoimmune animal models of arthritis has been well established; however, unanswered questions, such as the role of joint-homing T cells, remain. Animal models of arthritis are superb experimental tools in demonstrating how T cells trigger joint inflammation, and thus can help to further our knowledge of disease mechanisms and potential therapies. In this Review, we discuss the similarities and differences in T-cell subsets and functions between RA and mouse arthritis models. For example, various T-cell subsets are involved in both human and mouse arthritis, but differences might exist in the cytokine regulation and plasticity of these cells. With regard to joint-homing T cells, an abundance of synovial T cells is present in humans compared with mice. On the other hand, local expansion of type 17 T-helper (TH17) cells is observed in some animal models, but not in RA. Finally, whereas T-cell depletion therapy essentially failed in RA, antibody targeting of T cells can work, at least preventatively, in most arthritis models. Clearly, additional human and animal studies are needed to fill the gap in our understanding of the specific contribution of T-cell subsets to arthritis in mice and men.

  3. Length-scale dependent mechanical properties of Al-Cu eutectic alloy: Molecular dynamics based model and its experimental verification

    Science.gov (United States)

    Tiwary, C. S.; Chakraborty, S.; Mahapatra, D. R.; Chattopadhyay, K.

    2014-05-01

    This paper attempts to gain an understanding of the effect of lamellar length scale on the mechanical properties of two-phase metal-intermetallic eutectic structure. We first develop a molecular dynamics model for the in-situ grown eutectic interface followed by a model of deformation of Al-Al2Cu lamellar eutectic. Leveraging the insights obtained from the simulation on the behaviour of dislocations at different length scales of the eutectic, we present and explain the experimental results on Al-Al2Cu eutectic with various different lamellar spacing. The physics behind the mechanism is further quantified with help of atomic level energy model for different length scale as well as different strain. An atomic level energy partitioning of the lamellae and the interface regions reveals that the energy of the lamellae core are accumulated more due to dislocations irrespective of the length-scale. Whereas the energy of the interface is accumulated more due to dislocations when the length-scale is smaller, but the trend is reversed when the length-scale is large beyond a critical size of about 80 nm.

  4. In vivo characterisation of the inflammatory reaction following mesh implantation in transgenic mice models.

    Science.gov (United States)

    Fet, N; Alizai, P H; Fragoulis, A; Wruck, C; Pufe, T; Tolba, R H; Neumann, U P; Klinge, U

    2014-06-01

    Hernia repair with prosthetic meshes represents one of the most common surgical procedures in the field of surgery. This intervention is always associated with an ensuing inflammatory response, angiogenesis and fibrotic encapsulation forming a foreign body granuloma (FBG) around the mesh fibres. Several studies have described this inflammatory reaction by characterising inflammatory cell infiltrate around the FBG after mesh explantation. However, very little is known about the real-time progression of such an inflammatory response. The aim of this study was to investigate the feasibility of monitoring the ongoing inflammatory response to mesh implantation using bioluminescence in vivo. Three luciferase transgenic mice strains (FVB/N-Tg(Vegfr2-luc)-Xen, BALB/C-Tg(NFκB-RE-luc)-Xen and Tg(INS/EpRE-Luc)T20Rbl) were used. Mice were anaesthetized with 2 % isoflurane, and two incisions were made on the left and right sides of the abdomen of the mice. A 1-cm(2) propylene mesh was implanted subcutaneously in the right incision wound of each mouse, and the left wound served as control. Two hundred microliters of D-luciferin was injected into the mice, and bioluminescence measurements were done prior to the surgical intervention and subsequently every 3 days. After mesh explantation, histological analysis was done. Statistical analysis was done using prism GraphPad software. Bioluminescence results revealed different time points of maximum signal for the different mice strains. VEGFR2 gene expression peaked on day 6, NFkB on day 12 and ARE on day 3 post mesh implantation. We also observed much higher bioluminescent signal around the FBG surrounding the mesh as compared to the control wound, with p response over a given period of time.

  5. Comment on "Can assimilation of crowdsourced data in hydrological modelling improve flood prediction?" by Mazzoleni et al. (2017)

    Science.gov (United States)

    Viero, Daniele P.

    2018-01-01

    Citizen science and crowdsourcing are gaining increasing attention among hydrologists. In a recent contribution, Mazzoleni et al. (2017) investigated the integration of crowdsourced data (CSD) into hydrological models to improve the accuracy of real-time flood forecasts. The authors used synthetic CSD (i.e. not actually measured), because real CSD were not available at the time of the study. In their work, which is a proof-of-concept study, Mazzoleni et al. (2017) showed that assimilation of CSD improves the overall model performance; the impact of irregular frequency of available CSD, and that of data uncertainty, were also deeply assessed. However, the use of synthetic CSD in conjunction with (semi-)distributed hydrological models deserves further discussion. As a result of equifinality, poor model identifiability, and deficiencies in model structure, internal states of (semi-)distributed models can hardly mimic the actual states of complex systems away from calibration points. Accordingly, the use of synthetic CSD that are drawn from model internal states under best-fit conditions can lead to overestimation of the effectiveness of CSD assimilation in improving flood prediction. Operational flood forecasting, which results in decisions of high societal value, requires robust knowledge of the model behaviour and an in-depth assessment of both model structure and forcing data. Additional guidelines are given that are useful for the a priori evaluation of CSD for real-time flood forecasting and, hopefully, for planning apt design strategies for both model calibration and collection of CSD.

  6. Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness.

