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Sample records for chemical mouse models

  1. A Chemical Mutagenesis Screen Identifies Mouse Models with ERG Defects.

    Science.gov (United States)

    Charette, Jeremy R; Samuels, Ivy S; Yu, Minzhong; Stone, Lisa; Hicks, Wanda; Shi, Lan Ying; Krebs, Mark P; Naggert, Jürgen K; Nishina, Patsy M; Peachey, Neal S

    2016-01-01

    Mouse models provide important resources for many areas of vision research, pertaining to retinal development, retinal function and retinal disease. The Translational Vision Research Models (TVRM) program uses chemical mutagenesis to generate new mouse models for vision research. In this chapter, we report the identification of mouse models for Grm1, Grk1 and Lrit3. Each of these is characterized by a primary defect in the electroretinogram. All are available without restriction to the research community. PMID:26427409

  2. Choice of mouse strain influences the outcome in a mouse model of chemical-induced asthma.

    Directory of Open Access Journals (Sweden)

    Vanessa De Vooght

    Full Text Available BACKGROUND: The development of occupational asthma is the result of interactions between environmental factors and individual susceptibility. We assessed how our model of chemical-induced asthma is influenced by using different mouse strains. METHODOLOGY/PRINCIPAL FINDINGS: On days 1 and 8, male mice of 7 different strains (BALB/c, BP/2, A/J, C57Bl/6, DBA/2, CBA and AKR were dermally treated with toluene-2,4-diisocyanate (TDI (0.3% or vehicle (acetone/olive oil, AOO, 2:3 on each ear (20 microl. On day 15, they received an oropharyngeal instillation of TDI (0.01% or AOO (1:4. Airway reactivity to methacholine, total and differential cell counts in bronchoalveolar lavage (BAL and total serum IgE and IgG(2a levels were measured. Lymphocyte subpopulations in auricular lymph nodes and in vitro release of cytokines by ConA stimulated lymphocytes were assessed. In TDI-sensitized and challenged mice, airway hyper-reactivity was only observed in BALB/c, BP/2, A/J and AKR mice; airway inflammation was most pronounced in BALB/c mice; numbers of T-helper (CD4(+, T-activated (CD4(+CD25(+, T-cytotoxic (CD8(+ and B- lymphocytes (CD19(+ were increased in the auricular lymph nodes of BALB/c, BP/2, A/J and CBA mice; elevated concentrations of IL-4, IL-10, IL-13 and IFN-gamma were detected in supernatant of lymphocytes from BALB/c, BP/2, A/J, C57Bl/6 and CBA mice cultured with concanavaline A, along with an increase in total serum IgE. CONCLUSION: The used mouse strain has considerable and variable impacts on different aspects of the asthma phenotype. The human phenotypical characteristics of chemically-induced occupational asthma were best reproduced in Th2-biased mice and in particular in BALB/c mice.

  3. Mouse models of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Yunguang Tong; Wancai Yang; H. Phillip Koeffler

    2011-01-01

    Colorectal cancer is one of the most common malignancies in the world. Many mouse models have been developed to evaluate features of colorectal cancer in humans. These can be grouped into genetically-engineered, chemically-induced, and inoculated models. However, none recapitulates all of the characteristics of human colorectal cancer. It is critical to use a specific mouse model to address a particular research question. Here, we review commonly used mouse models for human colorectal cancer.

  4. Demonstration of feasibility of in vivo gene therapy for Gaucher disease using a chemically induced mouse model.

    Science.gov (United States)

    Marshall, John; McEachern, Kerry Anne; Kyros, Julie A Cavanagh; Nietupski, Jennifer B; Budzinski, Tracey; Ziegler, Robin J; Yew, Nelson S; Sullivan, Jennifer; Scaria, Abraham; van Rooijen, Nico; Barranger, John A; Cheng, Seng H

    2002-08-01

    Progress towards developing gene therapy for Gaucher disease has been hindered by the lack of an animal model. Here we describe a mouse model of Gaucher disease which has a chemically induced deficiency of glucocerebrosidase and that accumulates elevated levels of glucosylceramide (GL-1) in the lysosomes of Kupffer cells. Administration of mannose-terminated glucocerebrosidase (Cerezyme) resulted in the reduction of GL-1 levels in the livers of these animals. Gene transduction of hepatocytes with a plasmid DNA vector encoding human glucocerebrosidase (pGZB-GC) generated high-level expression and secretion of the enzyme into systemic circulation with consequent normalization of Kupffer cell GL-1 levels. This suggested that the de novo synthesized and unmodified enzyme produced by hepatocyte transduction was also capable of being delivered to the cells that are primarily affected in Gaucher disease. Immunolocalization studies also revealed that preferential transduction and expression of human glucocerebrosidase in the Kupffer cells with subsequent reduction in the GL-1 levels could be attained with a low dose of a recombinant adenoviral vector encoding the human enzyme (Ad2/CMV-GC). This observation raises the possibility of gene therapy for Gaucher disease that involves directly transducing the affected histiocytes using recombinant adenoviral vectors. Together, these data demonstrate the potential for use of in vivo gene therapy vectors for treating Gaucher disease. PMID:12161184

  5. Burn mouse models

    DEFF Research Database (Denmark)

    Calum, Henrik; Høiby, Niels; Moser, Claus

    2014-01-01

    Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third-degree b......Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third...... with infected burn wound compared with the burn wound only group. The burn mouse model resembles the clinical situation and provides an opportunity to examine or develop new strategies like new antibiotics and immune therapy, in handling burn wound victims much....

  6. Mouse models of medulloblastoma

    Institute of Scientific and Technical Information of China (English)

    Xiaochong Wu; Paul A. Northcott; Sidney Croul; Michael D. Taylor

    2011-01-01

    Medulloblastoma is the most common malignant pediatric brain tumor. Despite its prevalence and importance in pediatric neuro-oncology, the genes and pathways responsible for its initiation, maintenance,and progression remain poorly understood. Genetically engineered mouse models are an essential tool for uncovering the molecular and cellular basis of human diseases, including cancer, and serve a valuable role as preclinical models for testing targeted therapies. In this review, we summarize how such models have been successfully applied to the study of medulloblastoma over the past decade and what we might expect in the coming years.

  7. Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

    Directory of Open Access Journals (Sweden)

    Chia-Yu Chang

    2015-01-01

    Full Text Available Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM and open field test (OFT in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST and forced swimming test (FST in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

  8. Expression of biomarker genes of differentiation in D3 mouse embryonic stem cells after exposure to different embryotoxicant and non-embryotoxicant model chemicals

    Directory of Open Access Journals (Sweden)

    Andrea C. Romero

    2015-12-01

    Full Text Available There is a necessity to develop in vitro methods for testing embryotoxicity (Romero et al., 2015 [1]. We studied the progress of D3 mouse embryonic stem cells differentiation exposed to model embryotoxicants and non-embryotoxicants chemicals through the expression of biomarker genes. We studied a set of 16 different genes biomarkers of general cellular processes (Cdk1, Myc, Jun, Mixl, Cer and Wnt3, ectoderm formation (Nrcam, Nes, Shh and Pnpla6, mesoderm formation (Mesp1, Vegfa, Myo1e and Hdac7 and endoderm formation (Flk1 and Afp. We offer dose response in order to derive the concentration causing either 50% or 200% of expression of the biomarker gene. These records revealed to be a valuable end-point to predict in vitro the embryotoxicity of chemicals (Romero et al., 2015 [1].

  9. Mouse models for cancer research

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Lynette Moore; Ping Ji

    2011-01-01

    Mouse models of cancer enable researchers to leamn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Joumnal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue.

  10. Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model

    OpenAIRE

    Fan, Xingjun; Reneker, Lixing W.; Obrenovich, Mark E.; Strauch, Christopher; Cheng, Rongzhu; Jarvis, Simon M; Ortwerth, Beryl J.; Monnier, Vincent M.

    2006-01-01

    Senile cataracts are associated with progressive oxidation, fragmentation, cross-linking, insolubilization, and yellow pigmentation of lens crystallins. We hypothesized that the Maillard reaction, which leads browning and aroma development during the baking of foods, would occur between the lens proteins and the highly reactive oxidation products of vitamin C. To test this hypothesis, we engineered a mouse that selectively overexpresses the human vitamin C transporter SVCT2 in the lens. Conse...

  11. Multistage chemical carcinogenesis in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Slaga, T.J.; Fischer, S.M.; Weeks, C.E.; Klein-Szanto, A.J.P.

    1979-01-01

    Skin tumors in mice can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct acting carcinogen or a procarcinogen which has to be metabolized before being active and is essentially an irreversible step which probably involves a somatic cell mutation. There is a good correlation between the skin tumor initiating activites of several polycyclic aromatic hydrocarbons (PAH) and their ability to bind covalently to epidermal DNA. Laboratory results suggest that bay region diol-epoxides are the ultimate carcinogenic form of PAH carcinogens. Potent inhibitors and stimulators of PAH tumor initiation appear to affect the level of the PAH diol-epoxide reacting with specific DNA bases. Reecent data suggests that the tumor promotion stage involves at least three important steps: (1) the induction of embryonic looking cells (dark cells) in adult epidermis; (2) an increased production of epidermal prostaglandins and polyamines; (3) sustained proliferation of dark cells. Retinoic acid specifically inhibits step two whereas the anti-inflammatory steriod fluocinolone acetonide is a potent inhibitor of steps one and three. The mechanism and the importance of a specific sequence for each step in chemical carcinogenesis in mouse skin are detailed.

  12. Mouse Models of Rheumatoid Arthritis.

    Science.gov (United States)

    Caplazi, P; Baca, M; Barck, K; Carano, R A D; DeVoss, J; Lee, W P; Bolon, B; Diehl, L

    2015-09-01

    Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients. PMID:26063174

  13. Mouse models of Fanconi anemia

    International Nuclear Information System (INIS)

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  14. Mouse models of Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

    2009-07-31

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  15. Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity.

    Science.gov (United States)

    Chen, Yaqin; Wu, Zhihong; Zhao, Shuiping; Xiang, Rong

    2016-01-01

    Obesity, which is characteristic by chronic inflammation, is defined as abnormal or excessive fat accumulation in adipose tissues. Endoplasmic reticulum (ER) stress is increased in adipose tissue of obese state and is known to be strongly associated with chronic inflammation. The aim of this study was to investigate the effect of ER stress on adipokine secretion in obese mice and explore the potential mechanisms. In this study, we found high-fat diet induced-obesity contributed to strengthened ER stress and triggered chronic inflammation in adipose tissue. Chemical chaperones, 4-PBA and TUDCA, modified metabolic disorders and decreased the levels of inflammatory cytokines in obese mice fed a high-fat diet. The alleviation of ER stress is in accordance with the decrease of free cholesterol in adipose tissue. Furthermore chemical chaperones suppress NF-κB activity in adipose tissue of obese mice in vivo. In vitro studies showed IKK/NF-κB may be involved in the signal transduction of adipokine secretion dysfunction induced by ER stress. The present study revealed the possibility that inhibition of ER stress may be a novel drug target for metabolic abnormalities associated with obesity. Further studies are now needed to characterize the initial incentive of sustained ER stress in obese. PMID:27271106

  16. Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals

    International Nuclear Information System (INIS)

    Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone-dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA (registered) )CD-1-Tg(Cyp19-luc)-Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n = 14; p = 0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30 mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p < 0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for

  17. Mouse models for colorectal cancer

    OpenAIRE

    KARIM, BAKTIAR O.; Huso, David L.

    2013-01-01

    Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with the number of affected people increasing. There are many risk factors that increase CRC risk, including family or personal history of CRC, smoking, consumption of red meat, obesity, and alcohol consumption. Conversely, increased screening, maintaining healthy body weight, not smoking, and limiting intake of red meat are all associated with reduced CRC morbidity and mortality. Mouse models of ...

  18. Mouse models for human diseases

    OpenAIRE

    Lee, AYW; Chung, SK; Chung, SSM

    1997-01-01

    Mice are increasingly being used as models for the study of various human diseases. This is primarily because among mammalian modals, they are most amenable to genetic manipulations. As we attempt to understand the molecular mechanism of diseases, it is imperative that the genes involved in the disease process be identified. One approach is to study mouse mutants with symptoms analogous to human diseases, and try to identify the genes responsible. Another approach is to manipulate the express...

  19. Mouse models of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

  20. Mouse models for methylmalonic aciduria.

    Directory of Open Access Journals (Sweden)

    Heidi L Peters

    Full Text Available Methylmalonic aciduria (MMA is a disorder of organic acid metabolism resulting from a functional defect of methylmalonyl-CoA mutase (MCM. MMA is associated with significant morbidity and mortality, thus therapies are necessary to help improve quality of life and prevent renal and neurological complications. Transgenic mice carrying an intact human MCM locus have been produced. Four separate transgenic lines were established and characterised as carrying two, four, five or six copies of the transgene in a single integration site. Transgenic mice from the 2-copy line were crossed with heterozygous knockout MCM mice to generate mice hemizygous for the human transgene on a homozygous knockout background. Partial rescue of the uniform neonatal lethality seen in homozygous knockout mice was observed. These rescued mice were significantly smaller than control littermates (mice with mouse MCM gene. Biochemically, these partial rescue mice exhibited elevated methylmalonic acid levels in urine, plasma, kidney, liver and brain tissue. Acylcarnitine analysis of blood spots revealed elevated propionylcarnitine levels. Analysis of mRNA expression confirms the human transgene is expressed at higher levels than observed for the wild type, with highest expression in the kidney followed closely by brain and liver. Partial rescue mouse fibroblast cultures had only 20% of the wild type MCM enzyme activity. It is anticipated that this humanised partial rescue mouse model of MMA will enable evaluation of long-term pathophysiological effects of elevated methylmalonic acid levels and be a valuable model for the investigation of therapeutic strategies, such as cell transplantation.

  1. Mouse Models of Tumor Immunotherapy.

    Science.gov (United States)

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients. PMID:26922998

  2. Mouse Models of Bone Marrow Transplantation

    OpenAIRE

    Reddy, Pavan; Negrin, Robert; Hill, Geoffrey R.

    2008-01-01

    Over the last 50 years, mouse models of bone marrow transplantation have provided the critical links between graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) pathophysiology and clinical practice. The initial insight from mouse models that GVHD and GVL were T cell dependent has long been confirmed clinically. More recent translations from mouse models have included the important role of inflammatory cytokines in GVHD. Newly developed concepts relating to the ability of antigen...

  3. Mouse models of congenital cataract.

    Science.gov (United States)

    Graw, J

    1999-06-01

    Mouse mutants affecting lens development are excellent models for corresponding human disorders. The mutant aphakia has been characterised by bilaterally aphakic eyes (Varnum and Stevens, J Hered 1968;59:147-50); the corresponding gene was mapped to chromosome 19 (Varnum and Stevens, Mouse News Lett 1975;53:35). Recent investigations in our laboratory refined the linkage of 0.6 cM proximal to the marker D19Mit10. Several candidate genes have been excluded (Chuk1, Fgf8, Lbp1, Npm3, Pax2, Pitx3). The Cat3 mutations are characterised by vacuolated lenses caused by alterations in the initial secondary lens fibre cell differentiation. Secondary malformations develop at the cornea and iris, but the retina remains unaffected. The mutation has been mapped to chromosome 10 close to the markers D10Mit41 and D10Mit95. Several candidate genes have been excluded (Dcn, Elk3, Ldc, Mell8, Tr2-11). The series of Cat2 mutations have been mapped close to the gamma-crystallin genes (Cryg; Löster et al., Genomics 1994;23:240-2). The Cat2nop mutation is characterised by a mutation in the third exon of Crygb leading to a truncated gamma B-crystallin and the termination of lens fibre cell differentiation. The Cat2 mutants are interesting models for human cataracts caused by mutations in the human CRYG genes at chromosome 2q32-35. PMID:10627821

  4. Mouse Models of Williams-Beuren Syndrome

    OpenAIRE

    Osborne, L.R.

    2009-01-01

    In an attempt to dissect the contribution of individual genes to the complex and varied phenotype associated with Williams-Beuren syndrome (WBS), researchers have turned to mouse models. The mouse genome is easily manipulated to produce animals that are genetic copies of humans with genetic conditions, be it with null mutations, hypomorphic mutations, point mutations or even large deletions encompassing many genes. Over the past few years, several mouse models knocking out genes f...

  5. Mouse model of intracerebellar haemorrhage.

    Science.gov (United States)

    Tijjani Salihu, Abubakar; Muthuraju, Sangu; Aziz Mohamed Yusoff, Abdul; Ahmad, Farizan; Zulkifli Mustafa, Mohd; Jaafar, Hasnan; Idris, Zamzuri; Rahman Izaini Ghani, Abdul; Malin Abdullah, Jafri

    2016-10-01

    The present study aimed to investigate the behavior and neuronal morphological changes in the perihaemorrhagic tissue of the mouse intracerebellar haemorrhage experimental model. Adult male Swiss albino mice were stereotactically infused with collagenase type VII (0.4U/μl of saline) unilaterally in to the cerebellum, following anaesthesia. Motor deficits were assessed using open field and composite score for evaluating the mouse model of cerebellar ataxia at 1, 3, 7, 14 and 21 days after collagenase infusion. The animals were sacrificed at the same time interval for evaluation of perihaematomal neuronal degeneration using haematoxylin and eosin staining and Annexin V-FITC/Propidium iodide assay. At the end of the study, it was found that infusion of 0.4U collagenase produces significant locomotor and ataxic deficit in the mice especially within the first week post surgery, and that this gradually improved within three weeks. Neuronal degeneration evident by cytoplasmic shrinkage and nuclear pyknosis was observed at the perihaematomal area after one day; especially at 3 and 7 days post haemorrhage. By 21 days, both the haematoma and degenerating neurons in the perihaematomal area were phagocytosed and the remaining neuronal cells around the scar tissue appeared normal. Moreover, Annexin-V/propidium iodide-positive cells were observed at the perihaematomal area at 3 and 7 days implying that the neurons likely die via apoptosis. It was concluded that a population of potentially salvageable neurons exist in the perihaematomal area after cerebellar haemorrhage throughout a wide time window that could be amenable to treatment. PMID:27327104

  6. Mouse models of intestinal inflammation and cancer.

    Science.gov (United States)

    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With

  7. Keratin expression in chemically induced mouse lung adenomas.

    OpenAIRE

    Gunning, W T; Goldblatt, P. J.; Stoner, G D

    1992-01-01

    Chemically induced mouse lung tumors exhibit distinctive growth patterns, characterized by an alveolar or solid appearance, a papillary appearance, or a combination of the two. Lung tumors induced in strain A/J mice by either benzo(a)pyrene (BP) or by N-nitrosoethylurea (ENU) were examined for expression of low- and high-molecular-weight cytokeratins. Simple cytokeratins (low molecular weight) were found in all epithelial cells of the normal mouse lung and in all tumor types, whereas higher-m...

  8. Mouse Models for Filovirus Infections

    Directory of Open Access Journals (Sweden)

    Kelly L. Warfield

    2012-09-01

    Full Text Available The filoviruses marburg- and ebolaviruses can cause severe hemorrhagic fever (HF in humans and nonhuman primates. Because many cases have occurred in geographical areas lacking a medical research infrastructure, most studies of the pathogenesis of filoviral HF, and all efforts to develop drugs and vaccines, have been carried out in biocontainment laboratories in non-endemic countries, using nonhuman primates (NHPs, guinea pigs and mice as animal models. NHPs appear to closely mirror filoviral HF in humans (based on limited clinical data, but only small numbers may be used in carefully regulated experiments; much research is therefore done in rodents. Because of their availability in large numbers and the existence of a wealth of reagents for biochemical and immunological testing, mice have become the preferred small animal model for filovirus research. Since the first experiments following the initial 1967 marburgvirus outbreak, wild-type or mouse-adapted viruses have been tested in immunocompetent or immunodeficient mice. In this paper, we review how these types of studies have been used to investigate the pathogenesis of filoviral disease, identify immune responses to infection and evaluate antiviral drugs and vaccines. We also discuss the strengths and weaknesses of murine models for filovirus research, and identify important questions for further study.

  9. Models of Chemical Evolution

    OpenAIRE

    Matteucci, Francesca

    2003-01-01

    The basic principles underlying galactic chemical evolution and the most important results of chemical evolution models are discussed. In particular, the chemical evolution of the Milky Way galaxy, for which we possess the majority of observational constraints, is described. Then, it is shown how different star formation histories influence the chemical evolution of galaxies of different morphological type. Finally, the role of abundances and abundance ratios as cosmic clocks is emphasized an...

  10. Development of Orthotopic Pancreatic Tumor Mouse Models

    OpenAIRE

    Qiu, Wanglong; Gloria H. Su

    2013-01-01

    Genetically engineered mouse models of pancreatic cancer that recapitulate human pancreatic tumorigenesis have been established. However, the cost associated with generating and housing these mice can be prohibitive. Tumor latency and progression to invasive diseases in these models are also highly variable. Xenograft mouse models of human pancreatic cancer including heterotopic and orthotopic have been widely used in preclinical studies for their comparatively low cost and rapid, predictable...

  11. Optimizing mouse models for precision cancer prevention.

    Science.gov (United States)

    Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory

    2016-03-01

    As cancer has become increasingly prevalent, cancer prevention research has evolved towards placing a greater emphasis on reducing cancer deaths and minimizing the adverse consequences of having cancer. 'Precision cancer prevention' takes into account the collaboration of intrinsic and extrinsic factors in influencing cancer incidence and aggressiveness in the context of the individual, as well as recognizing that such knowledge can improve early detection and enable more accurate discrimination of cancerous lesions. However, mouse models, and particularly genetically engineered mouse (GEM) models, have yet to be fully integrated into prevention research. In this Opinion article, we discuss opportunities and challenges for precision mouse modelling, including the essential criteria of mouse models for prevention research, representative success stories and opportunities for more refined analyses in future studies. PMID:26893066

  12. Modelling the chemical evolution

    OpenAIRE

    Hensler, Gerhard; Recchi, Simone

    2010-01-01

    Advanced observational facilities allow to trace back the chemical evolution of the Universe, on the one hand, from local objects of different ages and, secondly, by direct observations of redshifted objects. The chemical enrichment serves as one of the cornerstones of cosmological evolution. In order to understand this chemical evolution in morphologically different astrophysical objects models are constructed based on analytical descriptions or numerical methods. For the comparison of their...

  13. N-hydroxylation of 4-aminobiphenyl by CYP2E1 produces oxidative stress in a mouse model of chemically induced liver cancer.

    Science.gov (United States)

    Wang, Shuang; Sugamori, Kim S; Tung, Aveline; McPherson, J Peter; Grant, Denis M

    2015-04-01

    4-Aminobiphenyl (ABP) is a trace component of cigarette smoke and hair dyes, a suspected human carcinogen and a potent rodent liver carcinogen. Postnatal exposure of mice to ABP results in a higher incidence of liver tumors in males than in females, paralleling the sex difference in human liver cancer incidence. A traditional model of ABP tumorigenesis involves initial CYP1A2-mediated N-hydroxylation, which eventually leads to production of mutagenic ABP-DNA adducts that initiate tumor growth. However, several studies have found no correlation between sex or CYP1A2 function and the DNA-damaging, mutagenic, or tumorigenic effects of ABP. Oxidative stress may be an important etiological factor for liver cancer, and it has also been linked to ABP exposure. The goals of this study were to identify novel enzyme(s) that contribute to ABP N-oxidation, and to investigate a potential role for oxidative stress in ABP liver tumorigenicity. Isozyme-selective inhibition experiments using liver microsomes from wild-type and genetically modified mice identified CYP2E1 as a major ABP N-hydroxylating enzyme. The N-hydroxylation of ABP by transiently expressed CYP2E1 produced oxidative stress in cultured mouse hepatoma cells. In vivo postnatal exposure of mice to a tumorigenic dose of ABP also produced oxidative stress in male wild-type mice, but not in male Cyp2e1(-/-) mice or in female mice. However, a stronger NRF2-associated antioxidant response was observed in females. Our results identify CYP2E1 as a novel ABP-N-oxidizing enzyme, and suggest that sex differences in CYP2E1-dependent oxidative stress and antioxidant responses to ABP may contribute to the observed sex difference in tumor incidence. PMID:25601990

  14. The wobbler mouse, an ALS animal model

    OpenAIRE

    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 similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now,...

  15. Pathology of Mouse Models of Accelerated Aging.

    Science.gov (United States)

    Harkema, L; Youssef, S A; de Bruin, A

    2016-03-01

    Progeroid mouse models display phenotypes in multiple organ systems that suggest premature aging and resemble features of natural aging of both mice and humans. The prospect of a significant increase in the global elderly population within the next decades has led to the emergence of "geroscience," which aims at elucidating the molecular mechanisms involved in aging. Progeroid mouse models are frequently used in geroscience as they provide insight into the molecular mechanisms that are involved in the highly complex process of natural aging. This review provides an overview of the most commonly reported nonneoplastic macroscopic and microscopic pathologic findings in progeroid mouse models (eg, osteoporosis, osteoarthritis, degenerative joint disease, intervertebral disc degeneration, kyphosis, sarcopenia, cutaneous atrophy, wound healing, hair loss, alopecia, lymphoid atrophy, cataract, corneal endothelial dystrophy, retinal degenerative diseases, and vascular remodeling). Furthermore, several shortcomings in pathologic analysis and descriptions of these models are discussed. Progeroid mouse models are valuable models for aging, but thorough knowledge of both the mouse strain background and the progeria-related phenotype is required to guide interpretation and translation of the pathology data. PMID:26864891

  16. Mouse models for understanding human developmental anomalies

    International Nuclear Information System (INIS)

    The mouse experimental system presents an opportunity for studying the nature of the underlying mutagenic damage and the molecular pathogenesis of this class of anomalies by virtue of the accessibility of the zygote and its descendant blastomeres. Such studies could contribute to the understanding of the etiology of certain sporadic but common human malformations. The vulnerability of the zygotes to mutagens as demonstrated in the studies described in this report should be a major consideration in chemical safety evaluation. It raises questions regarding the danger to human zygotes when the mother is exposed to drugs and environmental chemicals

  17. Modeling chemical kinetics graphically

    NARCIS (Netherlands)

    A. Heck

    2012-01-01

    In literature on chemistry education it has often been suggested that students, at high school level and beyond, can benefit in their studies of chemical kinetics from computer supported activities. Use of system dynamics modeling software is one of the suggested quantitative approaches that could h

  18. Modeling in Chemical Engineering

    Directory of Open Access Journals (Sweden)

    Jaap van Brakel

    2000-10-01

    Full Text Available Models underlying the use of similarity considerations, dimensionless numbers, and dimensional analysis in chemical engineering are discussed. Special attention is given to the many levels at which models and ceteris paribus conditions play a role and to the modeling of initial and boundary conditions. It is shown that both the laws or dimensionless number correlations and the systems to which they apply are models. More generally, no matter which model or description one picks out, what is being modeled is itself a model of something else. Instead of saying that the artifact S models the given B, it is therefore better to say that S and B jointly make up B and S.

  19. Genetically engineered mouse models of pituitary tumors

    OpenAIRE

    DavidACano; AlfonsoSoto-Moreno

    2014-01-01

    Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary tumor formation remain poorly understood, particularly in sporadic adenomas, thus making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs) of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, w...

  20. The wobbler mouse, an ALS animal model

    DEFF Research Database (Denmark)

    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...... disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of...

  1. Chemically-induced Mouse Lung Tumors: Applications to Human Health Assessments

    Science.gov (United States)

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to better understand the mouse lung tumor data’s role in human health assessments. Three environmental chemicals - naphthalene, styrene, and ethylbe...

  2. Mouse Models of Diabetic Nephropathy

    OpenAIRE

    Brosius, Frank C.; Alpers, Charles E.; Bottinger, Erwin P.; Breyer, Matthew D.; Coffman, Thomas M.; Gurley, Susan B.; Harris, Raymond C.; Kakoki, Masao; Kretzler, Matthias; Leiter, Edward H.; Levi, Moshe; McIndoe, Richard A.; Sharma, Kumar; Smithies, Oliver; Susztak, Katalin

    2009-01-01

    Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Despite its prevalence, identification of specific factors that cause or predict diabetic nephropathy has been delayed in part by lack of reliable animal models that mimic the disease in humans. The Animal Models of Diabetic Complications Consortium (AMDCC) was created 8 years ago by the National Institutes of Health to develop and characterize models of diabetic nephropathy and other complications. This interim rep...

  3. Theory of Chemical Modeling

    Science.gov (United States)

    Kühn, Michael

    In order to deal with the complexity of natural systems simplified models are employed to illustrate the principal and regulatory factors controlling a chemical system. Following the aphorism of Albert Einstein: Everything should be made as simple as possible, but not simpler, models need not to be completely realistic to be useful (Stumm and Morgan 1996), but need to meet a successful balance between realism and practicality. Properly constructed, a model is neither too simplified that it is unrealistic nor too detailed that it cannot be readily evaluated and applied to the problem of interest (Bethke 1996). The results of a model have to be at least partially observable or experimentally verifiable (Zhu and Anderson 2002). Geochemical modeling theories are presented here in a sequence of increasing complexity from geochemical equilibrium models to kinetic, reaction path, and finally coupled transport and reaction models. The description is far from complete but provides the needs for the set up of reactive transport models of hydrothermal systems as done within subsequent chapters. Extensive reviews of geochemical models in general can be found in the literature (Appelo and Postma 1999, Bethke 1996, Melchior and Bassett 1990, Nordstrom and Ball 1984, Paschke and van der Heijde 1996).

  4. LLNL Chemical Kinetics Modeling Group

    Energy Technology Data Exchange (ETDEWEB)

    Pitz, W J; Westbrook, C K; Mehl, M; Herbinet, O; Curran, H J; Silke, E J

    2008-09-24

    The LLNL chemical kinetics modeling group has been responsible for much progress in the development of chemical kinetic models for practical fuels. The group began its work in the early 1970s, developing chemical kinetic models for methane, ethane, ethanol and halogenated inhibitors. Most recently, it has been developing chemical kinetic models for large n-alkanes, cycloalkanes, hexenes, and large methyl esters. These component models are needed to represent gasoline, diesel, jet, and oil-sand-derived fuels.

  5. Mouse Models for Filovirus Infections

    OpenAIRE

    Kelly L Warfield; Bradfute, Steven B; Mike Bray

    2012-01-01

    The filoviruses marburg- and ebolaviruses can cause severe hemorrhagic fever (HF) in humans and nonhuman primates. Because many cases have occurred in geographical areas lacking a medical research infrastructure, most studies of the pathogenesis of filoviral HF, and all efforts to develop drugs and vaccines, have been carried out in biocontainment laboratories in non-endemic countries, using nonhuman primates (NHPs), guinea pigs and mice as animal models. NHPs appear to closely mirror filovir...

  6. Mouse Genetic Models of Human Brain Disorders

    OpenAIRE

    Celeste eLeung; Zhengping eJia

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectua...

  7. Digenic Inheritance in Cystinuria Mouse Model.

    Directory of Open Access Journals (Sweden)

    Meritxell Espino

    Full Text Available Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months and late stage (8-months of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/- present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/- and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.

  8. Genetically engineered mouse models of pituitary tumors

    Directory of Open Access Journals (Sweden)

    DavidACano

    2014-08-01

    Full Text Available Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary tumor formation remain poorly understood, particularly in sporadic adenomas, thus making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, we review various GEMMs of pituitary tumors, highlighting their contributions and limitations, and discuss opportunities for research in the field.

  9. A Mouse Model for Human Anal Cancer

    OpenAIRE

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncoge...

  10. Mouse models of anemia of cancer.

    Directory of Open Access Journals (Sweden)

    Airie Kim

    Full Text Available Anemia of cancer (AC may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI, with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC.

  11. Chemically-induced mouse lung tumors: applications to human health assessments [Poster 2014

    Science.gov (United States)

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to discuss issues related to the use of mouse lung tumor data in human health assessments. Naphthalene, styrene, and ethylbenzene were chosen for the anal...

  12. A humanized mouse model of tuberculosis.

    Directory of Open Access Journals (Sweden)

    Veronica E Calderon

    Full Text Available Mycobacterium tuberculosis (M.tb is the second leading infectious cause of death worldwide and the primary cause of death in people living with HIV/AIDS. There are several excellent animal models employed to study tuberculosis (TB, but many have limitations for reproducing human pathology and none are amenable to the direct study of HIV/M.tb co-infection. The humanized mouse has been increasingly employed to explore HIV infection and other pathogens where animal models are limiting. Our goal was to develop a small animal model of M.tb infection using the bone marrow, liver, thymus (BLT humanized mouse. NOD-SCID/γc(null mice were engrafted with human fetal liver and thymus tissue, and supplemented with CD34(+ fetal liver cells. Excellent reconstitution, as measured by expression of the human CD45 pan leukocyte marker by peripheral blood populations, was observed at 12 weeks after engraftment. Human T cells (CD3, CD4, CD8, as well as natural killer cells and monocyte/macrophages were all observed within the human leukocyte (CD45(+ population. Importantly, human T cells were functionally competent as determined by proliferative capacity and effector molecule (e.g. IFN-γ, granulysin, perforin expression in response to positive stimuli. Animals infected intranasally with M.tb had progressive bacterial infection in the lung and dissemination to spleen and liver from 2-8 weeks post infection. Sites of infection in the lung were characterized by the formation of organized granulomatous lesions, caseous necrosis, bronchial obstruction, and crystallization of cholesterol deposits. Human T cells were distributed throughout the lung, liver, and spleen at sites of inflammation and bacterial growth and were organized to the periphery of granulomas. These preliminary results demonstrate the potential to use the humanized mouse as a model of experimental TB.

  13. Mouse Model of Coxiella burnetii Aerosolization.

    Science.gov (United States)

    Melenotte, Cléa; Lepidi, Hubert; Nappez, Claude; Bechah, Yassina; Audoly, Gilles; Terras, Jérôme; Raoult, Didier; Brégeon, Fabienne

    2016-07-01

    Coxiella burnetii is mainly transmitted by aerosols and is responsible for multiple-organ lesions. Animal models have shown C. burnetii pathogenicity, but long-term outcomes still need to be clarified. We used a whole-body aerosol inhalation exposure system to mimic the natural route of infection in immunocompetent (BALB/c) and severe combined immunodeficient (SCID) mice. After an initial lung inoculum of 10(4) C. burnetii cells/lung, the outcome, serological response, hematological disorders, and deep organ lesions were described up to 3 months postinfection. C. burnetii-specific PCR, anti-C. burnetii immunohistochemistry, and fluorescent in situ hybridization (FISH) targeting C. burnetii-specific 16S rRNA completed the detection of the bacterium in the tissues. In BALB/c mice, a thrombocytopenia and lymphopenia were first observed, prior to evidence of C. burnetii replication. In all SCID mouse organs, DNA copies increased to higher levels over time than in BALB/c ones. Clinical signs of discomfort appeared in SCID mice, so follow-up had to be shortened to 2 months in this group. At this stage, all animals presented bone, cervical, and heart lesions. The presence of C. burnetii could be attested in situ for all organs sampled using immunohistochemistry and FISH. This mouse model described C. burnetii Nine Mile strain spread using aerosolization in a way that corroborates the pathogenicity of Q fever described in humans and completes previously published data in mouse models. C. burnetii infection occurring after aerosolization in mice thus seems to be a useful tool to compare the pathogenicity of different strains of C. burnetii. PMID:27160294

  14. A mouse model of in utero transplantation.

    Science.gov (United States)

    Nijagal, Amar; Le, Tom; Wegorzewska, Marta; Mackenzie, Tippi C

    2011-01-01

    The transplantation of stem cells and viruses in utero has tremendous potential for treating congenital disorders in the human fetus. For example, in utero transplantation (IUT) of hematopoietic stem cells has been used to successfully treat patients with severe combined immunodeficiency. In several other conditions, however, IUT has been attempted without success. Given these mixed results, the availability of an efficient non-human model to study the biological sequelae of stem cell transplantation and gene therapy is critical to advance this field. We and others have used the mouse model of IUT to study factors affecting successful engraftment of in utero transplanted hematopoietic stem cells in both wild-type mice and those with genetic diseases. The fetal environment also offers considerable advantages for the success of in utero gene therapy. For example, the delivery of adenoviral, adeno-associated viral, retroviral, and lentiviral vectors into the fetus has resulted in the transduction of multiple organs distant from the site of injection with long-term gene expression. in utero gene therapy may therefore be considered as a possible treatment strategy for single gene disorders such as muscular dystrophy or cystic fibrosis. Another potential advantage of IUT is the ability to induce immune tolerance to a specific antigen. As seen in mice with hemophilia, the introduction of Factor IX early in development results in tolerance to this protein. In addition to its use in investigating potential human therapies, the mouse model of IUT can be a powerful tool to study basic questions in developmental and stem cell biology. For example, one can deliver various small molecules to induce or inhibit specific gene expression at defined gestational stages and manipulate developmental pathways. The impact of these alterations can be assessed at various timepoints after the initial transplantation. Furthermore, one can transplant pluripotent or lineage specific progenitor

  15. Reduction of chemical reaction models

    Science.gov (United States)

    Frenklach, Michael

    1991-01-01

    An attempt is made to reconcile the different terminologies pertaining to reduction of chemical reaction models. The approaches considered include global modeling, response modeling, detailed reduction, chemical lumping, and statistical lumping. The advantages and drawbacks of each of these methods are pointed out.

  16. Criteria for Validating Mouse Models of Psychiatric Diseases

    OpenAIRE

    Chadman, Kathryn K.; Yang, Mu; Crawley, Jacqueline N.

    2009-01-01

    Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing th...

  17. Urinary virulence of Proteus mirabilis in two experimental mouse models.

    OpenAIRE

    Peerbooms, P G; Marian, A.; Verweij, J. J.; MacLaren, D. M.

    1982-01-01

    Two experimental mouse models were tested for their suitability in measuring urinary virulence of Proteus mirabilis. In the first model, the kidney-infecting dose and lethal dose were measured. In the second model, the kinetics of the numbers of bacteria in the kidneys and other organs of the mouse were monitored for 13 h after injection.

  18. REDOX DISRUPTING POTENTIAL OF TOXCAST CHEMICALS RANKED BY ACTIVITY IN MOUSE EMBRYONIC STEM CELLS

    Science.gov (United States)

    To gain insight regarding the adverse outcome pathways leading to developmental toxicity following exposure to chemicals, we evaluated ToxCast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay and identified a redox sensitive pathway that correlated with al...

  19. Redox Disrupting Potential of ToxCast™Chemicals Ranked by Activity in Mouse Embryonic Stem Cells

    Science.gov (United States)

    Little is known regarding the adverse outcome pathways responsible for developmental toxicity following exposure to chemicals. An evaluation of Toxoast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay revealed a redox sensitive pathway that correlated with...

  20. A Transgenic Mouse Model of Poliomyelitis.

    Science.gov (United States)

    Koike, Satoshi; Nagata, Noriyo

    2016-01-01

    Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model. PMID:26983733

  1. A mouse model for testing remyelinating therapies.

    Science.gov (United States)

    Bai, C Brian; Sun, Sunny; Roholt, Andrew; Benson, Emily; Edberg, Dale; Medicetty, Satish; Dutta, Ranjan; Kidd, Grahame; Macklin, Wendy B; Trapp, Bruce

    2016-09-01

    Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex. Spontaneous remyelination occurred significantly faster in the cerebral cortex than in white matter and reactive astrocytes were more abundant in white matter lesions. Remyelination of white matter and cerebral cortex was therapeutically enhanced by daily injections of thyroid hormone triiodothyronine (T3). In summary, we describe an in vivo demyelination/remyelination paradigm that can be powered to determine efficacy of therapies that enhance white matter and cortical remyelination. PMID:27384502

  2. Immunochemical characterization of inhibitory mouse cortical neurons: Three chemically distinct classes of inhibitory cells

    OpenAIRE

    Xu, Xiangmin; Roby, Keith D.; Edward M Callaway

    2010-01-01

    The cerebral cortex has diverse types of inhibitory neurons. In rat cortex, past research has shown that parvalbumin (PV), somatostatin (SOM), calretinin (CR), and cholecystokinin (CCK) label four distinct chemical classes of GABAergic interneurons. However, in contrast to rat cortex, previous studies indicate that there is significant co-localization of SOM and CR in mouse cortical inhibitory neurons. In the present study, we further characterized immunochemical distinctions among mouse inhi...

  3. Mouse infection models for space flight immunology

    Science.gov (United States)

    Chapes, Stephen Keith; Ganta, Roman Reddy; Chapers, S. K. (Principal Investigator)

    2005-01-01

    Several immunological processes can be affected by space flight. However, there is little evidence to suggest that flight-induced immunological deficits lead to illness. Therefore, one of our goals has been to define models to examine host resistance during space flight. Our working hypothesis is that space flight crews will come from a heterogeneous population; the immune response gene make-up will be quite varied. It is unknown how much the immune response gene variation contributes to the potential threat from infectious organisms, allergic responses or other long term health problems (e.g. cancer). This article details recent efforts of the Kansas State University gravitational immunology group to assess how population heterogeneity impacts host health, either in laboratory experimental situations and/or using the skeletal unloading model of space-flight stress. This paper details our use of several mouse strains with several different genotypes. In particular, mice with varying MHCII allotypes and mice on the C57BL background with different genetic defects have been particularly useful tools with which to study infections by Staphylococcus aureus, Salmonella typhimurium, Pasteurella pneumotropica and Ehrlichia chaffeensis. We propose that some of these experimental challenge models will be useful to assess the effects of space flight on host resistance to infection.

  4. Modeling of turbulent chemical reaction

    Science.gov (United States)

    Chen, J.-Y.

    1995-01-01

    Viewgraphs are presented on modeling turbulent reacting flows, regimes of turbulent combustion, regimes of premixed and regimes of non-premixed turbulent combustion, chemical closure models, flamelet model, conditional moment closure (CMC), NO(x) emissions from turbulent H2 jet flames, probability density function (PDF), departures from chemical equilibrium, mixing models for PDF methods, comparison of predicted and measured H2O mass fractions in turbulent nonpremixed jet flames, experimental evidence of preferential diffusion in turbulent jet flames, and computation of turbulent reacting flows.

  5. Characterization of a mouse model of headache.

    Science.gov (United States)

    Huang, Dongyue; Ren, Lynn; Qiu, Chang-Shen; Liu, Ping; Peterson, Jonathan; Yanagawa, Yuchio; Cao, Yu-Qing

    2016-08-01

    Migraine and other primary headache disorders affect a large population and cause debilitating pain. Establishing animal models that display behavioral correlates of long-lasting and ongoing headache, the most common and disabling symptom of migraine, is vital for the elucidation of disease mechanisms and identification of drug targets. We have developed a mouse model of headache, using dural application of capsaicin along with a mixture of inflammatory mediators (IScap) to simulate the induction of a headache episode. This elicited intermittent head-directed wiping and scratching as well as the phosphorylation of c-Jun N-terminal kinase in trigeminal ganglion neurons. Interestingly, dural application of IScap preferentially induced FOS protein expression in the excitatory but not inhibitory cervical/medullary dorsal horn neurons. The duration of IScap-induced behavior and the number of FOS-positive neurons correlated positively in individual mice; both were reduced to the control level by the pretreatment of antimigraine drug sumatriptan. Dural application of CGRP(8-37), the calcitonin gene-related peptide (CGRP) receptor antagonist, also effectively blocked IScap-induced behavior, which suggests that the release of endogenous CGRP in the dura is necessary for IScap-induced nociception. These data suggest that dural IScap-induced nocifensive behavior in mice may be mechanistically related to the ongoing headache in humans. In addition, dural application of IScap increased resting time in female mice. Taken together, we present the first detailed study using dural application of IScap in mice. This headache model can be applied to genetically modified mice to facilitate research on the mechanisms and therapeutic targets for migraine headache. PMID:27058678

  6. Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

    OpenAIRE

    Fujii, Ken; Nagata, Noriyo; Sato, Yuko; Ong, Kien Chai; Wong, Kum Thong; Yamayoshi, Seiya; Shimanuki, Midori; Shitara, Hiroshi; Taya, Choji; KOIKE, Satoshi

    2013-01-01

    EV71 infection with severe neurological complications has become a serious public health concern. However, suitable small animal models to study human EV71 pathogenesis are not available. We have generated a Tg mouse model by expressing the human EV71 receptor, Scavenger receptor B2, and found it to be susceptible to EV71 infection. This Tg mouse model exhibits neurological disease and pathology very similar to that observed in humans. The results confirm that the Scavenger receptor B2 recept...

  7. A Consensus Definition of Cataplexy in Mouse Models of Narcolepsy

    OpenAIRE

    Scammell, Thomas E.; Willie, Jon T.; Guilleminault, Christian; Siegel, Jerome M.

    2009-01-01

    People with narcolepsy often have episodes of cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of...

  8. Pre implanted mouse embryos as model for uranium toxicology studies

    International Nuclear Information System (INIS)

    Full text: The search of 'in vitro' toxicology model that can predict toxicology effects 'in vivo' is a permanent challenge. A toxicology experimental model must to fill to certain requirements: to have a predictive character, an appropriate control to facilitate the interpretation of the data among the experimental groups, and to be able to control the independent variables that can interfere or modify the results that we are analyzing. The preimplantation embryos posses many advantages in this respect: they are a simple model that begins with the development of only one cell. The 'in vitro' model reproduces successfully the 'in vivo' situation. Due to the similarity that exists among the embryos of mammals during this period the model is practically valid for other species. The embryo is itself a stem cell, the toxicology effects are early observed in his clonal development and the physical-chemical parameters are easily controllable. The purpose of the exhibition is to explain the properties of the pre implanted embryo model for toxicology studies of uranium and to show our experimental results. The cultivation 'in vitro' of mouse embryos with uranylo nitrate demonstrated that the uranium causes from the 13 μgU/ml delay of development, decrease the number of cells per embryo and hipoploidy in the embryonic blastomere. (author)

  9. Characterization of a pneumococcal meningitis mouse model

    Directory of Open Access Journals (Sweden)

    Mook-Kanamori Barry

    2012-03-01

    Full Text Available Abstract Background S. pneumoniae is the most common causative agent of meningitis, and is associated with high morbidity and mortality. We aimed to develop an integrated and representative pneumococcal meningitis mouse model resembling the human situation. Methods Adult mice (C57BL/6 were inoculated in the cisterna magna with increasing doses of S. pneumoniae serotype 3 colony forming units (CFU; n = 24, 104, 105, 106 and 107 CFU and survival studies were performed. Cerebrospinal fluid (CSF, brain, blood, spleen, and lungs were collected. Subsequently, mice were inoculated with 104 CFU S. pneumoniae serotype 3 and sacrificed at 6 (n = 6 and 30 hours (n = 6. Outcome parameters were bacterial outgrowth, clinical score, and cytokine and chemokine levels (using Luminex® in CSF, blood and brain. Meningeal inflammation, neutrophil infiltration, parenchymal and subarachnoidal hemorrhages, microglial activation and hippocampal apoptosis were assessed in histopathological studies. Results Lower doses of bacteria delayed onset of illness and time of death (median survival CFU 104, 56 hrs; 105, 38 hrs, 106, 28 hrs. 107, 24 hrs. Bacterial titers in brain and CSF were similar in all mice at the end-stage of disease independent of inoculation dose, though bacterial outgrowth in the systemic compartment was less at lower inoculation doses. At 30 hours after inoculation with 104 CFU of S. pneumoniae, blood levels of KC, IL6, MIP-2 and IFN- γ were elevated, as were brain homogenate levels of KC, MIP-2, IL-6, IL-1β and RANTES. Brain histology uniformly showed meningeal inflammation at 6 hours, and, neutrophil infiltration, microglial activation, and hippocampal apoptosis at 30 hours. Parenchymal and subarachnoidal and cortical hemorrhages were seen in 5 of 6 and 3 of 6 mice at 6 and 30 hours, respectively. Conclusion We have developed and validated a murine model of pneumococcal meningitis.