    Science.gov (United States)

    O'Callaghan, James P; Kelly, Kimberly A; Locker, Alicia R; Miller, Diane B; Lasley, Steve M

    2015-06-01

    Gulf War Illness (GWI) is a multi-symptom disorder with features characteristic of persistent sickness behavior. Among conditions encountered in the Gulf War (GW) theater were physiological stressors (e.g., heat/cold/physical activity/sleep deprivation), prophylactic treatment with the reversible AChE inhibitor, pyridostigmine bromide (PB), the insect repellent, N,N-diethyl-meta-toluamide (DEET), and potentially the nerve agent, sarin. Prior exposure to the anti-inflammatory glucocorticoid, corticosterone (CORT), at levels associated with high physiological stress, can paradoxically prime the CNS to produce a robust proinflammatory response to neurotoxicants and systemic inflammation; such neuroinflammatory effects can be associated with sickness behavior. Here, we examined whether CORT primed the CNS to mount neuroinflammatory responses to GW exposures as a potential model of GWI. Male C57BL/6 mice were treated with chronic (14 days) PB/ DEET, subchronic (7-14 days) CORT, and acute exposure (day 15) to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. DFP alone caused marked brain-wide neuroinflammation assessed by qPCR of tumor necrosis factor-α, IL6, chemokine (C-C motif) ligand 2, IL-1β, leukemia inhibitory factor, and oncostatin M. Pre-treatment with high physiological levels of CORT greatly augmented (up to 300-fold) the neuroinflammatory responses to DFP. Anti-inflammatory pre-treatment with minocycline suppressed many proinflammatory responses to CORT+DFP. Our findings are suggestive of a possible critical, yet unrecognized interaction between the stressor/environment of the GW theater and agent exposure(s) unique to this war. Such exposures may in fact prime the CNS to amplify future neuroinflammatory responses to pathogens, injury, or toxicity. Such occurrences could potentially result in the prolonged episodes of sickness behavior observed in GWI. Gulf War (GW) veterans were exposed to stressors, prophylactic

  7. The Mechanism of Memory Enhancement of Acteoside (Verbascoside) in the Senescent Mouse Model Induced by a Combination of D-gal and AlCl3.

    Science.gov (United States)

    Peng, Xiao-Ming; Gao, Li; Huo, Shi-Xia; Liu, Xin-Min; Yan, Ming

    2015-08-01

    Acteoside (verbsacoside), one of the main active phenylethanoid glycosides from Cistanche deserticola, is known to have antioxidant and neuroprotective activity, and herbs containing it are used to enhance memory. However, there is relatively little direct experimental evidence to support the use of acteoside in Alzheimer's disease (AD). The purpose of this study was to elucidate the effects of acteoside in improving learning and memory, using a mouse model of senescence induced by a combination of d-galactose and AlCl3 , and investigate its potential mechanisms compared with the positive controls vitamin E and piracetam. Acteoside was administered intragastrically at doses of 30, 60 and 120 mg/kg/day for 30 days after AD was induced. Memory function was evaluated using a step-down test. The number of neuron was analysed by haematoxylin and eosin staining and the number of Nissl bodies by Nissl staining. The expression of caspase-3 protein in hippocampus was detected by immunohistochemistry and western blot. Nitric oxide and total nitric oxide synthase level in hippocampus were also assessed. Our results showed that the latency of step down was shortened in AD model mice and the number of errors decreased after treatment with all doses of acteoside. Neurons and Nissl bodies in the hippocampus were increased significantly with higher doses (60 and 120 mg/kg/day) of acteoside. The content of nitric oxide, the activity of nitric oxide synthase and the expression of caspase-3 protein were decreased by 120 mg/kg/day acteoside compared with that of the AD model group. Our results support the results obtained previously using the Morris maze test in the same mouse model of senescence, and the use of traditional medicinal herbs containing acteoside for neuroprotection and memory loss. Copyright © 2015 John Wiley & Sons, Ltd.

  8. EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.

    Directory of Open Access Journals (Sweden)

    Claire E Le Pichon

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.

  9. Alimba et al (5)

    African Journals Online (AJOL)

    USER

    There was significant (p<0.05) increase in erythrocytes, haemoglobin ... for its anti-hemorrhoid and anti-inflammatory properties (Afolabi et al., 2008), ... genome instability which may lead to genetic related diseases ... membrane, behavioral pattern, morbidity and mortality. ..... extracts of Phyllanthus amarus in mice and rats.

  10. Effects of Combined Simultaneous and Sequential Endostar and Cisplatin Treatment in a Mice Model of Gastric Cancer Peritoneal Metastases

    Directory of Open Access Journals (Sweden)

    Lin Jia

    2017-01-01

    Full Text Available Objective. Aimed to study the effects of endostar and cisplatin using an in vivo imaging system (IVIS in a model of peritoneal metastasis of gastric cancer. Methods. NUGC-4 gastric cancer cells transfected with luciferase gene (NUGC-4-Luc were injected i.p. into nude mice. One week later, mice were randomly injected i.p.: group 1, cisplatin (d1–3 + endostar (d4–7; group 2, endostar (d1–4 + cisplatin (d5–7; group 3, endostar + cisplatin d1, 4, and 7; group 4, saline for two weeks. One week after the final administration, mice were sacrificed. Bioluminescent data, microvessel density (MVD, and lymphatic vessel density (LVD were analyzed. Results. Among the four groups, there were no significant differences in the weights and in the number of cancer cell photons on days 1 and 8 (P>0.05. On day 15, the numbers in groups 3 and 1 were less than that in group 2 (P0.05 or in LVD number among the four groups (P>0.05. Conclusions. IVIS® was more useful than weight, volume of ascites, and number of peritoneal nodules. The simultaneous group was superior to sequential groups in killing cancer cells and inhibiting vascular endothelium. Cisplatin-endostar was superior to endostar-cisplatin in killing cancer cells, while the latter in inhibiting peritoneal vascular endothelium.

  11. Effects of Combined Simultaneous and Sequential Endostar and Cisplatin Treatment in a Mice Model of Gastric Cancer Peritoneal Metastases.

    Science.gov (United States)

    Jia, Lin; Ren, Shuguang; Li, Tao; Wu, Jianing; Zhou, Xinliang; Zhang, Yan; Wu, Jianhua; Liu, Wei

    2017-01-01

    Objective . Aimed to study the effects of endostar and cisplatin using an in vivo imaging system (IVIS) in a model of peritoneal metastasis of gastric cancer. Methods . NUGC-4 gastric cancer cells transfected with luciferase gene (NUGC-4-Luc) were injected i.p. into nude mice. One week later, mice were randomly injected i.p.: group 1, cisplatin (d1-3) + endostar (d4-7); group 2, endostar (d1-4) + cisplatin (d5-7); group 3, endostar + cisplatin d1, 4, and 7; group 4, saline for two weeks. One week after the final administration, mice were sacrificed. Bioluminescent data, microvessel density (MVD), and lymphatic vessel density (LVD) were analyzed. Results . Among the four groups, there were no significant differences in the weights and in the number of cancer cell photons on days 1 and 8 ( P > 0.05). On day 15, the numbers in groups 3 and 1 were less than that in group 2 ( P 0.05) or in LVD number among the four groups ( P > 0.05). Conclusions . IVIS® was more useful than weight, volume of ascites, and number of peritoneal nodules. The simultaneous group was superior to sequential groups in killing cancer cells and inhibiting vascular endothelium. Cisplatin-endostar was superior to endostar-cisplatin in killing cancer cells, while the latter in inhibiting peritoneal vascular endothelium.

  12. Inhibition mechanism of compound ethanol extracts from wuweizi (fructus schisandrae chinensis) on renal interstitial fibrosis in diabetic nephropathy model mice.

    Science.gov (United States)

    Zhang, Yanqiu; Zhang, Daning; Zhang, Mianzhi

    2012-12-01

    To evaluate inhibition effect and mechanism of compound ethanol extracts from Wuweizi (Fructus Schisandrae Chinensis), Chuanxiong (Rhizoma Chuanxiong) and Muli (Cocha Ostreae) (FRC) on glomerular and tubular interstitial fibrosis in streptozocin (STZ)-induced diabetic nephropathy (ND) model mice. Twenty-seven male C57BL/6 mice were divided randomly into 3 groups: nondibetic (ND), STZ-induced diabetic (D), and STZ-induced diabetic that were treated with 5 g x kg(-1) x day(-1) of FRC by oral gavage (D(FRC)), with 9 in each group. The protein expressions of E-cadherin, alpha-smooth muscle actin (alpha-SMA), Plasminogen Activator Inhibitor-1 (PAL-1) in renal tissues were investigated by Western blotting. The expressions of fibronectin (FN) and alpha-SMA were detected by immunohistochemical method. The morphological changes of renal tissues were observed under a microscope. Renal tissues in the D(FRC) group showed a lessened degree of fibrosis. Meanwhile, the expressions of FN, alpha-SMA and PAI-1 were significantly lower in the D(FRC) group than those in the D group (all P < 0.05). FRC can ameliorate the DN in the C57BL/6 mice, and its mechanism may relate to inhibition on the epithelial to mesenchymal transdifferentiation, endothelial-myofibroblast transition and PAL-1 expression.

  13. TRAM-Derived Decoy Peptides inhibits the inflammatory response in mouse mammary epithelial cells and a mastitis model in mice.

    Science.gov (United States)

    Hu, Xiaoyu; Tian, Yuan; Wang, Tiancheng; Zhang, Wenlong; Wang, Wei; Gao, Xuejiao; Qu, Shihui; Cao, Yongguo; Zhang, Naisheng

    2015-10-05

    It has been proved that TRAM-Derived Decoy peptides have anti-inflammatory properties. In this study, we synthesized a TRAM-Derived decoy peptide (TM6), belongs to TRAM TIR domain, of which sequence is "N"-RQIKIWFQNRRMKWK, KENFLRDTWCNFQFY-"C" and evaluated the effects of TM6 on lipopolysaccharide-induced mastitis in mice. In vivo, LPS-induced mice mastitis model was established by injection of LPS through the duct of mammary gland. TM6 was injected 1h before or after LPS treatment. In vitro, primary mouse mammary epithelial cells were used to investigate the effects of TM6 on LPS-induced inflammatory responses. The results showed that TM6 inhibited LPS-induced mammary gland histopathologic changes, MPO activity, and TNF-α, IL-1β and IL-6 production in mice. In vitro, TM6 significantly inhibited LPS-induced TNF-α and IL-6 production, as well as NF-κB and MAPKs activation. In conclusion, this study demonstrated that TM6 had protective effects on LPS-mastitis and may be a promising therapeutic reagent for mastitis treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Ex Vivo and In Vivo Mice Models to Study Blastocystis spp. Adhesion, Colonization and Pathology: Closer to Proving Koch's Postulates.