  10. Oxytocin antagonist disrupts male mouse medial amygdala response to chemical-communication signals

    OpenAIRE

    Samuelsen, Chad L.; Meredith, Michael

    2011-01-01

    The male mouse medial amygdala is an important site for integration of main and accessory olfactory information. Exposure to biologically relevant chemical signals from the same species (conspecific) results in a general pattern of immediate early gene (IEG) expression in medial amygdala different from that elicited by chemical signals from other species (heterospecific), of no demonstrable biological relevance. The neuropeptide oxytocin (OT) in the medial amygdala has been shown to be necess...

  11. Inducing mutations in the mouse genome with the chemical mutagen ethylnitrosourea

    Directory of Open Access Journals (Sweden)

    S.M.G. Massironi

    2006-09-01

    Full Text Available When compared to other model organisms whose genome is sequenced, the number of mutations identified in the mouse appears extremely reduced and this situation seriously hampers our understanding of mammalian gene function(s. Another important consequence of this shortage is that a majority of human genetic diseases still await an animal model. To improve the situation, two strategies are currently used: the first makes use of embryonic stem cells, in which one can induce knockout mutations almost at will; the second consists of a genome-wide random chemical mutagenesis, followed by screening for mutant phenotypes and subsequent identification of the genetic alteration(s. Several projects are now in progress making use of one or the other of these strategies. Here, we report an original effort where we mutagenized BALB/c males, with the mutagen ethylnitrosourea. Offspring of these males were screened for dominant mutations and a three-generation breeding protocol was set to recover recessive mutations. Eleven mutations were identified (one dominant and ten recessives. Three of these mutations are new alleles (Otop1mlh, Foxn1sepe and probably rodador at loci where mutations have already been reported, while 4 are new and original alleles (carc, eqlb, frqz, and Sacc. This result indicates that the mouse genome, as expected, is far from being saturated with mutations. More mutations would certainly be discovered using more sophisticated phenotyping protocols. Seven of the 11 new mutant alleles induced in our experiment have been localized on the genetic map as a first step towards positional cloning.

  12. Mouse models to study dengue virus immunology and pathogenesis

    Directory of Open Access Journals (Sweden)

    Raphaël M. Zellweger

    2014-04-01

    Full Text Available The development of a compelling murine model of dengue virus (DENV infection has been challenging, because dengue virus clinical isolates do not readily replicate or cause pathology in immunocompetent mice. However, research using immunocompromised mice and/or mouse-adapted viruses allows to investigate questions that may be impossible to address in human studies. In this review, we discuss the potential strengths and limitations of existing mouse models of dengue disease. Human studies are descriptive by nature; moreover, the strain, time, and sequence of infection are often unknown. In contrast, in mice, the conditions of infection are well defined and a large number of experimental parameters can be varied at will. Therefore, mouse models offer an opportunity to experimentally test hypotheses that are based on epidemiological observations. In particular, gain-of-function or loss-of-function models can be established to assess how different components of the immune system (either alone or in combination contribute to protection or pathogenesis during secondary infections or after vaccination. In addition, mouse models have been used for pre-clinical testing of antiviral drug or for vaccine development studies. Conclusions based on mouse experiments must be extrapolated to DENV infection in humans with caution due to the inherent limitations of animal models. However, research in mouse models is a useful complement to in vitro and epidemiological data, and may delineate new areas that deserve attention during future human studies.

  13. Mouse Models for Studying the Formation and Propagation of Prions*

    OpenAIRE

    Watts, JC; Prusiner, SB

    2014-01-01

    Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse mode...

  14. The Mouse Genome Database (MGD): premier model organism resource for mammalian genomics and genetics

    OpenAIRE

    Blake, J. A.; Bult, C. J.; J.A. Kadin; J.E. Richardson; Eppig, J T

    2010-01-01

    The Mouse Genome Database (MGD) is the community model organism database for the laboratory mouse and the authoritative source for phenotype and functional annotations of mouse genes. MGD includes a complete catalog of mouse genes and genome features with integrated access to genetic, genomic and phenotypic information, all serving to further the use of the mouse as a model system for studying human biology and disease. MGD is a major component of the Mouse Genome Informatics (MGI, http://www...

  15. Genomic responses in mouse models poorly mimic human inflammatory diseases

    Science.gov (United States)

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  16. The gut microbiota in mouse models of inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Kalliopi eGkouskou

    2014-02-01

    Full Text Available The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of inflammatory bowel diseases have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn’s disease and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of inflammatory bowel diseases.

  17. Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia

    Directory of Open Access Journals (Sweden)

    Jonathan L Brigman

    2010-05-01

    Full Text Available The development of sophisticated, translatable mouse-based assays modeling the behavioral manifestations of neuropsychiatric diseases such as schizophrenia has lagged the advances in molecular and genomic techniques. Our laboratory has made efforts to fill this gap by investing in the development of novel assays, including adapting a touchscreen-based method for measuring cognitive and executive functions for use in mice. As part of these efforts, a recent study by Brigman et al. (2009 investigated the effects of subchronic phencyclidine (PCP treatment on mouse touchscreen-based pairwise visual discrimination and reversal learning. Here, we summarize the results of that study and place them in the larger context of ongoing efforts to develop valid mouse ‘models’ of schizophrenia, with a focus on reversal learning and other measures of cognitive flexibility. Touchscreen-based systems could provide a tractable platform for fully utilizing the mouse to elucidate the pathophysiology of cognitive inflexibility in schizophrenia and other neuropsychiatric disorders.

  18. Mouse Models for Assessing Protein Immunogenicity: Lessons and Challenges.

    Science.gov (United States)

    Jiskoot, Wim; Kijanka, Grzegorz; Randolph, Theodore W; Carpenter, John F; Koulov, Atanas V; Mahler, Hanns-Christian; Joubert, Marisa K; Jawa, Vibha; Narhi, Linda O

    2016-05-01

    The success of clinical and commercial therapeutic proteins is rapidly increasing, but their potential immunogenicity is an ongoing concern. Most of the studies that have been conducted over the past few years to examine the importance of various product-related attributes (in particular several types of aggregates and particles) and treatment regimen (such as dose, dosing schedule, and route of administration) in the development of unwanted immune responses have utilized one of a variety of mouse models. In this review, we discuss the utility and drawbacks of different mouse models that have been used for this purpose. Moreover, we summarize the lessons these models have taught us and some of the challenges they present. Finally, we provide recommendations for future research utilizing mouse models to improve our understanding of critical factors that may contribute to protein immunogenicity. PMID:27044944

  19. CML Mouse Model Generated from Leukemia Stem Cells.

    Science.gov (United States)

    Hu, Yiguo

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a high number of well-differentiated neutrophils in peripheral blood and myeloid cells in bone marrow (BM). CML is derived from the hematopoietic stem cells (HSCs) with the Philadelphia chromosome (Ph(+), t(9;22)-(q34;q11)), resulting in generating a fusion oncogene, BCR/ABL1. HSCs with Ph(+) are defined as leukemia stem cells (LSCs), a subpopulation cell at the apex of hierarchies in leukemia cells and responsible for the disease continuous propagation. Several kinds of CML models have been developed to reveal the mechanism of CML pathogenesis and evaluate therapeutic drugs in the past three decades. Here, we describe the procedures to generate a CML mouse model by introducing BCR/ABL1 into Lin(-)Sca1(+) cKit(+) population cells purified from mouse bone marrow. In CML retroviral transduction/transplantation mouse models, this modified model can mimic CML pathogenesis on high fidelity. PMID:27581136

  20. The value of incomplete mouse models of Alzheimer's disease

    International Nuclear Information System (INIS)

    To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of Aβ42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral β-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging. (orig.)

  1. Application of hepatitis B virus replication mouse model

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the value of the hepatitis B virus(HBV) replication mouse model with regard to several aspects of the study of HBV biology.METHODS:To evaluate the HBV replication mouse model in detecting the efficacy of anti-HBV agents,the interferon inducer polyinosinic-polytidylin acid(polyIC) and nucleotide analogues adefovir and entecavir were administered to mice injected with wild type pHBV4.1,and the inhibiting effect of these agents on HBV DNA replication was evaluated.To identify the model's value ...

  2. Chemical kinetics and combustion modeling

    Energy Technology Data Exchange (ETDEWEB)

    Miller, J.A. [Sandia National Laboratories, Livermore, CA (United States)

    1993-12-01

    The goal of this program is to gain qualitative insight into how pollutants are formed in combustion systems and to develop quantitative mathematical models to predict their formation rates. The approach is an integrated one, combining low-pressure flame experiments, chemical kinetics modeling, theory, and kinetics experiments to gain as clear a picture as possible of the process in question. These efforts are focused on problems involved with the nitrogen chemistry of combustion systems and on the formation of soot and PAH in flames.

  3. Mouse like rodents as objective biological marker of radiation and chemical contamination

    International Nuclear Information System (INIS)

    The focus of the paper is the study of nuclear-fuel enterprises or the combination of nuclear-fuel and chemical enterprises influence on the contents of glucocorticoids in suprarenal of mouse like rodents, as well as the level of serotonin in hypothalamus of the mice inhabiting the territory of such industrial enterprises. It is stated that the counting of glucocorticoids of the mice inhabiting the territory contaminated with radiation increases more than by two times, yet the mice inhabiting the territories effected by the combined impact of radiation and chemical waste suffer the major change of the adaptation hormones. Hypertrophy of the suprarenal of mouse like rodents indicates the effect of low dosage of chronic irradiation on small mammals' adaptation system, as well as the boost of this effect in case of the combination of radiation and chemical waste. The hypothalamus of mice inhabiting the contaminated territories shows convincing decrease of serotonin contents in comparison with that of the mammals inhabiting ecologically clean territories. The deficiency of serotonin in the brain can cause depression, anxiety and depending on individual personality nay cause aggression and submissive behavior. Mouse like rodents are objective signs for observation of the chronic impact of environmental factors

  4. Parkinson’s disease mouse models in translational research

    OpenAIRE

    Antony, Paul; Diederich, Nico; Balling, Rudi

    2011-01-01

    Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to addres...

  5. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  6. Mass spectrometry analysis of hepcidin peptides in experimental mouse models.

    Directory of Open Access Journals (Sweden)

    Harold Tjalsma

    Full Text Available The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1 and its paralogue Hepcidin-2 (Hep-2 at the peptide level. To this purpose, Fourier transform ion cyclotron resonance (FTICR and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i 3 mouse strains (C57Bl/6; DBA/2 and BABL/c upon stimulation with intravenous iron and LPS, ii homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X mutated mice and double affected mice, and iii mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics.

  7. Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis

    OpenAIRE

    Praet, Jelle; Guglielmetti, Caroline; Berneman, Zwi; Van der Linden, Annemie; Ponsaerts, Peter

    2014-01-01

    Abstract: The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cupri...

  8. Chemical modeling of waste sludges

    Energy Technology Data Exchange (ETDEWEB)

    Weber, C.F.; Beahm, E.C.

    1996-10-01

    The processing of waste from underground storage tanks at the Oak Ridge National Laboratory (ORNL) and other facilities will require an understanding of the chemical interactions of the waste with process chemicals. Two aspects of sludge treatment should be well delineated and predictable: (1) the distribution of chemical species between aqueous solutions and solids, and (2) potential problems due to chemical interactions that could result in process difficulties or safety concerns. It is likely that the treatment of waste tank sludge will begin with washing, followed by basic or acidic leaching. The dissolved materials will be in a solution that has a high ionic strength where activity coefficients are far from unity. Activity coefficients are needed in order to calculate solubilities. Several techniques are available for calculating these values, and each technique has its advantages and disadvantages. The techniques adopted and described here is the Pitzer method. Like any of the methods, prudent use of this approach requires that it be applied within concentration ranges where the experimental data were fit, and its use in large systems should be preceded by evaluating subsystems. While much attention must be given to the development of activity coefficients, other factors such as coprecipitation of species and Ostwald ripening must also be considered when one aims to interpret results of sludge tests or to predict results of treatment strategies. An understanding of sludge treatment processes begins with the sludge tests themselves and proceeds to a general interpretation with the aid of modeling. One could stop with only data from the sludge tests, in which case the table of data would become an implicit model. However, this would be a perilous approach in situations where processing difficulties could be costly or result in concerns for the environment or health and safety.

  9. Virtues and limitations of the preimplantation mouse embryo as a model system

    OpenAIRE

    Robert A Taft

    2007-01-01

    The mouse is the most widely used model of preimplantation embryo development, but is it a good model? Its small size, prolificacy and ease of handling make the mouse a relatively low cost, readily available and attractive alternative when embryos from other species are difficult or expensive to obtain. However, the real power of the mouse as a model lies in mouse genetics. The development of inbred mouse strains facilitated gene discovery as well as our understanding of gene function and reg...

  10. Chemical Models of Collapsing Envelopes

    CERN Document Server

    Bergin, E A

    1999-01-01

    We discuss recent models of chemical evolution in the developing and collapsing protostellar envelopes associated with low-mass star formation. In particular, the effects of depletion of gas-phase molecules onto grain surfaces is considered. We show that during the middle to late evolutionary stages, prior to the formation of a protostar, various species selectively deplete from the gas phase. The principal pattern of selective depletions is the depletion of sulfur-bearing molecules relative to nitrogen-bearing species: NH3 and N2H+. This pattern is shown to be insensitive to the details of the dynamics and marginally sensitive to whether the grain mantle is dominated by polar or non-polar molecules. Based on these results we suggest that molecular ions are good tracers of collapsing envelopes. The effects of coupling chemistry and dynamics on the resulting physical evolution are also examined. Particular attention is paid to comparisons between models and observations.

  11. Development and testing of a mouse simulated space flight model

    Science.gov (United States)

    Sonnenfeld, G.

    1985-01-01

    The development and testing of a mouse model for simulating some aspects of weightlessness that occur during space flight, and the carrying out of immunological flight experiments on animals was discussed. The mouse model is an antiorthostatic, hypokinetic, hypodynamic suspension model similar to the one used with rats. It is shown that this murine model yield similar results to the rat model of antiorthostatic suspension for simulating some aspects of weightlessness. It is also shown that mice suspended in this model have decreased interferon-alpha/beta production as compared to control, nonsuspended mice or to orthostatically suspended mice. It is suggested that the conditions occuring during space flight could possibly affect interferon production. The regulatory role of interferon in nonviral diseases is demonstrated including several bacterial and protozoan infections indicating the great significance of interferon in resistance to many types of infectious diseases.

  12. Stem cell transplantation in mouse models for Huntington's disease

    OpenAIRE

    Johann, Verena

    2005-01-01

    Cell replacement therapies for neurodegenerative diseases using stem cells require above all a good survival of the graft and therefore an understanding of the possible influence of the surrounding degenerating tissue on the grafted cells. In this thesis, I report on the experiments of stem cell transplantation in mouse models for Huntington´s disease. The most common rodent model for HD is the QA-lesion model, where quinolinic acid is injected unilaterally into the striatum of adult rats. We...

  13. A Neural Model of Demyelination of the Mouse Spinal Cord

    OpenAIRE

    Petreska, Biljana; Yovel, Yossi

    2008-01-01

    This paper presents a neural network model of demyelination of the mouse motor pathways, coupled to a central pattern generation (CPG) model for quadruped walking. Demyelination is the degradation of the myelin layer covering the axons which can be caused by several neurodegenerative autoimmune diseases such as multiple sclerosis. We use this model - to our knowledge first of its kind - to investigate the locomotion deficits that appear following demyelination of axons in the spinal cord. Our...

  14. Responses of the L5178Y mouse lymphoma cell forward mutation assay. V: 27 coded chemicals

    Energy Technology Data Exchange (ETDEWEB)

    McGregor, D.B.; Brown, A.G.; Howgate, S.; McBride, D.; Riach, C. (Inveresk Research International Limited, Musselburgh (Scotland)); Caspary, W.J. (National Inst. of Health, Research Triangle Park, NC (United States))

    1991-01-01

    Twenty-seven chemicals were tested for their mutagenic potential in the L5178Y tk{sup +}/tk{sup {minus}} mouse lymphoma cell forward mutation assay. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 {mu}g/ml. The chemicals were tested at least twice. Statistically significant responses were obtained with acid orange 10, aniline, benzaldehyde o-chloroaniline, chlorodibromomethane, cytembena, 1,2-dibromo-4-(1,2-dibromomethyl) cyclohexane, dieldrin, lithocholic acid, oxytetracycline, phenazopyridine HCl, 1phenyl-3-methyl-5-pyrazolone, sodium diethyldithiocarbamate, solvent yellow 14, tetraethylthiuram disulfide (disulfiram), 2,4-toluene diisocyanate, and 2,6-toluene diisocyanate. Apart from phenazopyridine HCl, acid orange 10, and solvent yellow 14, rat liver S9 mix was not a requirement for the mutagenic activity of these compounds.

  15. CHARACTERIZATION OF AEROMONAS VIRULENCE USING AN IMMUNOCOMPROMISED MOUSE MODEL

    Science.gov (United States)

    An immunocompromised mouse model was used to characterize Aeromonas strains for their ability to cause opportunistic, extraintestinal infections. A total of 34 isolates of Aeromonas (A. hydrophila [n = 12]), A. veronii biotype sobria [n = 7], A. caviae [n = 4], A. enchelia [n = 4...

  16. Towards a mouse model of depression : a psychoneuroendocrine approach

    NARCIS (Netherlands)

    Dalm, Sergiu

    2012-01-01

    Chronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new drugs are urgently needed. The objective of the research was to develop a mouse model of depression that

  17. NOD mouse model for Sjogren's syndrome: lack of longitudinal stability

    NARCIS (Netherlands)

    B.M. Lodde; F. Mineshiba; M.R. Kok; J. Wang; C. Zheng; M. Schmidt; A.P. Cotrim; M. Kriete; P.P. Tak; B.J. Baum

    2006-01-01

    OBJECTIVES: The non-obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjogren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated vi

  18. Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay.

    Directory of Open Access Journals (Sweden)

    Kelly J Chandler

    Full Text Available The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7 and cytotoxicity (DRAQ5™/Sapphire700™ were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀ values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500 revealed significant associations for a subset of chemicals (26 that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation.

  19. Rate equation model of phototransduction into the membranous disks of mouse rod cells

    CERN Document Server

    Takamoto, Rei; Awazu, Akinori

    2015-01-01

    A theoretical model was developed to investigate the rod phototransduction process in the mouse. In particular, we explored the biochemical reactions of several chemical components that contribute to the signaling process into/around the membranous disks in the outer segments of the rod cells. We constructed a rate equation model incorporating the molecular crowding effects of rhodopsin according to experimental results, which may hinder the diffusion of molecules on the disk mem- brane. The present model could effectively reproduce and explain the mechanisms of the following phenomena observed in experiments. First, the activations and relaxation of the wild-type mouse rod cell progressed more slowly than those of mutant cells containing half the amount of rhodopsin on the disk membrane. Second, the strong photoactivated state of the cell was sustained for a longer period when the light stimuli were strong. Finally, the lifetime of photoactivation exhibited a logarithmic increase with increasing light streng...

  20. Rapid genetic algorithm optimization of a mouse computational model: Benefits for anthropomorphization of neonatal mouse cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Corina Teodora Bot

    2012-11-01

    Full Text Available While the mouse presents an invaluable experimental model organism in biology, its usefulness in cardiac arrhythmia research is limited in some aspects due to major electrophysiological differences between murine and human action potentials (APs. As previously described, these species-specific traits can be partly overcome by application of a cell-type transforming clamp (CTC to anthropomorphize the murine cardiac AP. CTC is a hybrid experimental-computational dynamic clamp technique, in which a computationally calculated time-dependent current is inserted into a cell in real time, to compensate for the differences between sarcolemmal currents of that cell (e.g., murine and the desired species (e.g., human. For effective CTC performance, mismatch between the measured cell and a mathematical model used to mimic the measured AP must be minimal. We have developed a genetic algorithm (GA approach that rapidly tunes a mathematical model to reproduce the AP of the murine cardiac myocyte under study. Compared to a prior implementation that used a template-based model selection approach, we show that GA optimization to a cell-specific model results in a much better recapitulation of the desired AP morphology with CTC. This improvement was more pronounced when anthropomorphizing neonatal mouse cardiomyocytes to human-like APs than to guinea pig APs. CTC may be useful for a wide range of applications, from screening effects of pharmaceutical compounds on ion channel activity, to exploring variations in the mouse or human genome. Rapid GA optimization of a cell-specific mathematical model improves CTC performance and may therefore expand the applicability and usage of the CTC technique.

  1. Characterization of the bombesin receptor on mouse pancreatic acini by chemical cross-linking

    International Nuclear Information System (INIS)

    Bombesin (BN), gastrin-releasing peptide (GRP) and GRP(18-27) (neuromedin C) were equipotent and 30-fold more potent than neuromedin B (NMB) in inhibiting binding of 125I-GRP to and in stimulating amylase release from mouse pancreatic acini. In the present study we used 125I-GRP and chemical cross-linking techniques to characterize the mouse pancreatic BN receptor. After binding of 125I-GRP to membranes, and incubation with various chemical cross-linking agents, cross-linked radioactivity was analyzed by SDS-PAG electrophoresis and autoradiography. With each of 4 different chemical cross-linking agents, there was a single broad polypeptide band of Mr 80,000. Cross-linking did not occur in the absence of the cross-linking agent. Cross-linking was inhibited only by peptides that interact with the BN receptor such as GRP, NMB, GRP(18-27) or BN. Dose-inhibition curves for the ability of BN or NMB to inhibit binding of 125I-GRP to membranes or cross-linking to the 80,000 polypeptide demonstrated for both that BN was 15-fold more potent than NMB. The apparent molecular weight of the cross-linked polypeptide was unchanged by adding dithiothreitol. N-Glycanase treatment reduced the molecular weight of the cross-linked peptide to 40,000. The present results indicate that the BN receptor on mouse pancreatic acinar cell membranes resembles that recently described on various tumor cells in being a single glycoprotein with a molecular weight of 76,000. Because dithiothreitol had no effect, this glycoprotein is not a subunit of a larger disulfide-linked structure

  2. Characterization of the bombesin receptor on mouse pancreatic acini by chemical cross-linking

    Energy Technology Data Exchange (ETDEWEB)

    Huang, S.C.; Yu, D.H.; Wank, S.A.; Gardner, J.D.; Jensen, R.T. (National Institutes of Health, Bethesda, MD (USA))

    1990-11-01

    Bombesin (BN), gastrin-releasing peptide (GRP) and GRP(18-27) (neuromedin C) were equipotent and 30-fold more potent than neuromedin B (NMB) in inhibiting binding of {sup 125}I-GRP to and in stimulating amylase release from mouse pancreatic acini. In the present study we used {sup 125}I-GRP and chemical cross-linking techniques to characterize the mouse pancreatic BN receptor. After binding of {sup 125}I-GRP to membranes, and incubation with various chemical cross-linking agents, cross-linked radioactivity was analyzed by SDS-PAG electrophoresis and autoradiography. With each of 4 different chemical cross-linking agents, there was a single broad polypeptide band of Mr 80,000. Cross-linking did not occur in the absence of the cross-linking agent. Cross-linking was inhibited only by peptides that interact with the BN receptor such as GRP, NMB, GRP(18-27) or BN. Dose-inhibition curves for the ability of BN or NMB to inhibit binding of {sup 125}I-GRP to membranes or cross-linking to the 80,000 polypeptide demonstrated for both that BN was 15-fold more potent than NMB. The apparent molecular weight of the cross-linked polypeptide was unchanged by adding dithiothreitol. N-Glycanase treatment reduced the molecular weight of the cross-linked peptide to 40,000. The present results indicate that the BN receptor on mouse pancreatic acinar cell membranes resembles that recently described on various tumor cells in being a single glycoprotein with a molecular weight of 76,000. Because dithiothreitol had no effect, this glycoprotein is not a subunit of a larger disulfide-linked structure.

  3. Current Concepts: Mouse Models of Sjögren's Syndrome

    Directory of Open Access Journals (Sweden)

    Tegan N. Lavoie

    2011-01-01

    Full Text Available Sjögren's syndrome (SjS is a complex chronic autoimmune disease of unknown etiology which primarily targets the exocrine glands, resulting in eventual loss of secretory function. The disease can present as either primary SjS or secondary SjS, the latter of which occurs concomitantly with another autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or primary biliary cirrhosis. Current advancements in therapeutic prevention and treatment for SjS are impeded by lack of understanding in the pathophysiological and clinical progression of the disease. Development of appropriate mouse models for both primary and secondary SjS is needed in order to advance knowledge of this disease. This paper details important features, advantages, and pitfalls of current animal models of SjS, including spontaneous, transgenic, knockout, immunization, and transplantation chimera mouse models, and emphasizes the need for a better model in representing the human SjS phenotype.

  4. Genomic responses in mouse models poorly mimic human inflammatory diseases

    OpenAIRE

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E; Minei, Joseph P.

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the respon...

  5. Mouse models of human AML accurately predict chemotherapy response

    OpenAIRE

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S.; Zhao, Zhen; Rappaport, Amy R.; Luo, Weijun; McCurrach, Mila E.; Yang, Miao-Miao; Dolan, M. Eileen; Kogan, Scott C.; Downing, James R.; Lowe, Scott W.

    2009-01-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to co...

  6. A mouse model for HBV immunotolerance and immunotherapy

    OpenAIRE

    Yang, Dan; Liu, Longchao; Zhu, Danming; Peng, Hua; Su, Lishan; Fu, Yang-Xin; Zhang, Liguo

    2013-01-01

    Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization wit...

  7. Retinoic acid fails to reverse emphysema in adult mouse models

    OpenAIRE

    Fujita, M; Ye, Q.; Ouchi, H.; Nakashima, N; Hamada, N; Hagimoto, N; Kuwano, K.; Mason, R.; Nakanishi, Y

    2004-01-01

    Methods: The models used were an elastase induced emphysema model for acute alveolar destruction and a tumour necrosis factor (TNF)-α transgenic mouse which exhibits chronic air space enlargement, loss of elastic recoil, increased lung volume, and pulmonary hypertension comparable to human pulmonary emphysema. All-trans-retinoic acid (2 mg/kg) was injected for 12 successive days after the establishment of emphysema. The effects of treatment were evaluated using physiological and morphometric ...

  8. [Evaluation of imaging biomarker by transgenic mouse models].

    Science.gov (United States)

    Maeda, Jun; Higuchi, Makoto; Suhara, Tetsuya

    2009-04-01

    The invention of trangenic and gene knockout mice contributes to the understanding of various brain functions. With the previous-generation positron emission tomography (PET) camera it was impossible to visualize the mouse brain functions, while the newly developed small-animal PET camera with higher resolution is enough to visualize the mouse brain functions. In the present study, we investigated the visualization of functional brain images for a few transgenic mouse models using the small-animal PET. In neurodegenerative illnesses such as Alzheimer disease (AD), the relationship between etiopathology and main symptoms has been elucidated relatively well; therefore several transgenic mice have been already developed. We succeeded in visualizing amyloid images in human mutant amyloid precursor protein (APP) transgenic mice brains. This result suggested that small-animal PET enabled the quantitative analysis of pathologies in the Tg mouse brain. Psychiatric disorders are presumed to have underlying multiple neural dysfunctions. Despite some efficient medicinal therapies having been already established, the etiopathology of mental illness and its biological markers have not been clarified. Thus, we investigated in type II Ca-calmodulin-dependent protein kinase alpha (CaMKII alpha) heterozygous knockout (hKO) mouse, a major protein kinase in the brain. The CaMKII alpha hKO mice have several abnormal behavioral phenotypes, such as hyper aggression and lack of anxiogenic responses; therefore CaMKII alpha might involve in the pathogenesis of mood disorder and affect personal characterizations. Furthermore, serotonin (5-HT) 1A receptor density in the CaMKII alpha hKO mouse brain changed among various brain regions compared to wild mice. These mechanistic insights, PET assays of Tg mice that we have established here, provide an efficient methodology for preclinical evaluation of emerging diagnostic and therapeutic agents for neurodegenerative and psychiatric illnesses

  9. Quantification of mouse pulmonary cancer models by microcomputed tomography imaging

    International Nuclear Information System (INIS)

    The advances in preclinical cancer models, including orthotopic implantation models or genetically engineered mouse models of cancer, enable pursuing the molecular mechanism of cancer disease that might mimic genetic and biological processes in humans. Lung cancer is the major cause of cancer deaths; therefore, the treatment and prevention of lung cancer are expected to be improved by a better understanding of the complex mechanism of disease. In this study, we have examined the quantification of two distinct mouse lung cancer models by utilizing imaging modalities for monitoring tumor progression and drug efficacy evaluation. The utility of microcomputed tomography (micro-CT) for real-time/non-invasive monitoring of lung cancer progression has been confirmed by combining bioluminescent imaging and histopathological analyses. Further, we have developed a more clinically relevant lung cancer model by utilizing K-rasLSL-G12D/p53LSL-R270H mutant mice. Using micro-CT imaging, we monitored the development and progression of solitary lung tumor in K-rasLSL-G12D/p53LSL-R270H mutant mouse, and further demonstrated tumor growth inhibition by anticancer drug treatment. These results clearly indicate that imaging-guided evaluation of more clinically relevant tumor models would improve the process of new drug discovery and increase the probability of success in subsequent clinical studies. (author)

  10. Chemical Modeling of Cometary Anions

    Science.gov (United States)

    Cordiner, Martin; Charnley, S. B.

    2009-09-01

    The presence of negative ions (anions) in cometary comae is known from Giotto mass spectrometry of 1P/Halley. The anions O-, OH-, C-, CH- and CN- have been detected, as well as unidentified anions with masses 22-65 and 85-110 amu (Chaizy et al. 1991). Organic molecular anions are known to have a significant impact on the charge balance of interstellar clouds and circumstellar envelopes and have been shown to act as catalysts for the gas-phase synthesis of larger hydrocarbon molecules in the ISM, but their importance in cometary comae has not previously been explored. We present details of the first attempt to model the chemistry of anions in cometary comae. Based on the combined chemical and hydrodynamical model of Rodgers & Charnley (2002), we investigate the role of the hydrocarbon and nitrile anions Cn-, CnH- and CnN- in the coma. We calculate the effects of these anions on the charge balance and examine their impact on cometary coma chemistry. References: Chaizy, P. et al. 1991, Nature, 349, 393 Rodgers, S.D. & Charnley, S.B. 2002, MNRAS, 330, 660

  11. Molecular imaging of vessels in mouse models of disease

    International Nuclear Information System (INIS)

    Vascular imaging of angiogenesis in mouse models of disease requires multi modal imaging hardware capable of targeting both structure and function at different physical scales. The three dimensional (3D) structure and function vascular information allows for accurate differentiation between biological processes. For example, image analysis of vessel development in angiogenesis vs. arteriogenesis enables more accurate detection of biological variation between subjects and more robust and reliable diagnosis of disease. In the recent years a number of micro imaging modalities have emerged in the field as preferred means for this purpose. They provide 3D volumetric data suitable for analysis, quantification, validation, and visualization of results in animal models. This review highlights the capabilities of microCT, ultrasound and microPET for multimodal imaging of angiogenesis and molecular vascular targets in a mouse model of tumor angiogenesis. The basic principles of the imaging modalities are described and experimental results are presented.

  12. Mouse models of myeloproliferative neoplasms: JAK of all grades

    Directory of Open Access Journals (Sweden)

    Juan Li

    2011-05-01

    Full Text Available In 2005, several groups identified a single gain-of-function point mutation in the JAK2 kinase that was present in the majority of patients with myeloproliferative neoplasms (MPNs. Since this discovery, much effort has been dedicated to understanding the molecular consequences of the JAK2V617F mutation in the haematopoietic system. Three waves of mouse models have been produced recently (bone marrow transplantation, transgenic and targeted knock-in, which have facilitated the understanding of the molecular pathogenesis of JAK2V617F-positive MPNs, providing potential platforms for designing and validating novel therapies in humans. This Commentary briefly summarises the first two types of mouse models and then focuses on the more recently generated knock-in models.

  13. Osthole suppresses seizures in the mouse maximal electroshock seizure model.

    Science.gov (United States)

    Luszczki, Jarogniew J; Andres-Mach, Marta; Cisowski, Wojciech; Mazol, Irena; Glowniak, Kazimierz; Czuczwar, Stanislaw J

    2009-04-01

    The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one]--a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED(50) values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies. PMID:19236860

  14. A transgenic mouse model for trilateral retinoblastoma

    NARCIS (Netherlands)

    O'Brien, J.M.; Marcus, D.M.; Bernards, R.A.; Carpenter, J.L.; Windle, J.J.; Mellon, P.; Albert, D.M.

    1990-01-01

    We present a murine model of trilateral retinoblastoma. Ocular retinoblastoma and central nervous system tumors are observed in a line of mice formed by the transgenic expression of SV40 T-antigen. An oncogenic protein known to bind to the retinoblastoma gene product (p105-Rb) is specifically expres

  15. Mouse models of membranous nephropathy: the road less travelled by.

    Science.gov (United States)

    Borza, Dorin-Bogdan; Zhang, Jun-Jun; Beck, Laurence H; Meyer-Schwesinger, Catherine; Luo, Wentian

    2013-01-01

    Membranous nephropathy (MN) is a major cause of idiopathic nephrotic syndrome in adults, often progressing to end-stage kidney disease. The disease is mediated by IgG antibodies that form subepithelial immune complexes upon binding to antigens expressed by podocytes or planted in the subepithelial space. Subsequent activation of the complement cascade, podocyte injury by the membrane attack complex and the expansion of the glomerular basement membrane cause proteinuria and nephrotic syndrome. The blueprint for our current understanding of the pathogenic mechanisms of MN has largely been provided by studies in rat Heymann nephritis, an excellent animal model that closely replicates human disease. However, further progress in this area has been hindered by the lack of robust mouse models of MN that can leverage the power of genetic approaches for mechanistic studies. This critical barrier has recently been overcome by the development of new mouse models that faithfully recapitulate the clinical and morphologic hallmarks of human MN. In these mouse models, subepithelial ICs mediating proteinuria and nephrotic syndrome are induced by injection of cationized bovine serum albumin, by passive transfer of heterologous anti-podocyte antibodies, or by active immunization with the NC1 domain of α3(IV) collagen. These mouse models of MN will be instrumental for addressing unsolved questions about the basic pathomechanisms of MN and also for preclinical studies of novel therapeutics. We anticipate that the new knowledge to be gained from these studies will eventually translate into much needed novel mechanism-based therapies for MN, more effective, more specific, and less toxic. PMID:23885331

  16. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

    Science.gov (United States)

    Paschall, Amy V; Liu, Kebin

    2016-01-01

    Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo. PMID:27584043

  17. Nonspecific airway reactivity in a mouse model of asthma

    Energy Technology Data Exchange (ETDEWEB)

    Collie, D.D.; Wilder, J.A.; Bice, D.E.

    1995-12-01

    Animal models are indispensable for studies requiring an intact immune system, especially for studying the pathogenic mechanisms in atopic diseases, regulation of IgE production, and related biologic effects. Mice are particularly suitable and have been used extensively for such studies because their immune system is well characterized. Further, large numbers of mutants or inbred strains of mice are available that express deficiencies of individual immunologic processes, inflammatory cells, or mediator systems. By comparing reactions in such mice with appropriate control animals, the unique roles of individual cells or mediators may be characterized more precisely in the pathogenesis of atopic respiratory diseases including asthma. However, given that asthma in humans is characterized by the presence of airway hyperresponsiveness to specific and nonspecific stimuli, it is important that animal models of this disease exhibit similar physiologic abnormalities. In the past, the size of the mouse has limited its versatility in this regard. However, recent studies indicate the feasibility of measuring pulmonary responses in living mice, thus facilitating the physiologic evaluation of putative mouse models of human asthma that have been well charcterized at the immunologic and patholigic level. Future work will provide details of the morphometry of the methacholine-induced bronchoconstriction and will further seek to determine the relationship between cigarette smoke exposure and the development of NS-AHR in the transgenic mouse model.

  18. Sleep Phenotyping in a Mouse Model of Extreme Trait Anxiety

    OpenAIRE

    Jakubcakova, Vladimira; Flachskamm, Cornelia; Landgraf, Rainer; Kimura, Mayumi

    2012-01-01

    Background There is accumulating evidence that anxiety impairs sleep. However, due to high sleep variability in anxiety disorders, it has been difficult to state particular changes in sleep parameters caused by anxiety. Sleep profiling in an animal model with extremely high vs. low levels of trait anxiety might serve to further define sleep patterns associated with this psychopathology. Methodology/Principal Findings Sleep-wake behavior in mouse lines with high (HAB), low (LAB) and normal (NA...

  19. Real-Time Bioluminescence Imaging of Nitroreductase in Mouse Model.

    Science.gov (United States)

    Feng, Ping; Zhang, Huateng; Deng, Quankun; Liu, Wei; Yang, Linghui; Li, Guobo; Chen, Guo; Du, Lupei; Ke, Bowen; Li, Minyong

    2016-06-01

    Nitroreductase (NTR) is an endogenous reductase overexpressed in hypoxic tumors; however, its precise detection in living cells and animals remains a considerable challenge. Herein, we developed three reaction-based probes and a related bioluminescence assay for the real-time NTR detection. The high sensitivity and selectivity of probe 3, combined with its remarkable potential of bioluminescence imaging, affords a valuable approach for in vivo imaging of NTR in a tumor model mouse. PMID:27197544

  20. Cardiac Dysfunction in the BACHD Mouse Model of Huntington's Disease

    OpenAIRE

    Schroeder, Analyne M.; Huei Bin Wang; Saemi Park; Jordan, Maria C.; Fuying Gao; Giovanni Coppola; Fishbein, Michael C; Kenneth P Roos; Ghiani, Cristina A.; Colwell, Christopher S.

    2016-01-01

    While Huntington’s disease (HD) is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD ...

  1. Extracting Extra-Telomeric Phenotypes from Telomerase Mouse Models

    OpenAIRE

    Sung, Young Hoon; Ali, Muhammad; Lee, Han-Woong

    2013-01-01

    Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere-elongating enzyme, recen...

  2. Predictably irrational: assaying cognitive inflexibility in mouse models of schizophrenia

    OpenAIRE

    Brigman, Jonathan L.

    2010-01-01

    The development of sophisticated, translatable mouse-based assays modeling the behavioral manifestations of neuropsychiatric diseases such as schizophrenia has lagged the advances in molecular and genomic techniques. Our laboratory has made efforts to fill this gap by investing in the development of novel assays, including adapting a touchscreen-based method for measuring cognitive and executive functions for use in mice. As part of these efforts, a recent study by Brigman et al. (2009) inv...

  3. Towards a mouse model of depression: a psychoneuroendocrine approach

    OpenAIRE

    Dalm, Sergiu

    2012-01-01

    Chronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new drugs are urgently needed. The objective of the research was to develop a mouse model of depression that would express anhedonia, induced by chronic stress. Mice were repeatedly exposed to the non-physical presence of a rat. Alterations in stress system activity were measured. Anhedonia was assessed ...

  4. A mouse model of intestinal stem cell function and regeneration

    OpenAIRE

    Slorach, E M; Campbell, F. C.; Dorin, J. R.

    1999-01-01

    We present here an in vivo mouse model for intestinal stem cell function and differentiation that uses postnatal intestinal epithelial cell aggregates to generate a differentiated murine small intestinal mucosa with full crypt-villus architecture. The process of neomucosal formation is highly similar to that of intestinal regeneration. Both in vivo grafting and primary culture of these cells reveal two different epithelial cell populations, which display properties consistent with intestinal ...

  5. Substrate reduction therapy in mouse models of the glycosphingolipidoses.

    OpenAIRE

    Platt, Frances M.; Jeyakumar, Mylvaganam; Andersson, Ulrika; Heare, Tanya; Dwek, Raymond A.; Butters, Terry D.

    2003-01-01

    Substrate reduction therapy uses small molecules to slow the rate of glycolipid biosynthesis. One of these drugs, N-butyldeoxynojirimycin (NB-DNJ), shows efficacy in mouse models of Tay-Sachs, Sandhoff and Fabry diseases. This offers the prospect that NB-DNJ may be of therapeutic benefit, at least in the juvenile and adult onset variants of these disorders. The infantile onset variants will require an additional enzyme-augmenting modality if the pathology is to be significantly improved. A se...

  6. Hypothermic Endpoint for an Intranasal Invasive Pulmonary Aspergillosis Mouse Model

    OpenAIRE

    Adamson, Trinka W; Diaz-Arevalo, Diana; Gonzalez, Tracey M; Liu, Xueli; Kalkum, Markus

    2013-01-01

    Immunocompromised mice were infected intranasally with Aspergillus fumigatus as part of a vaccine efficacy study. Although body temperature was measured throughout the study, a formal evaluation of its usefulness as an endpoint criterion was not performed. We retrospectively evaluated survival data and temperature records to determine whether body temperature can be used as an objective predictor of death and included in the humane endpoint criteria for this mouse model. CF1 mice were immunos...

  7. Mathematical Modeling of Chemical Stoichiometry

    Science.gov (United States)

    Croteau, Joshua; Fox, William P.; Varazo, Kristofoland

    2007-01-01

    In beginning chemistry classes, students are taught a variety of techniques for balancing chemical equations. The most common method is inspection. This paper addresses using a system of linear mathematical equations to solve for the stoichiometric coefficients. Many linear algebra books carry the standard balancing of chemical equations as an…

  8. A Mouse Model of Zika Virus Pathogenesis.

    Science.gov (United States)

    Lazear, Helen M; Govero, Jennifer; Smith, Amber M; Platt, Derek J; Fernandez, Estefania; Miner, Jonathan J; Diamond, Michael S

    2016-05-11

    The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3(-/-)Irf5(-/-)Irf7(-/-) triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1(-/-)) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3(-/-), Irf5(-/-), and Mavs(-/-) knockout mice exhibited no overt illness. Ifnar1(-/-) mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1(-/-) mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis. PMID:27066744

  9. Curcumin shows excellent therapeutic effect on psoriasis in mouse model.

    Science.gov (United States)

    Kang, Di; Li, Bowen; Luo, Lei; Jiang, Wenbing; Lu, Qiumin; Rong, Mingqing; Lai, Ren

    2016-04-01

    Curcumin is an active herbal ingredient possessing surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. Recently, it has been reported to exhibit inhibitory activity on potassium channel subtype Kv1.3. As Kv1.3 channels are mainly expressed in T cells and play a key role in psoriasis, the effects of curcumin were investigated on inflammatory factors secretion in T cells and psoriasis developed in keratin (K) 14-vascular endothelial growth factor (VEGF) transgenic mouse model. Results showed that, 10 μM of curcumin significantly inhibited secretion of inflammatory factors including interleukin (IL)-17,IL-22, IFN-γ, IL-2, IL-8 and TNF-α in T cells by 30-60% in vitro. Notably, more than 50% of T cells proliferation was inhibited by application of 100 μM curcumin. Compared with severe psoriatic symptoms observed in the negative control mice, all psoriasis indexes including ear redness, weight, thickness and lymph node weight were significantly improved by oral application of curcumin in treatment mouse group. Histological examination indicated that curcumin had anti-inflammatory function in the experimental animals. More than 50% level of inflammatory factors including TNF-α, IFN-γ, IL-2, IL-12, IL-22 and IL-23 in mouse serum was decreased by curcumin treatment as well as cyclosporine. Compared with renal fibrosis observed in the mouse group treated by cyclosporine, no obvious side effect in mouse kidney was found after treated by curcumin. Taken together, curcumin, with high efficacy and safety, has a great potential to treat psoriasis. PMID:26826458

  10. Responses of the L5178Y mouse Lymphoma cell forward mutation assay. V: 27 coded chemicals.

    Science.gov (United States)

    McGregor, D B; Brown, A G; Howgate, S; McBride, D; Riach, C; Caspary, W J

    1991-01-01

    Twenty-seven chemicals were tested for their mutagenic potential in the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay using procedures based upon those described by McGregor et al. (McGregor DB, Martin R, Cattanach P, Edwards I, McBride D, Caspary WJ (1987): Environ Mol Mutagen 9:143-160). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Statistically significant responses were obtained with acid orange 10, aniline, benzaldehyde, o-chloroaniline, chlorodibromomethane, cytembena, 1,2-dibromo-4-(1,2-dibromomethyl) cyclohexane, dieldrin, lithocholic acid, oxytetracycline, phenazopyridine HCl, 1-phenyl-3-methyl-5-pyrazolone, sodium diethyldithiocarbamate, solvent yellow 14, tetraethylthiuram disulfide (disulfiram), 2,4-toluene diisocyanate, and 2,6-toluene diisocyanate. Apart from phenazopyridine HCl, acid orange 10, and solvent yellow 14, rat liver S9 mix was not a requirement for the mutagenic activity of these compounds. Chemical not identified as mutagens were N-4-acetylaminofluorene, chlorpheniramine maleate, chloropropamide, 1,4-dioxane, endrin, ethylene glycol, iron dextran, methapyrilene, sodium(2-ethylhexyl)alcohol PMID:1902415

  11. Genetic effects of combined chemical-X-ray treatments in male mouse germ cells

    International Nuclear Information System (INIS)

    Several studies have shown that the yield of genetic damage induced by radiation in male mouse germ cells can be modified by chemical treatments. Pre-treatments with radio-protecting agents have given contradictory results but this appears to be largely attributable to the different germ cell stages tested and dependent upon the level of radiation damage induced. Pre-treatments which enhance the yield of genetic damage have been reported although, as yet, no tests have been conducted with radio-sensitizers. Another form of interaction between chemicals and radiation is specifically found with spermatogonial stem cells. Chemicals that kill cells can, by population depletion, substantially and predictably modify the genetic response to subsequent radiation exposure over a period of several days, or even weeks. Enhancement and reduction in the genetic yield can be attained, dependent upon the interval between treatments, with the modification also varying with the type of genetic damage scored. Post-treatment with one chemical (TEM) has been shown to reduce the genetic response to radiation exposure. (author)

  12. Behavioral characterization of mouse models of neuroferritinopathy.

    Directory of Open Access Journals (Sweden)

    Sara Capoccia

    Full Text Available Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK promoter. Transgenic (Tg mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests. The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help

  13. Behavioral characterization of mouse models of neuroferritinopathy.

    Science.gov (United States)

    Capoccia, Sara; Maccarinelli, Federica; Buffoli, Barbara; Rodella, Luigi F; Cremona, Ottavio; Arosio, Paolo; Cirulli, Francesca

    2015-01-01

    Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing

  14. Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

    International Nuclear Information System (INIS)

    Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

  15. Chemical reactor modeling multiphase reactive flows

    CERN Document Server

    Jakobsen, Hugo A

    2014-01-01

    Chemical Reactor Modeling closes the gap between Chemical Reaction Engineering and Fluid Mechanics.  The second edition consists of two volumes: Volume 1: Fundamentals. Volume 2: Chemical Engineering Applications In volume 1 most of the fundamental theory is presented. A few numerical model simulation application examples are given to elucidate the link between theory and applications. In volume 2 the chemical reactor equipment to be modeled are described. Several engineering models are introduced and discussed. A survey of the frequently used numerical methods, algorithms and schemes is provided. A few practical engineering applications of the modeling tools are presented and discussed. The working principles of several experimental techniques employed in order to get data for model validation are outlined. The monograph is based on lectures regularly taught in the fourth and fifth years graduate courses in transport phenomena and chemical reactor modeling, and in a post graduate course in modern reactor m...