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    Sitara S R Ajjampur

    Full Text Available Blastocystis spp. are widely prevalent extra cellular, non-motile anerobic protists that inhabit the gastrointestinal tract. Although Blastocystis spp. have been associated with gastrointestinal symptoms, irritable bowel syndrome and urticaria, their clinical significance has remained controversial. We established an ex vivo mouse explant model to characterize adhesion in the context of tissue architecture and presence of the mucin layer. Using confocal microscopy with tissue whole mounts and two axenic isolates of Blastocystis spp., subtype 7 with notable differences in adhesion to intestinal epithelial cells (IEC, isolate B (ST7-B and isolate H (more adhesive, ST7-H, we showed that adhesion is both isolate dependent and tissue trophic. The more adhesive isolate, ST7-H was found to bind preferentially to the colon tissue than caecum and terminal ileum. Both isolates were also found to have mucinolytic effects. We then adapted a DSS colitis mouse model as a susceptible model to study colonization and acute infection by intra-caecal inoculation of trophic Blastocystis spp.cells. We found that the more adhesive isolate ST7-H was also a better colonizer with more mice shedding parasites and for a longer duration than ST7-B. Adhesion and colonization was also associated with increased virulence as ST7-H infected mice showed greater tissue damage than ST7-B. Both the ex vivo and in vivo models used in this study showed that Blastocystis spp. remain luminal and predominantly associated with mucin. This was further confirmed using colonic loop experiments. We were also successfully able to re-infect a second batch of mice with ST7-H isolates obtained from fecal cultures and demonstrated similar histopathological findings and tissue damage thereby coming closer to proving Koch's postulates for this parasite.

  15. Microwave-assisted combustion synthesis of NiAl intermetallics in a single mode applicator: Modeling and optimisation

    International Nuclear Information System (INIS)

    Poli, G.; Sola, R.; Veronesi, P.

    2006-01-01

    The microwave-assisted combustion synthesis of NiAl intermetallics in a single mode applicator has been simulated numerically and performed with the aim of achieving the highest yields, energy efficiency and process reproducibility. The electromagnetic field modeling of the microwave system allowed to chose the proper experimental set-up and the materials more suitable for the application, minimising the reflected power and the risks of arcing. In all the experimental conditions tested, conversions of 3-5 g 1:1 atomic ratio Ni and Al powder compacts into NiAl ranged from 98.7% to 100%, requiring from 30 to 180 s with power from 500 to 1500 W. The optimisation procedure allowed to determine and quantify the effects of the main process variables on the ignition time, the NiAl yields and the specific energy consumption, leading to a fast, reproducible and cost-effective process of microwave-assisted combustion synthesis of NiAl intermetallics

  16. Analytical modeling and simulation of subthreshold behavior in nanoscale dual material gate AlGaN/GaN HEMT

    Science.gov (United States)

    Kumar, Sona P.; Agrawal, Anju; Chaujar, Rishu; Gupta, Mridula; Gupta, R. S.

    2008-07-01

    A two-dimensional (2-D) analytical model for a Dual Material Gate (DMG) AlGaN/GaN High Electron Mobility Transistor (HEMT) has been developed to demonstrate the unique attributes of this device structure in suppressing short channel effects (SCEs). The model accurately predicts the channel potential, electric field variation along the channel, and sub-threshold drain current, taking into account the effect of lengths of the two gate metals, their work functions, barrier layer thicknesses, and applied drain biases. It is seen that the SCEs and hot carrier effects in DMG AlGaN/GaN HEMT are suppressed due to the work function difference of the two metal gates, thereby screening the drain potential variations by the gate near the drain. Besides, a more uniform electric field along the channel leads to improved carrier transport efficiency. The accuracy of the results obtained from our analytical model has been verified using ATLAS device simulations.

  17. Response of mouse skin to tattooing: use of SKH-1 mice as a surrogate model for human tattooing

    International Nuclear Information System (INIS)

    Gopee, Neera V.; Cui, Yanyan; Olson, Greg; Warbritton, Alan R.; Miller, Barbara J.; Couch, Letha H.; Wamer, Wayne G.; Howard, Paul C.

    2005-01-01

    Tattooing is a popular cosmetic practice involving more than 45 million US citizens. Since the toxicology of tattoo inks and pigments used to formulate tattoo inks has not been reported, we studied the immunological impact of tattooing and determined recovery time from this trauma. SKH-1 hairless mice were tattooed using commercial tattoo inks or suspensions of titanium dioxide, cadmium sulfide, or iron oxide, and sacrificed at 0.5, 1, 3, 4, 7, or 14 days post-tattooing. Histological evaluation revealed dermal hemorrhage at 0.5 and 1 day. Acute inflammation and epidermal necrosis were initiated at 0.5 day decreasing in incidence by day 14. Dermal necrosis and epidermal hyperplasia were prominent by day 3, reducing in severity by day 14. Chronic active inflammation persisted in all tattooed mice from day 3 to 14 post-tattooing. Inguinal and axillary lymph nodes were pigmented, the inguinal being most reactive as evidenced by lymphoid hyperplasia and polymorphonuclear infiltration. Cutaneous nuclear protein concentrations of nuclear factor-kappa B were elevated between 0.5 and 4 days. Inflammatory and proliferative biomarkers, cyclooxygenase-1, cyclooxygenase-2, and ornithine decarboxylase protein levels were elevated between 0.5 and 4 days in the skin and decreased to control levels by day 14. Interleukin-1 beta and interleukin-10 were elevated in the lymph nodes but suppressed in the tattooed skin, with maximal suppression occurring between days 0.5 and 4. These data demonstrate that mice substantially recover from the tattooing insult by 14 days, leaving behind pigment in the dermis and the regional lymph nodes. The response seen in mice is similar to acute injury seen in humans, suggesting that the murine model might be a suitable surrogate for investigating the toxicological and phototoxicological properties of ingredients used in tattooing

  18. Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice.

    Directory of Open Access Journals (Sweden)

    Henning Ohnesorge

    Full Text Available We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.C57BL/6 mice received morphine injections thrice daily using increasing doses (5-20 mg∙kg(-1 for 3 days (sub-acute, n=6 or 14 days (chronic, n=6 and additionally either s-ketamine (5 mg∙kg(-1, n=6 or clonidine (0.1 mg∙kg(-1, n=6. Tail flick test and the assessment of the mechanical withdrawal threshold of the hindpaw was performed during and 4 days after cessation of opioid treatment. Upon completion of the behavioural testing the mRNA-concentration of the NMDA receptor (NMDAR1 and β-arrestin 2 (Arrb2 were measured by PCR.Chronic opioid treatment resulted in a delay of the tail flick latency with a rapid on- and offset. Simultaneously the mice developed a static mechanical hyperalgesia with a delayed onset that that outlasted the morphine treatment. Sub-acute morphine administration resulted in a decrease of NMDAR1 and Arrb2 whereas during longer opioid treatment the expression NMDAR1 and Arrb2 mRNA increased again to baseline values. Coadministration of s-ketamine or clonidine resulted in a reversal of the mechanical hyperalgesia and inhibited the normalization of NMDAR1 mRNA expression but had no effect on the expression of Arrb2 mRNA.In the model of chronic morphine therapy the antinociceptive effects of morphine are represented by the thermal analgesia while the proniceptive effects are represented by the mechanical hyperalgesia. The results indicate that the regulation of the expression of NMDAR1 and Arrb2 may be associated to the development of OIH in mice.The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

  19. A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.

    Science.gov (United States)

    Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

    2014-03-15

    Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients. © 2013 UICC.

  20. Using Swiss Webster mice to model Fetal Alcohol Spectrum Disorders (FASD): An analysis of multilevel time-to-event data through mixed-effects Cox proportional hazards models.

    Science.gov (United States)

    Chi, Peter; Aras, Radha; Martin, Katie; Favero, Carlita

    2016-05-15

    Fetal Alcohol Spectrum Disorders (FASD) collectively describes the constellation of effects resulting from human alcohol consumption during pregnancy. Even with public awareness, the incidence of FASD is estimated to be upwards of 5% in the general population and is becoming a global health problem. The physical, cognitive, and behavioral impairments of FASD are recapitulated in animal models. Recently rodent models utilizing voluntary drinking paradigms have been developed that accurately reflect moderate consumption, which makes up the majority of FASD cases. The range in severity of FASD characteristics reflects the frequency, dose, developmental timing, and individual susceptibility to alcohol exposure. As most rodent models of FASD use C57BL/6 mice, there is a need to expand the stocks of mice studied in order to more fully understand the complex neurobiology of this disorder. To that end, we allowed pregnant Swiss Webster mice to voluntarily drink ethanol via the drinking in the dark (DID) paradigm throughout their gestation period. Ethanol exposure did not alter gestational outcomes as determined by no significant differences in maternal weight gain, maternal liquid consumption, litter size, or pup weight at birth or weaning. Despite seemingly normal gestation, ethanol-exposed offspring exhibit significantly altered timing to achieve developmental milestones (surface righting, cliff aversion, and open field traversal), as analyzed through mixed-effects Cox proportional hazards models. These results confirm Swiss Webster mice as a viable option to study the incidence and causes of ethanol-induced neurobehavioral alterations during development. Future studies in our laboratory will investigate the brain regions and molecules responsible for these behavioral changes. Copyright © 2016. Published by Elsevier B.V.

  1. Spontaneous, Immune-Mediated Gastric Inflammation in SAMP1/YitFc Mice, a Model of Crohn’s-Like Gastritis

    Science.gov (United States)

    Reuter, Brian K.; Pastorelli, Luca; Brogi, Marco; Garg, Rekha R.; McBride, James A.; Rowlett, Robert M.; Arrieta, Marie C.; Wang, Xiao-Ming; Keller, Erik J.; Feldman, Sanford H.; Mize, James R.; Cominelli, Fabio; Meddings, Jonathan B.; Pizarro, Theresa T.