  16. Vascularization of engineered cartilage constructs in a mouse model.

    Science.gov (United States)

    Burghartz, Marc; Gehrke, Thomas; Storck, Katharina; Staudenmaier, Rainer; Mandlik, Veronika; Schurr, Christian; Hoang, Nguyen; Hagen, Rudolf; Kleinsasser, Norbert

    2015-02-01

    Tissue engineering of cartilage tissue offers a promising method for reconstructing ear, nose, larynx and trachea defects. However, a lack of sufficient nutrient supply to cartilage constructs limits this procedure. Only a few animal models exist to vascularize the seeded scaffolds. In this study, polycaprolactone (PCL)-based polyurethane scaffolds are seeded with 1 × 10(6) human cartilage cells and implanted in the right hind leg of a nude mouse using an arteriovenous flow-through vessel loop for angiogenesis for the first 3 weeks. Equally seeded scaffolds but without access to a vessel loop served as controls. After 3 weeks, a transposition of the vascularized scaffolds into the groin of the nude mouse was performed. Constructs (verum and controls) were explanted 1 and 6 weeks after transposition. Constructs with implanted vessels were well vascularized. The amount of cells increased in vascularized constructs compared to the controls but at the same time noticeably less extracellular matrix was produced. This mouse model provides critical answers to important questions concerning the vascularization of engineered tissue, which offers a viable option for repairing defects, especially when the desired amount of autologous cartilage or other tissues is not available and the nutritive situation at the implantation site is poor. PMID:25381568

  17. New approaches for modelling cancer mechanisms in the mouse.

    Science.gov (United States)

    Maddison, Kathryn; Clarke, Alan R

    2005-01-01

    Mouse models of human cancer are vital to our understanding of the neoplastic process, and to advances in both basic and clinical research. Indeed, models of many of the major human tumours are now available and are subject to constant revision to more faithfully recapitulate human disease. Despite these advances, it is important to recognize that limitations do exist to the current range of models. The principal approach to modelling has relied upon the use of constitutive gene knockouts, which can often result in embryonic lethality, can potentially be affected by developmental compensation, and which do not mimic the sporadic development of a tumour expanding from a single cell in an otherwise normal environment. Furthermore, simple knockouts are usually designed to lead to loss of protein function, whereas a subset of cancer-causing mutations clearly results in gain of function. These drawbacks are well recognized and this review describes some of the approaches used to address these issues. Key amongst these is the development of conditional alleles that precisely mimic the mutations found in vivo, and which can be spatially and tissue-specifically controlled using 'smart' systems such as the tetracycline system and Cre-Lox technology. Examples of genes being manipulated in this way include Ki-Ras, Myc, and p53. These new developments in modelling mean that any mutant allele can potentially be turned on or off, or over- or under-expressed, in any tissue at any stage of the life-cycle of the mouse. This will no doubt lead to ever more accurate and powerful mouse models to dissect the genetic pathways that lead to cancer. PMID:15641017

  18. New Mouse Model for Dengue Virus Vaccine Testing

    OpenAIRE

    Johnson, Alison J.; Roehrig, John T.

    1999-01-01

    Several dengue (DEN) virus vaccines are in development; however, the lack of a reliable small animal model in which to test them is a major obstacle. Because evidence suggests that interferon (IFN) is involved in the human anti-DEN virus response, we tested mice deficient in their IFN functions as potential models. Intraperitoneally administered mouse-adapted DEN 2 virus was uniformly lethal in AG129 mice (which lack alpha/beta IFN and gamma IFN receptor genes), regardless of age. Immunized m...

  19. Assimilating chemical compound with a regional chemical model

    Science.gov (United States)

    Chang, C.; Yang, S.; Liang, M.; Hsu, S.; Tseng, Y.

    2012-12-01

    To constrain the source and sink of the chemical compounds at surface during model simulation, chemical compound assimilation with Local Ensemble Transform Kalman Filter (LETKF) has been implemented for the WRF-ChemT model. In this study, a two-tier system is applied to assimilating the meteorological and chemical variables in an OSSE framework. The unobserved surface flux is estimated according to the observations in the chemical component. A long-term nature run with total constant emission of 5.3×108 g/s is assumed to be the truth state in the OSSE. The simulated observations are obtained from the truth state by adding random errors. In order to generate the initial CO2 ensembles with similar spatial distribution as truth state without other prior information, the initial perturbation fields of CO2 are randomly chosen from three long-term runs with different emissions. The results indicate that in the constant emission case, the system can successfully estimate the unobserved chemical forcing and improve the distribution of the chemical compound. Under the scenario of diurnal forcing induced by human activities, the problem in estimating surface flux becomes more complex and difficult. A set of experiments with different initial chemical states suggest that the estimation of flux is sensitive to the quality of initial CO2 and CO2 surface flux. Strategies are designed to retrieve the time-varying information. The results show that with time-varying information and reliable initial ensembles, the estimation of surface flux have been significantly improved. Couple assimilation with meteorological and chemical components Surface flux estimation

  20. A chemical evolution model for galaxy clusters

    OpenAIRE

    Portinari, L.; A. Moretti(Fermilab, Batavia, IL, USA); Chiosi, C.

    2001-01-01

    We develop a toy-model for the chemical evolution of the intracluster medium, polluted by the galactic winds from elliptical galaxies. The model follows the "galaxy formation history" of cluster galaxies, constrained by the observed luminosity function.

  1. The Event Coordination Notation: Behaviour Modelling Beyond Mickey Mouse

    DEFF Research Database (Denmark)

    Jepsen, Jesper; Kindler, Ekkart

    The Event Coordination Notation (ECNO) allows modelling the desired behaviour of a software system on top of any object-oriented software. Together with existing technologies from Model-based Software Engineering (MBSE) for automatically generating the software for the structural parts, ECNO allows...... generating fully functional software from a combination of class diagrams and ECNO models. What is more, software generated from ECNO models, integrates with existing software and software generated by other technologies. ECNO started out from some challenges in behaviour modelling and some requirements on...... special aspect of ECNO or another; and it would be fair to call them “Mickey Mouse examples”. In this paper, we give a concise overview of the motivation, ideas, and concepts of ECNO. More importantly, we discuss a larger system, which was completely generated from the underlying models: a workflow...

  2. Altered ganglioside biosynthesis in mouse cell cultures following transformation with chemical carcinogens and x-irradiation

    International Nuclear Information System (INIS)

    Chemically and x-ray-transformed subclones of BALB/c 3T3 mouse embryo cells were found to have reduced amounts of the mono- and disialogangliosides galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide (G/sub M1/) and N-acetylneuraminylgalactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide (G/sub D1a/), and increased amounts of N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide (G/sub M2/). The activity of the enzyme UDP-Gal:G/sub M2/ galactosyltransferase was reduced to between 2.7 and 14.3 percent of normal in the transformed clones. Other ganglioside glycosyltransferase activities were unaffected. This enzymatic change was consistent with the observed alteration in ganglioside pattern in the transformed cells. The residual galactosyltransferase activity in the transformed cells was kinetically similar to the normal enzyme, suggesting that transformation alters ganglioside biosynthesis by blocking enzyme synthesis at the translational or transcriptional levels

  3. Chronic Myeloid Leukemia (CML) Mouse Model in Translational Research.

    Science.gov (United States)

    Peng, Cong; Li, Shaoguang

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of granulocytic cells without the loss of their capability to differentiate. CML is a clonal disease, originated at the level of Hematopoietic Stem Cells with the Philadelphia chromosome resulting from a reciprocal translocation between the chromosomes 9 and 22t(9;22)-(q34;q11). This translocation produces a fusion gene known as BCR-ABL which acquires uncontrolled tyrosine kinase activity, constantly turning on its downstream signaling molecules/pathways, and promoting proliferation of leukemia cell through anti-apoptosis and acquisition of additional mutations. To evaluate the role of each critical downstream signaling molecule of BCR-ABL and test therapeutic drugs in vivo, it is important to use physiological mouse disease models. Here, we describe a mouse model of CML induced by BCR-ABL retrovirus (MSCV-BCR-ABL-GFP; MIG-BCR-ABL) and how to use this model in translational research.Moreover, to expand the application of this retrovirus induced CML model in a lot of conditional knockout mouse strain, we modified this vector to a triple gene coexpression vector in which we can co-express BCR-ABL, GFP, and a third gene which will be tested in different systems. To apply this triple gene system in conditional gene knockout strains, we can validate the CML development in the knockout mice and trace the leukemia cell following the GFP marker. In this protocol, we also describe how we utilize this triple gene system to prove the function of Pten as a tumor suppressor in leukemogenesis. Overall, this triple gene system expands our research spectrum in current conditional gene knockout strains and benefits our CML translational research. PMID:27150093

  4. Recent advances in mouse models of obesityandnonalcoholic steatohepatitis-associatedhepatocarcinogenesis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth mostcommon cancer, and obesity has been establishedas a risk factor for HCC development. Nonalcoholicsteatohepatitis (NASH) is apparently the key linkbetween obesity and hepatocarcinogenesis, and obesityalso accelerates HCC development synergistically withother risk factors, such as hepatitis virus infectionand alcohol consumption. As an explanation for thepathogenesis of NASH, the so-called "two-hit" theoryhas been widely accepted, but recently, a better model,the so-called "multiple-hits hypothesis" was proposed,which states that many disease-promoting factors mayoccur in parallel, rather than consecutively. However,the overall mechanism remains largely unknown. Variouscell-cell and organ-organ interactions are involved inthe pathogenesis of NASH, and thus appropriate in vivodisease models are essential for a deeper understanding.However, replicating the full spectrum of human NASHhas been difficult, as NASH involves obesity, insulinresistance, steatohepatitis, fibrosis, and ultimately HCC,and the lack of an appropriate mouse model has beena considerable barrier to determining the missing linksamong obesity, NASH, and HCC. In recent years, severalinnovative mouse models presenting obesity- and NASHassociatedHCC have been established by modifieddiets, chemotoxic agents, genetic manipulation, or acombination of these factors, shedding some light onthis complex network and providing new therapeuticstrategies. Thus, in this paper, I review the mousemodels of obesity- and NASH-associated HCC, especiallyfocusing on recent advances and their clinical relevance.

  5. Mouse models of SCN5A-related cardiac arrhythmias

    Directory of Open Access Journals (Sweden)

    Flavien eCharpentier

    2012-06-01

    Full Text Available Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na+ channel NaV1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, atrial standstill and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This paper reviews some of the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. It also points out that these models also have their own limitations. Overall, mouse models appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodelling of other genes that might participate to the overall phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

  6. Screening ToxCast™ Phase I Chemicals in a Mouse Embryonic Stem Cell Adherent Cell Differentiation and Cytotoxicity (ACDC) Assay

    Science.gov (United States)

    An Adherent Cell Differentiation and Cytotoxicity (ACDC) in vitro assay with mouse embryonic stem cells was used to screen the ToxCast Phase I chemical library for effects on cellular differentiation and cell number. The U.S. Environmental Protection Agency (EPA) established the ...

  7. A new mouse model of metabolic syndrome and associated complications

    Science.gov (United States)

    Wang, Yun; Zheng, Yue; Nishina, Patsy M; Naggert, Jürgen K.

    2010-01-01

    Metabolic Syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the CLAMS™ animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LepR, SOCS1 and STAT3 phosphorylation were examined. Cardiac function was assessed by Echo- and Electro Cardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with a LOD score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JNK1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy. The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of metabolic syndrome and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy. PMID:19398498

  8. Chemical equilibrium modeling of detonation

    Energy Technology Data Exchange (ETDEWEB)

    Fried, Laurence E. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bastea, Sorin [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2010-05-19

    Energetic materials are unique for having a strong exothermic reactivity, which has made them desirable for both military and commercial applications. Energetic materials are commonly divided into high explosives, propellants, and pyrotechnics. We will focus on high explosive (HE) materials here, although there is a great deal of commonality between the classes of energetic materials. Furthermore the history of HE materials is long, their condensed-phase chemical properties are poorly understood.

  9. Cardiac manifestations in the mouse model of mucopolysaccharidosis I

    OpenAIRE

    Jordan, Maria C.; Zheng, Yi; Ryazantsev, Sergey; Rozengurt, Nora; Roos, Kenneth P.; Neufeld, Elizabeth F.

    2005-01-01

    Mucopolysaccharidosis I (MPS I, α-l-iduronidase deficiency disease) is a heritable lysosomal storage disorder involving multiple organs, including the heart. Malfunction of the heart is also a major manifestation in the mouse model of MPS I, progressing in severity from 6 to 10 months (of a one-year life span). In comparisons of MPS I with wild type mice, the heart was found enlarged, with thickened septal and posterior walls, primarily because of infiltration of the muscle by storage-laden c...

  10. Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

    Directory of Open Access Journals (Sweden)

    Chen Xi

    2011-11-01

    Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs. Our group has previously demonstrated that calcium (Ca2+ signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128. Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2 and spinocerebellar ataxia 3 (SCA3 mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. Results The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Conclusions Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that Ryan

  11. A new humanized mouse model for alopecia areata.

    Science.gov (United States)

    Gilhar, Amos; Keren, Aviad; Paus, Ralf

    2013-12-01

    Although alopecia areata (AA) is not life threatening, it may lead to severe psychological disturbances, reducing the quality of life in all ages. Thus, a new animal model is needed for shedding more light onto the pathogenesis of this cell-mediated, organ-specific autoimmune disease to identify more effective therapeutic strategies. Recently, we succeeded in developing a new humanized mouse model of AA, which includes transplantation of healthy human scalp skin obtained from normal volunteers on to severe-combined immunodeficient mice. This is followed by intradermal injection of either autologous or allogeneic peripheral blood mononuclear cells, which had been cultured with high dose of IL-2 and enriched for natural killer group 2D-positive (NKG2D+) and CD56+ cells. This protocol leads to rapid and predictable development of focal hair loss, with all the characteristic clinical, histological, and immunohistochemical features of AA. This humanized mouse AA model underscores the functional importance of NKG2D+ and CD56+ cells in AA pathogenesis and promises to be instrumental for identifying novel AA treatment strategies. PMID:24326548

  12. Chemically induced skin carcinogenesis: Updates in experimental models (Review)

    Science.gov (United States)

    NEAGU, MONICA; CARUNTU, CONSTANTIN; CONSTANTIN, CAROLINA; BODA, DANIEL; ZURAC, SABINA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

    2016-01-01

    Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands-on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro-inflammatory cytokines, and simultaneous inflammation sustained by pro-inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID:26986013

  13. Chemically induced skin carcinogenesis: Updates in experimental models (Review).

    Science.gov (United States)

    Neagu, Monica; Caruntu, Constantin; Constantin, Carolina; Boda, Daniel; Zurac, Sabina; Spandidos, Demetrios A; Tsatsakis, Aristidis M

    2016-05-01

    Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands‑on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro‑inflammatory cytokines, and simultaneous inflammation sustained by pro‑inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID:26986013

  14. Revisiting the mouse model of oxygen-induced retinopathy

    Directory of Open Access Journals (Sweden)

    Kim CB

    2016-05-01

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

  15. Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract

    Directory of Open Access Journals (Sweden)

    Burkhard eSchütz

    2015-03-01

    Full Text Available The mouse gastro-intestinal and biliary tract mucosal epithelia harbor choline acetyltransferase (ChAT-positive brush cells with taste cell-like traits. With the aid of two transgenic mouse lines that express green fluorescent protein (EGFP under the control of the ChAT promoter (EGFPChAT and by using in situ hybridization and immunohistochemistry we found that EGFPChAT cells were clustered in the epithelium lining the gastric groove. EGFPChAT cells were numerous in the gall bladder and bile duct, and found scattered as solitary cells along the small and large intestine. While all EGFPChAT cells were also ChAT-positive, expression of the high-affinity choline transporter (ChT1 was never detected. Except for the proximal colon, EGFPChAT cells also lacked detectable expression of the vesicular acetylcholine transporter (VAChT. EGFPChAT cells were found to be separate from enteroendocrine cells, however they were all immunoreactive for cytokeratin 18 (CK18, transient receptor potential melastatin-like subtype 5 channel (TRPM5, and for cyclooxygenases 1 (COX1 and 2 (COX2. The ex vivo stimulation of colonic EGFPChAT cells with the bitter substance denatonium resulted in a strong increase in intracellular calcium, while in other epithelial cells such an increase was significantly weaker and also timely delayed. Subsequent stimulation with cycloheximide was ineffective in both cell populations. Given their chemical coding and chemosensory properties, EGFPChAT brush cells thus may have integrative functions and participate in induction of protective reflexes and inflammatory events by utilizing ACh and prostaglandins for paracrine signaling.

  16. Verifying of endocrine disruptor chemical affect to the mouse testes: can raman spectroscopy support histology study?

    Science.gov (United States)

    Andriana, Bibin B.; Oshima, Yusuke; Takanezawa, Sota; Tay, Tat W.; Rosawati Soeratman, Catherine Linda; Alam, Mohammad S.; Mitsuoka, Hiroki; Zhu, Xiao B.; Suzuki, Toshiaki; Yamamoto, Yuko S.; Tsunekawa, Naoki; Kanai, Yoshiakira; Kurohmaru, Masamichi; Sato, Hidetoshi

    2009-02-01

    One of suspect environmental endocrine disruptors that affect mouse male reproduction by altering the morphology of Sertoli cells and spermatogenic cells is phthalate. The effects of mono(2-ethylhexyl)phthalate (MEHP), one of metabolites of di(2-ethylhexyl)phthalate , on immature mouse testes in vivo were examined. We have recently shown that MEHP induced Sertoli cells necrosis and spermatogenic cells apoptosis in mice by TUNEL method, F-actin staining, and ultrastructural study, but there is no data for biochemical changing of testes due to those methods could not explore. To verify in detail of it, we conducted Raman spectroscopy study with 785 nm wavelength laser line, 50mW of laser power and 3 minutes of exposure time to analysis the MEHP-treated testicular tissue, which has been fixatived by 4% paraformaldehyde (PFA). Five weeks old (5 w.o) male mice were used in this experiment. As the results, the alterations were observed by Raman spectroscopy that there are significantly differences of DNA, actin filament, type IV collagen and amide I between control group (0 μM MEHP) and treatment group (100 μM MEHP). These results significantly support histology staining observation (such as the apoptotic spermatogenic cells which is associated with DNA fragmentation and F-actin disruption) and ultrastructural observation (such as mitochondria rupture and disintegration of nucleus membrane). Raman spectroscopy can be used for 4% PFA-fixatived tissue observation. However, we recommend that Raman spectroscopy may be able to be expanded as an armamentarium not just for the clarification of histology staining and ultrastructural study, but furthermore, it may be as a non-invasion assessment for screening animal tissue toxicity of chemical in future.

  17. Estimating Lead (Pb) Bioavailability In A Mouse Model

    Science.gov (United States)

    Children are exposed to Pb through ingestion of Pb-contaminated soil. Soil Pb bioavailability is estimated using animal models or with chemically defined in vitro assays that measure bioaccessibility. However, bioavailability estimates in a large animal model (e.g., swine) can be...

  18. A new mouse model to explore therapies for preeclampsia.

    Directory of Open Access Journals (Sweden)

    Abdulwahab Ahmed

    Full Text Available BACKGROUND: Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE. DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF signaling by soluble VEGF receptor 1 (sFlt-1 is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies. CONCLUSIONS/SIGNIFICANCE: We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.

  19. Mouse models of cognitive disorders in trisomy 21: a review.

    Science.gov (United States)

    Sérégaza, Zohra; Roubertoux, Pierre L; Jamon, Marc; Soumireu-Mourat, Bernard

    2006-05-01

    Trisomy 21 (TRS21) is the most frequent genetic cause of mental retardation. Although the presence of an extra copy of HSA21 is known to be at the origin of the syndrome, we do not know which 225 HSA21 genes have an effect on cognitive processes. Mouse models of TRS21 have been developed using syntenies between HSA21 and MMU16, MMU10 and MMU17. Available mouse models carry extra fragments of MMU16 or of HSA21 that cover all of HSA21 (chimeric HSA21) or MMU16 (Ts16); some carry large parts of MMU16 (Ts65Dn, Ts1Cje, Ms1Cje), while others have reduced contiguous fragments covering the D21S17-ETS2 region or single transfected genes. This offers a nest design strategy for deciphering cognitive (learning, memory and exploration) and associated brain abnormalities involving each of these chromosomal regions. This review confirms the crucial but not exclusive contribution of the D21S17-ETS2 region encompassing 16 genes to cognitive disorders. PMID:16523244

  20. Strontium biokinetic model for mouse-like rodent

    International Nuclear Information System (INIS)

    Model describing the biokinetics of strontium for murine rodent is suggested. The model represents modification of the ICRP model for reference human with reduced number of compartments: Blood, Gastrointestinal tract, Soft tissues, Skeleton, Urinary bladder. To estimate transfer rates of the model the published experimental data on strontium retention in body of laboratory and wild mice were analyzed. A set of eleven transfer rates suggested for the strontium biokinetic model for murine rodent satisfactorily describes both the laboratory experiments (relative standard error of 9.5%) and data on radiostrontium content available for wild animals. Application of the model allows estimation of strontium distribution by organs and tissues both in the cases of acute and chronic exposure with assessment of strontium activity in organs with time since beginning of exposure. The developed strontium biokinetic model will be used for internal dose assessment for murine rodents inhabiting East-Ural Radioactive Trace, where 90Sr intake is a significant source of contemporary internal exposure. -- Highlights: ► We examined 20 published experiments on 90Sr retention in rodents. ► Strontium biokinetic model for mouse-like rodent is suggested. ► Model satisfactory describes retention both in laboratory and wild animals

  1. Chemical Kinetic Modeling of Advanced Transportation Fuels

    Energy Technology Data Exchange (ETDEWEB)

    PItz, W J; Westbrook, C K; Herbinet, O

    2009-01-20

    Development of detailed chemical kinetic models for advanced petroleum-based and nonpetroleum based fuels is a difficult challenge because of the hundreds to thousands of different components in these fuels and because some of these fuels contain components that have not been considered in the past. It is important to develop detailed chemical kinetic models for these fuels since the models can be put into engine simulation codes used for optimizing engine design for maximum efficiency and minimal pollutant emissions. For example, these chemistry-enabled engine codes can be used to optimize combustion chamber shape and fuel injection timing. They also allow insight into how the composition of advanced petroleum-based and non-petroleum based fuels affect engine performance characteristics. Additionally, chemical kinetic models can be used separately to interpret important in-cylinder experimental data and gain insight into advanced engine combustion processes such as HCCI and lean burn engines. The objectives are: (1) Develop detailed chemical kinetic reaction models for components of advanced petroleum-based and non-petroleum based fuels. These fuels models include components from vegetable-oil-derived biodiesel, oil-sand derived fuel, alcohol fuels and other advanced bio-based and alternative fuels. (2) Develop detailed chemical kinetic reaction models for mixtures of non-petroleum and petroleum-based components to represent real fuels and lead to efficient reduced combustion models needed for engine modeling codes. (3) Characterize the role of fuel composition on efficiency and pollutant emissions from practical automotive engines.

  2. Chemical Evolution models of Local Group galaxies

    OpenAIRE

    Tosi., M

    2003-01-01

    Status quo and perspectives of standard chemical evolution models of Local Group galaxies are summarized, discussing what we have learnt from them, what we know we have not learnt yet, and what I think we will learn in the near future. It is described how Galactic chemical evolution models have helped showing that: i) stringent constraints on primordial nucleosynthesis can be derived from the observed Galactic abundances of the light elements, ii) the Milky Way has been accreting external gas...

  3. Regression of retinopathy by squalamine in a mouse model.

    Science.gov (United States)

    Higgins, Rosemary D; Yan, Yun; Geng, Yixun; Zasloff, Michael; Williams, Jon I

    2004-07-01

    The goal of this study was to determine whether an antiangiogenic agent, squalamine, given late during the evolution of oxygen-induced retinopathy (OIR) in the mouse, could improve retinal neovascularization. OIR was induced in neonatal C57BL6 mice and the neonates were treated s.c. with squalamine doses begun at various times after OIR induction. A system of retinal whole mounts and assessment of neovascular nuclei extending beyond the inner limiting membrane from animals reared under room air or OIR conditions and killed periodically from d 12 to 21 were used to assess retinopathy in squalamine-treated and untreated animals. OIR evolved after 75% oxygen exposure in neonatal mice with florid retinal neovascularization developing by d 14. Squalamine (single dose, 25 mg/kg s.c.) given on d 15 or 16, but not d 17, substantially improved retinal neovascularization in the mouse model of OIR. There was improvement seen in the degree of blood vessel tuft formation, blood vessel tortuosity, and central vasoconstriction with squalamine treatment at d 15 or 16. Single-dose squalamine at d 12 was effective at reducing subsequent development of retinal neovascularization at doses as low as 1 mg/kg. Squalamine is a very active inhibitor of OIR in mouse neonates at doses as low as 1 mg/kg given once. Further, squalamine given late in the course of OIR improves retinopathy by inducing regression of retinal neovessels and abrogating invasion of new vessels beyond the inner-limiting membrane of the retina. PMID:15128931

  4. Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

    Science.gov (United States)

    Zhan, Le; Yang, Ill; Kong, Bo; Shen, Jianliang; Gorczyca, Ludwik; Memon, Naureen; Buckley, Brian T; Guo, Grace L

    2016-01-15

    Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved in a variety of liver functions at the mRNA levels. PN increased liver gene expression of Cyp7a1 and markedly decreased that of Cyp8b1, Cyp7b1, Bsep, and Shp. CYP7A1 and CYP8B1 are important for synthesizing the total amount of BAs and regulating the hydrophobicity of BAs, respectively. Consistently, both the levels and the percentages of primary BAs as well as total non-12α-OH BAs increased significantly in the serum of PN mice compared with saline controls, whereas liver BA profiles were largely similar. The expression of several key liver-X receptor-α (LXRα) target genes involved in lipid synthesis was also increased in PN mouse livers. Retinoid acid-related orphan receptor-α (RORα) has been shown to induce the expression of Cyp8b1 and Cyp7b1, as well as to suppress LXRα function. Western blot showed significantly reduced nuclear migration of RORα protein in PN mouse livers. This study shows that continuous PN infusion with SOLE in mice leads to dysregulation of BA homeostasis. Alterations of liver RORα signaling in PN mice may be one of the mechanisms implicated in the pathogenesis of PNALD. PMID:26564717

  5. Development of A Mouse Model of Menopausal Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Smith

    2014-02-01

    Full Text Available Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; questions of the cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology.A potentially useful model is the germ cell-deficient Wv (white spotting variant mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation. Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer.Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.

  6. Animal Models in Autoimmune Diseases: Lessons Learned from Mouse Models for Sjögren’s Syndrome

    OpenAIRE

    Lee, Byung Ha; Gauna, Adrienne E.; Pauley, Kaleb M; Park, Yun-Jong; Cha, Seunghee

    2012-01-01

    The mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidate underlying causes of multi-factorial autoimmune conditions, including pathological immune components and specific signaling pathways. This review summarizes the more recent mouse models for Sjögren’s syndrome, a systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine ...

  7. PET/CT Imaging in Mouse Models of Myocardial Ischemia

    Directory of Open Access Journals (Sweden)

    Sara Gargiulo

    2012-01-01

    Full Text Available Different species have been used to reproduce myocardial infarction models but in the last years mice became the animals of choice for the analysis of several diseases, due to their short life cycle and the possibility of genetic manipulation. Many techniques are currently used for cardiovascular imaging in mice, including X-ray computed tomography (CT, high-resolution ultrasound, magnetic resonance imaging, and nuclear medicine procedures. Cardiac positron emission tomography (PET allows to examine noninvasively, on a molecular level and with high sensitivity, regional changes in myocardial perfusion, metabolism, apoptosis, inflammation, and gene expression or to measure changes in anatomical and functional parameters in heart diseases. Currently hybrid PET/CT scanners for small laboratory animals are available, where CT adds high-resolution anatomical information. This paper reviews mouse models of myocardial infarction and discusses the applications of dedicated PET/CT systems technology, including animal preparation, anesthesia, radiotracers, and images postprocessing.

  8. Effect of exercise on retrograde transport in a mouse model of amyotrophic lateral sclerosis

    OpenAIRE

    Whitney, Darryl Campbell

    2007-01-01

    The potential for exercise to improve function and delay disease progression in a mouse model of amyotrophic lateral sclerosis (ALS) has been examined in some detail. Recent studies have shown that retrograde transport is diminished throughout disease progression in this mouse model. The finding that exercise plus viral delivery of IGF-1 significantly improves lifespan of the G93A transgenic mouse highlights the need to investigate the mechanisms by which exercise may alter factors associated...

  9. Chemical and statistical soot modeling

    OpenAIRE

    Blanquart, Guillaume

    2008-01-01

    The combustion of petroleum based fuels like kerosene, gasoline, or diesel leads to the formation of several kind of pollutants. Among them, soot particles are particularly bad for their severe consequences on human health. Over the past decades, strict regulations have been placed on car and aircraft engines in order to limit these particulate matter emissions. Designing low emission engines requires the use of predictive soot models which can be applied to the combustion of real fuels. ...

  10. Toluene diisocyanate and methylene diphenyl diisocyanate: asthmatic response and cross-reactivity in a mouse model.

    Science.gov (United States)

    Pollaris, Lore; Devos, Fien; De Vooght, Vanessa; Seys, Sven; Nemery, Benoit; Hoet, Peter H M; Vanoirbeek, Jeroen A J

    2016-07-01

    Both 2,4-toluene diisocyanate (TDI) and 4,4-methylene diphenyl diisocyanate (MDI) can cause occupational asthma. In this study, we optimized our mouse model of chemical-induced asthma in the C57Bl/6 mice strain using the model agent TDI. Furthermore, we validated MDI in this mouse model and investigated whether cross-reactivity between TDI and MDI is present. On days 1 and 8, C57Bl/6 mice were dermally treated (20 µl/ear) with 3 % MDI, 2 % TDI or the vehicle acetone olive oil (AOO) (3:2). On day 15, they received a single oropharyngeal challenge with 0.04 % MDI, 0.01 % TDI or the vehicle AOO (4:1). One day later, airway hyperreactivity (AHR) and pulmonary inflammation in the bronchoalveolar lavage (BAL) were assessed. Furthermore, total serum IgE levels, lymphocyte subpopulations in auricular lymph nodes and cytokine levels in supernatants of lymphocytes were measured. Both dermal sensitization with TDI or MDI resulted in increased total serum IgE levels along with T and B cell proliferation in the auricular lymph nodes. The auricular lymphocytes showed an increased release of both Th2 and Th1 cytokines. Mice sensitized and challenged with either TDI or MDI showed AHR, along with a predominant neutrophil lung inflammation. Mice sensitized with MDI and challenged with TDI or the other way around showed no AHR, nor BAL inflammation. Both TDI and MDI are able to induce an asthma-like response in this mouse model. However, cross-reactivity between both diisocyanates remained absent. PMID:26468151

  11. Learning delays in a mouse model of Autism Spectrum Disorder.

    Science.gov (United States)

    Rendall, Amanda R; Truong, Dongnhu T; Fitch, R Holly

    2016-04-15

    Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder with core symptoms of atypical social interactions and repetitive behaviors. It has also been reported that individuals with ASD have difficulty with multisensory integration, and this may disrupt higher-order cognitive abilities such as learning and social communication. Impairments in the integration of sensory information could in turn reflect diminished cross-modal white matter connectivity. Moreover, the genetic contribution in ASD appears to be strong, with heritability estimates as high as 90%. However, no single gene has been identified, and over 1000 risk genes have been reported. One of these genes - contactin-associated-like-protein 2 (CNTNAP2) - was first associated with Specific Language Impairment, and more recently has been linked to ASD. CNTNAP2 encodes a cell adhesion protein regulating synaptic signal transmission. To better understand the behavioral and biological underlying mechanisms of ASD, a transgenic mouse model was created with a genetic knockout (KO) of the rodent homolog Cntnap2. Initial studies on this mouse revealed poor social interactions, behavioral perseveration, and reduced vocalizations-all strongly resembling human ASD symptoms. Cntnap2 KO mice also show abnormalities in myelin formation, consistent with a hypo-connectivity model of ASD. The current study was designed to further assess the behavioral phenotype of this mouse model, with a focus on learning and memory. Cntnap2 KO and wild-type mice were tested on a 4/8 radial arm water maze for 14 consecutive days. Error scores (total, working memory, reference memory, initial and repeated reference memory), latency and average turn angle were independently assessed using a 2×14 repeated measures ANOVA. Results showed that Cntnap2 KO mice exhibited significant deficits in working and reference memory during the acquisition period of the task. During the retention period (i.e., after asymptote in errors

  12. A Neonatal Mouse Spinal Cord Compression Injury Model.

    Science.gov (United States)

    Züchner, Mark; Glover, Joel C; Boulland, Jean-Luc

    2016-01-01

    Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life(1), this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques(1). Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections(1). PMID:27078037

  13. Mathematical modeling a chemical engineer's perspective

    CERN Document Server

    Rutherford, Aris

    1999-01-01

    Mathematical modeling is the art and craft of building a system of equations that is both sufficiently complex to do justice to physical reality and sufficiently simple to give real insight into the situation. Mathematical Modeling: A Chemical Engineer's Perspective provides an elementary introduction to the craft by one of the century's most distinguished practitioners.Though the book is written from a chemical engineering viewpoint, the principles and pitfalls are common to all mathematical modeling of physical systems. Seventeen of the author's frequently cited papers are reprinted to illus

  14. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Han-yu Dong

    2016-01-01

    Full Text Available To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position, prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds, and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

  15. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy.

    Science.gov (United States)

    Dong, Han-Yu; Jiang, Xin-Mei; Niu, Chun-Bo; Du, Lin; Feng, Jun-Yan; Jia, Fei-Yong

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus. PMID:26981106

  16. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

    Science.gov (United States)

    Dong, Han-yu; Jiang, Xin-mei; Niu, Chun-bo; Du, Lin; Feng, Jun-yan; Jia, Fei-yong

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus. PMID:26981106

  17. Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

    Institute of Scientific and Technical Information of China (English)

    Han-yu Dong; Xin-mei Jiang; Chun-bo Niu; Lin Du; Jun-yan Feng; Fei-yong Jia

    2016-01-01

    To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

  18. In Vivo Fluorescence Reflectance Imaging with Subcutaneous Mouse Tumor Models.

    Science.gov (United States)

    Cao, Jie; Zhou, Mingzhou

    2016-01-01

    Optical imaging is undoubtedly one of the most versatile and widely used imaging techniques in both research and clinical practice. Among optical imaging technologies, fluorescence imaging is the most popularly used and has become an essential tool in biomedical science. A key component of fluorescence imaging is fluorescence-producing reporters, including fluorescent dyes and conjugates, as well as fluorescent proteins. For in vivo imaging applications, fluorophores with long emission at the near-infrared (NIR) region are generally preferred to overcome the photon attenuation in living tissue. Here, we describe the in vivo fluorescence imaging of an integrin αυβ3 targeted NIR fluorescent probe (cRGD-ICG-Der-02) using subcutaneous mouse tumor models. PMID:27283414

  19. Lessons Learned from Mouse Mammary Tumor Virus in Animal Models.

    Science.gov (United States)

    Dudley, Jaquelin P; Golovkina, Tatyana V; Ross, Susan R

    2016-03-31

    Mouse mammary tumor virus (MMTV), which was discovered as a milk-transmitted, infectious, cancer-inducing agent in the 1930s, has been used as an animal model for the study of retroviral infection and transmission, antiviral immune responses, and breast cancer and lymphoma biology. The main target cells for MMTV infection in vivo are cells of the immune system and mammary epithelial cells. Although the host mounts an immune response to the virus, MMTV has evolved multiple means of evading this response. MMTV causes mammary tumors when the provirus integrates into the mammary epithelial and lymphoid cell genome during viral replication and thereby activates cellular oncogene expression. Thus, tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer. PMID:27034391

  20. UV-induced skin cancer in a hairless mouse model.

    Science.gov (United States)

    de Gruijl, F R; Forbes, P D

    1995-07-01

    Ultraviolet (UV) radiation is a very common carcinogen in our environment, but epidemiological data on the relationship between skin cancers and ambient solar UV radiation are very restricted. In hairless mice the process of UV carcinogenesis can be studied in depth. Experiments with this animal model have yielded quantitative data on how tumor development depends on dose, time and wavelength of the UV radiation. In combination with epidemiological data, these experimental results can be transposed to humans. Comparative studies on molecular, cellular and physiological changes in mouse and man can further our fundamental understanding of UV carcinogenesis in man. This is likely to improve risk assessments such as those related to stratospheric ozone depletion, and to yield well-targeted intervention schemes, e.g. prescribing a specific drug or diet, for high-risk individuals. PMID:7646487

  1. Neuroprotection in a novel mouse model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Katie Lidster

    Full Text Available Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment.

  2. Stochastic model of Tsc1 lesions in mouse brain.

    Directory of Open Access Journals (Sweden)

    Shilpa Prabhakar

    Full Text Available Tuberous sclerosis complex (TSC is an autosomal dominant disorder due to mutations in either TSC1 or TSC2 that affects many organs with hamartomas and tumors. TSC-associated brain lesions include subependymal nodules, subependymal giant cell astrocytomas and tubers. Neurologic manifestations in TSC comprise a high frequency of mental retardation and developmental disorders including autism, as well as epilepsy. Here, we describe a new mouse model of TSC brain lesions in which complete loss of Tsc1 is achieved in multiple brain cell types in a stochastic pattern. Injection of an adeno-associated virus vector encoding Cre recombinase into the cerebral ventricles of mice homozygous for a Tsc1 conditional allele on the day of birth led to reduced survival, and pathologic findings of enlarged neurons, cortical heterotopias, subependymal nodules, and hydrocephalus. The severity of clinical and pathologic findings as well as survival was shown to be dependent upon the dose and serotype of Cre virus injected. Although several other models of TSC brain disease exist, this model is unique in that the pathology reflects a variety of TSC-associated lesions involving different numbers and types of cells. This model provides a valuable and unique addition for therapeutic assessment.

  3. A STAT-1 knockout mouse model for Machupo virus pathogenesis

    Directory of Open Access Journals (Sweden)

    Shurtleff Amy C

    2011-06-01

    Full Text Available Abstract Background Machupo virus (MACV, a member of the Arenaviridae, causes Bolivian hemorrhagic fever, with ~20% lethality in humans. The pathogenesis of MACV infection is poorly understood, and there are no clinically proven treatments for disease. This is due, in part, to a paucity of small animal models for MACV infection in which to discover and explore candidate therapeutics. Methods Mice lacking signal transducer and activator of transcription 1 (STAT-1 were infected with MACV. Lethality, viral replication, metabolic changes, hematology, histopathology, and systemic cytokine expression were analyzed throughout the course of infection. Results We report here that STAT-1 knockout mice succumbed to MACV infection within 7-8 days, and presented some relevant clinical and histopathological manifestations of disease. Furthermore, the model was used to validate the efficacy of ribavirin in protection against infection. Conclusions The STAT-1 knockout mouse model can be a useful small animal model for drug testing and preliminary immunological analysis of lethal MACV infection.

  4. Automatic Segmentation Framework of Building Anatomical Mouse Model for Bioluminescence Tomography

    OpenAIRE

    Abdullah Alali

    2013-01-01

    Bioluminescence tomography is known as a highly ill-posed inverse problem. To improve the reconstruction performance by introducing anatomical structures as a priori knowledge, an automatic segmentation framework has been proposed in this paper to extract the mouse whole-body organs and tissues, which enables to build up a heterogeneous mouse model for reconstruction of bioluminescence tomography. Finally, an in vivo mouse experiment has been conducted to evaluate this framework by using an X...

  5. Combining Human Disease Genetics and Mouse Model Phenotypes towards Drug Repositioning for Parkinson’s disease

    OpenAIRE

    Chen, Yang; Cai, Xiaoshu; Xu, Rong

    2015-01-01

    Parkinson’s disease (PD) is a severe neurodegenerative disorder without effective treatments. Here, we present a novel drug repositioning approach to predict new drugs for PD leveraging both disease genetics and large amounts of mouse model phenotypes. First, we identified PD-specific mouse phenotypes using well-studied human disease genes. Then we searched all FDA-approved drugs for candidates that share similar mouse phenotype profiles with PD. We demonstrated the validity of our approach u...

  6. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells

    OpenAIRE

    Garabedian, Emily M.; Humphrey, Peter A.; Jeffrey I Gordon

    1998-01-01

    A transgenic mouse model of metastatic prostate cancer has been developed that is 100% penetrant in multiple pedigrees. Nucleotides −6500 to +34 of the mouse cryptdin-2 gene were used to direct expression of simian virus 40 T antigen to a subset of neuroendocrine cells in all lobes of the FVB/N mouse prostate. Transgene expression is initiated between 7 and 8 weeks of age and leads to development of prostatic intraepithelial neoplasia within a week. Prostatic intraepithelial neoplasia progres...

  7. Sleep phenotyping in a mouse model of extreme trait anxiety.

    Directory of Open Access Journals (Sweden)

    Vladimira Jakubcakova

    Full Text Available BACKGROUND: There is accumulating evidence that anxiety impairs sleep. However, due to high sleep variability in anxiety disorders, it has been difficult to state particular changes in sleep parameters caused by anxiety. Sleep profiling in an animal model with extremely high vs. low levels of trait anxiety might serve to further define sleep patterns associated with this psychopathology. METHODOLOGY/PRINCIPAL FINDINGS: Sleep-wake behavior in mouse lines with high (HAB, low (LAB and normal (NAB anxiety-related behaviors was monitored for 24 h during baseline and recovery after 6 h sleep deprivation (SD. The amounts of each vigilance state, sleep architecture, and EEG spectral variations were compared between the mouse lines. In comparison to NAB mice, HAB mice slept more and exhibited consistently increased delta power during non-rapid eye movement (NREM sleep. Their sleep patterns were characterized by heavy fragmentation, reduced maintenance of wakefulness, and frequent intrusions of rapid eye movement (REM sleep. In contrast, LAB mice showed a robust sleep-wake rhythm with remarkably prolonged sleep latency and a long, persistent period of wakefulness. In addition, the accumulation of delta power after SD was impaired in the LAB line, as compared to HAB mice. CONCLUSIONS/SIGNIFICANCE: Sleep-wake patterns were significantly different between HAB and LAB mice, indicating that the genetic predisposition to extremes in trait anxiety leaves a biological scar on sleep quality. The enhanced sleep demand observed in HAB mice, with a strong drive toward REM sleep, may resemble a unique phenotype reflecting not only elevated anxiety but also a depression-like attribute.

  8. Nucleotide excision repair- and p53-deficient mouse models in cancer research

    Energy Technology Data Exchange (ETDEWEB)

    Hoogervorst, Esther M. [Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (Netherlands); Utrecht University, Department of Pathobiology, Utrecht (Netherlands); Steeg, Harry van [Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (Netherlands); Vries, Annemieke de [Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (Netherlands)]. E-mail: Annemieke.de.Vries@rivm.nl

    2005-07-01

    Cancer is caused by the loss of controlled cell growth due to mutational (in)activation of critical genes known to be involved in cell cycle regulation. Three main mechanisms are known to be involved in the prevention of cells from becoming cancerous; DNA repair and cell cycle control, important to remove DNA damage before it will be fixed into mutations and apoptosis, resulting in the elimination of cells containing severe DNA damage. Several human syndromes are known to have (partially) deficiencies in these pathways, and are therefore highly cancer prone. Examples are xeroderma pigmentosum (XP) caused by an inborn defect in the nucleotide excision repair (NER) pathway and the Li-Fraumeni syndrome, which is the result of a germ line mutation in the p53 gene. XP patients develop skin cancer on sun exposed areas at a relatively early age, whereas Li-Fraumeni patients spontaneously develop a wide variety of early onset tumors, including sarcomas, leukemia's and mammary gland carcinomas. Several mouse models have been generated to mimic these human syndromes, providing us information about the role of these particular gene defects in the tumorigenesis process. In this review, spontaneous phenotypes of mice deficient for nucleotide excision repair and/or the p53 gene will be described, together with their responses upon exposure to either chemical carcinogens or radiation. Furthermore, possible applications of these and newly generated mouse models for cancer will be given.

  9. Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis

    International Nuclear Information System (INIS)

    Immunohistochemical methods have been widely used to determine the histogenesis of spontaneous and chemically-induced mouse lung tumors. Typically, antigens for either alveolar Type II cells or bronchiolar epithelial Clara cells are studied. In the present work, the morphological and immunohistochemical phenotype of a transgenic mouse designed to develop lung tumors arising from Clara cells was evaluated. In this model, Clara cell-specific transformation is accomplished by directed expression of the SV40 large T antigen (TAg) under the mouse Clara cell secretory protein (CC10) promoter. In heterozygous mice, early lesions at 1 month of age consisted of hyperplastic bronchiolar epithelial cells. These progressed to adenoma by 2 months as proliferating epithelium extended into adjacent alveolar spaces. By 4 months, a large portion of the lung parenchyma was composed of tumor masses. Expression of constitutive CC10 was diminished in transgenic animals at all time points. Only the occasional cell or segment of the bronchiolar epithelium stained positively for CC10 by immunohistochemistry, and all tumors were found to be uniformly negative for staining. These results were corroborated by Western blotting, where CC10 was readily detectable in whole lung homogenate from nontransgenic animals, but not detected in lung from transgenic animals at any time point. Tumors were also examined for expression of surfactant apoprotein C (SPC), an alveolar Type II cell-specific marker, and found to be uniformly negative for staining. These results indicate that, in this transgenic model, expression of CC10, which is widely used to determine whether lung tumors arise from Clara cells, was reduced and subsequently lost during Clara cell tumor progression

  10. Chemical Kinetic Modeling of 2-Methylhexane Combustion

    KAUST Repository

    Mohamed, Samah Y.

    2015-03-30

    Accurate chemical kinetic combustion models of lightly branched alkanes (e.g., 2-methylalkanes) are important for investigating the combustion behavior of diesel, gasoline, and aviation fuels. Improving the fidelity of existing kinetic models is a necessity, as new experiments and advanced theories show inaccuracy in certain portions of the models. This study focuses on updating thermodynamic data and kinetic model for a gasoline surrogate fuel, 2-methylhexane, with recently published group values and rate rules. These update provides a better agreement with rapid compression machine measurements of ignition delay time, while also strengthening the fundamental basis of the model.