    2011-01-01

    Background & Aims Crohn’s disease (CD) can develop in any region of the gastrointestinal tract, including the stomach. The etiology and pathogenesis of Crohn’s gastritis are poorly understood, treatment approaches are limited, and there are not many suitable animal models for study. We characterized the features and mechanisms of chronic gastritis in SAMP1/YitFc (SAMP) mice, a spontaneous model of CD-like ileitis, along with possible therapeutic approaches. Methods Stomachs from specific pathogen-free and germ-free SAMP and AKR mice (controls) were evaluated histologically; the presence of Helicobacter spp. was tested in fecal pellets by PCR analysis. In vivo gastric permeability was quantified by fractional excretion of sucrose and epithelial tight junction protein expression was measured by quantitative reverse transcription PCR analysis. The effects of a proton pump inhibitor (PPI) or corticosteroids were measured and the ability of pathogenic immune cells to mediate gastritis was assessed in adoptive transfer experiments. Results SAMP mice developed Helicobacter-negative gastritis, characterized by aggregates of mononuclear cells, diffuse accumulation of neutrophils, and disruption of epithelial architecture; SAMP mice also had increased in gastric permeability compared with controls, without alterations in expression of tight junction proteins. The gastritis and associated permeability defect observed in SAMP mice were independent of bacterial colonization and reduced by administration of corticosteroids but not a PPI. CD4+ T cells isolated from draining mesenteric lymph nodes of SAMP mice were sufficient to induce gastritis in recipient SCID mice. Conclusions In SAMP mice, gastritis develops spontaneously and has many features of CD-like ileitis. These mice are a useful model to study Helicobacter-negative, immune-mediated Crohn’s gastritis. PMID:21704001

  2. Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome.

    Science.gov (United States)

    Walls, G V; Stevenson, M; Lines, K E; Newey, P J; Reed, A A C; Bowl, M R; Jeyabalan, J; Harding, B; Bradley, K J; Manek, S; Chen, J; Wang, P; Williams, B O; Teh, B T; Thakker, R V

    2017-07-13

    The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 (CDC73) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional (Cdc73 +/- ) and conditional parathyroid-specific (Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type (Cdc73 +/+ and Cdc73 +/+ /PTH-Cre) littermates. Survival of Cdc73 +/- mice, when compared to Cdc73 +/+ mice was reduced (Cdc73 +/- =80%; Cdc73 +/+ =90% at 18 months of age, Pfourfold higher than that in parathyroid glands of wild-type littermates (P<0.0001). Cdc73 +/- , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73 +/- mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73 +/- mice did not develop bone or renal tumours but female Cdc73 +/- mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73 +/- mice had increased proliferation rates that were 2-fold higher than in Cdc73 +/+ mice (P<0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.

  3. Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer’s Disease and Affects Mice with Normal Aging

    Directory of Open Access Journals (Sweden)

    Raquel Baeta-Corral

    2018-02-01

    Full Text Available Coffee or caffeine has recently been suggested as prophylaxis for dementia. Although memory problems are hallmarks of Alzheimer’s disease, this dementia is also characterized by neuropsychiatric symptoms called Behavioral and Psychological Symptoms of Dementia (BPSD. The impact of preventive/therapeutic strategies on both cognitive and non-cognitive symptoms can be addressed in the 3xTg-AD mice, since they exhibit cognitive but also BPSD-like profiles. Here, we studied the long-term effects of a low dose of caffeine in male 3xTg-AD mice and as compared to age-matched non-transgenic (NTg counterparts with normal aging. Animals were treated (water or caffeine in drinking water from adulthood (6 months of age until middle-aged (13 months of age, that in 3xTg-AD mice correspond to onset of cognitive impairment and advanced stages, respectively. The low caffeine dosing used (0.3 mg/ml was previously found to give a plasma concentration profile in mice roughly equivalent to that of a human coffee drinker. There were significant effects of caffeine on most behavioral variables, especially those related to neophobia and other anxiety-like behaviors, emotionality, and cognitive flexibility. The 3xTg-AD and NTg mice were differently influenced by caffeine. Overall, the increase of neophobia and other anxiety-related behaviors resulted in an exacerbation of BPSD-like profile in 3xTg-AD mice. Learning and memory, strongly influenced by anxiety in 3xTg-AD mice, got little benefit from caffeine, only shown after a detailed analysis of navigation strategies. The worsened pattern in NTg mice and the use of search strategies in 3xTg-AD mice make both groups more similar. Circadian motor activity showed genotype differences, which were found to be enhanced by caffeine. Selective effects of caffeine on NTg were found in the modulation of behaviors related to emotional profile and risk assessment. Caffeine normalized splenomegaly of 3xTg-AD mice, a physical

  4. 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

  5. Modeling and optimization of cylindrical grinding of Al/SiC composites using genetic algorithms

    OpenAIRE

    Thiagarajan, C.; Sivaramakrishnan, R.; Somasundaram, S.

    2012-01-01

    The Al/SiC composites have received more commercial attention than other kinds of Metal Matrix Composites (MMCs) due to their high performance. However, a continuing problem with MMCs is that they are difficult to machine, due to the hardness and abrasive nature of the SiC particles. Grinding is often the method of choice for machining Al/SiC composites to acquire high dimensional accuracy and surface finish in large scale production. Based on the full factorial design (3(4)), a total of 81 e...

  6. Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD.

    Science.gov (United States)

    Lattante, Serena; de Calbiac, Hortense; Le Ber, Isabelle; Brice, Alexis; Ciura, Sorana; Kabashi, Edor

    2015-03-15

    Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Analytical charge control model for AlGaN/GaN MIS-HFETs including an undepleted barrier layer

    Energy Technology Data Exchange (ETDEWEB)

    Shenghui, Lu; Jiangfeng, Du; Qian, Luo; Qi, Yu; Wei, Zhou; Jianxin, Xia; Mohua, Yang, E-mail: lushenghui@sohu.co [State key Laboratory of Electronic Thin Films and Integrated Devices, University of Electronic Science and Technology of China, Chengdu 610054 (China)

    2010-09-15

    An analytical charge control model considering the insulator/AlGaN interface charge and undepleted Al-GaN barrier layer is presented for AlGaN/GaN metal-insulator-semiconductor heterostructure field effect transistors (MIS-HFETs) over the entire operation range of gate voltage. The whole process of charge control is analyzed in detail and partitioned into four regions: I-full depletion, II-partial depletion, III-neutral region and IV-electron accumulation at the insulator/AlGaN interface. The results show that two-dimensional electron gas (2DEG) saturates at the boundary of region II/III and the gate voltage should not exceed the 2DEG saturation voltage in order to keep the channel in control. In addition, the span of region II accounts for about 50% of the range of gate voltage before 2DEG saturates. The good agreement of the calculated transfer characteristic with the measured data confirms the validity of the proposed model. (semiconductor devices)

  8. Pycnogenol Ameliorates Depression-Like Behavior in Repeated Corticosterone-Induced Depression Mice Model

    Directory of Open Access Journals (Sweden)

    Lin Mei

    2014-01-01

    Full Text Available Oxidative stress is considered to be a mechanism of major depression. Pycnogenol (PYC is a natural plant extract from the bark of Pinus pinaster Aiton and has potent antioxidant activities. We studied the ameliorative effect of PYC on depression-like behavior in chronic corticosterone- (CORT- treated mice for 20 days. After the end of the CORT treatment period, PYC (0.2 mg/mL was orally administered in normal drinking water. Depression-like behavior was investigated by the forced swimming test. Immobility time was significantly longer by CORT exposure. When the CORT-treated mice were supplemented with PYC, immobility time was significantly shortened. Our results indicate that orally administered PYC may serve to reduce CORT-induced stress by radical scavenging activity.

  9. Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects.

    Directory of Open Access Journals (Sweden)

    Aviva Breuer

    Full Text Available Cannabidiol (CBD is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4'-F-CBD (HUF-101 (1, is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.

  10. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

    Directory of Open Access Journals (Sweden)

    Sofia Johansson

    Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

  11. Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis.

    Science.gov (United States)

    Harris, Richard A; Tindale, Lauren; Lone, Asad; Singh, Olivia; Macauley, Shannon L; Stanley, Molly; Holtzman, David M; Bartha, Robert; Cumming, Robert C

    2016-02-10

    Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer's disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-β. In vivo (1)H-magnetic resonance spectroscopy revealed an age-dependent decline in lactate levels within the frontal cortex of control mice, whereas lactate levels remained unaltered in APP/PS1 mice from 3 to 12 months of age. Analysis of hippocampal interstitial fluid by in vivo microdialysis revealed a significant elevation in lactate levels in APP/PS1 mice relative to control mice at 12 months of age. An age-dependent decline in the levels of key aerobic glycolysis enzymes and a concomitant increase in lactate transporter expression was detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory in control mice. Interestingly, in APP/PS1 mice the opposite effect was detected. In these mice, increased expression of lactate producing enzymes correlated with poorer memory performance. Immunofluorescent staining revealed localization of the aerobic glycolysis enzymes pyruvate dehydrogenase kinase and lactate dehydrogenase A within cortical and hippocampal neurons in control mice, as well as within astrocytes surrounding amyloid plaques in APP/PS1 mice. These observations collectively indicate that production of lactate, via aerobic glycolysis, is beneficial for memory function during normal aging. However, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to cognitive decline in AD. Lactate has recently emerged as a key metabolite necessary for memory consolidation. Lactate is the end product of aerobic glycolysis, a unique form of metabolism that occurs within certain regions of the brain. Here

  12. Refinement of the Al-rich part of the Al–Cu–Re phase diagram and atomic model of the ternary Al{sub 6.2}Cu{sub 2}Re phase

    Energy Technology Data Exchange (ETDEWEB)

    Samuha, S. [Department of Materials Engineering, Ben Gurion University of the Negev, Beer Sheva 84105 (Israel); NRCN, P.O. Box 9001, Beer Sheva 84190 (Israel); Grushko, B. [MaTecK, Jülich D 52428 (Germany); PGI-5, Forschungszentrum Jülich, Jülich D 52425 (Germany); Meshi, L., E-mail: Louisa@bgu.ac.il [Department of Materials Engineering, Ben Gurion University of the Negev, Beer Sheva 84105 (Israel); Ilse Katz Institute for Nanoscale Science & Technology, Ben Gurion University of the Negev, Beer Sheva 84105 (Israel)

    2016-06-15

    Partial isothermal sections at 800, 650 and 590 °C were constructed for an Al-rich compositional range of Al–Cu–Re. The maximal solubility of Cu in the Al{sub 11}Re{sub 4}, h-Al{sub 4}Re and l-Al{sub 4}Re phases was found to be ∼6, 4.5, and 2.3 at% respectively, while the solubility of Re in the Al–Cu θ, η{sub 1} and ε{sub 2} phases was below 0.5 at%. Below 740 °C, a ternary hexagonal phase (P6{sub 3}, a = 1.1029 and c = 1.2746 nm) is formed in a small compositional range close to Al{sub 65}Cu{sub 25}Re{sub 10}. Its structural model was deduced by direct methods applied on the precession electron diffraction tomography data. - Highlights: • Al–Cu–Re was studied at 540–1030 °C up to 25 at% Re and 60 at% Cu. • Al{sub 11}Re{sub 4}, h-Al{sub 4}Re and l-Al{sub 4}Re dissolve 6, 4.5 and 2.3 at% Cu, respectively. • Earlier reported ternary compound Al{sub 8}CuRe was not confirmed. • Earlier reported ternary compound Al{sub 7}Cu{sub 2}Re is probably Al{sub 6.2}Cu{sub 2}Re. • Crystal structure of hexagonal Al{sub 6.2}Cu{sub 2}Re was solved.