  11. A mouse model for HBV immunotolerance and immunotherapy.

    Science.gov (United States)

    Yang, Dan; Liu, Longchao; Zhu, Danming; Peng, Hua; Su, Lishan; Fu, Yang-Xin; Zhang, Liguo

    2014-01-01

    Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections. PMID:24076617

  12. Photodynamic therapy of oral Candida infection in a mouse model.

    Science.gov (United States)

    Freire, Fernanda; Ferraresi, Cleber; Jorge, Antonio Olavo C; Hamblin, Michael R

    2016-06-01

    Species of the fungal genus Candida, can cause oral candidiasis especially in immunosuppressed patients. Many studies have investigated the use of photodynamic therapy (PDT) to kill fungi in vitro, but this approach has seldom been reported in animal models of infection. This study investigated the effects of PDT on Candida albicans as biofilms grown in vitro and also in an immunosuppressed mouse model of oral candidiasis infection. We used a luciferase-expressing strain that allowed non-invasive monitoring of the infection by bioluminescence imaging. The phenothiazinium salts, methylene blue (MB) and new methylene blue (NMB) were used as photosensitizers (PS), combined or not with potassium iodide (KI), and red laser (660nm) at four different light doses (10J, 20J, 40J and 60J). The best in vitro log reduction of CFU/ml on biofilm grown cells was: MB plus KI with 40J (2.31 log; p<0.001); and NMB without KI with 60J (1.77 log; p<0.001). These conditions were chosen for treating the in vivo model of oral Candida infection. After 5days of treatment the disease was practically eradicated, especially using MB plus KI with 40J. This study suggests that KI can potentiate PDT of fungal infection using MB (but not NMB) and could be a promising new approach for the treatment of oral candidiasis. PMID:27074245

  13. Debridement increases survival in a mouse model of subcutaneous anthrax.

    Directory of Open Access Journals (Sweden)

    Zachary P Weiner

    Full Text Available Anthrax is caused by infection with Bacillus anthracis, a spore-forming gram-positive bacterium. A major virulence factor for B. anthracis is an immunomodulatory tripartite exotoxin that has been reported to alter immune cell chemotaxis and activation. It has been proposed that B. anthracis infections initiate through entry of spores into the regional draining lymph nodes where they germinate, grow, and disseminate systemically via the efferent lymphatics. If this model holds true, it would be predicted that surgical removal of infected tissues, debridement, would have little effect on the systemic dissemination of bacteria. This model was tested through the development of a mouse debridement model. It was found that removal of the site of subcutaneous infection in the ear increased the likelihood of survival and reduced the quantity of spores in the draining cervical lymph nodes (cLN. At the time of debridement 12 hours post-injection measurable levels of exotoxins were present in the ear, cLN, and serum, yet leukocytes within the cLN were activated; countering the concept that exotoxins inhibit the early inflammatory response to promote bacterial growth. We conclude that the initial entry of spores into the draining lymph node of cutaneous infections alone is not sufficient to cause systemic disease and that debridement should be considered as an adjunct to antibiotic therapy.

  14. Chemical uncertainties in modeling hot Jupiters atmospheres

    Science.gov (United States)

    Hebrard, Eric; Domagal-Goldman, Shawn

    2015-11-01

    Most predictions and interpretations of observations in beyond our Solar System have occurred through the use of 1D photo-thermo-chemical models. Their predicted atmospheric compositions are highly dependent on model parameters. Chemical reactions are based on empirical parameters that must be known at temperatures ranging from 100 K to above 2500 K and at pressures from millibars to hundreds of bars. Obtained from experiments, calculations and educated-guessed estimations, these parameters are always evaluated with substantial uncertainties. However, although of practical use, few models of exoplanetary atmospheres have considered these underlying chemical uncertainties and their consequences. Recent progress has been made recently that allow us to (1) evaluate the accuracy and precision of 1D models of planetary atmospheres, with quantifiable uncertainties on their predictions for the atmospheric composition and associated spectral features, (2) identify the ‘key parameters’ that contribute the most to the models predictivity and should therefore require further experimental or theoretical analysis, (3) reduce and optimize complex chemical networks for their inclusion in multidimensional atmospheric models.First, a global sampling approach based on low discrepancy sequences has been applied in order to propose error bars on simulations of the atmospheres HD 209458b and HD 189733b, using a detailed kinetic model derived from applied combustion models that was methodically validated over a range of temperatures and pressures typical for these hot Jupiters. A two-parameters temperature-dependent uncertainty factor has been assigned to each considered rate constant. Second, a global sensitivity approach based on high dimensional model representations (HDMR) has been applied in order to identify those reactions which make the largest contributions to the overall uncertainty of the simulated results. The HDMR analysis has been restricted to the most important

  15. Multimodality pH imaging in a mouse dorsal skin fold window chamber model

    Science.gov (United States)

    Leung, Hui Min; Schafer, Rachel; Pagel, Mark M.; Robey, Ian F.; Gmitro, Arthur F.

    2013-03-01

    Upregulate levels of expression and activity of membrane H+ ion pumps in cancer cells drives the extracellular pH (pHe,) to values lower than normal. Furthermore, disregulated pH is indicative of the changes in glycolytic metabolism in tumor cells and has been shown to facilitate extracellular tissue remodeling during metastasis Therefore, measurement of pHe could be a useful cancer biomarker for diagnostic and therapy monitoring evaluation. Multimodality in-vivo imaging of pHe in tumorous tissue in a mouse dorsal skin fold window chamber (DSFWC) model is described. A custom-made plastic window chamber structure was developed that is compatible with both imaging optical and MR imaging modalities and provides a model system for continuous study of the same tissue microenvironment on multiple imaging platforms over a 3-week period. For optical imaging of pHe, SNARF-1 carboxylic acid is injected intravenously into a SCID mouse with an implanted tumor. A ratiometric measurement of the fluorescence signal captured on a confocal microscope reveals the pHe of the tissue visible within the window chamber. This imaging method was used in a preliminary study to evaluate sodium bicarbonate as a potential drug treatment to reverse tissue acidosis. For MR imaging of pHe the chemical exchange saturation transfer (CEST) was used as an alternative way of measuring pHe in a DSFWC model. ULTRAVIST®, a FDA approved x-ray/CT contrast agent has been shown to have a CEST effect that is pH dependent. A ratiometric analysis of water saturation at 5.6 and 4.2 ppm chemical shift provides a means to estimate the local pHe.

  16. In-Space Chemical Propulsion System Model

    Science.gov (United States)

    Byers, David C.; Woodcock, Gordon; Benfield, Michael P. J.

    2004-01-01

    Multiple, new technologies for chemical systems are becoming available and include high temperature rockets, very light propellant tanks and structures, new bipropellant and monopropellant options, lower mass propellant control components, and zero boil off subsystems. Such technologies offer promise of increasing the performance of in-space chemical propulsion for energetic space missions. A mass model for pressure-fed, Earth and space-storable, advanced chemical propulsion systems (ACPS) was developed in support of the NASA MSFC In-Space Propulsion Program. Data from flight systems and studies defined baseline system architectures and subsystems and analyses were formulated for parametric scaling relationships for all ACPS subsystem. The paper will first provide summary descriptions of the approaches used for the systems and the subsystems and then present selected analyses to illustrate use of the model for missions with characteristics of current interest.

  17. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

    Science.gov (United States)

    Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

    2015-07-15

    Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path

  18. Single-Dose Radiation-Induced Oral Mucositis Mouse Model

    Science.gov (United States)

    Maria, Osama Muhammad; Syme, Alasdair; Eliopoulos, Nicoletta; Muanza, Thierry

    2016-01-01

    The generation of a self-resolved radiation-induced oral mucositis (RIOM) mouse model using the highest possibly tolerable single ionizing radiation (RT) dose was needed in order to study RIOM management solutions. We used 10-week-old male BALB/c mice with average weight of 23 g for model production. Mice were treated with an orthovoltage X-ray irradiator to induce the RIOM ulceration at the intermolar eminence of the animal tongue. General anesthesia was injected intraperitoneally for proper animal immobilization during the procedure. Ten days after irradiation, a single RT dose of 10, 15, 18, 20, and 25 Gy generated a RIOM ulcer at the intermolar eminence (posterior upper tongue surface) with mean ulcer floor (posterior epithelium) heights of 190, 150, 25, 10, and 10 μm, respectively, compared to 200 μm in non-irradiated animals. The mean RIOM ulcer size % of the total epithelialized upper surface of the animal tongue was RT dose dependent. At day 10, the ulcer size % was 2, 5, 27, and 31% for 15, 18, 20, and 25 Gy RT, respectively. The mean relative surface area of the total epithelialized upper surface of the tongue was RT dose dependent, since it was significantly decreased to 97, 95, 88, and 38% with 15, 18, 20, and 25 Gy doses, respectively, at day 10 after RT. Subcutaneous injection of 1 mL of 0.9% saline/6 h for 24 h yielded a 100% survival only with 18 Gy self-resolved RIOM, which had 5.6 ± 0.3 days ulcer duration. In conclusion, we have generated a 100% survival self-resolved single-dose RIOM male mouse model with long enough duration for application in RIOM management research. Oral mucositis ulceration was radiation dose dependent. Sufficient hydration of animals after radiation exposure significantly improved their survival. PMID:27446800

  19. Mechanistically distinct mouse models for CRX-associated retinopathy.

    Directory of Open Access Journals (Sweden)

    Nicholas M Tran

    2014-02-01

    Full Text Available Cone-rod homeobox (CRX protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP, Cone-Rod Dystrophy (CoRD and Leber Congenital Amaurosis (LCA, with variable severity. Heterozygous Crx Knock-Out (KO mice ("+/-" have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN mouse models: Crx(E168d2 ("E168d2" and Crx(R90W ("R90W". E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 ("E168d2/+" but not R90W ("R90W/+" mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/- mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX([E168d2] and CRX([R90W] proteins fail to activate transcription in vitro, but CRX([E168d2] interferes more strongly with the function of wild type (WT CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of novel

  20. Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing

    OpenAIRE

    Besaratinia, Ahmad; Pfeifer, Gerd P

    2010-01-01

    Tumor-driving mutations in the TP53 gene occur frequently in human cancers. These inactivating mutations arise predominantly from a single-point mutation in the DNA-binding domain of this tumor suppressor gene (i.e., exons 4–9). The human p53 knock-in (Hupki) mouse model was constructed using gene-targeting technology to create a mouse strain that harbors human wild-type TP53 DNA sequences in both copies of the mouse TP53 gene. Replacement of exons 4–9 of the endogenous mouse TP53 alleles in ...

  1. Modelling Chemical Reasoning to Predict Reactions

    CERN Document Server

    Segler, Marwin H S

    2016-01-01

    The ability to reason beyond established knowledge allows Organic Chemists to solve synthetic problems and to invent novel transformations. Here, we propose a model which mimics chemical reasoning and formalises reaction prediction as finding missing links in a knowledge graph. We have constructed a knowledge graph containing 14.4 million molecules and 8.2 million binary reactions, which represents the bulk of all chemical reactions ever published in the scientific literature. Our model outperforms a rule-based expert system in the reaction prediction task for 180,000 randomly selected binary reactions. We show that our data-driven model generalises even beyond known reaction types, and is thus capable of effectively (re-) discovering novel transformations (even including transition-metal catalysed reactions). Our model enables computers to infer hypotheses about reactivity and reactions by only considering the intrinsic local structure of the graph, and because each single reaction prediction is typically ac...

  2. Chemical and Hydrodynamical Models of Cometary Comae

    Science.gov (United States)

    Charnley, Steven

    2012-01-01

    Multi-fluid modelling of the outflowing gases which sublimate from cometary nuclei as they approach the Sun is necessary for understanding the important physical and chemical processes occurring in this complex plasma. Coma chemistry models can be employed to interpret observational data and to ultimately determine chemical composition and structure of the nuclear ices and dust. We describe a combined chemical and hydrodynamical model [1] in which differential equations for the chemical abundances and the energy balance are solved as a function of distance from the cometary nucleus. The presence of negative ions (anions) in cometary comae is known from Giotto mass spectrometry of 1P/Halley. The anions O(-), OH(-), C(-), CH(-) and CN(-) have been detected, as well as unidentified anions with masses 22-65 and 85-110 amu [2]. Organic molecular anions such as C4H(-) and C6H(-) are known to have a significant impact on the charge balance of interstellar clouds and circumstellar envelopes and have been shown to act as catalysts for the gas-phase synthesis of larger hydrocarbon molecules in the ISM, but their importance in cometary comae has not yet been fully explored. We present details of new models for the chemistry of cometary comae that include atomic and molecular anions and calculate the impact of these anions on the coma physics and chemistry af the coma.

  3. Using chemical organization theory for model checking

    OpenAIRE

    Kaleta, Christoph; Richter, Stephan; Dittrich, Peter

    2009-01-01

    Motivation: The increasing number and complexity of biomodels makes automatic procedures for checking the models' properties and quality necessary. Approaches like elementary mode analysis, flux balance analysis, deficiency analysis and chemical organization theory (OT) require only the stoichiometric structure of the reaction network for derivation of valuable information. In formalisms like Systems Biology Markup Language (SBML), however, information about the stoichiometric coefficients re...

  4. Predicting carcinogenicity of diverse chemicals using probabilistic neural network modeling approaches

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com [Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research, New Delhi (India); Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India); Gupta, Shikha; Rai, Premanjali [Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research, New Delhi (India); Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India)

    2013-10-15

    Robust global models capable of discriminating positive and non-positive carcinogens; and predicting carcinogenic potency of chemicals in rodents were developed. The dataset of 834 structurally diverse chemicals extracted from Carcinogenic Potency Database (CPDB) was used which contained 466 positive and 368 non-positive carcinogens. Twelve non-quantum mechanical molecular descriptors were derived. Structural diversity of the chemicals and nonlinearity in the data were evaluated using Tanimoto similarity index and Brock–Dechert–Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) models were constructed for classification and function optimization problems using the carcinogenicity end point in rat. Validation of the models was performed using the internal and external procedures employing a wide series of statistical checks. PNN constructed using five descriptors rendered classification accuracy of 92.09% in complete rat data. The PNN model rendered classification accuracies of 91.77%, 80.70% and 92.08% in mouse, hamster and pesticide data, respectively. The GRNN constructed with nine descriptors yielded correlation coefficient of 0.896 between the measured and predicted carcinogenic potency with mean squared error (MSE) of 0.44 in complete rat data. The rat carcinogenicity model (GRNN) applied to the mouse and hamster data yielded correlation coefficient and MSE of 0.758, 0.71 and 0.760, 0.46, respectively. The results suggest for wide applicability of the inter-species models in predicting carcinogenic potency of chemicals. Both the PNN and GRNN (inter-species) models constructed here can be useful tools in predicting the carcinogenicity of new chemicals for regulatory purposes. - Graphical abstract: Figure (a) shows classification accuracies (positive and non-positive carcinogens) in rat, mouse, hamster, and pesticide data yielded by optimal PNN model. Figure (b) shows generalization and predictive

  5. Cardiac Dysfunction in the BACHD Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Analyne M Schroeder

    Full Text Available While Huntington's disease (HD is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3 months of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis and ultimately apoptosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol treatment; however, the medication exacerbated fibrotic lesions in the heart. Gene expression analysis indicated a strong tilt toward apoptosis in the young mutant heart as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the large changes occurring in the cardiovascular disease, cellular metabolism, and cellular transport clusters. The BACHD model of HD exhibits a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher cardiovascular risk in HD.

  6. Dermal lymphatic dilation in a mouse model of alopecia areata.

    Science.gov (United States)

    Sundberg, John P; Pratt, C Herbert; Silva, Kathleen A; Kennedy, Victoria E; Stearns, Timothy M; Sundberg, Beth A; King, Lloyd E; HogenEsch, Harm

    2016-04-01

    Mouse models of various types of inflammatory skin disease are often accompanied by increased dermal angiogenesis. The C3H/HeJ inbred strain spontaneously develops alopecia areata (AA), a cell mediated autoimmune disorder that can be controllably expanded using full thickness skin grafts to young unaffected mice. This provides a reproducible and progressive model for AA in which the vascularization of the skin can be examined. Mice receiving skin grafts from AA or normal mice were evaluated at 5, 10, 15, and 20weeks after engraftment. Lymphatics are often overlooked as they are small slit-like structures above the hair follicle that resemble artifact-like separation of collagen bundles with some fixatives. Lymphatics are easily detected using lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) by immunohistochemistry to label their endothelial cells. Using LYVE1, there were no changes in distribution or numbers of lymphatics although they were more prominent (dilated) in the mice with AA. Lyve1 transcripts were not significantly upregulated except at 10weeks after skin grafting when clinical signs of AA first become apparent. Other genes involved with vascular growth and dilation or movement of immune cells were dysregulated, mostly upregulated. These findings emphasize aspects of AA not commonly considered and provide potential targets for therapeutic intervention. PMID:26960166

  7. Development of a Nongenetic Mouse Model of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Gilbert

    2011-01-01

    Full Text Available Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D. The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1 low-fat diet (LFD; low-fat control; LFC, (2 LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ injection, (3, (4, (5, (6 LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7 high-fat diet (HFD, (8 HFD with 1 STZ injection, (9, (10, (11, (12 HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

  8. The tumor suppressor kinase LKB1: lessons from mouse models

    Institute of Scientific and Technical Information of China (English)

    Saara Ollila; Tomi P. M(a)kel(a)

    2011-01-01

    Mutations in the tumor suppressor gene LKB1 are important in hereditary Peutz-Jeghers syndrome,as well as in sporadic cancers including lung and cervical cancer.LKB1 is a kinase-activating Kinase,and a number of LKB1-dependent phosphorylation cascades regulate fundamental cellular and organismal processes in at least metabolism,polarity,cytoskeleton organization,and proliferation.Conditional targeting approaches are beginning to demonstrate the relevance and specificity of these signaling pathways in development and homeostasis of multiple organs.More than one of the pathways also appear to contribute to tumor growth following Lkb1 deficiencies based on a number of mouse tumor models.Lkb1-dependent activation of AMPK and subsequent inactivation of mammalian target of rapamycin signaling are implicated in several of the models,and other less well characterized pathways are also involved.Conditional targeting studies of Lkb1 also point an important role of LKB1 in epithelial-masenchymal interactions,significantly expanding knowledge on the relevance of LKB1 in human disease.

  9. Reproductive Phenotypes of Mouse Models Illuminate Human Infertility

    Directory of Open Access Journals (Sweden)

    Adelfalk C

    2011-01-01

    Full Text Available Infertility represents a significant health problem in industrialized nations because reproductive activity is increasingly delayed and couples face a risk of impaired fetal health at advanced maternal age (35 years. Furthermore, approx. fifteen percent of couples have difficulties to conceive within a year of unprotected intercourse. Reduced reproductive success often relates to a defective meiotic process that would normally lead to formation of ova and sperm. The understanding of the mechanisms of meiosis and fertility has largely benefitted from knockout and transgenic mouse models that display a fertility phenotype. Using information from meiosis-deficient mice has impacted on the diagnosis of infertility of unknown origin of human patients. In this paper we discuss insights gained in the etiology of infertility by looking at murine genetic models with a reproductive phenotype due to disruptions in genes acting during meiotic prophase. We focus on genes that are important for recombinational DNA repair, meiotic chromosome structure and reproductive aging and will compare these phenotypes to human conditions with reproductive impairmen

  10. Lung Cancer Signatures in Plasma Based on Proteome Profiling of Mouse Tumor Models

    OpenAIRE

    Taguchi, Ayumu; Politi, Katerina; Pitteri, Sharon J.; Lockwood, William W; Faça, Vitor M.; Kelly-Spratt, Karen; Wong, Chee-Hong; Zhang, Qing; Chin, Alice; Park, Kwon-Sik; Goodman, Gary; Gazdar, Adi F.; Sage, Julien; Dinulescu, Daniela M.; Kucherlapati, Raju

    2011-01-01

    We investigated the potential of in-depth quantitative proteomics to reveal plasma protein signatures that reflect lung tumor biology. We compared plasma protein profiles of four mouse models of lung cancer with profiles of models of pancreatic, ovarian, colon, prostate, and breast cancer and two models of inflammation. A protein signature for Titf1/Nkx2-1, a known lineage-survival oncogene in lung cancer, was found in plasmas of mouse models of lung adenocarcinoma. An EGFR signature was foun...

  11. Modeling Breast Tumor Development with a Humanized Mouse Model.

    Science.gov (United States)

    Arendt, Lisa M

    2016-01-01

    The tumor microenvironment plays a critical role in breast cancer growth and progression to metastasis. Here, we describe a method to examine stromal-epithelial interactions during tumor formation and progression utilizing human-derived mammary epithelial cells and breast stromal cells. This method outlines the isolation of each cell type from reduction mammoplasty tissue, the culture and genetic modification of both epithelial and stromal cells using lentiviral technology, and the method of humanizing and implantation of transformed epithelial cells into the cleared mammary fat pads of immunocompromised mice. This model system may be a useful tool to dissect signaling interactions that contribute to invasive tumor behavior and therapeutic resistance. PMID:27581027

  12. Development of a chemically defined medium and discovery of new mitogenic growth factors for mouse hepatocytes: mitogenic effects of FGF1/2 and PDGF.

    Directory of Open Access Journals (Sweden)

    William C Bowen

    Full Text Available Chemically defined serum-free media for rat hepatocytes have been useful in identifying EGFR ligands and HGF/MET signaling as direct mitogenic factors for rat hepatocytes. The absence of such media for mouse hepatocytes has prevented screening for discovery of such mitogens for mouse hepatocytes. We present results obtained by designing such a chemically defined medium for mouse hepatocytes and demonstrate that in addition to EGFR ligands and HGF, the growth factors FGF1 and FGF2 are also important mitogenic factors for mouse hepatocytes. Smaller mitogenic response was also noticed for PDGF AB. Mouse hepatocytes are more likely to enter into spontaneous proliferation in primary culture due to activation of cell cycle pathways resulting from collagenase perfusion. These results demonstrate unanticipated fundamental differences in growth biology of hepatocytes between the two rodent species.

  13. Conditional Expression of Human 15-Lipoxygenase-1 in Mouse Prostate Induces Prostatic Intraepithelial Neoplasia: The FLiMP Mouse Model

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    Uddhav P. Kelavkar

    2006-06-01

    Full Text Available The incidence and mortality of prostate cancer (PCa vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1, which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN, and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt, FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC, and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN. In summary, targeted overexpression of h

  14. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

    Science.gov (United States)

    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  15. Transplanted bone marrow stromal cells are not cellular origin of hepatocellular carcinomas in a mouse model of carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Jin-Fang Zheng; Li-Jian Liang

    2008-01-01

    AIM: To investigate the malignant potential of hepatic stem cells derived from the bone marrow stromal cells (BHSCs) in a mouse model of chemical hepatocarcinogenesis.METHODS: BMSCs from male BAUB/c mice were harvested and cultured, then transplanted into female syngenic BALB/c mice via portal vein. Hepato-carcinogenesis was induced by 6 months of treatment with diethylnitrosamine (DEN).Six months later, the liver was removed from each treated mouse and evaluated by immunohistochemistry and fluorescence in situ hybddization (FISH).RESULTS: Twenty-six percent of recipient mice survived and developed multiple hepatocellular carcinomas (HCCs).Immunohistochemically, HCC expressed placental form of glutathione-S-transferase (GST-P) and α-fetoprotein,but did not express cytokeratin 19. Y chromosome positive hepatocytes were detected by fluorescent in situ hybridization (FISH) in the liver of mice treated with DEN after BMSCs transplantation while no such hepatocytes were identified in the liver of mice not treated with DEN.No HCC was positive for the Y chromosome by FISH.CONCLUSION: Hepatic stem cells dedved from the bone marrow stromal cells have a low malignant potential in our mouse model of chemical hepatocarcingenesis.

  16. Transgenic mouse model for the formation of Hirano bodies

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    Stramiello Michael

    2011-10-01

    Full Text Available Abstract Background Hirano bodies are actin-rich cytoplasmic inclusions found predominantly in the brain in association with a variety of conditions including aging and Alzheimer's disease. The function of Hirano bodies in normal aging and in progression of disease has not been extensively investigated due to a lack of experimental model systems. We have developed a transgenic mouse model by expression of a gain-of-function actin cross-linking protein mutant. Results We used the Cre/loxP system to permit tissue specific expression of Hirano bodies, and employed the murine Thy 1 promoter to drive expression of Cre recombinase in the brain. Hirano bodies were observed in the cerebral cortex and hippocampus of homozygous double transgenic 6 month old mice containing Cre. The Hirano bodies were eosinophilic rods, and also exhibited the paracrystalline F-actin filament organization that is characteristic of these inclusions. Mice with Hirano bodies appear healthy and fertile, but exhibited some alterations in both short-term and long-term synaptic plasticity, including paired-pulse depression rather than facilitation, and decreased magnitude of early LTP. Conclusions Hirano bodies are not lethal and appear to have little or no effect on histology and tissue organization. Hirano bodies do modulate synaptic plasticity and exert clearly discernable effects on LTP and paired-pulse paradigms. This model system will allow us to investigate the impact of Hirano bodies in vivo, the pathways for formation and degradation of Hirano bodies, and whether Hirano bodies promote or modulate development of pathology and disease progression.

  17. Increased opioid dependence in a mouse model of panic disorder

    Directory of Open Access Journals (Sweden)

    Xavier Gallego

    2010-02-01

    Full Text Available Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3. Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 locus coeruleus neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in locus coeruleus and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

  18. Assessing functional performance in the mdx mouse model.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; van Putten, Maaike

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential pharmaceutical compounds and gene therapy approaches have progressed into clinical trials. With improvement in muscle function being the most important end point in these trials, a lot of emphasis has been placed on setting up reliable, reproducible, and easy to perform functional tests to pre clinically assess muscle function, strength, condition, and coordination in the mdx mouse model for DMD. Both invasive and noninvasive tests are available. Tests that do not exacerbate the disease can be used to determine the natural history of the disease and the effects of therapeutic interventions (e.g. forelimb grip strength test, two different hanging tests using either a wire or a grid and rotarod running). Alternatively, forced treadmill running can be used to enhance disease progression and/or assess protective effects of therapeutic interventions on disease pathology. We here describe how to perform these most commonly used functional tests in a reliable and reproducible manner. Using these protocols based on standard operating procedures enables comparison of data between different laboratories. PMID:24747372

  19. Clobetasol promotes remyelination in a mouse model of neuromyelitis optica.

    Science.gov (United States)

    Yao, Xiaoming; Su, Tao; Verkman, A S

    2016-01-01

    Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can produce marked neurological deficit. Current NMO therapies include immunosuppressants, plasma exchange and B-cell depletion. Here, we evaluated 14 potential remyelinating drugs emerging from prior small molecule screens done to identify drugs for repurposing in multiple sclerosis and other demyelinating neurological diseases. Compounds were initially evaluated in oligodendrocyte precursor cell (OPC) and cerebellar slice cultures, and then in a mouse model of NMO produced by intracerebral injection of anti-AQP4 autoantibody (AQP4-IgG) and human complement characterized by demyelination with minimal axonal damage. The FDA-approved drug clobetasol promoted differentiation in OPC cultures and remyelination in cerebellar slice cultures and in mice. Intraperitoneal administration of 2 mg/kg/day clobetasol reduced myelin loss by ~60 %, even when clobetasol was administered after demyelination occurred. Clobetasol increased the number of mature oligodendrocytes within lesions without significantly altering initial astrocyte damage or inflammation. These results provide proof-of-concept for the potential utility of a remyelinating approach in the treatment of NMO. PMID:27117475

  20. Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery.

    Science.gov (United States)

    Baribault, Helene

    2016-01-01

    Type 2 diabetes is a fast-growing epidemic in industrialized countries, associated with obesity, lack of physical exercise, aging, family history, and ethnic background. Diagnostic criteria are elevated fasting or postprandial blood glucose levels, a consequence of insulin resistance. Early intervention can help patients to revert the progression of the disease together with lifestyle changes or monotherapy. Systemic glucose toxicity can have devastating effects leading to pancreatic beta cell failure, blindness, nephropathy, and neuropathy, progressing to limb ulceration or even amputation. Existing treatments have numerous side effects and demonstrate variability in individual patient responsiveness. However, several emerging areas of discovery research are showing promises with the development of novel classes of antidiabetic drugs.The mouse has proven to be a reliable model for discovering and validating new treatments for type 2 diabetes mellitus. We review here commonly used methods to measure endpoints relevant to glucose metabolism which show good translatability to the diagnostic of type 2 diabetes in humans: baseline fasting glucose and insulin, glucose tolerance test, insulin sensitivity index, and body type composition. Improvements on these clinical values are essential for the progression of a novel potential therapeutic molecule through a preclinical and clinical pipeline. PMID:27150090

  1. RANKL, osteopontin, and osteoclast homeostasis in a hyperocclusion mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Cameron G.; Ito, Yoshihiro; Dangaria, Smit; Luan, Xianghong; Diekwisch, Thomas G.H. (UIC)

    2009-10-21

    The biological mechanisms that maintain the position of teeth in their sockets establish a dynamic equilibrium between bone resorption and apposition. In order to reveal some of the dynamics involved in the tissue responses towards occlusal forces on periodontal ligament (PDL) and alveolar bone homeostasis, we developed the first mouse model of hyperocclusion. Swiss-Webster mice were kept in hyperocclusion for 0, 3, 6, and 9 d. Morphological and histological changes in the periodontium were assessed using micro-computed tomography (micro-CT) and ground sections with fluorescent detection of vital dye labels. Sections were stained for tartrate-resistant acid phosphatase, and the expression of receptor activator of nuclear factor-{kappa}B ligand (RANKL) and osteopontin (OPN) was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). Traumatic occlusion resulted in enamel surface abrasion, inhibition of alveolar bone apposition, significant formation of osteoclasts at 3, 6 and 9 d, and upregulation of OPN and RANKL. Data from this study suggest that both OPN and RANKL contribute to the stimulation of bone resorption in the hyperocclusive state. In addition, we propose that the inhibition of alveolar bone apposition by occlusal forces is an important mechanism for the control of occlusal height that might work in synergy with RANKL-induced bone resorption to maintain normal occlusion.

  2. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    Science.gov (United States)

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; De, Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D.; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S.

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

  3. Raccoonpoxvirus safety in immunocompromised and pregnant mouse models.

    Science.gov (United States)

    Jones, Gwendolyn J B; Boles, Corey; Roper, Rachel L

    2014-06-30

    Numerous poxviruses infect humans and animal hosts, and a poxvirus vaccine with an improved safety profile is needed as the current vaccinia virus vaccine is contraindicated in individuals that have a history of eczema or heart disease, or are immunocompromised or pregnant. In addition, poxviruses make excellent vaccine vectors for other infectious diseases and cancer. Raccoonpoxvirus is a naturally occurring attenuated North American poxvirus, and thus it is of interest as a vaccine vector platform. This study explores the effects of raccoonpoxvirus in SCID and Nude immunocompromised and pregnant mouse models to assess its virulence and probable safety for human and animal populations. We also analyzed the safety of recombinant raccoonpox carrying a gene expressing a foreign antigen, rabies virus glycoprotein, designed for heterologous vaccine protection. Our data show that recombinant raccoonpoxviruses are avirulent in many cases and are much safer than vaccinia virus (strain WR). Raccoonpoxviruses also have the advantage of being able to replicate in mammalian cells. This allows increased immunogenicity and production efficiency, giving an advantage over non replicating vectors such as Modified Vaccinia Ankara MVA or canarypoxvirus. PMID:24837508

  4. Mouse model for ROS1-rearranged lung cancer.

    Directory of Open Access Journals (Sweden)

    Yasuhito Arai

    Full Text Available Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC. However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.

  5. Mouse Model for ROS1-Rearranged Lung Cancer

    Science.gov (United States)

    Takahashi, Hiroyuki; Nakamura, Hiromi; Hama, Natsuko; Kohno, Takashi; Tsuta, Koji; Yoshida, Akihiko; Asamura, Hisao; Mutoh, Michihiro; Hosoda, Fumie; Tsuda, Hitoshi; Shibata, Tatsuhiro

    2013-01-01

    Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22–q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer. PMID:23418494

  6. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

    OpenAIRE

    Keene, C. Dirk; Darvas, Martin; Kraemer, Brian; Liggitt, Denny; Sigurdson, Christina; Ladiges, Warren

    2016-01-01

    Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer’s disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is ...

  7. Multidimensional chemical modelling, II. Irradiated outflow walls

    CERN Document Server

    Bruderer, Simon; Doty, Steven D; van Dishoeck, Ewine F; Bourke, Tyler L

    2009-01-01

    Observations of the high-mass star forming region AFGL 2591 reveal a large abundance of CO+, a molecule known to be enhanced by far UV (FUV) and X-ray irradiation. In chemical models assuming a spherically symmetric envelope, the volume of gas irradiated by protostellar FUV radiation is very small due to the high extinction by dust. The abundance of CO+ is thus underpredicted by orders of magnitude. In a more realistic model, FUV photons can escape through an outflow region and irradiate gas at the border to the envelope. Thus, we introduce the first 2D axi-symmetric chemical model of the envelope of a high-mass star forming region to explain the CO+ observations as a prototypical FUV tracer. The model assumes an axi-symmetric power-law density structure with a cavity due to the outflow. The local FUV flux is calculated by a Monte Carlo radiative transfer code taking scattering on dust into account. A grid of precalculated chemical abundances, introduced in the first part of this series of papers, is used to ...

  8. Methylome repatterning in a mouse model of Maternal PKU Syndrome.

    Science.gov (United States)

    Dobrowolski, S F; Lyons-Weiler, J; Biery, A; Spridik, K; Vockley, G; Kranik, E; Skvorak, K; Sultana, T

    2014-11-01

    Maternal PKU Syndrome (MPKU) is an embryopathy resulting from in utero phenylalanine (PHE) toxicity secondary to maternal phenylalanine hydroxylase deficient phenylketonuria (PKU). Clinical phenotypes in MPKU include mental retardation, microcephaly, in utero growth restriction, and congenital heart defects. Numerous in utero toxic exposures alter DNA methylation in the fetus. The PAH(enu2) mouse is a model of classical PKU while offspring born of hyperphenylalaninemic dams model MPKU. We investigated offspring of PAH(enu2) dams to determine if altered patterns of DNA methylation occurred in response to in utero PHE exposure. As neurologic deficit is the most prominent MPKU phenotype, methylome patterns were assessed in brain tissue using methylated DNA immunoprecipitation and paired-end sequencing. Brain tissues were assessed in E18.5-19 fetuses of PHE unrestricted PAH(enu2) dams, PHE restricted PAH(enu2) dams, and heterozygous(wt/enu2) control dams. Extensive methylome repatterning was observed in offspring of hyperphenylalaninemic dams while the offspring of PHE restricted dams displayed attenuated methylome repatterning. Methylation within coding regions was dominated by noncoding RNA genes. Differential methylation of promoters targeted protein coding genes. To assess the impact of methylome repatterning on gene expression, brain tissue in experimental and control animals were queried with microarrays assessing expression of microRNAs and protein coding genes. Altered expression of methylome-modified microRNAs and protein coding genes was extensive in offspring of hyperphenylalaninemic dams while minimal changes were observed in offspring of PHE restricted dams. Several genes displaying significantly reduced expression have roles in neurological function or genetic disease with neurological phenotypes. These data indicate in utero PHE toxicity alters DNA methylation in the brain which has downstream impact upon gene expression. Altered gene expression may

  9. A gastrointestinal rotavirus infection mouse model for immune modulation studies

    Directory of Open Access Journals (Sweden)

    van Amerongen Geert

    2011-03-01

    Full Text Available Abstract Background Rotaviruses are the single most important cause of severe diarrhea in young children worldwide. The current study was conducted to assess whether colostrum containing rotavirus-specific antibodies (Gastrogard-R® could protect against rotavirus infection. In addition, this illness model was used to study modulatory effects of intervention on several immune parameters after re-infection. Methods BALB/c mice were treated by gavage once daily with Gastrogard-R® from the age of 4 to 10 days, and were inoculated with rhesus rotavirus (RRV at 7 days of age. A secondary inoculation with epizootic-diarrhea infant-mouse (EDIM virus was administered at 17 days of age. Disease symptoms were scored daily and viral shedding was measured in fecal samples during the post-inoculation periods. Rotavirus-specific IgM, IgG and IgG subclasses in serum, T cell proliferation and rotavirus-specific delayed-type hypersensitivity (DTH responses were also measured. Results Primary inoculation with RRV induced a mild but consistent level of diarrhea during 3-4 days post-inoculation. All mice receiving Gastrogard-R® were 100% protected against rotavirus-induced diarrhea. Mice receiving both RRV and EDIM inoculation had a lower faecal-viral load following EDIM inoculation then mice receiving EDIM alone or Gastrogard-R®. Mice receiving Gastrogard-R® however displayed an enhanced rotavirus-specific T-cell proliferation whereas rotavirus-specific antibody subtypes were not affected. Conclusions Preventing RRV-induced diarrhea by Gastrogard-R® early in life showed a diminished protection against EDIM re-infection, but a rotavirus-specific immune response was developed including both B cell and T cell responses. In general, this intervention model can be used for studying clinical symptoms as well as the immune responses required for protection against viral re-infection.

  10. Effects of chemical combinations on the parthenogenetic activation of mouse oocytes

    OpenAIRE

    HAN, BAO-SHENG; GAO, JUN-LING

    2013-01-01

    The aim of this study was to identify an optimal method for the parthenogenetic activation of mouse oocytes. Ethanol (EH), strontium chloride (SrCl2) and ionomycin calcium salt were each combined with cytochalasin B to induce the parthenogenetic activation of CD-1® mouse oocytes. Among the EH combination groups, the blastocyst formation and hatching rates of the group that was activated with EH and CB for 5 min were significantly higher compared with those of the groups that were activated fo...

  11. Exploring Contextual Models in Chemical Patent Search

    Science.gov (United States)

    Urbain, Jay; Frieder, Ophir

    We explore the development of probabilistic retrieval models for integrating term statistics with entity search using multiple levels of document context to improve the performance of chemical patent search. A distributed indexing model was developed to enable efficient named entity search and aggregation of term statistics at multiple levels of patent structure including individual words, sentences, claims, descriptions, abstracts, and titles. The system can be scaled to an arbitrary number of compute instances in a cloud computing environment to support concurrent indexing and query processing operations on large patent collections.

  12. Assessment of a 42 metal salts chemical library in mouse embryonic stem cells

    Science.gov (United States)

    The developmental effects of xenobiotics on differentiation can be profiled using mouse embryonic stem cells (mESCs). The adherent cell differentiation and cytotoxicity (ACDC) technique was used to evaluate a library of 42 metal and metaloid salts. Jl mESCs were allowed to prolif...

  13. Oxalobacter formigenes Colonization and Oxalate Dynamics in a Mouse Model.

    Science.gov (United States)

    Li, Xingsheng; Ellis, Melissa L; Knight, John

    2015-08-01

    Animal and human studies have provided compelling evidence that colonization of the intestine with Oxalobacter formigenes reduces urinary oxalate excretion and lowers the risk of forming calcium oxalate kidney stones. The mechanism providing protection appears to be related to the unique ability of O. formigenes to rely on oxalate as a major source of carbon and energy for growth. However, much is not known about the factors that influence colonization and host-bacterium interactions. We have colonized mice with O. formigenes OxCC13 and systematically investigated the impacts of diets with different levels of calcium and oxalate on O. formigenes intestinal densities and urinary and intestinal oxalate levels. Measurement of intestinal oxalate levels in mice colonized or not colonized with O. formigenes demonstrated the highly efficient degradation of soluble oxalate by O. formigenes relative to other microbiota. The ratio of calcium to oxalate in diets was important in determining colonization densities and conditions where urinary oxalate and fecal oxalate excretion were modified, and the results were consistent with those from studies we have performed with colonized and noncolonized humans. The use of low-oxalate purified diets showed that 80% of animals retained O. formigenes colonization after a 1-week dietary oxalate deprivation. Animals not colonized with O. formigenes excreted two times more oxalate in feces than they had ingested. This nondietary source of oxalate may play an important role in the survival of O. formigenes during periods of dietary oxalate deprivation. These studies suggest that the mouse will be a useful model to further characterize interactions between O. formigenes and the host and factors that impact colonization. PMID:25979889

  14. Novel autoimmune response in a tauopathy mouse model

    Directory of Open Access Journals (Sweden)

    Carlos J Nogueras-Ortiz

    2014-01-01

    Full Text Available Molecular diagnostic tools with non-invasive properties that allow detection of pathological events in Alzheimer’s disease (AD and other neurodegenerative tauopathies are essential for the development of therapeutics. Several diagnostic strategies based on the identification of biomarkers have been proposed. However, its specificity among neurodegenerative disorders is disputable as the association with pathological events remains elusive. Recently, we showed that Amphiphysin-1 (AMPH1 protein’s abundance is reduced in the central nervous system (CNS of the tauopathy mouse model JNPL3 and AD brains. AMPH1 is a synaptic protein that plays an important role in clathrin-mediated endocytosis and associates with BIN1, one of the most important risk loci for AD. Also, it has been associated with a rare neurological disease known as Stiff-Person Syndrome (SPS. Auto-antibodies against AMPH1 are used as diagnostic biomarkers for a paraneoplastic variant of SPS. Therefore, we set up to evaluate the presence and abundance of auto-AMPH1 antibodies in tau-mediated neurodegeneration. Immunoblots and enzyme-linked immunosorbent assays (ELISA were conducted to detect the presence of auto-AMPH1 antibodies in sera from euthanized mice that developed neurodegeneration (JNPL3 and healthy control mice (NTg. Results showed increased levels of auto-AMPH1 antibodies in JNPL3 sera compared to NTg controls. The abundance of auto-AMPH1 antibodies correlated with motor impairment and AMPH1 protein level decrease in the CNS. The results suggest that auto-AMPH1 antibodies could serve as a biomarker for the progression of tau-mediated neurodegeneration in JNPL3 mice.

  15. Mouse Models of Down Syndrome as a Tool to Unravel the Causes of Mental Disabilities

    OpenAIRE

    Carmen Martínez-Cué; Jesús Flórez; Noemí Rueda

    2012-01-01

    Down syndrome (DS) is the most common genetic cause of mental disability. Based on the homology of Hsa21 and the murine chromosomes Mmu16, Mmu17 and Mmu10, several mouse models of DS have been developed. The most commonly used model, the Ts65Dn mouse, has been widely used to investigate the neural mechanisms underlying the mental disabilities seen in DS individuals. A wide array of neuromorphological alterations appears to compromise cognitive performance in trisomic mice. Enhanced inhibition...

  16. Review: The history and role of naturally occurring mouse models with Pde6b mutations

    OpenAIRE

    Han, Juanjuan; Dinculescu, Astra; Dai, Xufeng; Du, Wei; Smith, W. Clay; Pang, Jijing

    2013-01-01

    Mouse models are useful tools for developing potential therapies for human inherited retinal diseases, such as retinitis pigmentosa (RP), since more strains are being identified with the same mutant genes and phenotypes as humans with corresponding retinal degenerative diseases. Mutations in the beta subunit of the human rod phosphodiesterase (PDE6B) gene are a common cause of autosomal recessive RP (arRP). This article focuses on two well-established naturally occurring mouse models of arRP ...

  17. Mouse models for induced genetic instability at endogenous loci.

    Science.gov (United States)

    Reliene, Ramune; Schiestl, Robert H

    2003-10-13

    Exposure to environmental factors and genetic predisposition of an individual may lead individually or in combination to various genetic diseases including cancer. These diseases may be a consequence of genetic instability resulting in large-scale genomic rearrangements, such as DNA deletions, duplications, and translocations. This review focuses on mouse assays detecting genetic instability at endogenous loci. The frequency of DNA deletions by homologous recombination at the pink-eyed unstable (p(un)) locus is elevated in mice with mutations in ATM, Trp53, Gadd45, and WRN genes and after exposure to carcinogens. Other quantitative in vivo assays detecting loss of heterozygosity events, such as the mammalian spot assay, Dlb-1 mouse and Aprt mouse assays, are also reviewed. These in vivo test systems may predict hazardous effects of an environmental agent and/or genetic predisposition to cancer. PMID:14557804

  18. TRIMELLITIC ANHYDRIDE-INDUCED EOSINOPHILLA IN A MOUSE MODEL OF OCCUPATIONAL ASTHMA

    Science.gov (United States)

    Trimellitic anhydride (TMA) is a low molecular weight chemical known to cause occupational asthma. The present study was designed to determine if TMA could elicit eosinophil infiltration into the lung of a sensitized mouse similarly to previous studies with the protein allergen ...

  19. Nonlocal PNJL model and imaginary chemical potential

    International Nuclear Information System (INIS)

    In order to get constraints for the modeling of the QCD phase diagram at real chemical potential (μR), we investigate the phase structure of two-flavor QCD at finite imaginary chemical potential (μI) and temperature (T) using the nonlocal Polyakov-loop extended Nambu-Jona-Lasinio (PNJL) model including quark wave function renormalization. We show that this nonlocal PNJL model reproduces characteristic properties of QCD such as the Roberge-Weiss (RW) periodicity and the RW transition at finite θ=μI/T. To reproduce lattice QCD data of crossover lines for the chiral and deconfinement transitions near θ=π/3, we introduce additional local and nonlocal vector-type four-quark interactions in this model. These interactions have strong influences on the thermodynamics at moderate and high μR. Details of wave function renormalization do not affect the crossover lines, but have a significant impact on the determination of the strength of the nonlocal vector-type four-quark interaction.

  20. New trajectory driven aerosol and chemical process model: chemical and aerosol Lagrangian model (CALM)

    OpenAIRE

    Tunved, P.; D. G. Partridge; Korhonen, H.

    2010-01-01

    A new Chemical and Aerosol Lagrangian Model (CALM) have been developed and tested. The model incorporates all central aerosol dynamical processes, from nucleation, condensation, coagulation and deposition to cloud formation and in-cloud processing. The model is tested and evaluated against observations performed at the SMEAR II station located at Hyytiälä (61°51' N, 24°17' E) over a time period of two years, 2000–2001. The model shows good agreement with measurements thro...

  1. Automatic Assessment of Craniofacial Growth in a Mouse Model of Crouzon Syndrome

    DEFF Research Database (Denmark)

    Thorup, Signe Strann; Larsen, Rasmus; Darvann, Tron Andre; Ólafsdóttir, Hildur; Paulsen, Rasmus Reinhold; Hermann, Nuno Vibe; Larsen, Per; Perlyn, Chad A.; Kreiborg, Sven

    . CONCLUSIONS: Image registrations made it possible to automatically quantify and visualize average craniofacial growth in normal and Crouzon mouse models, and significantly different growth patterns were found between the two. The methodology generalizes to quantification of shape and growth in other mouse...... the human counterpart. Quantifying growth in the Crouzon mouse model could test hypotheses of the relationship between craniosynostosis and dysmorphology, leading to better understanding of the causes of Crouzon syndrome as well as providing knowledge relevant for surgery planning. METHODS: Automatic...... growth vectors for each mouse-type; growth models were created using linear interpolation and visualized as 3D animations. Spatial regions of significantly different growth were identified using the local False Discovery Rate method, estimating the expected percentage of false predictions in a set of...

  2. Automatic Assessment of Craniofacial Growth in a Mouse Model of Crouzon Syndrome

    DEFF Research Database (Denmark)

    Thorup, Signe Strann; Larsen, Rasmus; Darvann, Tron Andre;

    2009-01-01

    the human counterpart. Quantifying growth in the Crouzon mouse model could test hypotheses of the relationship between craniosynostosis and dysmorphology, leading to better understanding of the causes of Crouzon syndrome as well as providing knowledge relevant for surgery planning. METHODS: Automatic...... growth vectors for each mouse-type; growth models were created using linear interpolation and visualized as 3D animations. Spatial regions of significantly different growth were identified using the local False Discovery Rate method, estimating the expected percentage of false predictions in a set of....... CONCLUSIONS: Image registrations made it possible to automatically quantify and visualize average craniofacial growth in normal and Crouzon mouse models, and significantly different growth patterns were found between the two. The methodology generalizes to quantification of shape and growth in other mouse...

  3. Cumulus parameterizations in chemical transport models

    Science.gov (United States)

    Mahowald, Natalie M.; Rasch, Philip J.; Prinn, Ronald G.

    1995-12-01

    Global three-dimensional chemical transport models (CTMs) are valuable tools for studying processes controlling the distribution of trace constituents in the atmosphere. A major uncertainty in these models is the subgrid-scale parametrization of transport by cumulus convection. This study seeks to define the range of behavior of moist convective schemes and point toward more reliable formulations for inclusion in chemical transport models. The emphasis is on deriving convective transport from meteorological data sets (such as those from the forecast centers) which do not routinely include convective mass fluxes. Seven moist convective parameterizations are compared in a column model to examine the sensitivity of the vertical profile of trace gases to the parameterization used in a global chemical transport model. The moist convective schemes examined are the Emanuel scheme [Emanuel, 1991], the Feichter-Crutzen scheme [Feichter and Crutzen, 1990], the inverse thermodynamic scheme (described in this paper), two versions of a scheme suggested by Hack [Hack, 1994], and two versions of a scheme suggested by Tiedtke (one following the formulation used in the ECMWF (European Centre for Medium-Range Weather Forecasting) and ECHAM3 (European Centre and Hamburg Max-Planck-Institut) models [Tiedtke, 1989], and one formulated as in the TM2 (Transport Model-2) model (M. Heimann, personal communication, 1992). These convective schemes vary in the closure used to derive the mass fluxes, as well as the cloud model formulation, giving a broad range of results. In addition, two boundary layer schemes are compared: a state-of-the-art nonlocal boundary layer scheme [Holtslag and Boville, 1993] and a simple adiabatic mixing scheme described in this paper. Three tests are used to compare the moist convective schemes against observations. Although the tests conducted here cannot conclusively show that one parameterization is better than the others, the tests are a good measure of the

  4. Specific MAPK inhibitors prevent hyperglycemia-induced renal diseases in type 1 diabetic mouse model.

    Science.gov (United States)

    Hong, Zhe; Hong, Zongyuan; Wu, Denglong; Nie, Hezhongrong

    2016-08-01

    Mitogen-activated protein kinase (MAPK) and renin-angiotensin system (RAS) play critical roles in the process of renal diseases, but their interaction has not been comprehensively discussed. In the present studies, we investigated the renoprotective effects of MPAK inhibitors on renal diseases in type 1 diabetic mouse model, and clarify the crosstalk among MAPK signaling. Type 1 diabetic mouse model was established in male C57BL/6 J mice, and treated with or without 10 mg/kg MAPK blockers, including ERK inhibitor PD98059, p38 inhibitor SB203850, and JNK inhibitor SP600125 for four weeks. Hyperglycemia induced renal injuries, but treating them with MAPK inhibitors significantly decreased glomerular volume and glycogen in renal tissues. Although slightly changed body weight and fasting blood glucose levels, MAPK inhibitors attenuated blood urea nitrogen, urea protein, and microalbuminuria. Administration also reduced the diabetes-induced RAS activation, including angiotensin II converting enzyme (c) and Ang II, which contributed to its renal protective effects in the diabetic mice. In addition, the anti-RAS of MAPK inhibitor treatment markedly reduced gene expression of tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase, fibrotic accumulation, and transforming growth factor-β1 levels in renal tissues. Furthermore, chemical inhibitors and genetic siRNA results identified the crosstalk among the three MAPK signaling, and proved JNK signaling played a critical role in MAPK-mediated ACE pathway in hyperglycemia state. Collectively, these results support the therapeutic effects of MAPK-specific inhibitors, especially JNK inactivation, on hyperglycemia-induced renal damages. PMID:27389030

  5. Effects of the inhaled treatment of liriope radix on an asthmatic mouse model.

    Science.gov (United States)

    Kim, Ki-Suk; Cho, Dong-Hyuk; Yang, Hea Jung; Choi, Eun-Kyeong; Shin, Min Hee; Kim, Kang-Hoon; Ahn, Kwang Seok; Ha, In Jin; Na, Yun-Cheol; Um, Jae Young; Chung, Won Seok; Jung, Hee-Jae; Jung, Sung-Ki; Jang, Hyeung-Jin

    2015-01-01

    As a treatment for allergic asthma, inhaled treatments such as bronchodilators that contain β2-agonists have an immediate effect, which attenuates airway obstructions and decreases airway hypersensitivity. However, bronchodilators only perform on a one off basis, but not consistently. Asthma is defined as a chronic inflammatory disease of the airways accompanying the overproduction of mucus, airway wall remodeling, bronchial hyperreactivity and airway obstruction. Liriope platyphylla radix extract (LPP), a traditional Korean medicine, has been thoroughly studied and found to be an effective anti-inflammatory medicine. Here, we demonstrate that an inhaled treatment of LPP can attenuate airway hyperresponsiveness (AHR) in an ovalbumin-induced asthmatic mouse model, compared to the saline-treated group (p < 0.01). Moreover, LPP decreases inflammatory cytokine levels, such as eotaxin (p < 0.05), IL-5 (p < 0.05), IL-13 (p < 0.001), RANTES (p < 0.01), and TNF-α (p < 0.05) in the bronchoalveolar lavage (BAL) fluid of asthmatic mice. A histopathological study was carried out to determine the effects of LPP inhalation on mice lung tissue. We performed UPLC/ESI-QTOF-MS, LC/MS, and GC/MS analyses to analyze the chemical constituents of LPP, finding that these are ophiopogonin D, spicatoside A, spicatoside B, benzyl alcohol, and 5-hydroxymethylfurfural. This study demonstrates the effect of an inhaled LPP treatment both on airway AHR and on the inflammatory response in an asthmatic mouse model. Hence, LPP holds significant promise as a nasal inhalant for the treatment of asthmatic airway disease. PMID:25967662

  6. Thermodynamic performance for a chemical reactions model

    International Nuclear Information System (INIS)

    This paper presents the analysis efficiency of a chemical reaction model of four states, such that their activated states can occur at any point (fixed but arbitrary) of the transition from one state to another. This mechanism operates under a single heat reservoir temperature, unlike the internal combustion engines where there are two thermal sources. Different efficiencies are compared to this model, which operate at different optimum engine regimes. Thus, some analytical methods are used to give an approximate expression, facilitating the comparison between them. Finally, the result is compared with that obtained by other authors considered a general model of an isothermal molecular machine. Taking into account the above, the results seems to follow a similar behaviour for all the optimized engines, which resemble that observed in the case of heat engine efficiencies

  7. The house mouse: a model for genetic and evolutionary studies

    Czech Academy of Sciences Publication Activity Database

    Bímová, Barbora

    42-43, - (2008), s. 83-90. ISSN 0085-0748 R&D Projects: GA AV ČR IAA600930506; GA AV ČR KJB600930701 Institutional research plan: CEZ:AV0Z60930519 Keywords : house mouse * speciation * behavioral isolation Subject RIV: EB - Genetics ; Molecular Biology

  8. Development of a metastatic fluorescent Lewis Lung carcinoma mouse model

    DEFF Research Database (Denmark)

    Rask, Lene; Fregil, Marianne; Høgdall, Estrid;

    2013-01-01

    Cancer metastasis is the foremost cause of death in cancer patients. A series of observable pathological changes takes place during progression and metastasis of cancer, but the underlying genetic changes remain unclear. Therefore, new approaches are required, including insights from cancer mouse...

  9. Model steatogenic compounds (amiodarone, valproic acid, and tetracycline alter lipid metabolism by different mechanisms in mouse liver slices.

    Directory of Open Access Journals (Sweden)

    Ewa Szalowska

    Full Text Available Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI, valproic acid (VA, and tetracycline (TET. Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA or compounds impairing mitochondrial functions (i.e. TET. Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism.

  10. Reduction of Photo Bleaching and Long Term Archiving of Chemically Cleared GFP-Expressing Mouse Brains

    OpenAIRE

    Klaus Becker; Christian Markus Hahn; Saiedeh Saghafi; Nina Jährling; Martina Wanis; Hans-Ulrich Dodt

    2014-01-01

    Tissue clearing allows microscopy of large specimens as whole mouse brains or embryos. However, lipophilic tissue clearing agents as dibenzyl ether limit storage time of GFP-expressing samples to several days and do not prevent them from photobleaching during microscopy. To preserve GFP fluorescence, we developed a transparent solid resin formulation, which maintains the specimens' transparency and provides a constant signal to noise ratio even after hours of continuous laser irradiation. If ...

  11. The vomeronasal organ is required for the male mouse medial amygdala response to chemical-communication signals, as assessed by immediate early gene expression

    OpenAIRE

    Samuelsen, Chad L.; Meredith, Michael

    2009-01-01

    Many species use chemical signals to convey information relevant to social and reproductive status between members of the same species (conspecific), but some chemical signals may also provide information to another species (heterospecific). Both of these types of complex chemical signals may be detected by the vomeronasal organ, which sends projections to the accessory olfactory bulb and on to the medial amygdala. Previous reports in hamster and mouse suggest that the medial amygdala sorts t...

  12. Live dynamic imaging and analysis of developmental cardiac defects in mouse models with optical coherence tomography

    Science.gov (United States)

    Lopez, Andrew L.; Wang, Shang; Garcia, Monica; Valladolid, Christian; Larin, Kirill V.; Larina, Irina V.

    2015-03-01

    Understanding mouse embryonic development is an invaluable resource for our interpretation of normal human embryology and congenital defects. Our research focuses on developing methods for live imaging and dynamic characterization of early embryonic development in mouse models of human diseases. Using multidisciplinary methods: optical coherence tomography (OCT), live mouse embryo manipulations and static embryo culture, molecular biology, advanced image processing and computational modeling we aim to understand developmental processes. We have developed an OCT based approach to image live early mouse embryos (E8.5 - E9.5) cultured on an imaging stage and visualize developmental events with a spatial resolution of a few micrometers (less than the size of an individual cell) and a frame rate of up to hundreds of frames per second and reconstruct cardiodynamics in 4D (3D+time). We are now using these methods to study how specific embryonic lethal mutations affect cardiac morphology and function during early development.

  13. Lyssavirus infection: 'low dose, multiple exposure' in the mouse model.

    Science.gov (United States)

    Banyard, Ashley C; Healy, Derek M; Brookes, Sharon M; Voller, Katja; Hicks, Daniel J; Núñez, Alejandro; Fooks, Anthony R

    2014-03-01

    The European bat lyssaviruses (EBLV-1 and EBLV-2) are zoonotic pathogens present within bat populations across Europe. The maintenance and transmission of lyssaviruses within bat colonies is poorly understood. Cases of repeated isolation of lyssaviruses from bat roosts have raised questions regarding the maintenance and intraspecies transmissibility of these viruses within colonies. Furthermore, the significance of seropositive bats in colonies remains unclear. Due to the protected nature of European bat species, and hence restrictions to working with the natural host for lyssaviruses, this study analysed the outcome following repeat inoculation of low doses of lyssaviruses in a murine model. A standardized dose of virus, EBLV-1, EBLV-2 or a 'street strain' of rabies (RABV), was administered via a peripheral route to attempt to mimic what is hypothesized as natural infection. Each mouse (n=10/virus/group/dilution) received four inoculations, two doses in each footpad over a period of four months, alternating footpad with each inoculation. Mice were tail bled between inoculations to evaluate antibody responses to infection. Mice succumbed to infection after each inoculation with 26.6% of mice developing clinical disease following the initial exposure across all dilutions (RABV, 32.5% (n=13/40); EBLV-1, 35% (n=13/40); EBLV-2, 12.5% (n=5/40)). Interestingly, the lowest dose caused clinical disease in some mice upon first exposure ((RABV, 20% (n=2/10) after first inoculation; RABV, 12.5% (n=1/8) after second inoculation; EBLV-2, 10% (n=1/10) after primary inoculation). Furthermore, five mice developed clinical disease following the second exposure to live virus (RABV, n=1; EBLV-1, n=1; EBLV-2, n=3) although histopathological examination indicated that the primary inoculation was the most probably cause of death due to levels of inflammation and virus antigen distribution observed. All the remaining mice (RABV, n=26; EBLV-1, n=26; EBLV-2, n=29) survived the tertiary and

  14. The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis

    OpenAIRE

    Daniel J. Daugherty; Olga Chechneva; Florian Mayrhofer; Wenbin Deng

    2016-01-01

    The mitochondrial translocator protein (TSPO) has been implicated in CNS diseases. Here, we sought to determine the specific role of TSPO in experimental autoimmune encephalomyelitis (EAE), the most studied animal model of multiple sclerosis (MS). To fundamentally elucidate the functions of TSPO, we first developed a viable TSPO knockout mouse. A conditional TSPO knockout mouse was generated by utilizing the Cre-Lox system. We generated a TSPO floxed mouse, and then crossed this mouse with a ...

  15. Intraperitoneal Injection of Multiplacentas Pooled Cells Treatment on a Mouse Model with Aplastic Anemia

    OpenAIRE

    Jun Li; Hong Chen; Yan-Bo Lv; Qiang Wang; Zheng-Jun Xie; Li-Hua Ma; Jie He; Wei Xue; Shan Yu; Jun Guo; Ting-Hua Wang; Tian-Xi Wu; Xing-Hua Pan

    2016-01-01

    Coinfusion of hematopoietic and mesenchymal stem cells is more effective than hematopoietic stem cell transplantation alone. It is necessary to explore a safe and routine mixed stem cell intraperitoneal transplantation method. Multiplacentas pooled cells were intraperitoneally injected into a radiation- and immunity-induced mouse aplastic anemia model with single time. Then, mouse survival time, peripheral blood hemoglobin count, bone marrow architecture, and donor cell engraftment were asses...

  16. PANIC-ATTAC: A Mouse Model for Inducible and Reversible β-Cell Ablation

    OpenAIRE

    Wang, Zhao V.; Mu, James; Schraw, Todd D.; Gautron, Laurent; Elmquist, Joel K.; Zhang, Bei B.; Brownlee, Michael; Scherer, Philipp E

    2008-01-01

    OBJECTIVE—Islet transplantations have been performed clinically, but their practical applications are limited. An extensive effort has been made toward the identification of pancreatic β-cell stem cells that has yielded many insights to date, yet targeted reconstitution of β-cell mass remains elusive. Here, we present a mouse model for inducible and reversible ablation of pancreatic β-cells named the PANIC-ATTAC (pancreatic islet β-cell apoptosis through targeted activation of caspase 8) mous...

  17. MAGNETIC RESONANCE IMAGING AND SPECTROSCOPY IN A MOUSE MODEL OF SCHIZOPHRENIA

    OpenAIRE

    Torres, German; Hallas, Brian H.; Gross, Kenneth W.; Spernyak, Joseph A.; Horowitz, Judith M.

    2007-01-01

    Metabolic brain abnormalities, as demonstrated by 1H-magnetic resonance spectroscopy techniques, are common occurrences in adult schizophrenia. As mice share important biochemical and genomic similarities with humans, we tested whether brain metabolic abnormalities also occur in a transgenic mouse model of schizophrenia. In vivo 1H-magnetic resonance spectroscopy at 4.7 T of the chakragati mouse brain revealed abnormalities in relative levels of choline 3.20 ppm and N-acetylaspartate 2.01 ppm...

  18. Small-diameter biodegradable scaffolds for functional vascular tissue engineering in the mouse model

    OpenAIRE

    Roh, Jason D.; Nelson, Gregory N.; Brennan, Matthew P.; Mirensky, Tamar L.; Yi, Tai; Hazlett, Ty; Tellides, George; Sinusas, Albert J.; Pober, Jordan S.; Saltzman, W. Mark; Kyriakides, Themis R.; Breuer, Christopher K

    2007-01-01

    The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (I.D.) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester seala...

  19. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy

    OpenAIRE

    Kappen, Claudia; Kruger, Claudia; Macgowan, Jacalyn; Salbaum, J. Michael

    2010-01-01

    Pregnancies complicated by maternal diabetes have long been known to carry a higher risk for congenital malformations, such as neural tube defects. Using the FVB inbred mouse strain and the Streptozotocin-induced diabetes model, we tested whether the incidence of neural tube defects in diabetic pregnancies can be modulated by maternal diet. In a comparison of two commercial mouse diets, which are considered nutritionally replete, we found that maternal consumption of the unfavorable diet was ...

  20. Protective Effect of Arginine on Oxidative Stress in Transgenic Sickle Mouse Models

    OpenAIRE

    Dasgupta, Trisha; Hebbel, Robert P.; Kaul, Dhananjay K.

    2006-01-01

    Sickle cell disease (SCD) is characterized by reperfusion injury and chronic oxidative stress. Oxidative stress and hemolysis in SCD result in inactivation of nitric oxide (NO) and depleted arginine levels. We hypothesized that augmenting NO production by arginine supplementation will reduce oxidative stress in SCD. To this end, we measured the effect of arginine (5% in mouse chow) on NO metabolites (NOx), lipid peroxidation (LPO) and selected antioxidants in transgenic sickle mouse models. U...

  1. Type 2 diabetes model TSOD mouse is exposed to oxidative stress at young age

    OpenAIRE

    Murotomi, Kazutoshi; Umeno, Aya; Yasunaga, Mayu; Shichiri, Mototada; Ishida, Noriko; Abe, Hiroko; Yoshida, Yasukazu; Nakajima, Yoshihiro

    2014-01-01

    Tsumura Suzuki Obese Diabetes (TSOD) mouse, a model of obese type 2 diabetes, older than around 11 weeks of age develops diabetic phenotypes. Previous studies have indicated that the development of diabetes is partly due to three loci associated with body weight and glucose homeostasis. However, little is known about the initial events triggering the development of the diabetic phenotypes in TSOD mouse. Here, we investigated the alteration of diabetes-related parameters, including the levels ...

  2. Impaired Satiation and Increased Feeding Behaviour in the Triple-Transgenic Alzheimer's Disease Mouse Model

    OpenAIRE

    Adedolapo Adebakin; Jenna Bradley; Sarah Gümüsgöz; Elizabeth J Waters; Lawrence, Catherine B.

    2012-01-01

    Alzheimer's disease (AD) is associated with non-cognitive symptoms such as changes in feeding behaviour that are often characterised by an increase in appetite. Increased food intake is observed in several mouse models of AD including the triple transgenic (3×TgAD) mouse, but the mechanisms underlying this hyperphagia are unknown. We therefore examined feeding behaviour in 3×TgAD mice and tested their sensitivity to exogenous and endogenous satiety factors by assessing food intake and activat...

  3. Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model

    OpenAIRE

    Hillegass, Jedd M; Shukla, Arti; Lathrop, Sherrill A.; MacPherson, Maximilian B; Beuschel, Stacie L; Butnor, Kelly J.; Testa, Joseph R.; Harvey I Pass; Carbone, Michele; Steele, Chad; Mossman, Brooke T.

    2010-01-01

    Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived ...

  4. Chemically induced skin carcinogenesis in a transgenic mouse line (TG.AC) carrying a v-Ha-ras gene.

    Science.gov (United States)

    Spalding, J W; Momma, J; Elwell, M R; Tennant, R W

    1993-07-01

    A transgenic mouse line (TG.AC) created in the FVB/N strain, carries a v-Ha-ras gene fused to a zeta-globin promoter gene. These trangenic mice have the properties of genetically initiated skin and have been shown to be sensitive to 12-O-tetradecanoylphorbol-13-acetate (TPA), a well-described promoter of skin papillomas in the two-stage mouse skin tumorigenesis model. It was of interest to determine whether the TG.AC mouse strain was also responsive to other known promoters. Groups of heterozygous or homozygous TG.AC mice were treated topically, 2x/week, for up to 20 weeks with benzoyl peroxide (BPO), 2-butanol peroxide (2-BUP), phenol (PH), acetic acid (AA), TPA and acetone (ACN), the vehicle control. Skin papillomas were induced in all groups treated with TPA, BPO and 2-BUP. Papillomas were observed in some treatment groups as early as 3 weeks. The relative activity of the promoters was TPA > 2-BUP > BPO > PH = AA = ACN. No papillomas were observed in any of the uninitiated FVB/N mice treated in a similar manner and which served as treatment control groups. Studies to determine the sensitivity of TG.AC mice to TPA, indicated that a total dose of 25-30 micrograms of TPA administered in 3 or 10 applications, was sufficient to induce an average incidence of 11-15 papillomas per mouse. The papilloma incidence continued to increase and was maintained up to 15 weeks after TPA treatment was terminated. The short latency period and high incidence of papilloma induction indicate that TG.AC mice have a high sensitivity to known skin promoters. The TG.AC line should prove to be a sensitive model for identifying putative tumor promoters or complete carcinogens. PMID:8330346

  5. Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

    OpenAIRE

    Katie Lidster; Samuel J Jackson; Zubair Ahmed; Peter Munro; Pete Coffey; Gavin Giovannoni; Baker, Mark D.; David Baker

    2013-01-01

    Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transge...

  6. Insights Gained from Modeling High-Grade Glioma in the Mouse

    OpenAIRE

    Rankin, Sherri L; Zhu, Guo; Baker, Suzanne J.

    2012-01-01

    High grade gliomas (HGG) are devastating primary brain tumors with universally poor prognoses. Advances toward effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic ge...

  7. Defining the role of polyamines in colon carcinogenesis using mouse models

    Directory of Open Access Journals (Sweden)

    Natalia A Ignatenko

    2011-01-01

    Full Text Available Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.

  8. A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses

    Energy Technology Data Exchange (ETDEWEB)

    Salek, Reza M.; Pears, Michael R. [University of Cambridge, Department of Biochemistry and Cambridge Systems Biology Centre (United Kingdom); Cooper, Jonathan D. [King' s College London, Pediatric Storage Disorders Laboratory, Department of Neuroscience, Institute of Psychiatry (United Kingdom); Mitchison, Hannah M. [Royal Free and University College Medical School, Department of Paediatrics and Child Health (United Kingdom); Pearce, David A. [Sanford School of Medicine of the University of South Dakota, Department of Pediatrics (United States); Mortishire-Smith, Russell J. [Johnson and Johnson PR and D (Belgium); Griffin, Julian L., E-mail: jlg40@mole.bio.cam.ac.uk [University of Cambridge, Department of Biochemistry and the Cambridge Systems Biology Centre (United Kingdom)

    2011-04-15

    The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in {gamma}-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.

  9. Reduction of photo bleaching and long term archiving of chemically cleared GFP-expressing mouse brains.

    Directory of Open Access Journals (Sweden)

    Klaus Becker

    Full Text Available Tissue clearing allows microscopy of large specimens as whole mouse brains or embryos. However, lipophilic tissue clearing agents as dibenzyl ether limit storage time of GFP-expressing samples to several days and do not prevent them from photobleaching during microscopy. To preserve GFP fluorescence, we developed a transparent solid resin formulation, which maintains the specimens' transparency and provides a constant signal to noise ratio even after hours of continuous laser irradiation. If required, high-power illumination or long exposure times can be applied with virtually no loss in signal quality and samples can be archived for years.

  10. Reduction of photo bleaching and long term archiving of chemically cleared GFP-expressing mouse brains.

    Science.gov (United States)

    Becker, Klaus; Hahn, Christian Markus; Saghafi, Saiedeh; Jährling, Nina; Wanis, Martina; Dodt, Hans-Ulrich

    2014-01-01

    Tissue clearing allows microscopy of large specimens as whole mouse brains or embryos. However, lipophilic tissue clearing agents as dibenzyl ether limit storage time of GFP-expressing samples to several days and do not prevent them from photobleaching during microscopy. To preserve GFP fluorescence, we developed a transparent solid resin formulation, which maintains the specimens' transparency and provides a constant signal to noise ratio even after hours of continuous laser irradiation. If required, high-power illumination or long exposure times can be applied with virtually no loss in signal quality and samples can be archived for years. PMID:25463047

  11. A mouse model of osteonecrotic femoral head induced by methylprednisolone and lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Ha Thi -Ngan Le

    2016-03-01

    Full Text Available Introduction: Osteonecrosis of the femoral head is caused by various factors, including prolonged use of steroid drugs, use of alcohol, vascular injuries and hemoglobinopathies. This study aims to develop a mouse model for glucocorticoid-induced avascular necrosis (AVN of the femoral head.Methods: Adult mice were randomly divided into two groups: experimental and control. Group A (the experimental group was given (via intramuscular injection 10 mg/kg of lipopolysaccharide (LPS and 30 mg/kg of methylprednisolone (MPS. Each mouse additionally received MPS in divided oral doses of 13 mg/kg for 10 consecutive days. Group B (the control group received normal saline at the same location and same volume as those in Group A. Histological changes of the femoral heads were observed by electron microscopy at 3, 5, and 7 weeks after the last chemical injection. The percentage of empty lacunae was measured randomly and the expression of fibrocartilage was evaluated using an image analyz and shy;ing system. The expression of CD31 and VEGF-R2 were observed by immunohistochemistry. The bone marrow-derived mononuclear cells were stained with propidium iodide and cell cycle was analyzed by flow cytometry. Results:The results showed that at weeks 3 and 5, mice in Group A showed an increase in body weight. From weeks 5 to 7, mouse body weight in both groups remained constant. No difference in bone morphology was observed at week 7. The percentage of empty lacunae was 5.87 2.49% at week 5 and 21.58 8.10% at week 7. After 7 weeks, chondrocyte degeneration and fibrocartilage expression were observed. Moreover, the density of CD31 and VEGF-R2 markers increased in the femoral head. The rate of apoptosis in the bone marrow increased at week 3 then decreased. Conclusion: The data show that MPS, combined with LPS, can induce in mice features typical of early AVN of the femoral head. [Biomed Res Ther 2016; 3(3.000: 548-556

  12. Uncertainties in Galactic Chemical Evolution Models

    Science.gov (United States)

    Côté, Benoit; Ritter, Christian; O’Shea, Brian W.; Herwig, Falk; Pignatari, Marco; Jones, Samuel; Fryer, Chris L.

    2016-06-01

    We use a simple one-zone galactic chemical evolution model to quantify the uncertainties generated by the input parameters in numerical predictions for a galaxy with properties similar to those of the Milky Way. We compiled several studies from the literature to gather the current constraints for our simulations regarding the typical value and uncertainty of the following seven basic parameters: the lower and upper mass limits of the stellar initial mass function (IMF), the slope of the high-mass end of the stellar IMF, the slope of the delay-time distribution function of Type Ia supernovae (SNe Ia), the number of SNe Ia per M ⊙ formed, the total stellar mass formed, and the final mass of gas. We derived a probability distribution function to express the range of likely values for every parameter, which were then included in a Monte Carlo code to run several hundred simulations with randomly selected input parameters. This approach enables us to analyze the predicted chemical evolution of 16 elements in a statistical manner by identifying the most probable solutions, along with their 68% and 95% confidence levels. Our results show that the overall uncertainties are shaped by several input parameters that individually contribute at different metallicities, and thus at different galactic ages. The level of uncertainty then depends on the metallicity and is different from one element to another. Among the seven input parameters considered in this work, the slope of the IMF and the number of SNe Ia are currently the two main sources of uncertainty. The thicknesses of the uncertainty bands bounded by the 68% and 95% confidence levels are generally within 0.3 and 0.6 dex, respectively. When looking at the evolution of individual elements as a function of galactic age instead of metallicity, those same thicknesses range from 0.1 to 0.6 dex for the 68% confidence levels and from 0.3 to 1.0 dex for the 95% confidence levels. The uncertainty in our chemical evolution model

  13. Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington's disease

    Directory of Open Access Journals (Sweden)

    Damian M Cummings

    2010-06-01

    Full Text Available Since the identification of the gene responsible for HD (Huntington's disease, many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI (knock-in mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.

  14. Olfaction in three genetic and two MPTP-induced Parkinson's disease mouse models.

    Directory of Open Access Journals (Sweden)

    Stefan Kurtenbach

    Full Text Available Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson's disease (PD mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs and an olfactory behavior test (cookie-finding test. We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated α-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated α-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium.

  15. Quantitative analysis of the relative mutagenicity of five chemical constituents of tobacco smoke in the mouse lymphoma assay.

    Science.gov (United States)

    Guo, Xiaoqing; Heflich, Robert H; Dial, Stacey L; Richter, Patricia A; Moore, Martha M; Mei, Nan

    2016-05-01

    Quantifying health-related biological effects, like genotoxicity, could provide a way of distinguishing between tobacco products. In order to develop tools for using genotoxicty data to quantitatively evaluate the risk of tobacco products, we tested five carcinogens found in cigarette smoke, 4-aminobiphenyl (4-ABP), benzo[a]pyrene (BaP), cadmium (in the form of CdCl2), 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline (MeIQ) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the mouse lymphoma assay (MLA). The resulting mutagenicity dose responses were analyzed by various quantitative approaches and their strengths and weaknesses for distinguishing responses in the MLA were evaluated. L5178Y/Tk (+/-) 3.7.2C mouse lymphoma cells were treated with four to seven concentrations of each chemical for 4h. Only CdCl2 produced a positive response without metabolic activation (S9); all five chemicals produced dose-dependent increases in cytotoxicity and mutagenicity with S9. The lowest dose exceeding the global evaluation factor, the benchmark dose producing a 10%, 50%, 100% or 200% increase in the background frequency (BMD10, BMD50, BMD100 and BMD200), the no observed genotoxic effect level (NOGEL), the lowest observed genotoxic effect level (LOGEL) and the mutagenic potency expressed as a mutant frequency per micromole of chemical, were calculated for all the positive responses. All the quantitative metrics had similar rank orders for the agents' ability to induce mutation, from the most to least potent as CdCl2(-S9) > BaP(+S9) > CdCl2(+S9) > MeIQ(+S9) > 4-ABP(+S9) > NNK(+S9). However, the metric values for the different chemical responses (i.e. the ratio of the greatest value to the least value) for the different chemicals ranged from 16-fold (BMD10) to 572-fold (mutagenic potency). These results suggest that data from the MLA are capable of discriminating the mutagenicity of various constituents of cigarette smoke, and that quantitative analyses are available

  16. Ultrastructural study of Rift Valley fever virus in the mouse model

    International Nuclear Information System (INIS)

    Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed in the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV–host interactions and further characterize the mouse model of RVF.

  17. Priceless GEMMs: genetically engineered mouse models for colorectal cancer drug development.

    Science.gov (United States)

    Roper, Jatin; Hung, Kenneth E

    2012-08-01

    To establish effective drug development for colorectal cancer (CRC), preclinical models that are robust surrogates for human disease are crucial. Mouse models are an attractive platform because of their relatively low cost, short life span, and ease of use. There are two main categories of mouse CRC models: xenografts derived from implantation of CRC cells or tumors in immunodeficient mice; and genetically engineered mouse models (GEMMs) derived from modification of human cancer predisposition genes, resulting in spontaneous tumor formation. Here, we review xenografts and GEMMs and focus on their potential application in translational research. Furthermore, we describe newer GEMMs for sporadic CRC that are particularly suitable for drug testing. Finally, we discuss recent advances in small-animal imaging, such as optical colonoscopy, which allow in vivo assessment of tumors. With the increasing sophistication of GEMMs, our preclinical armamentarium provides new hope for the ongoing war against CRC. PMID:22739258

  18. Ultrastructural study of Rift Valley fever virus in the mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Reed, Christopher; Steele, Keith E.; Honko, Anna; Shamblin, Joshua; Hensley, Lisa E. [United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD (United States); Smith, Darci R., E-mail: darci.smith1@us.army.mil [United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD (United States)

    2012-09-15

    Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed in the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV-host interactions and further characterize the mouse model of RVF.

  19. New trajectory-driven aerosol and chemical process model Chemical and Aerosol Lagrangian Model (CALM)

    OpenAIRE

    Tunved, P.; D. G. Partridge; Korhonen, H.

    2010-01-01

    A new Chemical and Aerosol Lagrangian Model (CALM) has been developed and tested. The model incorporates all central aerosol dynamical processes, from nucleation, condensation, coagulation and deposition to cloud formation and in-cloud processing. The model is tested and evaluated against observations performed at the SMEAR II station located at Hyytiälä (61° 51' N, 24° 17' E) over a time period of two years, 2000–2001. The model shows good agreement with measurements throughout mos...

  20. The Impact of Modeling Assumptions in Galactic Chemical Evolution Models

    CERN Document Server

    Côté, Benoit; Ritter, Christian; Herwig, Falk; Venn, Kim A

    2016-01-01

    We use the OMEGA galactic chemical evolution code to investigate how the assumptions used for the treatment of galactic inflows and outflows impact numerical predictions. The goal is to determine how our capacity to reproduce the chemical evolution trends of a galaxy is affected by the choice of implementation used to include those physical processes. In pursuit of this goal, we experiment with three different prescriptions for galactic inflows and outflows and use OMEGA within a Markov Chain Monte Carlo code to recover the set of input parameters that best reproduces the chemical evolution of nine elements in the dwarf spheroidal galaxy Sculptor. Despite their different degrees of intended physical realism, we found that all three prescriptions can reproduce in an almost identical way the stellar abundance trends observed in Sculptor. While the three models have the same capacity to fit the data, the best values recovered for the parameters controlling the number of Type Ia supernovae and the strength of gal...

  1. Construction of a digital and physical mouse model aimed at the study of electrical shock

    Science.gov (United States)

    Nguyen, Thu T. A.; Shupp, Jeffrey W.; Moffatt, Lauren T.; Ramella-Roman, Jessica C.

    2014-03-01

    Optical methods have been used to investigate electrical injury on animal models such as live mice, rats, and rabbits. Here we introduce a completely digital phantom of a mouse, with the aim of investigating electrical injury through spectroscopic imaging techniques. The basis of our phantom is a three-dimensional digital mouse reconstructed from co-registered computed tomographic images and cryosection by a different group. Image processing algorithms were applied to make the model suitable to Finite Element Analysis of thermal and electrical transport. Our digital model is capable of simulating temperature, voltage, current changes along the animal body during and after electrical shocks.

  2. Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies

    Directory of Open Access Journals (Sweden)

    Melemedjian Ohannes K

    2008-03-01

    Full Text Available Abstract Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG, which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

  3. Chemoreception Regulates Chemical Access to Mouse Vomeronasal Organ: Role of Solitary Chemosensory Cells

    OpenAIRE

    Tatsuya Ogura; Kurt Krosnowski; Lana Zhang; Mikhael Bekkerman; Weihong Lin

    2010-01-01

    Controlling stimulus access to sensory organs allows animals to optimize sensory reception and prevent damage. The vomeronasal organ (VNO) detects pheromones and other semiochemicals to regulate innate social and sexual behaviors. This semiochemical detection generally requires the VNO to draw in chemical fluids, such as bodily secretions, which are complex in composition and can be contaminated. Little is known about whether and how chemical constituents are monitored to regulate the fluid a...

  4. Cytotoxicity of MEIC chemicals Nos. 11-30 in 3T3 mouse fibroblasts with and without microsomal activation

    DEFF Research Database (Denmark)

    Rasmussen, Eva

    1999-01-01

    The cytotoxicity of MEIC chemicals Nos, 11-30 was evaluated by determination of neutral red uptake in Balb/c 3T3 mouse fibroblasts with and without the addition of a microsomal activation mixture. The use of microsomes significantly decreased the cytotoxicity of malathion, 2,4-dichlorophenoxyacetic...... acid, propranolol, thioridazine, lithium sulfate, copper sulfate and thallium sulfate, whereas the cytotoxicity of 1,1,1-trichloroethylene, phenol, nicotine, and paraquat was significantly increased by use of the microsomal activation mixture. These cytotoxicity data are in line with observations in...... other studies on microsomal modulation of the cytotoxicity of the test substances. Moderate to good correlations were found between the cytotoxicity data and rodent lethality data, and the addition of microsomes slightly improved the in vitro/in vivo concordance. The evidence to support the relevance of...

  5. Overexpression and amplification of the c-myc gene in mouse tumors induced by chemical and radiations

    International Nuclear Information System (INIS)

    We examined expression of the c-myc gene by the dot blot hybridization of total cellular RNA from mouse primary tumors induced by chemicals and radiations. Expression of the c-myc gene was found to be elevated in 69 cases among 177 independently induced tumors of 12 different types. DNA from tumors overexpressing the myc gene was analyzed by Southern blotting. No case of rearrangement was detected. However, amplification of the c-myc gene was found in 7 cases of primary sarcomas. These included 4 cases out of 24 methylcholanthrene-induced sarcomas and 3 cases out of 7 α-tocopherol-induced sacromas. We also analyzed 8 cases of sarcomas induced by radiations, but could not find changes in the gene structure of the c-myc gene. Thus, our data indicate tumor type specificity and agent specificity of c-myc gene amplification. (author)

  6. Evaluation of Mammary Gland Development and Function in Mouse Models

    OpenAIRE

    Plante, Isabelle; Stewart, Michael K.G.; Laird, Dale W.

    2011-01-01

    The human mammary gland is composed of 15-20 lobes that secrete milk into a branching duct system opening at the nipple. Those lobes are themselves composed of a number of terminal duct lobular units made of secretory alveoli and converging ducts1. In mice, a similar architecture is observed at pregnancy in which ducts and alveoli are interspersed within the connective tissue stroma. The mouse mammary gland epithelium is a tree like system of ducts composed of two layers of cells, an inner la...

  7. Chemical cleaning specification: few tube test model

    International Nuclear Information System (INIS)

    The specification is for the waterside chemical cleaning of the 2 1/4 Cr - 1 Mo steel steam generator tubes. It describes the reagents and conditions for post-chemical cleaning passivation of the evaporator tubes

  8. An Intraductal Human-in-mouse Transplantation Model Mimics the Subtypes of Ductal Carcinoma In Situ

    OpenAIRE

    Behbod, Fariba; Kittrell, Frances S; LaMarca, Heather; Kerbawy, Sofia; Heestand, Jessica C; Young, Evelin; Mukhopadhyay, Purna; Yeh, Hung-Wen; Allred, D. Craig; Medina, Daniel; Edwards, David; Hu, Min; Polyak, Kornelia; Rosen, Jeffrey M.

    2009-01-01

    Introduction: Human models of noninvasive breast tumors are limited, and the existing in vivo models do not mimic inter- and intratumoral heterogeneity. Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions. The aim of this study was to develop an in vivo model whereby the natural progression of human DCIS might be reproduced and studied. To accomplish this goal, the intraductal human-in-mouse (HIM) transplantation model was developed. The resulting model...

  9. A mesoscale chemical transport model (MEDIUM) nested in a global chemical transport model (MEDIANTE)

    Energy Technology Data Exchange (ETDEWEB)

    Claveau, J.; Ramaroson, R. [Office National d`Etudes et de Recherches Aerospatiales (ONERA), 92 - Chatillon (France)

    1997-12-31

    The lower stratosphere and upper troposphere (UT-LS) are frequently subject to mesoscale or local scale exchange of air masses occurring along discontinuities. This exchange (e.g. downward) can constitute one of the most important source of ozone from the stratosphere down to the middle troposphere where strong mixing dilutes the air mass and competing the non-linear chemistry. The distribution of the chemical species in the troposphere and the lower stratosphere depends upon various source emissions, e.g. from polluted boundary layer or from aircraft emissions. Global models, as well as chemical transport models describe the climatological state of the atmosphere and are not able to describe correctly the stratosphere and troposphere exchange. Mesoscale models go further in the description of smaller scales and can reasonably include a rather detailed chemistry. They can be used to assess the budget of NO{sub x} from aircraft emissions in a mesoscale domain. (author) 4 refs.

  10. Application of Fuzzy Regression Model to the Prediction of Field Mouse Occurrence Rate

    Institute of Scientific and Technical Information of China (English)

    XU Fei

    2009-01-01

    Expressions were given to describe the closeness between the estimated value and observed value for two asymmetric exponential fuzzy numbers. Based on that, the model was given to solve the question of fuzzy multivariable regression with fuzzy input, fuzzy output and crisp coefficients. Finally, with this model, the prediction of field mouse occurrence rate had been done and the satisfied result was obtained.

  11. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    Science.gov (United States)

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models-mainly mouse models-have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  12. Chemical leasing business models: a contribution to the effective risk management of chemical substances.

    Science.gov (United States)

    Ohl, Cornelia; Moser, Frank

    2007-08-01

    Chemicals indisputably contribute greatly to the well-being of modern societies. Apart from such benefits, however, chemicals often pose serious threats to human health and the environment when improperly handled. Therefore, the European Commission has proposed a regulatory framework for the Registration, Evaluation and Authorization of Chemicals (REACH) that requires companies using chemicals to gather pertinent information on the properties of these substances. In this article, we argue that the crucial aspect of this information management may be the honesty and accuracy of the transfer of relevant knowledge from the producer of a chemical to its user. This may be particularly true if the application of potentially hazardous chemicals is not part of the user's core competency. Against this background, we maintain that the traditional sales concept provides no incentives for transferring this knowledge. The reason is that increased user knowledge of a chemical's properties may raise the efficiency of its application. That is, excessive and unnecessary usage will be eliminated. This, in turn, would lower the amount of chemicals sold and in competitive markets directly decrease profits of the producer. Through the introduction of chemical leasing business models, we attempt to present a strategy to overcome the incentive structure of classical sales models, which is counterproductive for the transfer of knowledge. By introducing two models (a Model A that differs least and a Model B that differs most from traditional sales concepts), we demonstrate that chemical leasing business models are capable of accomplishing the goal of Registration, Evaluation and Authorization of Chemicals: to effectively manage the risk of chemicals by reducing the total quantity of chemicals used, either by a transfer of applicable knowledge from the lessor to the lessee (Model A) or by efficient application of the chemical by the lessor him/herself (Model B). PMID:17958507

  13. Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain.

    Science.gov (United States)

    de Araujo, Aline Dantas; Mobli, Mehdi; Castro, Joel; Harrington, Andrea M; Vetter, Irina; Dekan, Zoltan; Muttenthaler, Markus; Wan, JingJing; Lewis, Richard J; King, Glenn F; Brierley, Stuart M; Alewood, Paul F

    2014-01-01

    Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general. PMID:24476666

  14. Chemical Kinetic Modeling of Biofuel Combustion

    Science.gov (United States)

    Sarathy, Subram Maniam

    Bioalcohols, such as bioethanol and biobutanol, are suitable replacements for gasoline, while biodiesel can replace petroleum diesel. Improving biofuel engine performance requires understanding its fundamental combustion properties and the pathways of combustion. This study's contribution is experimentally validated chemical kinetic combustion mechanisms for biobutanol and biodiesel. Fundamental combustion data and chemical kinetic mechanisms are presented and discussed to improve our understanding of biofuel combustion. The net environmental impact of biobutanol (i.e., n-butanol) has not been studied extensively, so this study first assesses the sustainability of n-butanol derived from corn. The results indicate that technical advances in fuel production are required before commercializing biobutanol. The primary contribution of this research is new experimental data and a novel chemical kinetic mechanism for n-butanol combustion. The results indicate that under the given experimental conditions, n-butanol is consumed primarily via abstraction of hydrogen atoms to produce fuel radical molecules, which subsequently decompose to smaller hydrocarbon and oxygenated species. The hydroxyl moiety in n-butanol results in the direct production of the oxygenated species such as butanal, acetaldehyde, and formaldehyde. The formation of these compounds sequesters carbon from forming soot precursors, but they may introduce other adverse environmental and health effects. Biodiesel is a mixture of long chain fatty acid methyl esters derived from fats and oils. This research study presents high quality experimental data for one large fatty acid methyl ester, methyl decanoate, and models its combustion using an improved skeletal mechanism. The results indicate that methyl decanoate is consumed via abstraction of hydrogen atoms to produce fuel radicals, which ultimately lead to the production of alkenes. The ester moiety in methyl decanoate leads to the formation of low molecular

  15. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer's disease

    DEFF Research Database (Denmark)

    Baron, Rona; Babcock, Alicia A; Nemirovsky, Anna;

    2014-01-01

    earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with...... a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to...

  16. Inner Ear Morphology Is Perturbed in Two Novel Mouse Models of Recessive Deafness

    OpenAIRE

    Miller, Kerry A.; Williams, Louise H.; Rose, Elizabeth; Kuiper, Michael; Dahl, Hans-Henrik M.; Manji, Shehnaaz S. M.

    2012-01-01

    Human MYO7A mutations can cause a variety of conditions involving the inner ear. These include dominant and recessive non-syndromic hearing loss and syndromic conditions such as Usher syndrome. Mouse models of deafness allow us to investigate functional pathways involved in normal and abnormal hearing processes. We present two novel mouse models with mutations in the Myo7a gene with distinct phenotypes. The mutation in Myo7aI487N/I487N ewaso is located within the head motor domain of Myo7a. M...

  17. The use of mouse models to understand and improve cognitive deficits in Down syndrome

    Directory of Open Access Journals (Sweden)

    Ishita Das

    2011-09-01

    Full Text Available Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.

  18. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Xiaojun [The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Park, Eunmi [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 (United States); Fischer, Susan M. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78967 (United States); Hu, Yinling, E-mail: huy2@mail.nih.gov [Cancer and Inflammation Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701 (United States)

    2013-02-15

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.

  19. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    International Nuclear Information System (INIS)

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside

  20. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

    Directory of Open Access Journals (Sweden)

    C. Dirk Keene

    2016-06-01

    Full Text Available Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD, have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1 cerebrospinal fluid (CSF AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2 structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG, and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3 cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines

  1. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines.

    Science.gov (United States)

    Keene, C Dirk; Darvas, Martin; Kraemer, Brian; Liggitt, Denny; Sigurdson, Christina; Ladiges, Warren

    2016-01-01

    Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards

  2. Chemical Mechanism Solvers in Air Quality Models

    OpenAIRE

    Linford, John C.; Adrian Sandu; Rolf Sander; Hong Zhang

    2011-01-01

    The solution of chemical kinetics is one of the most computationally intensive tasks in atmospheric chemical transport simulations. Due to the stiff nature of the system, implicit time stepping algorithms which repeatedly solve linear systems of equations are necessary. This paper reviews the issues and challenges associated with the construction of efficient chemical solvers, discusses several families of algorithms, presents strategies for increasing computational efficiency, and gives insi...

  3. A Novel Three-Dimensional Mouse Embryonic Implantation Model In Vitro

    Institute of Scientific and Technical Information of China (English)

    SONG Yu-xuan; CAO Bin-yun

    2007-01-01

    To regenerate three-dimensional endometrium in vitro as a novel model for studying the mechanism of implantation of embryos, the luminal epithelial cells and stromal cells of the rabbit uterus were separated and cultured in vitro. The type Ⅰ mouse tail collagen was used as scaffolding material. The stromal cells were inoculated in the type Ⅰ mouse tail collagen, and the luminal epithelial cells were inoculated on the type Ⅰ mouse tail collagen to regenerate the endometrium in vitro. The regenerated endometrium was cultured in DMEM-F/12 media containing 100 nmol L-1 progesterone, 10 nM β-estradiol, and 10% fetal bovine serum (FBS) for 3 d. The media were then replaced with CZB containing 100 nM progesterone, 10 nmol L-1 β-estradiol, and 10% FBS, and the mouse blastulas were co-cultured with it. The results of scanning electronic micrography showed that the epithelial cells on the surface of the reconstructed endometrium were covered with numerous slender microvilli and some epithelial cells protruded pinopodes. After culturing for 12 h with the mouse blastula, the shedding, attachment, and implantation of the blastula were observed. The blastula can escape from zona pellucida and attach to the three-dimensional endometrium and is then implanted into it. Thisstudy showed that the reconstructed three-dimensional endometrium can serve as a robust embryo implantation model in vitro.

  4. Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis.

    Science.gov (United States)

    Wu, Xiaoli; Sandhu, Sumit; Nabi, Zinnatun; Ding, Hao

    2012-10-01

    Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic. PMID:22238064

  5. Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.

    Science.gov (United States)

    Morini, Elisabetta; Dietrich, Paula; Salani, Monica; Downs, Heather M; Wojtkiewicz, Gregory R; Alli, Shanta; Brenner, Anthony; Nilbratt, Mats; LeClair, John W; Oaklander, Anne Louise; Slaugenhaupt, Susan A; Dragatsis, Ioannis

    2016-03-15

    Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect. PMID:26769677

  6. Contamination weeping: A chemical ion exchange model

    International Nuclear Information System (INIS)

    Experiments have been conducted to determine the applicability of a chemical ion-exchange model to characterize the problem of nuclear fuel transportation cask contamination and release (''weeping''). Surface charge characteristics of Cr2O3 and stainless steel (304) powders have been measured to determine the potential for ion exchange at metal oxide -- aqueous interfaces. The solubility of pool contaminant Co and Cs electrolytes at varying pH and the adsorption characteristics of these ions on Cr2O3 and stainless steel powders in aqueous slurries have been studied. Experiments show that Co ions do reversibly adsorb on these powder surfaces and, more specifically, that adsorption occurs in the nominal pH range (pH = 4--6) of a boric acid-moderated spent fuel pool. Desorption has been demonstrated to occur at pH ≤ 3. Cs ions also have been shown to have an affinity for these surfaces although the reversibility of Cs+ bonding by H+ ion exchange has not been fully demonstrated. These results have significant implications for effective decontamination and coating processes used on nuclear fuel transportation casks. 9 refs., 5 figs., 1 tab

  7. A physiologically-based kinetic model for the prediction of plasma cholesterol concentrations in the mouse.

    Science.gov (United States)

    van de Pas, Niek C A; Woutersen, Ruud A; van Ommen, Ben; Rietjens, Ivonne M C M; de Graaf, Albert A

    2011-05-01

    The LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) concentrations are determined by the activity of a complex network of reactions in several organs. Physiologically-based kinetic (PBK) computational models can be used to describe these different reactions in an integrated, quantitative manner. A PBK model to predict plasma cholesterol levels in the mouse was developed, validated, and analyzed. Kinetic parameters required for defining the model were obtained using data from published experiments. To construct the model, a set of appropriate submodels was selected from a set of 65,536 submodels differing in the kinetic expressions of the reactions. A submodel was considered appropriate if it had the ability to correctly predict an increased or decreased plasma cholesterol level for a training set of 5 knockout mouse strains. The model thus defined consisted of 8 appropriate submodels and was validated using data from an independent set of 9 knockout mouse strains. The model prediction is the average prediction of 8 appropriate submodels. Remarkably, these submodels had in common that the rate of cholesterol transport from the liver to HDL was not dependent on hepatic cholesterol concentrations. The model appeared able to accurately predict in a quantitative way the plasma cholesterol concentrations of all 14 knockout strains considered, including the frequently used Ldlr-/- and Apoe-/- mouse strains. The model presented is a useful tool to predict the effect of knocking out genes that act in important steps in cholesterol metabolism on total plasma cholesterol, HDL-C and LDL-C in the mouse. PMID:21320632

  8. The chemical transport model Oslo CTM3

    Directory of Open Access Journals (Sweden)

    O. A. Søvde

    2012-06-01

    Full Text Available We present here the global chemical transport model Oslo CTM3, an update of the Oslo CTM2. The update comprises a faster transport scheme, an improved wet scavenging scheme for large scale rain, updated photolysis rates and a new lightning parameterization. Oslo CTM3 is better parallelized and allows for stable, large time steps for advection, enabling more complex or high resolution simulations. Thorough comparisons between the Oslo CTM3, Oslo CTM2 and measurements are performed, and in general the Oslo CTM3 is found to reproduce measurements well. Inclusion of tropospheric sulfur chemistry and nitrate aerosols in CTM3 is shown to be important to reproduce tropospheric O3, OH and the CH4 lifetime well. Using the same meteorology to drive the two models, shows that some features related to transport are better resolved by the CTM3, such as polar cap transport, while features like transport close to the vortex edge are resolved better in the Oslo CTM2 due to its required shorter transport time step. The longer transport time steps in CTM3 result in larger errors e.g. near the jets, and when necessary, this can be remedied by using a shorter time step. An additional, more accurate and time consuming, treatment of polar cap transport is presented, however, both perform acceptably. A new treatment of the horizontal distribution of lightning is presented and found to compare well with measurements. Vertical distributions of lighting are updated, and tested against the old vertical distribution. The new profiles are found to produce more NOx in the tropical middle troposphere, and less at the surface and at high altitudes.

  9. Chemoreception regulates chemical access to mouse vomeronasal organ: role of solitary chemosensory cells.

    Directory of Open Access Journals (Sweden)

    Tatsuya Ogura

    Full Text Available Controlling stimulus access to sensory organs allows animals to optimize sensory reception and prevent damage. The vomeronasal organ (VNO detects pheromones and other semiochemicals to regulate innate social and sexual behaviors. This semiochemical detection generally requires the VNO to draw in chemical fluids, such as bodily secretions, which are complex in composition and can be contaminated. Little is known about whether and how chemical constituents are monitored to regulate the fluid access to the VNO. Using transgenic mice and immunolabeling, we found that solitary chemosensory cells (SCCs reside densely at the entrance duct of the VNO. In this region, most of the intraepithelial trigeminal fibers innervate the SCCs, indicating that SCCs relay sensory information onto the trigeminal fibers. These SCCs express transient receptor potential channel M5 (TRPM5 and the phospholipase C (PLC beta2 signaling pathway. Additionally, the SCCs express choline acetyltransferase (ChAT and vesicular acetylcholine transporter (VAChT for synthesizing and packaging acetylcholine, a potential transmitter. In intracellular Ca2+ imaging, the SCCs responded to various chemical stimuli including high concentrations of odorants and bitter compounds. The responses were suppressed significantly by a PLC inhibitor, suggesting involvement of the PLC pathway. Further, we developed a quantitative dye assay to show that the amount of stimulus fluid that entered the VNOs of behaving mice is inversely correlated to the concentration of odorous and bitter substances in the fluid. Genetic knockout and pharmacological inhibition of TRPM5 resulted in larger amounts of bitter compounds entering the VNOs. Our data uncovered that chemoreception of fluid constituents regulates chemical access to the VNO and plays an important role in limiting the access of non-specific irritating and harmful substances. Our results also provide new insight into the emerging role of SCCs in

  10. Modeling release of chemicals from multilayer materials into food

    Directory of Open Access Journals (Sweden)

    Huang Xiu-Ling

    2016-01-01

    Full Text Available The migration of chemicals from materials into food is predictable by various mathematical models. In this article, a general mathematical model is developed to quantify the release of chemicals through multilayer packaging films based on Fick's diffusion. The model is solved numerically to elucidate the effects of different diffusivity values of different layers, distribution of chemical between two adjacent layers and between material and food, mass transfer at the interface of material and food on the migration process.

  11. T2 weighted MRI for assessing renal lesions in transgenic mouse models of tuberous sclerosis

    International Nuclear Information System (INIS)

    Objective: Transgenic mouse models of tuberous sclerosis (TSC) develop renal cysts, cystadenomas, solid adenomas and carcinomas. Identification and characterisation of these lesions in vivo may help in TSC pre-clinical trials. This study was to evaluate T2 weighted MRI for assessment of renal lesions in two Tsc mouse models. Materials and Methods: Tsc1+/−, Tsc2+/− and wild type mice were subjected to a first MRI scan at 12 months of age and a second scan 2 months later. One Tsc2+/− mouse was treated with rapamycin for two months after the initial scan. Immediately following the second scan, mice were sacrificed and MRI images were compared to renal histological findings. Results: MRI identified all types of Tsc-associated renal lesions in both Tsc1+/− and Tsc2+/− mice. The smallest detectable lesions were 3. Eighty three percent of all renal lesions detected in the first scan were re-identified in the second scan. By MRI, these lesions demonstrated significant growth in the 9 untreated Tsc1+/− and Tsc2+/− mice but shrinkage in the rapamycin treated Tsc2+/− mouse. Between the two scans, MRI also revealed significant increase in both the total number and volume of lesions in untreated mice and decrease in the rapamycin treated mouse, respectively. In comparison to histological analysis MRI detected most cysts and cystadenomas (66%) but only a minority of solid tumours (29%). Conclusion: These results suggest that T2 weighted MRI may be a useful tool for assessing some renal lesions in pre-clinical studies using Tsc mouse models. However, improved sensitivity for T2 weighted MRI is required, particularly for solid renal lesions

  12. T2 weighted MRI for assessing renal lesions in transgenic mouse models of tuberous sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Kalogerou, Maria; Zhang, Yadan; Yang, Jian; Garrahan, Nigel [Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN (United Kingdom); Paisey, Stephen; Tokarczuk, Paweł; Stewart, Andrew [School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX (United Kingdom); Gallacher, John [Department of Primary Care and Public Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4YS (United Kingdom); Sampson, Julian R. [Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN (United Kingdom); Shen, Ming Hong, E-mail: shenmh@cf.ac.uk [Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN (United Kingdom)

    2012-09-15

    Objective: Transgenic mouse models of tuberous sclerosis (TSC) develop renal cysts, cystadenomas, solid adenomas and carcinomas. Identification and characterisation of these lesions in vivo may help in TSC pre-clinical trials. This study was to evaluate T2 weighted MRI for assessment of renal lesions in two Tsc mouse models. Materials and Methods: Tsc1{sup +/−}, Tsc2{sup +/−} and wild type mice were subjected to a first MRI scan at 12 months of age and a second scan 2 months later. One Tsc2{sup +/−} mouse was treated with rapamycin for two months after the initial scan. Immediately following the second scan, mice were sacrificed and MRI images were compared to renal histological findings. Results: MRI identified all types of Tsc-associated renal lesions in both Tsc1{sup +/−} and Tsc2{sup +/−} mice. The smallest detectable lesions were <0.1 mm{sup 3}. Eighty three percent of all renal lesions detected in the first scan were re-identified in the second scan. By MRI, these lesions demonstrated significant growth in the 9 untreated Tsc1{sup +/−} and Tsc2{sup +/−} mice but shrinkage in the rapamycin treated Tsc2{sup +/−} mouse. Between the two scans, MRI also revealed significant increase in both the total number and volume of lesions in untreated mice and decrease in the rapamycin treated mouse, respectively. In comparison to histological analysis MRI detected most cysts and cystadenomas (66%) but only a minority of solid tumours (29%). Conclusion: These results suggest that T2 weighted MRI may be a useful tool for assessing some renal lesions in pre-clinical studies using Tsc mouse models. However, improved sensitivity for T2 weighted MRI is required, particularly for solid renal lesions.

  13. Human androgen deficiency: insights gained from androgen receptor knockout mouse models

    OpenAIRE

    Kesha Rana; Davey, Rachel A; Zajac, Jeffrey D

    2014-01-01

    The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immu...

  14. A Comparison of Neuroinflammation to Implanted Microelectrodes in Rat and Mouse Models

    OpenAIRE

    Potter-Baker, Kelsey A.; Ravikumar, Madhumitha; Burke, Alan A.; Meador, William D.; Householder, Kyle T.; Buck, Amy C.; Sunil, Smrithi; Stewart, Wade G.; Anna, Jake P.; Tomaszewski, William H.; Capadona, Jeffrey R.

    2014-01-01

    Rat models have emerged as a common tool to study neuroinflammation to intracortical microelectrodes. While a number of studies have attempted to understand the factors resulting in neuroinflammation using rat models, a complete understanding of key mechanistic pathways remains elusive. Transgenic mouse models, however, could facilitate a deeper understanding of mechanistic pathways due to an ease of genetic alteration. Therefore, the goal of the present study is to compare neuroinflammation ...

  15. Sexually Dimorphic, Developmental, and Chronobiological Behavioral Profiles of a Mouse Mania Model

    OpenAIRE

    Michael C Saul; Sharon A Stevenson; Gammie, Stephen C.

    2013-01-01

    Bipolar disorders are heritable psychiatric conditions often abstracted by separate animal models for mania and depression. The principal mania models involve transgenic manipulations or treatment with stimulants. An additional approach involves analysis of naturally occurring mania models including an inbred strain our lab has recently characterized, the Madison (MSN) mouse strain. These mice show a suite of behavioral and neural genetic alterations analogous to manic aspects of bipolar diso...

  16. Altered exploration and sensorimotor gating of the chakragati mouse model of schizophrenia

    OpenAIRE

    Young, Jared W.; RATTY, Anil; Gavin S Dawe; Geyer, Mark A.

    2014-01-01

    Schizophrenia is a prevalent neurodevelopmental psychiatric disorder with poor prognosis and limited understanding of its etiology. This limited etiological understanding renders developing animal models of schizophrenia difficult. While attempts are made to recreate putative etiologies in models, these models may only enable the generation of treatments targeted at the mechanisms manipulated. Although the chakragati mouse was not created as a result of a specific gene targe...

  17. Mouse model of ischemic acute kidney injury: technical notes and tricks

    OpenAIRE

    Wei, Qingqing; Zheng DONG

    2012-01-01

    Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models, both in vitro and in vivo, have been used to study the pathogenic mechanisms of ischemic AKI and to test renoprotective strategies. Among them, the mouse model of renal clamping is popular, mainly due to the availability of transgenic models and the relatively small animal size for drug testing. However, the ...

  18. Hypothalamic food intake regulation in a cancer-cachectic mouse model

    OpenAIRE

    Dwarkasing, Jvalini T; van Dijk, Miriam; Dijk, Francina J.; Boekschoten, Mark V.; Faber, Joyce; Argilès, Josep M.; Laviano, Alessandro; Müller, Michael; Witkamp, Renger F.; van Norren, Klaske

    2013-01-01

    Background Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an increased food intake subsequently to the loss of body weight. We hypothesise that in this model, appetite-regulating systems in the hypothalamus, which apparently fail in anorexia, are still able t...

  19. Rationale and Practical Techniques for Mouse Models of Early Vein Graft Adaptations

    OpenAIRE

    Yu, Peng; Nguyen, Binh T.; Tao, Ming; Campagna, Christina; Ozaki, C. Keith

    2010-01-01

    Mouse models serve as relatively new yet powerful research tools to study intimal hyperplasia and wall remodeling of vein bypass graft failure. Several model variations have been reported in the past decade. However, the approach demands thoughtful preparation, selected sophisticated equipment, microsurgical technical expertise, advanced tissue processing and data acquisition. This review compares several described models, and aims (building on our personal experiences) to practically aid the...

  20. Maternal separation with early weaning: a novel mouse model of early life neglect

    OpenAIRE

    Elwafi Hani M; Bordner Kelly A; George Elizabeth D; Simen Arthur A

    2010-01-01

    Abstract Background Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is...

  1. New Mouse Model May Aid in Developing Effective Therapies for Ovarian Cancer | Poster

    Science.gov (United States)

    By Frank Blanchard, Staff Writer A new genetically engineered mouse model appears promising as an effective tool for preclinical testing of novel therapies for ovarian cancer, which tends to be diagnosed in late stage. There are few effective treatments for the disease.

  2. Activity-Dependent Changes in MAPK Activation in the Angelman Syndrome Mouse Model

    Science.gov (United States)

    Filonova, Irina; Trotter, Justin H.; Banko, Jessica L.; Weeber, Edwin J.

    2014-01-01

    Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal "UBE3A" gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular…

  3. SOY ISOFLAVONES AND SAPONINS PROVIDE MODEST PROTECTION FROM COLON CANCER IN A MOUSE MODEL

    Science.gov (United States)

    Colon cancer risk is highly correlated with dietary factors. We have systematically investigated soy protein and bioactive compounds found in soy, isoflavones (IF) and saponins (SAP) using a mouse model of colon cancer. In previous studies, we found soy IF were protective of azoxymethane (AOM)-ind...

  4. Neuroprotective Effects of Voluntary Exercise in an Inherited Retinal Degeneration Mouse Model

    OpenAIRE

    Hanif, Adam M.; Lawson, Eric C.; Prunty, Megan; Gogniat, Marissa; Aung, Moe H.; Chakraborty, Ranjay; Boatright, Jeffrey H.; Pardue, Machelle T.

    2015-01-01

    Voluntary running wheel exercise significantly decreases the rate of photoreceptor degeneration and visual acuity loss associated with the rd10 mouse model. Furthermore, systemic administration of a TrkB antagonist, ANA-12, blocks the protective effects on structure and function.

  5. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

    Science.gov (United States)

    The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

  6. Comparative Exposure to Soy Biodiesel Emissions in an Allergic Mouse Model

    Science.gov (United States)

    We assessed the immunological effects following inhalation of emissions from 100% Soy biodiesel (S100) or a 20% mix with conventional petrodiesel (S20), in a house dust mite (HDM) allergic Balb/cJ mouse model. Female mice (8/group) were exposed whole body (4 hr/d, 5 d/wk, 4wk) to...

  7. A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta

    NARCIS (Netherlands)

    Abdolvahab, Mohadeseh Haji; Brinks, Vera; Schellekens, Huub

    2014-01-01

    Interferon beta may induce antibodies in multiple sclerosis patients and the incidence of immunogenicity depends on the type of product. These antibodies can reduce the efficacy of interferon beta. Two transgenic immune tolerant mouse models for human interferon beta (hIFNβ) (C57Bl/6, and C57Bl/6×FV

  8. Mouse models of graft-versus-host disease: advances and limitations

    Directory of Open Access Journals (Sweden)

    Mark A. Schroeder

    2011-05-01

    Full Text Available The limiting factor for successful hematopoietic stem cell transplantation (HSCT is graft-versus-host disease (GvHD, a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future.

  9. Local and systemic effects of angiotensin receptor blockade in an emphysema mouse model

    OpenAIRE

    Raupach, Tobias; Lüthje, Lars; Kögler, Harald; de Duve, Christian; Schweda, Frank; Hasenfuß, Gerd; Andreas, Stefan

    2011-01-01

    Abstract Objectives COPD with emphysema causes marked neurohumoral activation. Angiotensin II receptors are highly expressed within the lung and interfere with mechanisms involved in the progression of emphysema. This study examined the effects of an angiotensin II receptor blocker (ARB) on pulmonary and systemic manifestations of emphysema in a mouse model. Methods Female NMRI mice received five intratracheal instillations of porcine pancreatic ela...

  10. The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models

    International Nuclear Information System (INIS)

    The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200 mg/kg. Blood, liver and kidney samples were obtained at 24 h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity. - Highlights: • New mouse models were developed with varying P450 activities in the proximal tubule. • These mouse models were treated with chloroform, a nephrotoxicant. • Studies showed the importance of local P450s in chloroform-induced nephrotoxicity

  11. The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Senyan [Kidney Institute and Division of Nephrology, Changzheng Hospital, Shanghai 200003 (China); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States); Yao, Yunyi; Lu, Shijun; Aldous, Kenneth; Ding, Xinxin [Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States); Mei, Changlin, E-mail: chlmei1954@126.com [Kidney Institute and Division of Nephrology, Changzheng Hospital, Shanghai 200003 (China); Gu, Jun, E-mail: jungu@wadsworth.org [Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States)

    2013-10-01

    The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200 mg/kg. Blood, liver and kidney samples were obtained at 24 h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity. - Highlights: • New mouse models were developed with varying P450 activities in the proximal tubule. • These mouse models were treated with chloroform, a nephrotoxicant. • Studies showed the importance of local P450s in chloroform-induced nephrotoxicity.

  12. In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models

    OpenAIRE

    Brož, Daniela Kenzelmann; Attardi, Laura D.

    2010-01-01

    p53 is a crucial tumor suppressor, as evidenced by the high propensity for p53 mutation during human cancer development. Already more than a decade ago, p53 knockout mice confirmed that p53 is critical for preventing tumorigenesis. More recently, a host of p53 knock-in mouse strains has been generated, with the aim of either more precisely modeling p53 mutations in human cancer or better understanding p53's regulation and downstream activities. In the first category, several mouse strains exp...

  13. Defective Surfactant Secretion in a Mouse Model of Hermansky-Pudlak Syndrome

    OpenAIRE

    Guttentag, Susan H.; Akhtar, Amana; Tao, Jian-Qin; Atochina, Elena; Rusiniak, Michael E.; Swank, Richard T.; Bates, Sandra R.

    2005-01-01

    Hermansky-Pudlak syndrome (HPS) in humans represents a family of disorders of lysosome-related organelle biogenesis associated with severe, progressive pulmonary disease. Human case reports and a mouse model of HPS, the pale ear/pearl mouse (ep/pe), exhibit giant lamellar bodies (GLB) in type II alveolar epithelial cells. We examined surfactant proteins and phospholipid from ep/pe mice to elucidate the process of GLB formation. The 2.8-fold enrichment of tissue phospholipids in ep/pe mice res...

  14. Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease

    Science.gov (United States)

    Ambade, Aditya; Satishchandran, Abhishek; Gyongyosi, Benedek; Lowe, Patrick; Szabo, Gyongyi

    2016-01-01

    AIM: To establish a mouse model of alcohol-driven hepatocellular carcinoma (HCC) that develops in livers with alcoholic liver disease (ALD). METHODS: Adult C57BL/6 male mice received multiple doses of chemical carcinogen diethyl nitrosamine (DEN) followed by 7 wk of 4% Lieber-DeCarli diet. Serum alanine aminotransferase (ALT), alpha fetoprotein (AFP) and liver Cyp2e1 were assessed. Expression of F4/80, CD68 for macrophages and Ly6G, MPO, E-selectin for neutrophils was measured. Macrophage polarization was determined by IL-1β/iNOS (M1) and Arg-1/IL-10/CD163/CD206 (M2) expression. Liver steatosis and fibrosis were measured by oil-red-O and Sirius red staining respectively. HCC development was monitored by magnetic resonance imaging, confirmed by histology. Cellular proliferation was assessed by proliferating cell nuclear antigen (PCNA). RESULTS: Alcohol-DEN mice showed higher ALTs than pair fed-DEN mice throughout the alcohol feeding without weight gain. Alcohol feeding resulted in increased ALT, liver steatosis and inflammation compared to pair-fed controls. Alcohol-DEN mice had reduced steatosis and increased fibrosis indicating advanced liver disease. Molecular characterization showed highest levels of both neutrophil and macrophage markers in alcohol-DEN livers. Importantly, M2 macrophages were predominantly higher in alcohol-DEN livers. Magnetic resonance imaging revealed increased numbers of intrahepatic cysts and liver histology confirmed the presence of early HCC in alcohol-DEN mice compared to all other groups. This correlated with increased serum alpha-fetoprotein, a marker of HCC, in alcohol-DEN mice. PCNA immunostaining revealed significantly increased hepatocyte proliferation in livers from alcohol-DEN compared to pair fed-DEN or alcohol-fed mice. CONCLUSION: We describe a new 12-wk HCC model in adult mice that develops in livers with alcoholic hepatitis and defines ALD as co-factor in HCC. PMID:27122661

  15. The relationship between chemically-induced meiotic delay and aneuploidy in mouse oocytes and zygotes

    Energy Technology Data Exchange (ETDEWEB)

    Mailhes, J.B.; Marchetti, F. [Louisiana State Univ. Medical Center, Shreveport, LA (United States)

    1993-12-31

    Aneuploidy is a relatively common genetic disorder that results in human morbidity and mortality. Approximately 30% of embryonic and fetal deaths and 3.45 per thousand livebirths are associated with an abnormal number of chromosomes. Unfortunately, very little is known about the etiology and mechanism of chromosome missegregation. This situation dictates that considerable research be directed toward understanding the causes of aneuploidy. Although several hypotheses have been advanced for the etiology of aneuploidy, there still exists a paucity of information about the direct cuases and mechanisms of aneuploidy production. Without such specific knowledge, there is little hope of reducing the incidence of aneuploidy in humans. Some progress has been made. We now know that various chemicals can induce aneuploidy by interacting with certain cellular organelles, especially components of the spindle apparatus. These results have been demonstrated in various organisms and cell types both in vivo and in vitro. Since the ultimate objective of aneuploidy research is to obtain information that can be used to reduce the aneuploidy burden in humans, we have concentrated our research efforts on studying chemically-induced aneuploidy in mammalian germ cells and zygotes.

  16. Ganglioside GD2-specific trifunctional surrogate antibody Surek demonstrates therapeutic activity in a mouse melanoma model

    Directory of Open Access Journals (Sweden)

    Ruf Peter

    2012-11-01

    Full Text Available Abstract Background Trifunctional bispecific antibodies (trAb are a special class of bispecific molecules recruiting and activating T cells and accessory immune cells simultaneously at the targeted tumor. The new trAb Ektomab that targets the melanoma-associated ganglioside antigen GD2 and the signaling molecule human CD3 (hCD3 on T cells demonstrated potent T-cell activation and tumor cell destruction in vitro. However, the relatively low affinity for the GD2 antigen raised the question of its therapeutic capability. To further evaluate its efficacy in vivo it was necessary to establish a mouse model. Methods We generated the surrogate trAb Surek, which possesses the identical anti-GD2 binding arm as Ektomab, but targets mouse CD3 (mCD3 instead of hCD3, and evaluated its chemical and functional quality as a therapeutic antibody homologue. The therapeutic and immunizing potential of Surek was investigated using B78-D14, a B16 melanoma transfected with GD2 and GD3 synthases and showing strong GD2 surface expression. The induction of tumor-associated and autoreactive antibodies was evaluated. Results Despite its low affinity of approximately 107 M-1 for GD2, Surek exerted efficient tumor cell destruction in vitro at an EC50 of 70ng/ml [0.47nM]. Furthermore, Surek showed strong therapeutic efficacy in a dose-dependent manner and is superior to the parental GD2 mono-specific antibody, while the use of a control trAb with irrelevant target specificity had no effect. The therapeutic activity of Surek was strictly dependent on CD4+ and CD8+ T cells, and cured mice developed a long-term memory response against a second challenge even with GD2-negative B16 melanoma cells. Moreover, tumor protection was associated with humoral immune responses dominated by IgG2a and IgG3 tumor-reactive antibodies indicating a Th1-biased immune response. Autoreactive antibodies against the GD2 target antigen were not induced. Conclusion Our data suggest that Surek revealed

  17. Chemical Leasing business models and corporate social responsibility.

    Science.gov (United States)

    Moser, Frank; Jakl, Thomas; Joas, Reihard; Dondi, Francesco

    2014-11-01

    Chemical Leasing is a service-oriented business model that shifts the focus from increasing sales volume of chemicals towards a value-added approach. Recent pilot projects have shown the economic benefits of introducing Chemical Leasing business models in a broad range of sectors. A decade after its introduction, the promotion of Chemical Leasing is still predominantly done by the public sector and international organizations. We show in this paper that awareness-raising activities to disseminate information on this innovative business model mainly focus on the economic benefits. We argue that selling Chemical Leasing business models solely on the grounds of economic and ecological considerations falls short of branding it as a corporate social responsibility initiative, which, for this paper, is defined as a stakeholder-oriented concept that extends beyond the organization's boundaries and is driven by an ethical understanding of the organization's responsibility for the impact of its business activities. For the analysis of Chemical Leasing business models, we introduce two case studies from the water purification and metal degreasing fields, focusing on employees and local communities as two specific stakeholder groups of the company introducing Chemical Leasing. The paper seeks to demonstrate that Chemical Leasing business models can be branded as a corporate social responsibility initiative by outlining the vast potential of Chemical Leasing to improve occupational health and safety and to strengthen the ability of companies to protect the environment from the adverse effects of the chemicals they apply. PMID:24943884

  18. A chemical model of meteoric ablation

    Directory of Open Access Journals (Sweden)

    T. Vondrak

    2008-07-01

    Full Text Available Most of the extraterrestrial dust entering the Earth's atmosphere ablates to produce metal vapours, which have significant effects on the aeronomy of the upper mesosphere and lower thermosphere. A new Chemical Ablation Model (CAMOD is described which treats the physics and chemistry of ablation, by including the following processes: sputtering by inelastic collisions with air molecules before the meteoroid melts; evaporation of atoms and oxides from the molten particle; diffusion-controlled migration of the volatile constituents (Na and K through the molten particle; and impact ionization of the ablated fragments by hyperthermal collisions with air molecules. Evaporation is based on thermodynamic equilibrium in the molten meteoroid (treated as a melt of metal oxides, and between the particle and surrounding vapour phase. The loss rate of each element is then determined assuming Langmuir evaporation. CAMOD successfully predicts the meteor head echo appearance heights, observed from incoherent scatter radars, over a wide range of meteoroid velocities. The model also confirms that differential ablation explains common-volume lidar observations of K, Ca and Ca+ in fresh meteor trails. CAMOD is then used to calculate the injection rates into the atmosphere of a variety of elements as a function of altitude, integrated over the meteoroid mass and velocity distributions. The most abundant elements (Fe, Mg and Si have peak injection rates around 85 km, with Na and K about 8 km higher. The more refractory element Ca ablates around 82 km with a Na:Ca ratio of 4:1, which does therefore not explain the depletion of atomic Ca to Na, by more than 2 orders of magnitude, in the upper mesosphere. Diffusion of the most volatile elements (Na and K does not appear to be rate-limiting except in the fastest meteoroids. Non-thermal sputtering causes ~35% mass loss from the fastest (~60–70 km s−1 and smallest (10−17–10

  19. A Mouse Model for Studying Nutritional Programming: Effects of Early Life Exposure to Soy Isoflavones on Bone and Reproductive Health.

    Science.gov (United States)

    Ward, Wendy E; Kaludjerovic, Jovana; Dinsdale, Elsa C

    2016-01-01

    Over the past decade, our research group has characterized and used a mouse model to demonstrate that "nutritional programming" of bone development occurs when mice receive soy isoflavones (ISO) during the first days of life. Nutritional programming of bone development can be defined as the ability for diet during early life to set a trajectory for better or compromised bone health at adulthood. We have shown that CD-1 mice exposed to soy ISO during early neonatal life have higher bone mineral density (BMD) and greater trabecular inter-connectivity in long bones and lumbar spine at young adulthood. These skeletal sites also withstand greater forces before fracture. Because the chemical structure of ISO resembles that of 17-β-estradiol and can bind to estrogen receptors in reproductive tissues, it was prudent to expand analyses to include measures of reproductive health. This review highlights aspects of our studies in CD-1 mice to understand the early life programming effects of soy ISO on bone and reproductive health. Preclinical mouse models can provide useful data to help develop and guide the design of studies in human cohorts, which may, depending on findings and considerations of safety, lead to dietary interventions that optimize bone health. PMID:27187422

  20. A Mouse Model for Studying Nutritional Programming: Effects of Early Life Exposure to Soy Isoflavones on Bone and Reproductive Health

    Science.gov (United States)

    Ward, Wendy E.; Kaludjerovic, Jovana; Dinsdale, Elsa C.

    2016-01-01

    Over the past decade, our research group has characterized and used a mouse model to demonstrate that “nutritional programming” of bone development occurs when mice receive soy isoflavones (ISO) during the first days of life. Nutritional programming of bone development can be defined as the ability for diet during early life to set a trajectory for better or compromised bone health at adulthood. We have shown that CD-1 mice exposed to soy ISO during early neonatal life have higher bone mineral density (BMD) and greater trabecular inter-connectivity in long bones and lumbar spine at young adulthood. These skeletal sites also withstand greater forces before fracture. Because the chemical structure of ISO resembles that of 17-β-estradiol and can bind to estrogen receptors in reproductive tissues, it was prudent to expand analyses to include measures of reproductive health. This review highlights aspects of our studies in CD-1 mice to understand the early life programming effects of soy ISO on bone and reproductive health. Preclinical mouse models can provide useful data to help develop and guide the design of studies in human cohorts, which may, depending on findings and considerations of safety, lead to dietary interventions that optimize bone health. PMID:27187422

  1. Development and function of human innate immune cells in a humanized mouse model

    Science.gov (United States)

    Rongvaux, Anthony; Willinger, Tim; Martinek, Jan; Strowig, Till; Gearty, Sofia V.; Teichmann, Lino L.; Saito, Yasuyuki; Marches, Florentina; Halene, Stephanie; Palucka, A. Karolina; Manz, Markus G.; Flavell, Richard A.

    2014-01-01

    Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models are unable to support development of human innate immune cells, including myeloid cells and NK cells. Here we describe a mouse strain, called MI(S)TRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked in to their respective mouse loci. The human cytokines support the development and function of monocytes/macrophages and natural killer cells derived from human fetal liver or adult CD34+ progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MI(S)TRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology. PMID:24633240

  2. Small-diameter biodegradable scaffolds for functional vascular tissue engineering in the mouse model.

    Science.gov (United States)

    Roh, Jason D; Nelson, Gregory N; Brennan, Matthew P; Mirensky, Tamar L; Yi, Tai; Hazlett, Tyrone F; Tellides, George; Sinusas, Albert J; Pober, Jordan S; Saltzman, W M; Kyriakides, Themis R; Breuer, Christopher K

    2008-04-01

    The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (ID) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester sealant scaled for use in a mouse model. Scaffolds constructed from either polyglycolic acid or poly-l-lactic acid nonwoven felts demonstrated sufficient porosity, biomechanical profile, and biocompatibility to function as vascular grafts. The scaffolds implanted as either inferior vena cava or aortic interposition grafts in SCID/bg mice demonstrated excellent patency without evidence of thromboembolic complications or aneurysm formation. A foreign body immune response was observed with marked macrophage infiltration and giant cell formation by post-operative week 3. Organized vascular neotissue, consisting of endothelialization, medial generation, and collagen deposition, was evident within the internal lumen of the scaffolds by post-operative week 6. These results present the ability to create sub-1mm ID biodegradable tubular scaffolds that are functional as vascular grafts, and provide an experimental approach for the study of vascular tissue engineering using mouse models. PMID:18164056

  3. Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay

    Science.gov (United States)

    The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing development...

  4. Chemical weather forecasting: a new concept of integrated modelling

    OpenAIRE

    Baklanov, A.

    2010-01-01

    During the last decade a new field of atmospheric modelling – the chemical weather forecasting (CWF) – is quickly developing and growing. However, in the most of the current studies and publications, this field is considered in a simplified concept of the off-line running chemical transport models with operational numerical weather prediction (NWP) data as a driver. A new concept and methodology considering the chemical weather as two-way interacting meteorologic...

  5. Development of regionalized multimedia chemical fate models for China

    OpenAIRE

    Zhu, Ying

    2016-01-01

    To balance the economic development with environmental safety and human health, China has released chemicals management legislation for which chemical prioritization and risk assessment are key issues. To support these ambitions two versions of an environmental fate and behaviour model SESAMe (Sino Evaluative Simplebox-MAMI models), have been developed with different resolutions and structures in this thesis. SESAMe is applied to hypothetical chemicals to investigate the influence of environm...

  6. Humanized Mouse Models to Study Cell-Mediated Immune Responses to Liver-Stage Malaria Vaccines.

    Science.gov (United States)

    Good, Michael F; Hawkes, Michael T; Yanow, Stephanie K

    2015-11-01

    Malaria vaccine development is hampered by the lack of small animal models that recapitulate human immune responses to Plasmodium falciparum. We review the burgeoning literature on humanized mice for P. falciparum infection, including challenges in engraftment of human immune cells, hepatocytes, and erythrocytes. Recent advances in immune-compromised mouse models and stem cell technology have already enabled proof of concept that the entire parasite life cycle can be sustained in a murine model and that adaptive human immune responses to several parasite stages can be measured. Nonetheless, optimization is needed to achieve a reproducible and relevant murine model for malaria vaccine development. This review is focused on the complexities of T cell development in a mouse humanized with both a lymphoid system and hepatocytes. An understanding of this will facilitate the use of humanized mice in the development of liver-stage vaccines. PMID:26458783

  7. Application of Novel Rotation Angular Model for 3D Mouse System Based on MEMS Accelerometers

    Institute of Scientific and Technical Information of China (English)

    QIAN Li; CHEN Wen-yuan; XU Guo-ping

    2009-01-01

    A new scheme is proposed to model 3D angular motion of a revolving regular object with miniature, low-cost micro electro mechanical systems (MEMS) accelerometers (instead of gyroscope), which is employed in 3D mouse system. To sense 3D angular motion, the static property of MEMS accelerometer, sensitive to gravity acceleration, is exploited. With the three outputs of configured accelerometers, the proposed model is implemented to get the rotary motion of the rigid object. In order to validate the effectiveness of the proposed model, an input device is developed with the configuration of the scheme. Experimental results show that a simulated 3D cube can accurately track the rotation of the input device. The result indicates the feasibility and effectiveness of the proposed model in the 3D mouse system.

  8. Immune Response to Human Metapneumovirus Infection: What We Have Learned from the Mouse Model

    Directory of Open Access Journals (Sweden)

    Nagarjuna R. Cheemarla

    2015-09-01

    Full Text Available Human Metapneumovirus (hMPV is a leading respiratory viral pathogen associated with bronchiolitis, pneumonia, and asthma exacerbation in young children, the elderly and immunocompromised individuals. The development of a potential vaccine against hMPV requires detailed understanding of the host immune system, which plays a significant role in hMPV pathogenesis, susceptibility and vaccine efficacy. As a result, animal models have been developed to better understand the mechanisms by which hMPV causes disease. Several animal models have been evaluated and established so far to study the host immune responses and pathophysiology of hMPV infection. However, inbred laboratory mouse strains have been one of the most used animal species for experimental modeling and therefore used for the studies of immunity and immunopathogenesis to hMPV. This review summarizes the contributions of the mouse model to our understanding of the immune response against hMPV infection.

  9. Voltammetry as a Model for Teaching Chemical Instrumentation.

    Science.gov (United States)

    Gunasingham, H.; Ang, K. P.

    1985-01-01

    Voltammetry is used as a model for teaching chemical instrumentation to chemistry undergraduates at the National University of Singapore. Lists six criteria used to select a successful teaching model and shows how voltammetry satisfies each criterion. (JN)

  10. A Novel Bioluminescence Orthotopic Mouse Model for Advanced Lung Cancer

    OpenAIRE

    Li, Bo; Torossian, Artour; Li, Wenyan; Schleicher, Stephen; Niu, Kathy; Giacalone, Nicholas J; Kim, Sung June; Chen, Heidi; Gonzalez, Adriana; Moretti, Luigi; Lu, Bo

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model ...

  11. Ghrelin and eating behavior: evidence and insights from genetically-modified mouse models

    OpenAIRE

    Aki eUchida; Zigman, Jeffrey M.; Mario ePerello

    2013-01-01

    Ghrelin is an octanoylated peptide hormone, produced by endocrine cells of the stomach, which acts in the brain to increase food intake and body weight. Our understanding of the mechanisms underlying ghrelin’s effects on eating behaviors has been greatly improved by the generation and study of several genetically manipulated mouse models.These models include mice overexpressing ghrelin and also mice with genetic deletion of ghrelin, the ghrelin receptor [the growth hormone secretagogue recep...

  12. Infertility in Females with Cystic Fibrosis Is Multifactorial: Evidence from Mouse Models

    OpenAIRE

    Hodges, Craig A.; Palmert, Mark R.; Drumm, Mitchell L.

    2008-01-01

    Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men with CF has been thoroughly investigated, the infertility observed in women with CF has not been well studied. To investigate female infertility associated with CF, we used two independently derived mouse models of CF. Both of these models displayed decreased fertility characterized by a reduction in litter number and litter size. Our findings suggest that much of the reduced fertility in these mice orig...

  13. Optimized Mouse Model for the Imaging of Tumor Metastasis upon Experimental Therapy

    OpenAIRE

    Sergio Lavilla-Alonso; Usama Abo-Ramadan; Juha Halavaara; Sophie Escutenaire; Turgut Tatlisumak; Kalle Saksela; Anna Kanerva; Akseli Hemminki; Sari Pesonen

    2011-01-01

    Development of new cancer treatments focuses increasingly on the relation of cancer tissue with its microenvironment. A major obstacle for the development of new anti-cancer therapies has been the lack of relevant animal models that would reproduce all the events involved in disease progression from the early-stage primary tumor until the development of mature metastatic tissue. To this end, we have developed a readily imageable mouse model of colorectal cancer featuring highly reproducible f...

  14. Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration

    OpenAIRE

    Hesketh, Emily E.; Czopek, Alicja; Clay, Michael; Borthwick, Gary; Ferenbach, David; Kluth, David; Hughes, Jeremy

    2014-01-01

    Renal ischaemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in patients and occlusion of renal blood flow is unavoidable during renal transplantation. Experimental models that accurately and reproducibly recapitulate renal IRI are crucial in dissecting the pathophysiology of AKI and the development of novel therapeutic agents. Presented here is a mouse model of renal IRI that results in reproducible AKI. This is achieved by a midline laparotomy approach for the sur...

  15. Bladder Dysfunction in a Transgenic Mouse Model of Multiple System Atrophy

    OpenAIRE

    Boudes, Mathieu; Uvin, Pieter; Pinto, Silvia; Voets, Thomas; Fowler, Clare J.; Gregor K. Wenning; De Ridder, Dirk; Stefanova, Nadia

    2013-01-01

    Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α-synucleinopathy and define its applicability as a preclinical model...

  16. Establishment of mouse lung tumor models and development of new therapeutic approaches

    OpenAIRE

    Savai, Rajkumar

    2005-01-01

    Two mouse models of lung cancer were used to investigate cancer progression, cancer treatment, and cancer imaging. One model was established by subcutaneous injection of human adenocarcinoma A549 cells and lewis lung carcinoma (LLC1) cells, the other by intratracheal instillation of LLC1 cells. In the first study, the role of HIF-1 in tumor progression was investigated. Overexpression of HIF-1alpha by genetic alteration of adenocarcinoma cells decreased tumor size, due to decreased pr...

  17. Photodynamic therapy for breast cancer in a BALB/c mouse model

    OpenAIRE

    Ahn, Tae-Gyu; Lee, Byoung-Rai; Choi, Eun-Young; Kim, Dong Won; Han, Sei-Jun

    2012-01-01

    Objective Photodynamic therapy (PDT) has been used for superficial neoplasms and its usage has been recently extended to deeper lesions. The purpose of this study was to observe whether or not PDT can cure breast cancer in the solid tumor model, and to define the critical point of laser amount for killing the cancer cells. Methods Twenty four BALB/c mouse models with subcutaneous EMT6 mammary carcinomas were prepared. Mice were divided into eight groups depending on the amount of illumination...

  18. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression

    OpenAIRE

    Flavie eDarcet; Indira eMendez-David; Laurent eTritschler; Gardier, Alain M.; Jean-Philippe eGuilloux; Denis Joseph David

    2014-01-01

    Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders. Such deficits have been observed in various animal models based on environmental stress.Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel object r...

  19. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression

    OpenAIRE

    Darcet, Flavie; Mendez-David, Indira; Tritschler, Laurent; Gardier, Alain M.; Guilloux, Jean-Philippe; David, Denis J.

    2014-01-01

    Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel ...

  20. Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

    OpenAIRE

    Bertrand Perroud; Paymaan Jafar-Nejad; Wikoff, William R.; Gatchel, Jennifer R.; Lu Wang; Barupal, Dinesh K.; Juan Crespo-Barreto; Oliver Fiehn; Zoghbi, Huda Y.; Rima Kaddurah-Daouk

    2013-01-01

    We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+)). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatogra...

  1. DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Tyler eCash-Padgett

    2013-09-01

    Full Text Available DISC1 was discovered in a Scottish pedigree in which a chromosomal translocation that breaks this gene segregates with psychiatric disorders, mainly depression and schizophrenia. Linkage and association studies in diverse populations support DISC1 as a susceptibility gene to a variety of neuropsychiatric disorders. Many Disc1 mouse models have been generated to study its neuronal functions. These mouse models display variable phenotypes, some of them relevant to schizophrenia, others to depression.The Disc1 mouse models are popular genetic models for studying gene-environment interactions in schizophrenia. Five different Disc1 models have been combined with environmental factors. The environmental stressors employed can be classified as either early immune activation or later social paradigms. These studies cover major time points along the neurodevelopmental trajectory: prenatal, early postnatal, adolescence, and adulthood. Various combinations of molecular, anatomical and behavioral methods have been used to assess the outcomes. Additionally, three of the studies sought to rescue the resulting abnormalities.Here we provide background on the environmental paradigms used, summarize the results of these studies combining Disc1 mouse models with environmental stressors and discuss what we can learn and how to proceed. A major question is how the genetic and environmental factors determine which psychiatric disorder will be clinically manifested. To address this we can take advantage of the many Disc1 models available and expose them to the same environmental stressor. The complementary experiment would be to expose the same model to different environmental stressors. DISC1 is an ideal gene for this approach, since in the Scottish pedigree the same chromosomal translocation results in different psychiatric conditions.

  2. Genetically engineered mouse models for skin research: taking the next step

    OpenAIRE

    Chen, Jiang; Roop, Dennis R.

    2008-01-01

    Genetically engineered mouse models are invaluable to investigators in nearly all areas of biomedical research. The use of genetically engineered mice has allowed researchers to explore fundamental functions of genes in a mammal that shares substantial similarities with human physiology and pathology. Genetically engineered mice are often used as animal models of human diseases that are vital tools in investigating disease development and in developing and testing novel therapies. Gene target...

  3. Bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy

    OpenAIRE

    Noe, Natalie; Dillon, Lloye; Lellek, Veronika; Diaz, Francisca; Hida, Aline; Carlos T. Moraes; Wenz, Tina

    2012-01-01

    Mitochondrial dysfunction frequently affects the central nervous system. Here, we investigated the effect of bezafibrate treatment on neuronal mitochondrial function and its impact on the progression of a mitochondrial encephalopathy. We used a murine model with a forebrain-specific cytochrome c oxidase deficiency caused by conditional deletion of the COX10 gene. In this mouse model, bezafibrate-administration improved the phenotype of the mice associated with an increase in mitochondrial pro...

  4. Protective Properties of 2-Acetylcyclopentanone in a Mouse Model of Acetaminophen Hepatotoxicity

    OpenAIRE

    Zhang, Lihai; Gavin, Terrence; Geohagen, Brian C.; Liu, Qiang; Downey, Katherine J.; LoPachin, Richard M.

    2013-01-01

    Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile- or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with ...

  5. AKT1E17K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer

    Science.gov (United States)

    Malanga, Donatella; Belmonte, Stefania; Colelli, Fabiana; Scarfò, Marzia; De Marco, Carmela; Oliveira, Duarte Mendes; Mirante, Teresa; Camastra, Caterina; Gagliardi, Monica; Rizzuto, Antonia; Mignogna, Chiara; Paciello, Orlando; Papparella, Serenella; Fagman, Henrik; Viglietto, Giuseppe

    2016-01-01

    The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6–2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype. PMID:26859676

  6. The chemical coding of 5-hydroxytryptamine containing enteroendocrine cells in the mouse gastrointestinal tract.

    Science.gov (United States)

    Reynaud, Yohan; Fakhry, Josiane; Fothergill, Linda; Callaghan, Brid; Ringuet, Mitchell; Hunne, Billie; Bravo, David M; Furness, John B

    2016-06-01

    The majority of 5-HT (serotonin) in the body is contained in enteroendocrine cells of the gastrointestinal mucosa. From the time of their discovery over 80 years ago, the 5-HT-containing cells have been regarded as a class of cell that is distinct from enteroendocrine cells that contain peptide hormones. However, recent studies have cast doubt on the concept of there being distinct classes of enteroendocrine cells, each containing a single hormone or occasionally more than one hormone. Instead, data are rapidly accumulating that there are complex patterns of colocalisation of hormones that identify multiple subclasses of enteroendocrine cells. In the present work, multiple labelling immunohistochemistry is used to investigate patterns of colocalisation of 5-HT with enteric peptide hormones. Over 95 % of 5-HT cells in the duodenum also contained cholecystokinin and about 40 % of them also contained secretin. In the jejunum, about 75 % of 5-HT cells contained cholecystokinin but not secretin and 25 % contained 5-HT plus both cholecystokinin and secretin. Small proportions of 5-HT cells contained gastrin or somatostatin in the stomach, PYY or GLP-1 in the small intestine and GLP-1 or somatostatin in the large intestine. Rare or very rare 5-HT cells contained ghrelin (stomach), neurotensin (small and large intestines), somatostatin (small intestine) and PYY (in the large intestine). It is concluded that 5-HT-containing enteroendocrine cells are heterogeneous in their chemical coding and by implication in their functions. PMID:26803512

  7. Property Modelling for Applications in Chemical Product and Process Design

    DEFF Research Database (Denmark)

    Gani, Rafiqul

    group parameter is missing, the atom connectivity based model is employed to predict the missing group interaction. In this way, a wide application range of the property modeling tool is ensured. Based on the property models, targeted computer-aided techniques have been developed for design and analysis...... of organic chemicals, polymers, mixtures as well as separation processes. The presentation will highlight the framework (ICAS software) for property modeling, the property models and issues such as prediction accuracy, flexibility, maintenance and updating of the database. Also, application issues......Physical-chemical properties of pure chemicals and their mixtures play an important role in the design of chemicals based products and the processes that manufacture them. Although, the use of experimental data in design and analysis of chemicals based products and their processes is desirable...

  8. Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa.

    Science.gov (United States)

    Roche, Sarah L; Wyse-Jackson, Alice C; Byrne, Ashleigh M; Ruiz-Lopez, Ana M; Cotter, Thomas G

    2016-01-01

    Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period. We report novel findings that the mutation in the rd10 mouse results in retinal abnormalities earlier than was previously thought. Defects in rod and cone outer segments, bipolar cells, amacrine cells and photoreceptor synapses were apparent in the retina during early stages of postnatal retinal development and prior to the loss of photoreceptors. Additionally, we observed a dramatic response of glial cells during this period. Microglia responded as early as postnatal day (P) 5; ?13 days before any photoreceptor loss is detected with Müller glia and astrocytes exhibiting changes from P10 and P15 respectively. Overall, these findings present pathological aspects to the postnatal development of the rd10 retina, contributing significantly to our understanding of disease onset and progression in the rd10 mouse and provide a valuable resource for the study of retinal dystrophies. PMID:27160072

  9. A Mathematical Model of Skeletal Muscle Disease and Immune Response in the mdx Mouse

    Directory of Open Access Journals (Sweden)

    Abdul Salam Jarrah

    2014-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.

  10. Modelling Human Exposure to Chemicals in Food

    NARCIS (Netherlands)

    Slob W

    1993-01-01

    Exposure to foodborne chemicals is often estimated using the average consumption pattern in the human population. To protect the human population instead of the average individual, however, interindividual variability in consumption behaviour must be taken into account. This report shows how food

  11. Sodium homeostasis is preserved in a global 11β-hydroxysteroid dehydrogenase type 1 knockout mouse model

    DEFF Research Database (Denmark)

    Christensen, Thorbjørn H; Bailey, Matthew A; Kenyon, Christopher J;

    2015-01-01

    global deletion of 11βHSD1 in the mouse would give rise to a salt-wasting renal phenotype. What is the main finding and its importance? We subjected a mouse model of global 11βHSD1 deletion to studies of water and electrolyte balance, renal clearance, urinary steroid excretion, renin-angiotensin system...

  12. A genetically humanized mouse model for hepatitis C virus infection

    OpenAIRE

    Dorner, Marcus; Horwitz, Joshua A.; Robbins, Justin B.; Barry, Walter T.; Feng, Qian; Mu, Kathy; Jones, Christopher T.; Schoggins, John W.; Catanese, Maria Teresa; Burton, Dennis R.; Law, Mansun; Rice, Charles M.; Ploss, Alexander

    2011-01-01

    Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. While xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin (OCLN) comprise the minimal human factors required to re...

  13. A model for gas and nutrient exchange in the chorionic vasculature system of the mouse placenta

    Science.gov (United States)

    Mirbod, Parisa; Sled, John

    2015-11-01

    The aim of this study is to develop an analytical model for the oxygen and nutrient transport from the umbilical cord to the small villous capillaries. The nutrient and carbon dioxide removal from the fetal cotyledons in the mouse placental system has also been considered. This model describes the mass transfer between the fetal and the maternal red blood cells in the chorionic arterial vasculature system. The model reveals the detail fetal vasculature system and its geometry and the precise mechanisms of mass transfer through the placenta. The dimensions of the villous capillaries, the total length of the villous trees, the total villi surface area, and the total resistance to mass transport in the fetal villous trees has also been defined. This is the first effort to explain the reason why there are at least 7 lobules in the mouse placenta from the fluid dynamics point of view.

  14. Breeding a PKU-mouse model on Phe-free diet, is it possible?

    DEFF Research Database (Denmark)

    Dagnæs-Hansen, Frederik; Johansen, Karen Singers; Vorup-Jensen, Thomas; Pakula, Malgorzata Maria; Hansen, Birgit Holm; Jensen, Thomas G.; Aagaard, Lars

    2014-01-01

    The PKU-mouse model mutated in the PAH gene was developed in the 1990s in the laboratory of Dr. Alexandra Shedlovsky at the McArdle Laboratory for Cancer Research, University of Wisconsin. The mutation was generated by ENU (N-ethyl-N-nitrosourea) treatment of BTBR males. Several mutation was found...... mutation is therefore widely used model in PKU research. The Pahenu2 mutation has been transferred to the inbred C57BL/6 mouse strain. Breeding colonies on both inbred strains have been established at Aarhus University. Recently an attempt to breed homozygous animals on a Phe-free diet was attempted in...... order to reduce the number of surplus animals bred by heterozygous mothers. Preliminary data from this colony will be presented and as well as research implication of a model of maternal PKU....

  15. Mouse models in liver cancer research: A review of current literature

    Institute of Scientific and Technical Information of China (English)

    Martijn WH Leenders; Maarten W Nijkamp; Inne HM Borel Rinkes

    2008-01-01

    Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in EasL-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used,especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common Lype of primary liver cancer, accounting for 70%-85% of cases.

  16. Immune-deficient mouse models for analysis of human stem cells.

    Science.gov (United States)

    Meyerrose, Todd E; Herrbrich, Phillip; Hess, David A; Nolta, Jan A

    2003-12-01

    The field of murine models of xenotransplantation has grown immensely over the past two decades. The explosive growth in this field is in part due to the fact that good in vitro methods do not exist yet to allow examination of human stem cell homing into the bone marrow compartment versus other tissues, long-term survival of human stem cells, or differentiation into tissues outside of the hematopoietic system. Since these important aspects of human stem cell biology can be examined in vivo using immune-deficient mice, the number of different strains and models is constantly increasing. The current review discusses the merits and drawbacks of each immune-deficient mouse xenograft system as it stands to date and reviews how each immune-deficient mouse model has been used to further our knowledge of human hematopoietic stem cell biology. PMID:14682062

  17. Engineered Barrier System: Physical and Chemical Environment Model

    International Nuclear Information System (INIS)

    The conceptual and predictive models documented in this Engineered Barrier System: Physical and Chemical Environment Model report describe the evolution of the physical and chemical conditions within the waste emplacement drifts of the repository. The modeling approaches and model output data will be used in the total system performance assessment (TSPA-LA) to assess the performance of the engineered barrier system and the waste form. These models evaluate the range of potential water compositions within the emplacement drifts, resulting from the interaction of introduced materials and minerals in dust with water seeping into the drifts and with aqueous solutions forming by deliquescence of dust (as influenced by atmospheric conditions), and from thermal-hydrological-chemical (THC) processes in the drift. These models also consider the uncertainty and variability in water chemistry inside the drift and the compositions of introduced materials within the drift. This report develops and documents a set of process- and abstraction-level models that constitute the engineered barrier system: physical and chemical environment model. Where possible, these models use information directly from other process model reports as input, which promotes integration among process models used for total system performance assessment. Specific tasks and activities of modeling the physical and chemical environment are included in the technical work plan ''Technical Work Plan for: In-Drift Geochemistry Modeling'' (BSC 2004 [DIRS 166519]). As described in the technical work plan, the development of this report is coordinated with the development of other engineered barrier system analysis model reports

  18. Insights from zebrafish and mouse models on the activity and safety of ar-turmerone as a potential drug candidate for the treatment of epilepsy.

    Directory of Open Access Journals (Sweden)

    Adriana Monserrath Orellana-Paucar

    Full Text Available In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, β-turmerone and α-atlantone in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ. In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf] in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.

  19. Review: insights gained from modelling high-grade glioma in the mouse.

    Science.gov (United States)

    Rankin, S L; Zhu, G; Baker, S J

    2012-06-01

    High-grade gliomas (HGGs) are devastating primary brain tumours with poor outcomes. Advances towards effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumour initiation, progression and phenotype, the influence of tumour micro-environment, and the analysis of cell types that can give rise to glioma. HGGs are a heterogeneous group of tumours, and the complexity of diverse mutations within common signalling pathways as well as the developmental and cell-type context of transformation contributes to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely simulate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing. PMID:22035336

  20. Development of a transgenic mouse model to study the immunogenicity of recombinant human insulin.

    Science.gov (United States)

    Torosantucci, Riccardo; Brinks, Vera; Kijanka, Grzegorz; Halim, Liem Andhyk; Sauerborn, Melody; Schellekens, Huub; Jiskoot, Wim

    2014-05-01

    Mouse models are commonly used to assess the immunogenicity of therapeutic proteins and to investigate the immunological processes leading to antidrug antibodies. The aim of this work was to develop a transgenic (TG) Balb/c mouse model for evaluating the immunogenicity of recombinant human insulin (insulin) formulations. Validation of the model was performed by measuring the antibody response against plain and particulate insulin in TG and nontransgenic (NTG) mice. Intraperitoneal administration of insulin (20 μg/dose, 12 doses over a period of 4 weeks) did not break the immune tolerance of the TG mice, whereas it did elicit antibodies in NTG mice. The immune tolerance of TG mice could be circumvented, albeit at low titers, by administering insulin covalently bound to 50-nm polystyrene nanoparticles. The TG mouse model was employed to compare the immunogenicity of oxidized aggregated insulin, oxidized nonaggregated insulin, and three commercially available formulations of insulin variants (i.e., Levemir®, Insulatard®, and Actrapid®). Oxidized insulin, aggregated or nonaggregated, was moderately immunogenic in TG mice (50% and 33% responders, respectively), whereas the immunogenicity of the commercial formulations was low. This model can be used to compare the immunogenicity of insulin formulations and to study immune mechanisms of antibody formation against insulin. PMID:24619587

  1. MicroRNAs and Induced Pluripotent Stem Cells for Human Disease Mouse Modeling

    Directory of Open Access Journals (Sweden)

    Chingiz Underbayev

    2012-01-01

    Full Text Available Human disease animal models are absolutely invaluable tools for our understanding of mechanisms involved in both physiological and pathological processes. By studying various genetic abnormalities in these organisms we can get a better insight into potential candidate genes responsible for human disease development. To this point a mouse represents one of the most used and convenient species for human disease modeling. Hundreds if not thousands of inbred, congenic, and transgenic mouse models have been created and are now extensively utilized in the research labs worldwide. Importantly, pluripotent stem cells play a significant role in developing new genetically engineered mice with the desired human disease-like phenotype. Induced pluripotent stem (iPS cells which represent reprogramming of somatic cells into pluripotent stem cells represent a significant advancement in research armament. The novel application of microRNA manipulation both in the generation of iPS cells and subsequent lineage-directed differentiation is discussed. Potential applications of induced pluripotent stem cell—a relatively new type of pluripotent stem cells—for human disease modeling by employing human iPS cells derived from normal and diseased somatic cells and iPS cells derived from mouse models of human disease may lead to uncovering of disease mechanisms and novel therapies.

  2. Molecular analysis of metastasis in a polyomavirus middle T mouse model: the role of osteopontin

    International Nuclear Information System (INIS)

    In order to study metastatic disease, we employed the use of two related polyomavirus middle T transgenic mouse tumor transplant models of mammary carcinoma (termed Met and Db) that display significant differences in metastatic potential. Through suppression subtractive hybridization coupled to the microarray, we found osteopontin (OPN) to be a highly expressed gene in the tumors of the metastatic mouse model, and a lowly expressed gene in the tumors of the lowly metastatic mouse model. We further analyzed the role of OPN in this model by examining sense and antisense constructs using in vitro and in vivo methods. With in vivo metastasis assays, the antisense Met cells showed no metastatic tumor formation to the lungs of recipient mice, while wild-type Met cells, with higher levels of OPN, showed significant amounts of metastasis. The Db cells showed a significantly reduced metastasis rate in the in vivo metastasis assay as compared with the Met cells. Db cells with enforced overexpression of OPN showed elevated levels of OPN but did not demonstrate an increase in the rate of metastasis compared with the wild-type Db cells. We conclude that OPN is an essential regulator of the metastatic phenotype seen in polyomavirus middle T-induced mammary tumors. Yet OPN expression alone is not sufficient to cause metastasis. These data suggest a link between metastasis and phosphatidylinositol-3-kinase-mediated transcriptional upregulation of OPN, but additional phosphatidylinositol-3-kinase-regulated genes may be essential in precipitating the metastasis phenotype in the polyomavirus middle T model

  3. Fulminant liver failure models with subsequent encephalopathy in the mouse

    Institute of Scientific and Technical Information of China (English)

    Ann-Marie T Baine; Tomohide Hori; Feng Chen; Lindsay B Gardner; Shinji Uemoto; Justin H Nguyen

    2011-01-01

    BACKGROUND:  A reliable model of fulminant liver failure (FLF) is urgently required in this research field. This study aimed to develop a murine FLF model. METHODS: We used three groups of male C57BL/6 mice:control, with azoxymethane treatment (AOM group), and with galactosamine and tumor necrosis factor-alpha treatment (Gal+TNF-α group). The effects of body temperature (BT) control on survival in all three groups were investigated. Using BT control, we compared the survival, histopathological findings and biochemical/coagulation profiles between the two experimental groups. The effects of hydration on international normalized ratios of prothrombin time (PT-INRs) were also checked. Dose-dependent survival curves were constructed for both experimental groups. Neurological behavior was assessed using a coma scale. RESULTS: No unexpected BT effects were seen in the control group. The AOM group, but not the Gal+TNF-α group, showed a significant difference in survival curves between those with and without BT care. Histopathological assessment showed consistent FLF findings in both experimental groups with BT care. There were significant differences between the experimental groups in aspartate aminotransferase levels and PT-INRs, and significant differences in PT-INRs between the sufficiently and insufficiently hydrated groups. There were significant differences between FLF models in the duration of each coma stage, with significant differences in stages 1 and 3 as percentages of the disease state (stages 1-4). The two FLF models with BT care showed different survival curves in the dose-dependent survival study. CONCLUSIONS: AOM provides a good FLF model, but requires a specialized environment and careful BT control. Other FLF models may also be useful, depending on the research purpose. Thoughtful attention to caregiving and close observation are indispensable for successful FLF models.

  4. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  5. FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia.

    Directory of Open Access Journals (Sweden)

    Yogesh K Chutake

    Full Text Available Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.The humanized mouse model of Friedreich ataxia (YG8sR, which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R. We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.

  6. Detailed Chemical Kinetic Modeling of Cyclohexane Oxidation

    Energy Technology Data Exchange (ETDEWEB)

    Silke, E J; Pitz, W J; Westbrook, C K; Ribaucour, M

    2006-11-10

    A detailed chemical kinetic mechanism has been developed and used to study the oxidation of cyclohexane at both low and high temperatures. Reaction rate constant rules are developed for the low temperature combustion of cyclohexane. These rules can be used for in chemical kinetic mechanisms for other cycloalkanes. Since cyclohexane produces only one type of cyclohexyl radical, much of the low temperature chemistry of cyclohexane is described in terms of one potential energy diagram showing the reaction of cyclohexyl radical + O{sub 2} through five, six and seven membered ring transition states. The direct elimination of cyclohexene and HO{sub 2} from RO{sub 2} is included in the treatment using a modified rate constant of Cavallotti et al. Published and unpublished data from the Lille rapid compression machine, as well as jet-stirred reactor data are used to validate the mechanism. The effect of heat loss is included in the simulations, an improvement on previous studies on cyclohexane. Calculations indicated that the production of 1,2-epoxycyclohexane observed in the experiments can not be simulated based on the current understanding of low temperature chemistry. Possible 'alternative' H-atom isomerizations leading to different products from the parent O{sub 2}QOOH radical were included in the low temperature chemical kinetic mechanism and were found to play a significant role.

  7. Proteome analysis of mouse model systems: A tool to model human disease and for the investigation of tissue-specific biology.

    Science.gov (United States)

    Kislinger, Thomas; Gramolini, Anthony O

    2010-10-10

    The molecular dissections of the mechanistic pathways involved in human disease have always relied on the use of model organisms. Among the higher mammalian organisms, the laboratory mouse (Mus musculus) is the most widely used model. A large number of commercially-available, inbred strains are available to the community, including an ever growing collection of transgenic, knock-out, and disease models. Coupled to availability is the fact that animal colonies can be kept under standardized housing condition at most major universities and research institutes, with relative ease and cost efficiency (compared to larger vertebrates). As such, mouse models to study human biology and disease remains extremely attractive. In the current review we will provide an historic overview of the use of mouse models in proteome research with a focus on general tissue and organelle biology, comparative proteomics of human and mouse and the use of mouse models to study cardiac disease. PMID:20478424

  8. Mouse Mincle: Characterization as a Model for Human Mincle and Evolutionary Implications

    Directory of Open Access Journals (Sweden)

    Neela D. S. Rambaruth

    2015-04-01

    Full Text Available Mincle, the macrophage-inducible C-type lectin also known as CLEC-4E, binds to the mycobacterial glycolipid trehalose dimycolate and initiates a signaling cascade by serving as a receptor for Mycobacterium tuberculosis and other pathogenic mycobacterial species. Studies of the biological functions of human mincle often rely on mouse models, based on the assumption that the biological properties of the mouse receptor mimic those of the human protein. Experimental support for this assumption has been obtained by expression of the carbohydrate-recognition domain of mouse mincle and characterization of its interaction with small molecule analogs of trehalose dimycolate. The results confirm that the ligand-binding properties of mouse mincle closely parallel those of the human receptor. These findings are consistent with the conservation of key amino acid residues that have been shown to form the ligand-binding site in human and cow mincle. Sequence alignment reveals that these residues are conserved in a wide range of mammalian species, suggesting that mincle has a conserved function in binding ligands that may include endogenous mammalian glycans or pathogen glycans in addition to trehalose dimycolate.

  9. Novel basophil- or eosinophil-depleted mouse models for functional analyses of allergic inflammation.

    Directory of Open Access Journals (Sweden)

    Kunie Matsuoka

    Full Text Available Basophils and eosinophils play important roles in various host defense mechanisms but also act as harmful effectors in allergic disorders. We generated novel basophil- and eosinophil-depletion mouse models by introducing the human diphtheria toxin (DT receptor gene under the control of the mouse CD203c and the eosinophil peroxidase promoter, respectively, to study the critical roles of these cells in the immunological response. These mice exhibited selective depletion of the target cells upon DT administration. In the basophil-depletion model, DT administration attenuated a drop in body temperature in IgG-mediated systemic anaphylaxis in a dose-dependent manner and almost completely abolished the development of ear swelling in IgE-mediated chronic allergic inflammation (IgE-CAI, a typical skin swelling reaction with massive eosinophil infiltration. In contrast, in the eosinophil-depletion model, DT administration ameliorated the ear swelling in IgE-CAI whether DT was administered before, simultaneously, or after, antigen challenge, with significantly lower numbers of eosinophils infiltrating into the swelling site. These results confirm that basophils and eosinophils act as the initiator and the effector, respectively, in IgE-CAI. In addition, antibody array analysis suggested that eotaxin-2 is a principal chemokine that attracts proinflammatory cells, leading to chronic allergic inflammation. Thus, the two mouse models established in this study are potentially useful and powerful tools for studying the in vivo roles of basophils and eosinophils. The combination of basophil- and eosinophil-depletion mouse models provides a new approach to understanding the complicated mechanism of allergic inflammation in conditions such as atopic dermatitis and asthma.

  10. Parameter Estimates in Differential Equation Models for Chemical Kinetics

    Science.gov (United States)

    Winkel, Brian

    2011-01-01

    We discuss the need for devoting time in differential equations courses to modelling and the completion of the modelling process with efforts to estimate the parameters in the models using data. We estimate the parameters present in several differential equation models of chemical reactions of order n, where n = 0, 1, 2, and apply more general…

  11. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

    OpenAIRE

    Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd R.

    2016-01-01

    Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tu...

  12. A grand model for chemical product design

    DEFF Research Database (Denmark)

    Fung, Ka Y.; Ng, Ka M.; Zhang, Lei;

    2016-01-01

    , a pricing model, an economic model as well as factors such as company strategy, government policies and regulations. This article introduces the model and highlights selected aspects of the model with two case studies. One is a die attach adhesive that illustrates how pricing affects profitability......, and how product composition changes with market conditions. Another is a hand lotion that illustrates how product quality affects the profit.(C) 2016 Elsevier Ltd. All rights reserved....

  13. Intraperitoneal Injection of Multiplacentas Pooled Cells Treatment on a Mouse Model with Aplastic Anemia

    Science.gov (United States)

    Li, Jun; Chen, Hong; Lv, Yan-Bo; Wang, Qiang; Xie, Zheng-Jun; Ma, Li-Hua; He, Jie; Xue, Wei; Yu, Shan; Guo, Jun; Wang, Ting-Hua; Wu, Tian-Xi; Pan, Xing-Hua

    2016-01-01

    Coinfusion of hematopoietic and mesenchymal stem cells is more effective than hematopoietic stem cell transplantation alone. It is necessary to explore a safe and routine mixed stem cell intraperitoneal transplantation method. Multiplacentas pooled cells were intraperitoneally injected into a radiation- and immunity-induced mouse aplastic anemia model with single time. Then, mouse survival time, peripheral blood hemoglobin count, bone marrow architecture, and donor cell engraftment were assessed. The recipient mouse exhibited donor cell engraftment in both bone marrow and peripheral blood. Survival time and peripheral blood hemoglobin count increased in placenta pooled cells treated mice, compared with model-only controls (P = 0.048 and P = 0.000, resp.). However, placentas pooled cells failed to cause a significant decrease in bone marrow pimelosis area (P = 0.357). Intraperitoneally transplanted multiplacentas pooled cells can survive and engraft into a host body through blood circulation, which can increase the life span of an aplastic anemia model mice, and delay but not abrogate the development of aplastic anemia. Furthermore, they appear to play a role in increasing peripheral blood hemoglobin level response for increasing the life span of aplastic anemia model mice. PMID:26997957

  14. Lentivirus-mediated somatic recombination and development of a novel mouse model for sporadic colorectal cancer.

    Science.gov (United States)

    Vaish, Vivek; Kim, Joohwee; Shim, Minsub

    2016-07-01

    In this study, we have developed a novel mouse model for sporadic colorectal cancer (CRC) by utilizing APC conditional knockout (Apc(CKO) ) mouse and lentivirus encoding Cre recombinase and a reporter gene (EGFP or LacZ). Lentiviral transduction of colonic crypt stem cells allowed for the long-term expression of reporter gene as well as excision of floxed Apc alleles, which resulted in tumor development. Tumors represented adenoma stages along with the nuclear accumulation of β-catenin. Loss of E-cadherin at the cellular junctions and strong expression of Vimentin suggested the sign of active epithelial-mesenchymal transition. Moreover, nuclear staining of Ki67 inside epithelial cells of aberrant crypts demonstrated their higher proliferative nature. Erratic downstream signaling of activated Wnt/β-catenin, AKT/mTOR, and Notch pathways provided strong evidence towards the higher proliferative index of epithelial cells inside the aberrant crypts. These results do recapitulate the findings of previous APC mutant mouse models. Our model represents sporadic CRC more precisely as (i) tumors result from somatic mutations but not from germline; (ii) tumors develop in colon not in small intestine; (iii) few tumors develop at the distal end of colons. Additionally, our model allows for the long-term expression of the gene(s), which get integrated into the host cell genome and provides an ability to track the tumor growth. © 2016 Wiley Periodicals, Inc. PMID:27037682

  15. The value of incomplete mouse models of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Radde, Rebecca; Duma, Cecilia; Jucker, Mathias [University of Tuebingen, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tuebingen (Germany); Goedert, Michel [Medical Research Council Laboratory of Molecular Biology, Cambridge (United Kingdom)

    2008-03-15

    To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of A{beta}42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral {beta}-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging. (orig.)

  16. New trajectory-driven aerosol and chemical process model Chemical and Aerosol Lagrangian Model (CALM

    Directory of Open Access Journals (Sweden)

    P. Tunved

    2010-11-01

    Full Text Available A new Chemical and Aerosol Lagrangian Model (CALM has been developed and tested. The model incorporates all central aerosol dynamical processes, from nucleation, condensation, coagulation and deposition to cloud formation and in-cloud processing. The model is tested and evaluated against observations performed at the SMEAR II station located at Hyytiälä (61° 51' N, 24° 17' E over a time period of two years, 2000–2001. The model shows good agreement with measurements throughout most of the year, but fails in reproducing the aerosol properties during the winter season, resulting in poor agreement between model and measurements especially during December–January. Nevertheless, through the rest of the year both trends and magnitude of modal concentrations show good agreement with observation, as do the monthly average size distribution properties. The model is also shown to capture individual nucleation events to a certain degree. This indicates that nucleation largely is controlled by the availability of nucleating material (as prescribed by the [H2SO4], availability of condensing material (in this model 15% of primary reactions of monoterpenes (MT are assumed to produce low volatile species and the properties of the size distribution (more specifically, the condensation sink. This is further demonstrated by the fact that the model captures the annual trend in nuclei mode concentration. The model is also used, alongside sensitivity tests, to examine which processes dominate the aerosol size distribution physical properties. It is shown, in agreement with previous studies, that nucleation governs the number concentration during transport from clean areas. It is also shown that primary number emissions almost exclusively govern the CN concentration when air from Central Europe is advected north over Scandinavia. We also show that biogenic emissions have a large influence on the amount of potential CCN observed

  17. New trajectory driven aerosol and chemical process model: chemical and aerosol Lagrangian model (CALM

    Directory of Open Access Journals (Sweden)

    P. Tunved

    2010-06-01

    Full Text Available A new Chemical and Aerosol Lagrangian Model (CALM have been developed and tested. The model incorporates all central aerosol dynamical processes, from nucleation, condensation, coagulation and deposition to cloud formation and in-cloud processing. The model is tested and evaluated against observations performed at the SMEAR II station located at Hyytiälä (61°51' N, 24°17' E over a time period of two years, 2000–2001. The model shows good agreement with measurements throughout most of the year, but fails in reproducing the aerosol properties during the winter season, resulting in poor agreement between model and measurements especially during December–January. Nevertheless, through the rest of the year both trends and magnitude of modal concentrations show good agreement with observation, as do the monthly average size distribution properties. The model is also shown to capture individual nucleation events to a certain degree. This indicates that nucleation largely is controlled by the availability of nucleating material (as prescribed by the [H2SO4], availability of condensing material (in this model 15% of primary reactions of monoterpenes (MT are assumed to produce low volatile species and the properties of the size distribution (more specifically, the condensation sink. This is further demonstrated by the fact that the model captures the annual trend in nuclei mode concentration. The model is also used, alongside sensitivity tests, to examine which processes dominate the aerosol size distribution physical properties. It is shown, in agreement with previous studies, that nucleation governs the number concentration while transport from clean areas takes place. It is also shown that primary number emissions almost exclusively govern the CN concentration when air from Central Europe is advected north over Scandinavia. We also show that biogenic emissions have a large influence on the amount of potential CCN observed

  18. Skeletal metastasis: treatments, mouse models,and the Wnt signaling

    Institute of Scientific and Technical Information of China (English)

    Kenneth C.Valkenburg; Matthew R.Steensma; Bart O.Williams; Zhendong Zhong

    2013-01-01

    Skeletal metastases result in significant morbidity and mortality.This is particularly true of cancers with a strong predilection for the bone,such as breast,prostate,and lung cancers.There is currently no reliable cure for skeletal metastasis,and palliative therapy options are limited.The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target.Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments.In this review,we discuss pathologic process of bone metastasis,the roles of the Wnt signaling,and the available experimental models and treatments.

  19. Ventilatory Patterning in a Mouse Model of Stroke

    OpenAIRE

    Koo, Brian B; Strohl, Kingman P.; Gillombardo, Carl B.; Jacono, Frank J.

    2010-01-01

    Cheyne-Stokes respiration (CSR) is a breathing pattern characterized by waxing and waning of breath volume and frequency, and is often recognized following stroke, when causal pathways are often obscure. We used an animal model to address the hypothesis that cerebral infarction is a mechanism for producing breathing instability. Fourteen male A/J mice underwent either stroke (n=7) or sham (n=7) procedure. Ventilation was measured using whole body plethysmography. Respiratory rate (RR), tidal ...

  20. Dietary Zinc and Prostate Cancer in the TRAMP Mouse Model

    OpenAIRE

    Prasad, Ananda S; Mukhtar, Hasan; Beck, Frances W.J.; Adhami, Vaqar M.; Siddiqui, Imtiaz A.; Din, Maria; Hafeez, Bilal B.; KUCUK, Omer

    2010-01-01

    Circumstantial evidence indicates that zinc may have an important role in the prostate. Total zinc levels in the prostate are 10 times higher than in other soft tissues. Zinc concentrations in prostate epithethial cancer cells are decreased significantly. Zinc supplementation for prevention and treatment of prostate cancer in humans has yielded controversial results. No studies have been reported in animal models to show the effect of zinc supplementation on prevention of prostate cancer, thu...

  1. Resveratrol Neuroprotection in a Chronic Mouse Model of Multiple Sclerosis

    OpenAIRE

    Zoe eFonseca-Kelly; Mayssa eNassrallah; Jorge eUribe; Khan, Reas S.; Kimberly eDine; Mahasweta eDutt; Shindler, Kenneth S.

    2012-01-01

    Resveratrol is a naturally-occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, prevents neuronal loss without suppressing inflammation in mice with relapsing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In contrast, resveratrol has been reported to suppress inflammation in chronic EAE, although neuroprotective effects were not evaluated. The current st...

  2. A mighty mouse: building a better model of multiple sclerosis

    OpenAIRE

    Ransohoff, Richard M.

    2006-01-01

    The 2 cardinal cell populations mediating adaptive immunity are T and B lymphocytes. These cells play important but poorly understood roles in the immunopathological demyelinating disease multiple sclerosis (MS) and in a widely used animal model of human MS known as EAE. In the current issue of the JCI, 2 research teams report their parallel studies of double-transgenic mice expressing T and B cell receptors that recognize the same myelin protein (see the related articles beginning on pages 2...

  3. A nude mouse model of endometriosis and its biological behaviors

    Institute of Scientific and Technical Information of China (English)

    WANG Dan-bo; ZHANG Shu-lan; NIU Hui-yan; LU Jing-ming

    2005-01-01

    @@ Endometriosis (EM) as a common and intractable gynecological disease is characterized by unknown etiology and complex pathologic changes. Many factors of the disease are uncertain at the molecular level and it is difficult to study clinically. In this study, we attempted to establish a nude mice model of EM for dynamical observation of the genesis and development of the disease, morphological changes in tissue, and biological behaviors.

  4. A Susceptible Mouse Model for Zika Virus Infection.

    Science.gov (United States)

    Dowall, Stuart D; Graham, Victoria A; Rayner, Emma; Atkinson, Barry; Hall, Graham; Watson, Robert J; Bosworth, Andrew; Bonney, Laura C; Kitchen, Samantha; Hewson, Roger

    2016-05-01

    Zika virus (ZIKV) is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129) mice and the parent strain (129Sv/Ev) after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals. PMID:27149521

  5. A Susceptible Mouse Model for Zika Virus Infection.

    Directory of Open Access Journals (Sweden)

    Stuart D Dowall

    2016-05-01

    Full Text Available Zika virus (ZIKV is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129 mice and the parent strain (129Sv/Ev after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals.

  6. A Susceptible Mouse Model for Zika Virus Infection

    Science.gov (United States)

    Rayner, Emma; Atkinson, Barry; Hall, Graham; Watson, Robert J.; Bosworth, Andrew; Bonney, Laura C.; Kitchen, Samantha; Hewson, Roger

    2016-01-01

    Zika virus (ZIKV) is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129) mice and the parent strain (129Sv/Ev) after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals. PMID:27149521

  7. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Steve P. Crampton

    2014-09-01

    Full Text Available Systemic lupus erythematosus (SLE represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

  8. Anti-apoptotic treatment in mouse models of age-related hearing loss

    Institute of Scientific and Technical Information of China (English)

    Fengchan Han; Oumei Wang; Quanxiang Cai

    2016-01-01

    Age-related hearing loss (AHL), or presbycusis, is the most common neurodegenerative disorder and top communication deficit of the aged population. Genetic predisposition is one of the major factors in the development of AHL. Generally, AHL is associated with an age-dependent loss of sensory hair cells, spiral ganglion neurons and stria vascularis cells in the inner ear. Although the mechanisms leading to genetic hearing loss are not completely understood, caspase-family proteases function as important signals in the inner ear pathology. It is now accepted that mouse models are the best tools to study the mechanism of genetic hearing loss or AHL. Here, we provide a brief review of recent studies on hearing improvement in mouse models of AHL by anti-apoptotic treatment.

  9. The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome.

    Directory of Open Access Journals (Sweden)

    Scott T Kelley

    Full Text Available Women with polycystic ovary syndrome (PCOS have reproductive and metabolic abnormalities that result in an increased risk of infertility, diabetes and cardiovascular disease. The large intestine contains a complex community of microorganisms (the gut microbiome that is dysregulated in humans with obesity and type 2 diabetes. Using a letrozole-induced PCOS mouse model, we demonstrated significant diet-independent changes in the gut microbial community, suggesting that gut microbiome dysbiosis may also occur in PCOS women. Letrozole treatment was associated with a time-dependent shift in the gut microbiome and a substantial reduction in overall species and phylogenetic richness. Letrozole treatment also correlated with significant changes in the abundance of specific Bacteroidetes and Firmicutes previously implicated in other mouse models of metabolic disease in a time-dependent manner. Our results suggest that the hyperandrogenemia observed in PCOS may significantly alter the gut microbiome independently of diet.

  10. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model

    Science.gov (United States)

    Li, Tong; Braunstein, Kerstin E.; Zhang, Juhong; Lau, Ashley; Sibener, Leslie; Deeble, Christopher; Wong, Philip C.

    2016-01-01

    A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau. PMID:27373369

  11. The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome.

    Science.gov (United States)

    Kelley, Scott T; Skarra, Danalea V; Rivera, Alissa J; Thackray, Varykina G

    2016-01-01

    Women with polycystic ovary syndrome (PCOS) have reproductive and metabolic abnormalities that result in an increased risk of infertility, diabetes and cardiovascular disease. The large intestine contains a complex community of microorganisms (the gut microbiome) that is dysregulated in humans with obesity and type 2 diabetes. Using a letrozole-induced PCOS mouse model, we demonstrated significant diet-independent changes in the gut microbial community, suggesting that gut microbiome dysbiosis may also occur in PCOS women. Letrozole treatment was associated with a time-dependent shift in the gut microbiome and a substantial reduction in overall species and phylogenetic richness. Letrozole treatment also correlated with significant changes in the abundance of specific Bacteroidetes and Firmicutes previously implicated in other mouse models of metabolic disease in a time-dependent manner. Our results suggest that the hyperandrogenemia observed in PCOS may significantly alter the gut microbiome independently of diet. PMID:26731268

  12. Fucoidan Extracted from Fucus evanescens Prevents Endotoxin-Induced Damage in a Mouse Model of Endotoxemia

    Directory of Open Access Journals (Sweden)

    Tatyana A. Kuznetsova

    2014-01-01

    Full Text Available An important problem of treating patients with endotoxemia is to find drugs to reduce the negative effects of endotoxin on the organism. We tested fucoidan (sulfated polysaccharide from the brown alga Fucus evanescens as a potential drug in a mouse model of endotoxemia inducted by lipopolysaccharide (LPS. The survival time of mice injected with LPS increased under fucoidan treatment compared with the group of mice injected with LPS only. The preventive administration of fucoidan to mice with endotoxemia resulted in inhibition of increased levels of proinflammatory cytokines (TNFα and IL-6, as well as decreasing of the processes of hypercoagulability. The parenteral or per os administration of fucoidan resulted in decreasing the degree of microcirculatory disorders and secondary dystrophic-destructive changes in parenchymal organs of mice with endotoxemia. Taken together, these results demonstrate that fucoidan prevents endotoxin-induced damage in a mouse model of endotoxemia and increases the mice’s resistance to LPS.

  13. Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer's disease

    International Nuclear Information System (INIS)

    Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers' disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases. (orig.)

  14. Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Winkeler, A.; Waerzeggers, Y.; Klose, A.; Monfared, P.; Thomas, A.V.; Jacobs, A.H. [Max Planck Institute for Neurological Research with Klaus-Joachim-Zuelch-Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Laboratory for Gene Therapy and Molecular Imaging, Cologne (Germany); Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); Schubert, M. [Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); Heneka, M.T. [Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); University of Muenster, Department of Neurology, Muenster (Germany)

    2008-03-15

    Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers' disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases. (orig.)

  15. Assessment of the translational value of mouse lupus models using clinically relevant biomarkers.

    Science.gov (United States)

    Bender, Andrew T; Wu, Yin; Cao, Qiongfang; Ding, Yueyun; Oestreicher, Judith; Genest, Melinda; Akare, Sandeep; Ishizaka, Sally T; Mackey, Matthew F

    2014-06-01

    Lupus is an autoimmune disease with a poorly understood etiology that manifests with a diverse pathology. This heterogeneity has been a challenge to clinical drug development efforts. A related difficulty is the uncertain translational power of animal models used for evaluating potential drug targets and candidate therapeutics, because it is unlikely that any 1 preclinical model will recapitulate the spectrum of human disease. Therefore, multiple models, along with an understanding of the immune mechanisms that drive them, are necessary if we are to use them to identify valid drug targets and evaluate candidate therapies successfully. To this end, we have characterized several different mouse lupus models and report their differences with respect to biomarkers and symptoms that are representative of the human disease. We compared the pristane-induced mouse lupus disease model using 3 different strains (DBA/1, SJL, BALB/c), and the spontaneous NZB x NZW F1(NZB/W) mouse model. We show that the models differ significantly in their autoantibody profiles, disease manifestations such as nephritis and arthritis, and expression of type I interferon-regulated genes. Similar to the NZB/W model, pristane-induced disease in SJL mice manifests with nephritis and proteinuria, whereas the pristane-treated DBA/1 mice develop arthritis and an interferon-driven gene signature that closely resembles that in human patients. The elucidation of each model's strengths and the identification of translatable biomarkers yields insight for basic lupus research and drug development, and should assist in the proper selection of models for evaluating candidate targets and therapeutic strategies. PMID:24462761

  16. A dynamical model of the chemical bond

    OpenAIRE

    Hofmann, Holger F.

    1996-01-01

    A new approach to chemical bonding is introduced in order to provide an improved understanding of the connection between basic quantum mechanics and the covalent pair bond. It's focus is on the fact that the energy of the bond is largely given by the kinetic energy of the electrons, while the Coulomb forces are only comparable to the kinetic energy terms close to the atomic nuclei, where they define the shape and the size of the atomic orbitals. If atomic orbitals are used as a starting point...

  17. Animal models of melanoma: a somatic cell gene delivery mouse model allows rapid evaluation of genesimplicated in human melanoma%Animal models of melanoma: a somatic cell gene delivery mouse model allows rapid evaluation of genes implicated in human melanoma

    Institute of Scientific and Technical Information of China (English)

    Andrea J. McKinney; Sheri L. Holmen

    2011-01-01

    The increasing incidence and mortality associated with advanced stages of melanoma are cause for concern. Few treatment options are available for advanced melanoma and the 5-year survival rate is less than 15%. Targeted therapies may revolutionize melanoma treatment by providing less toxic and more effective strategies. However, maximizing effectiveness requires further understanding of the molecular alterations that drive tumor formation, progression, and maintenance, as well as elucidating the mechanisms of resistance. Several different genetic alterations identified in human melanoma have been recapitulated in mice. This review outlines recent progress made in the development of mouse models of melanoma and summarizes what these findings reveal about the human disease. We begin with a discussion of traditional models and conclude with the recently developed RCAS/TVA somatic cell gene delivery mouse model of melanoma.

  18. The p47phox mouse knock-out model of chronic granulomatous disease

    OpenAIRE

    1995-01-01

    Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice pr...

  19. Genetically Engineered Mouse Models Reveal the Importance of Proteases as Drug Targets in Osteoarthritis

    OpenAIRE

    Miller, Rachel E; Lu, Yongzhi; Tortorella, Micky D.; Malfait, Anne-Marie

    2013-01-01

    More than two decades of research has revealed a network of proteases that orchestrates cartilage degradation in osteoarthritis. This network includes not only metalloproteinases that degrade the major macromolecules in cartilage, aggrecan and type II collagen, but also serine proteases and cysteine proteases, such as cathepsin K. The current review summarizes the role of proteases in osteoarthritis progression, based on studies in genetically engineered mouse models. In addition, a brief ove...

  20. Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model

    OpenAIRE

    Qifeng Zhou; Scott Kesteven; Jianxin Wu; Parwez Aidery; Meinrad Gawaz; Michael Gramlich; Feneley, Michael P.; Harvey, Richard P.

    2015-01-01

    Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated t...

  1. Cumulus-specific genes are transcriptionally silent following somatic cell nuclear transfer in a mouse model*

    OpenAIRE

    Tong, Guo-qing; Heng, Boon-chin; Ng, Soon-chye

    2007-01-01

    This study investigated whether four cumulus-specific genes: follicular stimulating hormone receptor (FSHr), hyaluronan synthase 2 (Has2), prostaglandin synthase 2 (Ptgs2) and steroidogenic acute regulator protein (Star), were correctly reprogrammed to be transcriptionally silent following somatic cell nuclear transfer (SCNT) in a murine model. Cumulus cells of C57×CBA F1 female mouse were injected into enucleated oocytes, followed by activation in 10 µmol/L strontium chloride for 5 h and sub...

  2. Macrophages Play a Key Role in Angiogenesis and Adipogenesis in a Mouse Tissue Engineering Model

    OpenAIRE

    Debels, Heidi; Galea, Laurence; Han, Xiao-Lian; Palmer, Jason; van Rooijen, Nico; Morrison, Wayne; Abberton, Keren

    2013-01-01

    We have previously described a mouse adipose tissue engineering model using a silicon chamber enclosing the superficial epigastric pedicle in a Matrigel based environment. We have shown that when Zymosan, a sterile inflammatory agent, is added to the chamber, angiogenesis and adipogenesis are significantly improved. As Zymosan interacts with toll-like receptors on macrophages, the role of macrophages in new tissue development in the tissue engineering chamber was assessed. Morphological and h...

  3. Engineered bacterial communication prevents Vibrio cholerae virulence in an infant mouse model

    OpenAIRE

    Duan, Faping; March, John C.

    2010-01-01

    To investigate the possibility of using commensal bacteria as signal mediators for inhibiting the disease cholera, we stably transformed Escherichia coli Nissle 1917 (Nissle) to express the autoinducer molecule cholera autoinducer 1 (CAI-1) (shown previously to prevent virulence when present with another signaling molecule, autoinducer 2, at high concentrations) and determined the effect on Vibrio cholerae virulence gene expression and colonization in an infant mouse model. We found that pret...

  4. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

    OpenAIRE

    Rooney, Jachinta E.; Gurpur, Praveen B.; Burkin, Dean J.

    2009-01-01

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α7β1-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α7-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological ...

  5. Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model

    Science.gov (United States)

    Jung, Yong Gi; Lane, Andrew P.

    2016-01-01

    Objective To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (Etanercept) on an inducible olfactory inflammation (IOI) mouse model Study Design An in vivo study using a transgenic mouse model Setting Research laboratory Subjects and Methods To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis (CRS)-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally-controlled fashion specifically within the olfactory epithelium. In one group of mice (n=4), Etanercept was injected intraperitoneally (100 µg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n=2) underwent induction of TNF-α expression for 8 weeks, with Etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with equal number of control group. Results Compared to non-treated IOI mice, Etanercept -treated IOI mice showed significantly improved EOG responses after 2 weeks (p<0.001). After 8 weeks of induced inflammation, there was massive loss of olfactory epithelium and no EOG response in non-treated IOI mice. However, in Etanercept - treated mice, regeneration of olfactory epithelium was observed. Conclusion Concomitant administration of Etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that Etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. PMID:26932943

  6. Mouse model implicates GNB3 duplication in a childhood obesity syndrome

    OpenAIRE

    Goldlust, Ian S.; Hermetz, Karen E.; Catalano, Lisa M.; Barfield, Richard T.; Cozad, Rebecca; Wynn, Grace; Ozdemir, Alev Cagla; Conneely, Karen N.; Mulle, Jennifer G.; Dharamrup, Shikha; Hegde, Madhuri R.; Kim, Katherine H.; Angle, Brad; Colley, Alison; Webb, Amy E.

    2013-01-01

    We describe a genomic disorder that causes obesity, intellectual disability, and seizures. Children with this syndrome carry an unbalanced chromosome translocation that results in the duplication of over 100 genes, including G protein β3 (GNB3). Although GNB3 polymorphisms have been associated with obesity, hypertension, and diabetes, the mechanism of GNB3 pathogenesis is unknown. We created a transgenic mouse model that carries a duplication of GNB3, weighs significantly more than wild-type ...

  7. Establishment of Orthotopic Xuanwei Lung Cancer SCID Mouse Model 
and Analysis of Biological Properties

    OpenAIRE

    Yongchun ZHOU; Chen, Yan; Xicai WANG; Liu, Xin; Hutao SHI; Yao, Qian; Jin, Congguo; Wu, Zhiping; Huang, Yunchao

    2012-01-01

    Background and objective The incidence of Xuanwei lung cancer ranks first in China, and its pathogenesis requires in-depth investigation. This study aims to establish an orthotopic Xuanwei lung cancer severe combined immunodeficiency (SCID) mouse model and to provide a basic experimental platform for further study. Methods The Xuanwei lung cancer cell line XWLC-05 was inoculated into the lung tissue of SCID mice in high and low doses. The tumor formation rates, tumor characteristics, spontane...

  8. The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

    OpenAIRE

    Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H.; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M.; Gross, Adam K; Heusner, Carrie L.; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

    2013-01-01

    Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in ...

  9. Modifications of retinal neurons in a mouse model of retinitis pigmentosa

    OpenAIRE

    Strettoi, Enrica; Pignatelli, Vincenzo

    2000-01-01

    Animal models of retinitis pigmentosa include the rd mouse, in which a mutation of a rod-specific phosphodiesterase leads to the rapid loss of photoreceptors during the early postnatal life. Very little is known about changes occurring in inner retinal neurons after photoreceptor loss. These changes are important in view of the possibility of restoring vision in retinas with photoreceptor degeneration by means of cell transplantation or direct stimulation of inner ...

  10. A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism.

    OpenAIRE

    Alicja ePuścian; Szymon eŁęski; Tomasz eGórkiewicz; Ksenia eMeyza; Hans-Peter eLipp; Ewelina Anna Knapska

    2014-01-01

    Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repet...

  11. Modulation of Astrocyte Glutamate Transporters Decreases Seizures in a Mouse Model of Tuberous Sclerosis Complex

    OpenAIRE

    Zeng, Ling-Hui; Bero, Adam W.; Bo ZHANG; Holtzman, David M.; Wong, Michael

    2010-01-01

    Astrocyte dysfunction may contribute to epileptogenesis and other neurological deficits in Tuberous Sclerosis Complex (TSC). In particular, decreased expression and function of astrocyte glutamate transporters have been implicated in causing elevated extracellular glutamate levels, neuronal death, and epilepsy in a mouse model of TSC (Tsc1GFAPCKO mice), involving inactivation of the Tsc1 gene primarily in astrocytes. Here, we tested whether pharmacological induction of astrocyte glutamate tra...

  12. A Western-Type Diet Accelerates Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer

    OpenAIRE

    Llaverias, Gemma; Danilo, Christiane; Wang, Yu; Witkiewicz, Agnes K; Daumer, Kristin; Lisanti, Michael P; Frank, Philippe G

    2010-01-01

    Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model. Consumption of a Western-type diet—that is, enriched in both fat ...

  13. A FINITE ELEMENT MODEL OF IN VIVO MOUSE TIBIAL COMPRESSION LOADING: INFLUENCE OF BOUNDARY CONDITIONS

    Directory of Open Access Journals (Sweden)

    Hajar Razi

    2014-12-01

    Full Text Available Though bone is known to adapt to its mechanical challenges, the relationship between the local mechanical stimuli and the adaptive tissue response seems so far unclear. A major challenge appears to be a proper characterization of the local mechanical stimuli of the bones (e.g. strains. The finite element modeling is a powerful tool to characterize these mechanical stimuli not only on the bone surface but across the tissue. However, generating a predictive finite element model of biological tissue strains (e.g., physiological-like loading encounters aspects that are inevitably unclear or vague and thus might significantly influence the predicted findings. We aimed at investigating the influence of variations in bone alignment, joint contact surfaces and displacement constraints on the predicted strains in an in vivo mouse tibial compression experiment. We found that the general strain state within the mouse tibia under compressive loading was not affected by these uncertain factors. However, strain magnitudes at various tibial regions were highly influenced by specific modeling assumptions. The displacement constraints to control the joint contact sites appeared to be the most influential factor on the predicted strains in the mouse tibia. Strains could vary up to 150% by modifying the displacement constraints. To a lesser degree, bone misalignment (from 0 to 20° also resulted in a change of strain (+300 µε = 40%. The definition of joint contact surfaces could lead to up to 6% variation. Our findings demonstrate the relevance of the specific boundary conditions in the in vivo mouse tibia loading experiment for the prediction of local mechanical strain values using finite element modeling.

  14. BAFF Blockade Prevents Anti-Drug Antibody Formation in a Mouse Model of Pompe Disease

    OpenAIRE

    Doerfler, Phillip A.; Nayak, Sushrusha; Herzog, Roland W; Morel, Laurence; Barry J Byrne

    2015-01-01

    Antibodies formed against the therapeutic protein are a life-threatening complication that arises during enzyme replacement therapy for Pompe disease (acid α-glucosidase deficiency; GAA). To provide an effective alternative to current practices, we investigated the capacity of anti-B-cell activating factor (BAFF) as a novel drug candidate to prevent antibody formation in a Pompe disease mouse model. A BAFF-neutralizing antibody was administered prophylactically and with maintenance doses in a...

  15. Lack of Effect of Metformin on Mammary Carcinogenesis in Non-Diabetic Rat and Mouse Models

    OpenAIRE

    Thompson, Matthew D.; Clinton J. Grubbs; Bode, Ann M.; Reid, Joel M.; McGovern, Renee; Bernard, Phillip S.; Stijleman, Inge J.; Green, Jeffery E.; Bennett, Christina; Juliana, M. Margaret; Moeinpour, Fariba; Steele, Vernon E.; Lubet, Ronald A.

    2015-01-01

    Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared to sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in non-diabetic women, the efficacy of metformin in non-diabetic rat and mouse mammary cancer models was evaluated.

  16. Enteric Dysbiosis Associated with a Mouse Model of Alcoholic Liver Disease

    OpenAIRE

    Yan, Arthur W.; Fouts, Derrick E.; Brandl, Johannes; Starkel, Peter; Torralba, Manolito; Schott, Eckart; Tsukamoto, Hide; Nelson, Karen E; Brenner, David A.; Schnabl, Bernd

    2010-01-01

    The translocation of bacteria and bacterial products into the circulation contributes to alcoholic liver disease. Intestinal bacterial overgrowth is common in patients with alcoholic liver disease. The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in alcoholic liver disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation o...

  17. Selective atonal gene delivery improves balance function in a mouse model of vestibular disease

    OpenAIRE

    Schlecker, Christina; Praetorius, Mark; Brough, Douglas E.; Presler, Robert G.; Hsu, Chi; Plinkert, Peter K.; STAECKER, HINRICH

    2011-01-01

    Loss of balance is often due to loss of vestibular hair cells. In mammals, regeneration of functional hair cells in the mature sensory epithelium is limited; therefore, loss of sensory cells can lead to debilitating balance problems. Delivery of the transcription factor atonal (atoh1) after aminoglycoside ototoxicity has previously been shown to induce the transdifferentiation of supporting cells into new hair cells and restore function. A problem with mouse aminoglycoside models is that the ...

  18. Characterization of the MeCP2R168X knockin mouse model for Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Eike Wegener

    Full Text Available Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2(R168X mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2(R168X mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.

  19. Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model

    OpenAIRE

    Santos Verdaguer, M??nica; D'Amico, Davide; Spadoni, Omella; Amador Arjona, Alejandro; Stork, Oliver; Dierssen, Mara

    2013-01-01

    Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our ...

  20. Effects of Laminaria japonica polysaccharides on exercise endurance and oxidative stress in forced swimming mouse model

    OpenAIRE

    Yan, Feiwei; Hao, Haitao

    2016-01-01

    Background Polysaccharides are the major active ingredients responsible for the bioactivities of Laminaria japonica. However, the effects of L. japonica polysaccharides (LJP) on exercise endurance and oxidative stress have never been investigated. Therefore, this study was conducted to investigate the effects of LJP on exercise endurance and oxidative stress in a forced swimming mouse model. The animals were divided into four groups, namely the control (C), LJP-75, LJP-150, and LJP-300 groups...

  1. Aerobic Exercise Attenuates Airway Inflammatory Responses in a Mouse Model of Atopic Asthma

    OpenAIRE

    Pastva, Amy; Estell, Kim; Schoeb, Trenton R.; Atkinson, T. Prescott; Schwiebert, Lisa M

    2004-01-01

    Recent reports indicate that aerobic exercise improves the overall physical fitness and health of asthmatic patients. The specific exercise-induced improvements in the pathology of asthma and the mechanisms by which these improvements occur, however, are ill-defined; thus, the therapeutic potential of exercise in the treatment of asthma remains unappreciated. Using an OVA-driven mouse model, we examined the role of aerobic exercise in modulating inflammatory responses associated with atopic a...

  2. Usefulness of running wheel for detection of congestive heart failure in dilated cardiomyopathy mouse model.

    Directory of Open Access Journals (Sweden)

    Masami Sugihara

    Full Text Available BACKGROUND: Inherited dilated cardiomyopathy (DCM is a progressive disease that often results in death from congestive heart failure (CHF or sudden cardiac death (SCD. Mouse models with human DCM mutation are useful to investigate the developmental mechanisms of CHF and SCD, but knowledge of the severity of CHF in live mice is necessary. We aimed to diagnose CHF in live DCM model mice by measuring voluntary exercise using a running wheel and to determine causes of death in these mice. METHODOLOGY/PRINCIPAL FINDINGS: A knock-in mouse with a mutation in cardiac troponin T (ΔK210 (DCM mouse, which results in frequent death with a t(1/2 of 70 to 90 days, was used as a DCM model. Until 2 months of age, average wheel-running activity was similar between wild-type and DCM mice (approximately 7 km/day. At approximately 3 months, some DCM mice demonstrated low running activity (LO: 5 km/day. In the LO group, the lung weight/body weight ratio was much higher than that in the other groups, and the lungs were infiltrated with hemosiderin-loaded alveolar macrophages. Furthermore, echocardiography showed more severe ventricular dilation and a lower ejection fraction, whereas Electrocardiography (ECG revealed QRS widening. There were two patterns in the time courses of running activity before death in DCM mice: deaths with maintained activity and deaths with decreased activity. CONCLUSIONS/SIGNIFICANCE: Our results indicate that DCM mice with low running activity developed severe CHF and that running wheels are useful for detection of CHF in mouse models. We found that approximately half of ΔK210 DCM mice die suddenly before onset of CHF, whereas others develop CHF, deteriorate within 10 to 20 days, and die.

  3. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

    OpenAIRE

    Ehre, Camille; Worthington, Erin N.; Liesman, Rachael M.; Grubb, Barbara R.; Barbier, Diane; O’Neal, Wanda K; Sallenave, Jean-Michel; Pickles, Raymond J.; Boucher, Richard C.

    2012-01-01

    MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in...

  4. Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

    OpenAIRE

    Jessica Jen-Chu Wang; Christoph Rau; Rozeta Avetisyan; Shuxun Ren; Romay, Milagros C.; Gabriel Stolin; Ke Wei Gong; Yibin Wang; Lusis, Aldons J.

    2016-01-01

    We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with ...

  5. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS

    OpenAIRE

    Liao, Bing; Zhao, Weihua; Beers, David R.; Henkel, Jenny S; Appel, Stanley H.

    2012-01-01

    Neuroinflammation is a prominent pathological feature in the spinal cords of patients with amyotrophic lateral sclerosis (ALS), as well as in transgenic mouse models of inherited ALS, and is characterized by activated microglia. Earlier studies showed that activated microglia play important roles in both motoneuron protection and injury. More recent studies investigating the pathoprogression of disease in ALS mice have demonstrated that the in vivo activation states of microglia, including th...

  6. Effects of Raphani Semen on Immuno-response in the Mouse Model of allergi Asthma

    OpenAIRE

    Jai-Young, Park; Ki-Chul, Park; Hee-Soo,Park

    2002-01-01

    Objective: This study was eanied out to investigate the effects of Raphani Semen on immuno-response in the mouse model of allergic asthma. Methods: In this study, BALB/C mice were divided into 6 groups: Normal (Non-treated group), Control (Group with not treated after allergic sensitization and induction by ovalbumin), Treat I (Group with the oral administration of saline after allergic sensitization and induction by ovalbumin), Treat n (Allergic asthma group treated with acupuncture (BL ...

  7. GFAP expression as an indicator of disease severity in mouse models of Alexander disease

    Directory of Open Access Journals (Sweden)

    Albee Messing

    2013-03-01

    Full Text Available AxD (Alexander disease is a rare disorder caused by heterozygous mutations in GFAP (glial fibrillary acidic protein resulting in accumulation of the GFAP protein and elevation of Gfap mRNA. To test whether GFAP itself can serve as a biomarker of disease status or progression, we investigated two independent measures of GFAP expression in AxD mouse models, one using a genetic reporter of promoter activity and the other quantifying GFAP protein directly in a manner that could also be employed in human studies. Using a transgenic reporter line that expresses firefly luciferase under the control of the murine Gfap promoter (Gfap-luc, we found that luciferase activity reflected the regional CNS (central nervous system variability of Gfap mRNA in Gfap+/+ mice, and increased in mice containing a point mutation in Gfap that mimics a common human mutation in AxD (R239H in the human sequence, and R236H in the murine sequence. In a second set of studies, we quantified GFAP protein in CSF (cerebrospinal fluid taken from three different AxD mouse models and littermate controls. GFAP levels in CSF were increased in all three AxD models, in a manner corresponding to the concentrations of GFAP in brain. These studies demonstrate that transactivation of the Gfap promoter is an early and sustained indicator of the disease process in the mouse. Furthermore, GFAP in CSF serves as a potential biomarker that is comparable between mouse models and human patients.

  8. PATHOPHYSIOLOGIC BASIS OF LIVER DISEASE IN CYSTIC FIBROSIS EMPLOYING A ΔF508 MOUSE MODEL

    OpenAIRE

    Freudenberg, Folke; BRODERICK, ANNEMARIE L.; Yu, Bian B.; Leonard, Monika R.; Glickman, Jonathan N.; CAREY, MARTIN C.

    2008-01-01

    The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiologic manifestations employing a mouse model carrying ΔF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, this should lead to a hydrophobic bile salt profile and to “hyperbilirubinbilia” because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then...

  9. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells

    OpenAIRE

    Arnold, I C; Dehzad, N; Reuter, S; Martin, H.; Becher, B; Taube, C.; Müller, A.

    2011-01-01

    Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correla...

  10. Assessing the validity of current mouse genetic models of obsessive–compulsive disorder

    OpenAIRE

    Wang, Li; Simpson, Helen B.; Dulawa, Stephanie C.

    2009-01-01

    Obsessive–compulsive disorder (OCD) is a disorder characterized by unwanted and intrusive thoughts, images, or impulses and/or repetitive behavior. OCD is a major cause of disability; however, the genetic factors and pathophysiological mechanisms underlying this complex, heterogeneous disorder remain largely unknown. During the past decade, a number of putative mouse genetic models of OCD have been developed for the purpose of studying the neural mechanisms underlying this disorder and develo...

  11. Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

    OpenAIRE

    Imperlini, Esther; Orrù, Stefania; Corbo, Claudia; Daniele, Aurora; Salvatore, Francesco

    2014-01-01

    Phenylketonuria (PKU), if not detected and treated in newborns, causes severe neurological dysfunction and cognitive and behavioral deficiencies. Despite the biochemical characterization of PKU, the molecular mechanisms underlying PKU-associated brain dysfunction remain poorly understood. The aim of this study was to gain insights into the pathogenesis of this neurological damage by analyzing protein expression profiles in brain tissue of Black and Tan BRachyury-PahEnu2 mice (a mouse model of...

  12. An initial top-down proteomic analysis of the standard cuprizone mouse model of multiple sclerosis

    OpenAIRE

    Partridge, Melissa A.; Gopinath, Sumana; Myers, Simon J.; Jens R Coorssen

    2015-01-01

    An initial proteomic analysis of the cuprizone mouse model to characterise the breadth of toxicity by assessing cortex, skeletal muscle, spleen and peripheral blood mononuclear cells. Cuprizone treated vs. control mice for an initial characterisation. Select tissues from each group were pooled, analysed in triplicate using two-dimensional gel electrophoresis (2DE) and deep imaging and altered protein species identified using liquid chromatography tandem mass spectrometry (LC/MS/MS). Forty-thr...

  13. The primary locus of motor neuron death in an ALS–PDC mouse model

    OpenAIRE

    Lee, Grace; Chu, Tony; Shaw, Christopher A.

    2009-01-01

    A mouse model of amyotrophic lateral sclerosis–parkinsonism–dementia complex based on the consumption of cycad seed flour was used to determine whether the observed pathology of motor neuron loss begins in the distal axons or the spinal cord. Assessments of neuromuscular junction integrity and motor neurons were performed at multiple time points. Mice fed cycad pellets performed worse on the wire hang than controls. Microglial activation in cycad-fed mice was observed with motor neuron degene...

  14. COLLAGEN MUTATION CAUSES CHANGES OF THE MICRODAMAGE MORPHOLOGY IN BONE OF AN OI MOUSE MODEL

    OpenAIRE

    Dong, X. Neil; Zoghi, Mahyar; Ran, Qitao; Wang, Xiaodu

    2010-01-01

    Previous studies have postulated that ultrastructural changes may alter the pattern and capacity of microdamage accumulation in bone. Using an osteogenesis imperfecta (OI) mouse model, this study was performed to investigate the correlation of collagen mutation with the microdamage morphology and the associated brittleness of bone. In this study, femurs from mild OI and wild type mice were fatigued under four-point bending to create microdamage in the specimens. Then, the microdamage morpholo...

  15. Drinking Citrus Fruit Juice Inhibits Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model

    OpenAIRE

    Ohnishi, Arika; Asayama, Rie; Mogi, Masaki; Nakaoka, Hirotomo; Kan-no, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Iwanami, Jun; Horiuchi, Masatsugu

    2015-01-01

    Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Cit...

  16. Effect of Retinoic Acid in a Mouse Model of Allergic Rhinitis

    OpenAIRE

    Son, Hye-Lim; Park, Hyang-Rim; Park, Yong-Jin; Kim, Soo-Whan

    2015-01-01

    Purpose All-trans retinoic acid (ATRA) modulates immune responses by affecting T cells. Several studies have revealed that allergic inflammation of the lower airways is negatively associated with the vitamin A concentration. However, the role of ATRA in allergic inflammation of the upper airways is unclear. We investigated the effects of ATRA in an allergic rhinitis mouse model. Methods BALB/c mice except control groups (CON group) were sensitized with and challenged intra-nasally with Dermat...

  17. Regulatory T Cells Prevent Liver Fibrosis During HIV Type 1 Infection in a Humanized Mouse Model

    OpenAIRE

    Nunoya, Jun-ichi; Washburn, Michael L.; Kovalev, Grigoriy I; Su, Lishan

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1) disease is associated with aberrant immune activation, and coinfection with hepatitis C virus (HCV) exacerbates hepatic inflammation and fibrosis. However, the role of HIV-1 infection or host immune modulation in liver pathogenesis is not clearly defined. Here, we report that regulatory T (Treg) cells prevent liver immunopathogenesis during HIV-1 infection in a humanized mouse model. In the absence of Treg cells, HIV-1 infection induced liver fibros...

  18. Recent Technological Advances in Using Mouse Models to Study Ovarian Cancer

    OpenAIRE

    House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo

    2014-01-01

    Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered ...

  19. Core modular blood and brain biomarkers in social defeat mouse model for post traumatic stress disorder

    OpenAIRE

    Yang, Ruoting; Daigle Jr, Bernie J; Muhie, Seid Y; Hammamieh, Rasha; Jett, Marti; Petzold, Linda; Francis J Doyle

    2013-01-01

    Abstract Background Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects a substantial portion of combat veterans and poses serious consequences to long-term health. Consequently, the identification of diagnostic and prognostic blood biomarkers for PTSD is of great interest. Previously, we assessed genome-wide gene expression of seven brain regions and whole blood in a social defeat mouse model subjected to various stress co...

  20. A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

    OpenAIRE

    Michael C Saul; Gessay, Griffin M.; Gammie, Stephen C.

    2012-01-01

    Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments att...

  1. Immunohistochemical and electrophysiological characterization of the mouse model for Retinitis Pigmentosa, rd10

    OpenAIRE

    Biswas, Sonia

    2014-01-01

    In the human disease retinitis pigmentosa (RP) the photoreceptors degenerate over time but the retinal network, in particular the retinal output neurons, the ganglion cells (RGCs) persist, providing a target for electrical stimulation by retinal prostheses. However, remodelling of the retinal network might interfere with this therapeutic approach. In the widely used mouse model of retinal degeneration, rd1, the loss of photoreceptors leads to rhythmic electrical activity of 10 to 16 Hz in the...

  2. Lithium prevents parkinsonian behavioral and striatal phenotypes in an aged parkin mutant transgenic mouse model

    OpenAIRE

    LIEU, CHRISTOPHER A.; Dewey, Colleen M.; Chinta, Shankar J.; Rane, Anand; Rajagopalan, Subramanian; Batir, Sean; Kim, Yong-Hwan; Julie K. Andersen

    2014-01-01

    Lithium has long been used as a treatment for the psychiatric disease bipolar disorder. However, previous studies suggest that lithium provides neuroprotective effects in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease. The exact mechanism by which lithium exerts these effects still remains unclear. In the present study, we evaluated the effects of low-dose lithium treatment in an aged mouse model expressing a parkin mutation within dopaminergic neurons. We...

  3. A Non-Anesthetized Mouse Model for Recording Sensory Urinary Bladder Activity

    OpenAIRE

    Peter Zvara; Wright, Andrew J.; Kristopher Roach; Michal Ursiny; Bennett Shapiro; Dagrosa, Lawrence M.; Nelson, Mark T.; Heppner, Thomas J.

    2010-01-01

    The goal of this study was to develop an in vivo awake mouse model for extracellular bladder sensory nerve recording. A bipolar 125-µm silver electrode was positioned under a single postganglionic bladder nerve. Efferent nerve signals were eliminated by tying off the postganglionic bladder nerve between the major pelvic ganglion and the recording electrode. Sensory nerve activity was measured in the conscious animals 48 hours after surgery during continuous intravesical infusion of 0.9...

  4. Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex

    OpenAIRE

    Cohn, Ronald D.; Durbeej, Madeleine; Moore, Steven A.; Coral-Vazquez, Ramón; Prouty, Sally; Campbell, Kevin P.

    2001-01-01

    Cardiomyopathy is a multifactorial disease, and the dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of the disease. Using mouse models of cardiomyopathy made by ablating genes for components of the sarcoglycan complex, we show that long-term treatment with verapamil, a calcium channel blocker with vasodilator properties, can alleviate the severe cardiomyopathic phenotype, restoring normal serum levels for cardiac troponin I and nor...

  5. Deregulated Lipid Sensing by Intestinal CD36 in Diet-Induced Hyperinsulinemic Obese Mouse Model

    OpenAIRE

    Marjorie Buttet; Hélène Poirier; Véronique Traynard; Kévin Gaire; Thi Thu Trang Tran; Sinju Sundaresan; Philippe Besnard; Abumrad, Nada A.; Isabelle Niot

    2016-01-01

    The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of ...

  6. Toxocara in the mouse : A model for parasite-altered host behaviour ?

    OpenAIRE

    Holland, Celia

    2001-01-01

    The objective of this paper is to critically evaluate the significance of parasite-altered host behaviour in the Toxocara mouse model particularly in the light of the Manipulation Hypothesis. Murine behaviours were examined in both outbred and inbred strains of mice infected with different doses of Toxocara canis ova. Behaviours investigated included activity, exploration, response to novelty, anxiety, learning, memory and social behaviour. Subsequent modifications to the behaviour of infecte...

  7. A commentary on the utility of a new L-DOPA-responsive dystonia mouse model.

    Science.gov (United States)

    Rose, Samuel J; Hess, Ellen J

    2016-01-01

    In a recent issue of Brain, we reported on the generation and characterization of a mouse model of the rare disease L-DOPA-responsive dystonia (DRD). Here, we discuss the utility of these mice for understanding broader disease processes and treatment strategies. Using specific experimental designs that either work "forward" from genetic etiology or "backward" from the symptomatic presentation, we discuss how our data and future work can be used to understand broader themes. PMID:27141408

  8. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    OpenAIRE

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modif...

  9. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

    OpenAIRE

    Ma, Hongwei; Thapa, Arjun; Morris, Lynsie; Redmond, T Michael; Baehr, Wolfgang; Ding, Xi-Qin

    2014-01-01

    Photoreceptors degenerate in a wide array of hereditary retinal diseases and age-related macular degeneration. There is currently no treatment available for retinal degenerations. While outnumbered roughly 20:1 by rods in the human retina, it is the cones that mediate color vision and visual acuity, and their survival is critical for vision. In this communication, we investigate whether thyroid hormone (TH) signaling affects cone viability in retinal degeneration mouse models. TH signaling is...

  10. Exaggerated NMDA Mediated LTD in a Mouse Model of Down Syndrome and Pharmacological Rescuing by Memantine

    Science.gov (United States)

    Scott-McKean, Jonah J.; Costa, Alberto C. S.

    2011-01-01

    The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 [mu]M NMDA for 3 min and 50 [mu]M DHPG for 5 min, respectively. We found that Ts65Dn mice…

  11. Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1

    OpenAIRE

    Tuuli Sedman; Kertu Rünkorg; Maarja Krass; Hendrik Luuk; Mario Plaas; Eero Vasar; Vallo Volke

    2016-01-01

    Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effe...

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

    OpenAIRE

    Ihnatko, Robert; Post, Claes; Blomqvist, Anders

    2013-01-01

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

  13. Matriptase initiates epidermal prokallikrein activation and disease onset in a mouse model of Netherton syndrome

    OpenAIRE

    Sales, Katiuchia Uzzun; Masedunskas, Andrius; Bey, Alexandra L.; Rasmussen, Amber; Weigert, Roberto; List, Karin; Szabo, Roman; Overbeek, Paul A.; Thomas H Bugge

    2010-01-01

    Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome. The principal morbidities of the disease are stratum corneum detachment and chronic inflammation. We show that the membrane protease, matriptase, initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein-related cascade. Auto-activation of pro-inflammatory and stratum corneum detachment-associated pro-kallikrein-related peptidases was either low or...

  14. Antibiotic Selection of Escherichia coli Sequence Type 131 in a Mouse Intestinal Colonization Model

    OpenAIRE

    Boetius Hertz, Frederik; Løbner-Olesen, Anders; Frimodt-Møller, Niels

    2014-01-01

    The ability of different antibiotics to select for extended-spectrum β-lactamase (ESBL)-producing Escherichia coli remains a topic of discussion. In a mouse intestinal colonization model, we evaluated the selective abilities of nine common antimicrobials (cefotaxime, cefuroxime, dicloxacillin, clindamycin, penicillin, ampicillin, meropenem, ciprofloxacin, and amdinocillin) against a CTX-M-15-producing E. coli sequence type 131 (ST131) isolate with a fluoroquinolone resistance phenotype. Mice ...

  15. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet

    OpenAIRE

    Lussier, Danielle M.; Woolf, Eric C.; Johnson, John L.; Brooks, Kenneth S.; Blattman, Joseph N.; Scheck, Adrienne C.

    2016-01-01

    Background Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immun...

  16. Magnetic Nanoparticle-Based Hyperthermia for Head & Neck Cancer in Mouse Models

    OpenAIRE

    Zhao, Qun; Wang, Luning; Cheng, Rui; Mao, Leidong; Arnold, Robert D.; Howerth, Elizabeth W.; Chen, Zhuo G; Platt, Simon

    2012-01-01

    In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line). A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically...

  17. Gastroprotective effect of Desmodium gangeticum roots on gastric ulcer mouse models

    OpenAIRE

    Ayyavu Mahesh; Robert Jeyachandran; Dowlathabad Muralidhara Rao; Devarajan Thangadurai

    2012-01-01

    In the present study, the ethanolic root extract of Desmodium gangeticum (L.) DC., Fabaceae, (EDG), have been studied in various acute and chronic ulcer mouse models. Oral administration of root extract, significantly decrease the ulcer index and lesion number in a dose dependent manner against ethanol induced acute gastric ulcer in mice. In gastric ulcerated animal that received high dose of 150 mg/kg EDG, the mucosa showed no ulceration with slight focal congestion and the glands appeared n...

  18. Establishment of a mouse model to express bovine CD14 short hairpin RNA

    OpenAIRE

    Li, Xiangping; Huang, Shihai; Ren, Yanping; Wang, Meng; Kang, Chao; Xie, Liangliang; Shi, Deshun

    2015-01-01

    Background Cluster of differentiation 14 (CD14) functions as a co-receptor for Toll-like receptor (TLR)-4 and myeloid differentiation factor (MD)-2 in detecting bacterial lipopolysaccharide. Together, these complexes promote the phagocytosis and digestion of Gram-negative bacteria, and initiate immune responses. To date, much of our understanding of CD14 function during Gram-negative bacterial inflammation comes from studies on mouse knockout models and cell transfection. To identify the effe...

  19. Triclosan as a Systemic Antibacterial Agent in a Mouse Model of Acute Bacterial Challenge

    OpenAIRE

    Sharma, Shilpi; Ramya, T. N. C.; Surolia, Avadhesha; Surolia, Namita

    2003-01-01

    The upsurge of multiple-drug-resistant microbes warrants the development and/or use of effective antibiotics. Triclosan, though used in cosmetic and dermatological preparations for several decades, has not been used as a systemic antibacterial agent due to problems of drug administration. Here we report the striking efficacy of triclosan in a mouse model of acute systemic bacterial infection. Triclosan not only significantly extends the survival time of the infected mice, it also restores blo...

  20. Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis—A Literature Review

    OpenAIRE

    Leena Rivina; Robert Schiestl

    2012-01-01

    As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus) remains one of the best anim...

  1. Genomic analysis to define molecular basis of aggressiveness in a mouse model of oral cancer

    OpenAIRE

    Varun Chalivendra; Krishna Latha Kanchi; Onken, Michael D.; Ashley E. Winkler; Elaine Mardis; Ravindra Uppaluri

    2014-01-01

    To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC), our laboratory developed a carcinogen-induced mouse oral cancer (MOC) cell line model that encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS) and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of th...

  2. Modulation of Lupus Phenotype by Adiponectin Deficiency in Autoimmune Mouse Models

    OpenAIRE

    Parker, Jennifer; Menn-Josephy, Hanni; Laskow, Bari; Takemura, Yukihiro; Aprahamian, Tamar

    2010-01-01

    Adiponectin is an adipocyte-derived cytokine with anti-inflammatory properties. Paradoxically, circulating adiponectin levels are increased in a number of inflammatory diseases. Thus, we sought to define the role of adiponectin deficiency in mouse models of autoimmunity. Adiponectin-deficient mice on a C57BL/6 background do not develop an autoimmune phenotype. Autoimmunity was also not observed in adiponectin-deficient mice generated on the permissive MRL background. However, adiponectin defi...

  3. Bee Venom and Its Component Apamin as Neuroprotective Agents in a Parkinson Disease Mouse Model

    OpenAIRE

    Alvarez-Fischer, Daniel; Noelker, Carmen; Vulinović, Franca; Grünewald, Anne; Chevarin, Caroline; Klein, Christine; Oertel, Wolfgang H.; Hirsch, Etienne C.; Michel, Patrick P.; Hartmann, Andreas

    2013-01-01

    Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a...

  4. Mouse Models of Diabetes, Obesity and Related Kidney Disease.

    Science.gov (United States)

    Glastras, Sarah J; Chen, Hui; Teh, Rachel; McGrath, Rachel T; Chen, Jason; Pollock, Carol A; Wong, Muh Geot; Saad, Sonia

    2016-01-01

    Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice. PMID:27579698

  5. Proteomic profiling of lymphedema development in mouse model.

    Science.gov (United States)

    Lee, Joomin; Song, Haeun; Roh, Kangsan; Cho, Sungrae; Lee, Sukchan; Yeom, Chang-Hwan; Park, Seyeon

    2016-07-01

    The lymphatic vascular system plays an important role in tissue fluid homeostasis. Lymphedema is a chronic, progressive, and incurable condition that leads to lymphatic fluid retention; it may be primary (heritable) or secondary (acquired) in nature. Although there is a growing understanding of lymphedema, methods for the prevention and treatment of lymphedema are still limited. In this study, we investigated differential protein expressions in sham-operated and lymphedema-operated mice for 3 days, using two-dimensional gel electrophoresis (2-DE) and mass spectrometry analysis. Male improved methodology for culturing noninbred (ICR) mice developed lymphedema in the right hindlimb. Twenty functional proteins were found to be differentially expressed between lymphedema induced-right leg tissue and normal left leg tissue. Out of these proteins, the protein levels of apolipoprotein A-1 preprotein, alpha-actinin-3, mCG21744, parkinson disease, serum amyloid P-component precursor, annexin A8, mKIAA0098 protein, and fibrinogen beta chain precursor were differentially upregulated in the lymphedema mice compared with the sham-operated group. Western blotting analysis was used to validate the proteomics results. Our results showing differential up-regulation of serum amyloid P-component precursor, parkinson disease, and apolipoprotein A-1 preprotein in lymphedema model over sham-operated model suggest important insights into pathophysiological target for lymphedema. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27151289

  6. Mouse models for the study of postnatal cardiac hypertrophy

    Directory of Open Access Journals (Sweden)

    A. Del Olmo-Turrubiarte

    2015-06-01

    Full Text Available The main objective of this study was to create a postnatal model for cardiac hypertrophy (CH, in order to explain the mechanisms that are present in childhood cardiac hypertrophy. Five days after implantation, intraperitoneal (IP isoproterenol (ISO was injected for 7 days to pregnant female mice. The fetuses were obtained at 15, 17 and 19 dpc from both groups, also newborns (NB, neonates (7–15 days and young adults (6 weeks of age. Histopathological exams were done on the hearts. Immunohistochemistry and western blot demonstrated GATA4 and PCNA protein expression, qPCR real time the mRNA of adrenergic receptors (α-AR and β-AR, alpha and beta myosins (α-MHC, β-MHC and GATA4. After the administration of ISO, there was no change in the number of offsprings. We observed significant structural changes in the size of the offspring hearts. Morphometric analysis revealed an increase in the size of the left ventricular wall and interventricular septum (IVS. Histopathological analysis demonstrated loss of cellular compaction and presence of left ventricular small fibrous foci after birth. Adrenergic receptors might be responsible for changing a physiological into a pathological hypertrophy. However GATA4 seemed to be the determining factor in the pathology. A new animal model was established for the study of pathologic CH in early postnatal stages.

  7. An In Vivo Mouse Model for Human Prostate Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Aaron M. Havens

    2008-04-01

    Full Text Available We developed a sensitive real-time polymerase chain reaction (QPCR assay that allows us to track early lodging/homing events in vivo. We used this technology to develop a metastasis assay of human prostate cancer (PCa growth in severe combined immunodeficient mice. For this purpose, marked human PCa cell lines were implanted subcutaneously or in the prostate (orthotopically of severe combined immunodeficient mice as models of primary tumors. Mice were then sacrificed at various time points, and distant tissues were investigated for the presence of metastatic cells. At 3 weeks, a number of tissues were recovered and evaluated by QPCR for the presence of metastatic cells. The data demonstrate that several PCa cell lines are able to spread from the primary lesion and take up residence in distant sites. If the primary tumors were resected at 3 weeks, in several cases, metastastic lesions were identified over the course of 9 months. We propose that this new model may be particularly useful in exploring the molecular events in early metastasis, identifying the metastatic niche, and studying issues pertaining to dormancy.

  8. A Chemical Properties Simulator to Support Integrated Environmental Modeling (proceeding)

    Science.gov (United States)

    Users of Integrated Environmental Modeling (IEM) systems are responsible for defining individual chemicals and their properties, a process that is time-consuming at best and overwhelming at worst, especially for new chemicals with new structures. A software tool is needed to allo...

  9. Upper Secondary Teachers' Knowledge for Teaching Chemical Bonding Models

    Science.gov (United States)

    Bergqvist, Anna; Drechsler, Michal; Chang Rundgren, Shu-Nu

    2016-01-01

    Researchers have shown a growing interest in science teachers' professional knowledge in recent decades. The article focuses on how chemistry teachers impart chemical bonding, one of the most important topics covered in upper secondary school chemistry courses. Chemical bonding is primarily taught using models, which are key for understanding…

  10. New Mouse Models to Investigate the Efficacy of Drug Combinations in Human Chronic Myeloid Leukemia.

    Science.gov (United States)

    Lin, Hanyang; Woolfson, Adrian; Jiang, Xiaoyan

    2016-01-01

    Chronic myeloid leukemia (CML) comprises a simple and effective paradigm for generating new insights into the cellular origin, pathogenesis, and treatment of many types of human cancer. In particular, mouse models of CML have greatly facilitated the understanding of the underlying molecular mechanisms and pathogenesis of this disease and have led to the identification of new drug targets that in some cases offer the possibility of functional cure. There are currently three established CML mouse models: the BCR-ABL transgenic model, the BCR-ABL retroviral transduction/transplantation model, and the xenotransplant immunodeficient model. Each has its own unique advantages and disadvantages. Depending on the question of interest, some models may be more appropriate than others. In this chapter, we describe a newly developed xenotransplant mouse model to determine the efficacy of novel therapeutic agents, either alone or in combination. The model facilitates the evaluation of the frequency of leukemic stem cells with long-term leukemia-initiating activity, a critical subcellular population that causes disease relapse and progression, through the utilization of primary CD34(+) CML stem/progenitor cells obtained from CML patients at diagnosis and prior to drug treatment. We have also investigated the effectiveness of new combination treatment strategies designed to prevent the development of leukemia in vivo using BCR-ABL (+) blast crisis cells as a model system. These types of in vivo studies are important for the prediction of individual patient responses to drug therapy, and have the potential to facilitate the design of personalized combination therapy strategies. PMID:27581149

  11. Systematic construction of a conceptual minimal model of plasma cholesterol levels based on knockout mouse phenotypes.

    Science.gov (United States)

    van de Pas, Niek C A; Soffers, Ans E M F; Freidig, Andreas P; van Ommen, Ben; Woutersen, Ruud A; Rietjens, Ivonne M C M; de Graaf, Albert A

    2010-06-01

    Elevated plasma cholesterol, a well-known risk factor for cardiovascular diseases, is the result of the activity of many genes and their encoded proteins in a complex physiological network. We aim to develop a minimal kinetic computational model for predicting plasma cholesterol levels. To define the scope of this model, it is essential to discriminate between important and less important processes influencing plasma cholesterol levels. To this end, we performed a systematic review of mouse knockout strains and used the resulting dataset, named KOMDIP, for the identification of key genes that determine plasma cholesterol levels. Based on the described phenotype of mouse knockout models, 36 of the 120 evaluated genes were marked as key genes that have a pronounced effect on the plasma cholesterol concentration. The key genes include well-known genes, e.g., Apoe and Ldlr, as well as genes hardly linked to cholesterol metabolism so far, e.g., Plagl2 and Slc37a4. Based on the catalytic function of the genes, a minimal conceptual model was defined. A comparison with nine conceptual models from literature revealed that each of the individual published models is less complete than our model. Concluding, we have developed a conceptual model that can be used to develop a physiologically based kinetic model to quantitatively predict plasma cholesterol levels. PMID:20176131

  12. Effect of Endostar Combined with Gemcitabine on the Mouse Model of Human Pancreatic Cancer

    Institute of Scientific and Technical Information of China (English)

    林清风

    2007-01-01

    Objective To investigate the effects of recombinant human endostatin,that is,endostar combined with gemcitabine on the mouse model of human pancreatic cancer.Methods We use the cell line PANC-1 and the severe combined immune deficient mice to set up the mouse model of human pancreatic cancer,then devide them into three groups,treat them with gemcitabine,gemcitabine combined with endostar,and 0.9% saline water respectively.We observe the change of the tumor volumn,use ELISA method to detect the serum VEGF level,stain the micro vessel in the tumor tissue with immunohistochemistry method,and compare the data among the different groups respectively.Results On the twenty-eighth day,the tumor volume of the control group,the monotherapy group and the combination group,averaged 1 700 mm3,19.2 mm3,10.4 mm3,serum VEGF level 88.6 L,35.5,26.3 pg/mL and MVD 43.9,30.3,19.2 respectively,which had significant difference.Conclusion Endostar can strengthen the lethal effect of gemcitabine on the mouse model of human pancreatic cancer.

  13. Application of mouse model for effective evaluation of foot-and-mouth disease vaccine.

    Science.gov (United States)

    Lee, Seo-Yong; Ko, Mi-Kyeong; Lee, Kwang-Nyeong; Choi, Joo-Hyung; You, Su-Hwa; Pyo, Hyun-Mi; Lee, Myoung-Heon; Kim, Byounghan; Lee, Jong-Soo; Park, Jong-Hyeon

    2016-07-19

    Efficacy evaluation of foot-and-mouth disease (FMD) vaccines has been conducted in target animals such as cows and pigs. In particular, handling FMD virus requires a high level of biosafety management and facilities to contain the virulent viruses. The lack of a laboratory animal model has resulted in inconvenience when it comes to using target animals for vaccine evaluation, bringing about increased cost, time and labor for the experiments. The FMD mouse model has been studied, but most FMD virus (FMDV) strains are not known to cause disease in adult mice. In the present study, we created a series of challenge viruses that are lethal to adult C57BL/6 mice. FMDV types O, A, and Asia1, which are related to frequent FMD outbreaks, were adapted for mice and the pathogenesis of each virus was evaluated in the mouse model. Challenge experiments after vaccination using in-house and commercial vaccines demonstrated vaccine-mediated protection in a dose-dependent manner. In conclusion, we propose that FMD vaccine evaluation should be carried out using mouse-adapted challenge viruses as a swift, effective efficacy test of experimental or commercial vaccines. PMID:27340094

  14. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  15. Mouse models of liver fibrosis mimic human liver fibrosis of different etiologies.

    Science.gov (United States)

    Martínez, Allyson K; Maroni, Luca; Marzioni, Marco; Ahmed, Syed T; Milad, Mena; Ray, Debolina; Alpini, Gianfranco; Glaser, Shannon S

    2014-12-01

    The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted. PMID:25396098

  16. Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy.

    Science.gov (United States)

    Zimova, Ivana; Brezovakova, Veronika; Hromadka, Tomas; Weisova, Petronela; Cubinkova, Veronika; Valachova, Bernadeta; Filipcik, Peter; Jadhav, Santosh; Smolek, Tomas; Novak, Michal; Zilka, Norbert

    2016-09-01

    Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy. PMID:27567836

  17. Image Analysis-Based Approaches for Scoring Mouse Models of Colitis.

    Science.gov (United States)

    Rogers, R; Eastham-Anderson, J; DeVoss, J; Lesch, J; Yan, D; Xu, M; Solon, M; Hotzel, K; Diehl, L; Webster, J D

    2016-01-01

    Mouse models of inflammatory bowel disease are critical for basic and translational research that is advancing the understanding and treatment of this disease. Assessment of these mouse models frequently relies on histologic endpoints. In recent years, whole slide imaging and digital pathology-based image analysis platforms have become increasingly available for implementation into the pathology workflow. These automated image analysis approaches allow for nonbiased quantitative assessment of histologic endpoints. In this study, the authors sought to develop an image analysis workflow using a commercially available image analysis platform that requires minimal training in image analysis or programming, and this workflow was used to score 2 mouse models of colitis that are primarily characterized by immune cell infiltrates in the lamina propria. Although the software was unable to accurately and consistently segment hematoxylin and eosin-stained sections, automated quantification of CD3 immunolabeling resulted in strong correlations with the pathologist's score in all studies and allowed for the identification of 8 of the 9 differences among treatment groups that were identified by the pathologist. These results demonstrate not only the ability to incorporate solutions based on image analysis into the pathologist's workflow but also the importance of immunohistochemical or histochemical surrogates for the incorporation of image analysis in histologic assessments. PMID:25907770

  18. Responses of the L5178Y tk/sup +//tk/sup -/ mouse lymphoma cell forward mutation assay. II. 18 coded chemicals

    Energy Technology Data Exchange (ETDEWEB)

    McGregor, D.B.; Brown, A.; Cattanach, P.; Edwards, I.; McBride, D.; Caspary, W.J.

    1988-01-01

    Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk/sup +///sup -/ mouse lymphoma cell forward mutation assay by the use of procedures based upon those described previously. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 ..mu..g/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran, benzyl chloride, bromodichloromethane, butylated hydroxytoluene, chlorendic acid, o-chlorobenzalmalonitrile, 1,2,3,4-diepoxybutane, dimethyl formamide, dimethyl hydrogen phosphite, furfural, glutaraldehyde, hydroquinone, 8-hydroxyquinoline, and resorcinol. Apart from bromodichloromethane, butylated hydroxytoluene and dimethyl hydrogen phosphite, rat liver S9 mix was not a requirement for the activity of any of these compounds. Chemicals not identified as mutagens were water, tert-butyl alcohol, pyridine, and witch hazel.

  19. Optical molecular imaging technology in genetically engineered mouse models

    International Nuclear Information System (INIS)

    Optical molecular imaging technology has been rapidly developed to non-invasively, quantitatively and dynamically monitor the in vivo biological processes in real time. It is widely used in various fields of biomedicine and life sciences with advantages like easy operation, real-time study, high sensitivity and low cost image equipment. In recent years, the generation of transgenic animal models in combination with optical molecular imaging reporter genes has greatly facilitated the development of the imaging technology and expanded its application. In this article, we review the research progress by optical molecular imaging in genetically engineered mice (GEM) for 1) investigating tumorigenesis, growth or metastasis, 2) monitoring cell cycle, cell proliferation, apoptosis or angiogenesis, 3) evaluating the inflammation process and 4) providing a modality for pharmaceutical development. (authors)

  20. Atmosphere behavior in gas-closed mouse-algal systems - An experimental and modelling study

    Science.gov (United States)

    Averner, M. M.; Moore, B., III; Bartholomew, I.; Wharton, R.

    1984-01-01

    A NASA-sponsored research program initiated using mathematical modelling and laboratory experimentation aimed at examining the gas-exchange characteristics of artificial animal/plant systems closed to the ambient atmosphere is studied. The development of control techniques and management strategies for maintaining the atmospheric levels of carbon dioxide and oxygen at physiological levels is considered. A mathematical model simulating the behavior of a gas-closed mouse-algal system under varying environmental conditions is described. To verify and validate the model simulations, an analytical system with which algal growth and gas exchange characteristics can be manipulated and measured is designed, fabricated, and tested. The preliminary results are presented.