  13. Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer’s disease animal model

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    Xiao-Rui eCheng

    2013-10-01

    Full Text Available Harboring the behavioral and histopathological signatures of Alzheimer’s disease (AD, senescence accelerated mouse-prone 8 (SAMP8 mice are currently considered a robust model for studying AD. However, the underlying mechanisms, prioritized pathways and genes in SAMP8 mice linked to AD remain unclear. In this study, we provide a biological interpretation of the molecular underpinnings of SAMP8 mice. Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2, 6, and 12 months of age using cDNA microarray analysis. On the basis of PPI, MetaCore and the co-expression network, we constructed a distinct genetic sub-network in the brains of SAMP8 mice. Next, we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice. We found abnormal gene expression of RAF1, MAPT, PTGS2, CDKN2A, CAMK2A, NTRK2, AGER, ADRBK1, MCM3AP and STUB1, which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice. Specifically, we found microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b and miR-125b, that might regulate the expression of nodes in the sub-network. Taken together, these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective.

  14. The Mass1frings mutation underlies early onset hearing impairment in BUB/BnJ mice, a model for the auditory pathology of Usher syndrome IIC

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    Johnson, K.R.; Zheng, Q.Y.; Weston, M.D.; Ptacek, L.J.; Noben-Trauth, K.

    2010-01-01

    The human ortholog of the gene responsible for audiogenic seizure susceptibility in Frings and BUB/BnJ mice (mouse gene symbol Mass1) recently was shown to underlie Usher syndrome type IIC (USH2C). Here we report that the Mass1frings mutation is responsible for the early onset hearing impairment of BUB/BnJ mice. We found highly significant linkage of Mass1 with ABR threshold variation among mice from two backcrosses involving BUB/BnJ mice with mice of strains CAST/EiJ and MOLD/RkJ. We also show an additive effect of the Cdh23 locus in modulating the progression of hearing loss in backcross mice. Together, these two loci account for more than 70% of the total ABR threshold variation among the backcross mice at all ages. The modifying effect of the strain-specific Cdh23ahl variant may account for the hearing and audiogenic seizure differences observed between Frings and BUB/BnJ mice, which share the Mass1frings mutation. During postnatal cochlear development in BUB/BnJ mice, stereocilia bundles develop abnormally and remain immature and splayed into adulthood, corresponding with the early onset hearing impairment associated with Mass1frings. Progressive base–apex hair cell degeneration occurs at older ages, corresponding with the age-related hearing loss associated with Cdh23ahl. The molecular basis and pathophysiology of hearing loss suggest BUB/BnJ and Frings mice as models to study cellular and molecular mechanisms underlying USH2C auditory pathology. PMID:15820310

  15. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

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    Ken Murakami

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5. Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1 or transforming growth factor β1 (TGF-β1 levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

  16. Prednison provokes serum and vasoactive substances in a mice model of immune thrombocytopenia

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    Ling Zhang

    2016-09-01

    Conclusion: In this study, the β-EP, VIP, 5-HT and NE contents in ITP mice injected with GP-APS were changed by prednison. It shows that prednison as the first-line therapy for ITP with effective hemostasis function is likely to increasing the contents of VIP and 5-HT. These results suggest the therapeutic value of prednison for the treatment of ITP.

  17. Numerical Simulation of Tension Properties for Al-Cu Alloy Friction Stir-Welded Joints with GTN Damage Model

    Science.gov (United States)

    Sun, Guo-Qin; Sun, Feng-Yang; Cao, Fang-Li; Chen, Shu-Jun; Barkey, Mark E.

    2015-11-01

    The numerical simulation of tensile fracture behavior on Al-Cu alloy friction stir-welded joint was performed with the Gurson-Tvergaard-Needleman (GTN) damage model. The parameters of the GTN model were studied in each region of the friction stir-welded joint by means of inverse identification. Based on the obtained parameters, the finite element model of the welded joint was built to predict the fracture behavior and tension properties. Good agreement can be found between the numerical and experimental results in the location of the tensile fracture and the mechanical properties.

  18. Nonlocal superelastic model of size-dependent hardening and dissipation in single crystal Cu-Al-Ni shape memory alloys.

    Science.gov (United States)

    Qiao, Lei; Rimoli, Julian J; Chen, Ying; Schuh, Christopher A; Radovitzky, Raul

    2011-02-25

    We propose a nonlocal continuum model to describe the size-dependent superelastic effect observed in recent experiments of single crystal Cu-Al-Ni shape memory alloys. The model introduces two length scales, one in the free energy and one in the dissipation, which account for the size-dependent hardening and dissipation in the loading and unloading response of micro- and nanopillars subject to compression tests. The information provided by the model suggests that the size dependence observed in the dissipation is likely to be associated with a nonuniform evolution of the distribution of the austenitic and martensitic phases during the loading cycle. © 2011 American Physical Society

  19. Acute Toxicity Study of Zerumbone-Loaded Nanostructured Lipid Carrier on BALB/c Mice Model

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    Heshu Sulaiman Rahman

    2014-01-01

    Full Text Available Zerumbone- (ZER- loaded nanostructure lipid carrier (NLC (ZER-NLC prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50 of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration.

  20. Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

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    Iva Simeonova

    2013-06-01

    Full Text Available Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous m