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Sample records for aqp9 null mice

  1. Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice

    DEFF Research Database (Denmark)

    Spegel, Peter; Chawade, Aakash; Nielsen, Søren;

    2015-01-01

    profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%) and glucose (+24%), and reduction in threonate (all at q < 0.1) in Aqp9(-/-) db/db mice compared to controls. Metabolite profiling thus confirms a role......Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor-deficient (db/db) obese mice on a C57BL/6 × C57BLKS mixed genetic background. Furthermore, shRNA-mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in...... observed elevated plasma glucose in Aqp9(-/-) db/db mice (+1.1 mmol/L, life-time average), while plasma insulin concentration was reduced at the time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9(wt) db/db and Aqp9(-/-) db/db mice. Liver transcriptional...

  2. SL7207/pEGFP-N1-AQP9及SL7207/pshRNA-AQP9重组沙门菌的构建及表达%Construction and expression of recombinant Salmonella SL7207/pEGFP-N1-AQP9 and SL7207/pshRNA-AQP9

    Institute of Scientific and Technical Information of China (English)

    王川; 亢渝俊; 姜政; 王丕龙

    2012-01-01

    Objective To transform human aquaglyceroporin 9(AQP9) recombinant eukaryotic expression plasmid pEGFP Nl AQP9 and interference plasmid pshRNA AQP9 into attenuated Salmonella strain SL7207 by electroporation and detect their ex pression,in order to lay the foundation for elucidating the human AQP9 in pathogenesis of nonalcoholic fatty liver disease (NAFLD). Methods AQP9 gene was obtained by RT PCR from human hepatic tissue and cloned into pEGFP Nl vector,recombi nant eukaryotic expression plasmid pEGFP Nl AQP9 was constructed,designed and synthesized human AQP9 SiRNA,annealed to double stranded ShRNA, inserted to pGenesil 1 plasmid, interference plasmid pshRNA AQP9 was constructed, and then trans formed into attenuated Salmonella strain SL7207 by electroporation,the expression were detected by PCR and Western Blot,and we detected their stability. Results Recombinant plasmid pEGFP Nl AQP9 and pshRNA AQP9 were constructed, transformed into attenuated Salmonella strain SL7207,after transformed into SL7207,could express in recombinant Salmonella. Conclusion Recom binant Salmonella SL7207/pEGFP Nl AQP9 and SL7207/pshRNA AQP9 are successfully constructed,lay the foundation for fur ther study on the gene therapy of NAFLD with AQP9.%目的 将人水甘油通道蛋白9(AQP9)真核表达质粒pEGFP-N1-AQP9及干扰质粒pshRNA-AQP9通过电穿孔转化减毒沙门菌株SL7207,并验证其表达情况,为阐明AQP9在非酒精性脂肪肝病(NAFLD)中的作用奠定基础.方法 从人肝脏组织中通过RT-PCR获得AQP9基因,克隆到载体pEGFP-N1上,构建真核表达质粒pEGFP-N1-AQP9,设计合成针对人AQP9的siRNA,退火形成双链shRNA,并插入pGenesil-1质粒中,构建干扰质粒pshRNA-AQP9,电穿孔转化减毒沙门菌株SL7207,通过PCR、Western blot验证其表达情况,并检测其稳定性.结果 成功构建pEGFP-N1-AQP9及pshRNA-AQP9重组质粒,将其转化SL7207后,能在重组沙门菌中表达.结论 成功构建SL7207/pEGFP-N1-AQP9及SL7207/pshRNA-AQP

  3. Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment.

    Science.gov (United States)

    Lebeck, Janne; Cheema, Muhammad Umar; Skowronski, Mariusz T; Nielsen, Søren; Praetorius, Jeppe

    2015-02-01

    The peroxisome proliferator receptor α (PPARα) is a key regulator of the hepatic response to fasting with effects on both lipid and carbohydrate metabolism. A role in hepatic glycerol metabolism has also been found; however, the results are somewhat contradictive. Aquaporin 9 (AQP9) is a pore-forming transmembrane protein that facilitates hepatic uptake of glycerol. Its expression is inversely regulated by insulin in male rodents, with increased expression during fasting. Previous results indicate that PPARα plays a crucial role in the induction of AQP9 mRNA during fasting. In the present study, we use PPARα agonists to explore the effect of PPARα activation on hepatic AQP9 expression and on the abundance of enzymes involved in glycerol metabolism using both in vivo and in vitro systems. In male rats with free access to food, treatment with the PPARα agonist WY 14643 (3 mg·kg(-1)·day(-1)) caused a 50% reduction in hepatic AQP9 abundance with the effect being restricted to AQP9 expressed in periportal hepatocytes. The pharmacological activation of PPARα had no effect on the abundance of GlyK, whereas it caused an increased expression of hepatic GPD1, GPAT1, and L-FABP protein. In WIF-B9 and HepG2 hepatocytes, both WY 14643 and another PPARα agonist GW 7647 reduced the abundance of AQP9 protein. In conclusion, pharmacological PPARα activation results in a marked reduction in the abundance of AQP9 in periportal hepatocytes. Together with the effect on the enzymatic apparatus for glycerol metabolism, our results suggest that PPARα activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose. PMID:25477377

  4. Cadmium modulates adipocyte functions in metallothionein-null mice

    International Nuclear Information System (INIS)

    Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT−/−) mice, which cannot form atoxic Cd–MT complexes and are used for evaluating Cd as free ions, and wild type (MT+/+) mice. Cd administration more significantly reduced the adipocyte size of MT−/− mice than that of MT+/+ mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT−/− mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes. - Highlights: • Cd causes a marked reduction in adipocyte size in MT-null mice. • Cd enhances macrophage migration into adipose tissue and disrupt adipokine secretion. • MT gene alleviates Cd-induced adipocyte dysfunctions. • Cd enhances the degradation of stored lipids in adipocytes, mediated by perilipin. • Cd induces unusually small adipocytes and the abnormal expression of adipokines

  5. Cadmium modulates adipocyte functions in metallothionein-null mice

    Energy Technology Data Exchange (ETDEWEB)

    Kawakami, Takashige; Nishiyama, Kaori; Kadota, Yoshito; Sato, Masao; Inoue, Masahisa; Suzuki, Shinya, E-mail: suzukis@ph.bunri-u.ac.jp

    2013-11-01

    Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT{sup −/−}) mice, which cannot form atoxic Cd–MT complexes and are used for evaluating Cd as free ions, and wild type (MT{sup +/+}) mice. Cd administration more significantly reduced the adipocyte size of MT{sup −/−} mice than that of MT{sup +/+} mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT{sup −/−} mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes. - Highlights: • Cd causes a marked reduction in adipocyte size in MT-null mice. • Cd enhances macrophage migration into adipose tissue and disrupt adipokine secretion. • MT gene alleviates Cd-induced adipocyte dysfunctions. • Cd enhances the degradation of stored lipids in adipocytes, mediated by perilipin. • Cd induces unusually small adipocytes and the abnormal expression of adipokines.

  6. TRPV1-null mice are protected from diet-induced obesity

    OpenAIRE

    Motter, Arianne L.; Ahern, Gerard P.

    2008-01-01

    We explored a role for the capsaicin receptor TRPV1 in the regulation of feeding and body mass. On a 4.5% fat diet, wild-type and TRPV1-null mice gained equivalent body mass. On an 11% fat diet, however, TRPV1-null mice gained significantly less mass and adiposity; at 44 weeks the mean body weights of wild-type and TRPV1-null mice were ~51 and 34 g respectively. Both groups of mice consumed equivalent energy and absorbed similar amounts of lipids. TRPV1-null mice, however, exhibited a signifi...

  7. Impairment in motor learning of somatostatin null mutant mice.

    Science.gov (United States)

    Zeyda, T; Diehl, N; Paylor, R; Brennan, M B; Hochgeschwender, U

    2001-07-01

    Somatostatin was first identified as a hypothalamic factor which inhibits the release of growth hormone from the anterior pituitary (somatotropin release inhibitory factor, SRIF). Both SRIF and its receptors were subsequently found widely distributed within and outside the nervous system, in the adult as well as in the developing organism. Reflecting this wide distribution, somatostatin has been implicated regulating a diverse array of biological processes. These include body growth, homeostasis, sensory perception, autonomous functions, rate of intestinal absorption, behavior, including cognition and memory, and developmental processes. We produced null mutant mice lacking somatostatin through targeted mutagenesis. The mutant mice are healthy, fertile, and superficially indistinguishable from their heterozygous and wildtype littermates. A 'first round' phenotype screen revealed that mice lacking somatostatin have elevated plasma growth hormone levels, despite normal body size, and have elevated basal plasma corticosterone levels. In order to uncover subtle and unexpected differences, we carried out a systematic behavioral phenotype screen which identified a significant impairment in motor learning revealed when increased demands were made on motor coordination. Motor coordination and motor learning require an intact cerebellum. While somatostatin is virtually absent from the adult cerebellum, the ligand and its receptor(s) are transiently expressed at high levels in the developing cerebellum. This result suggests the functional significance of transient expression of SRIF and its receptors in the development of the cerebellum. PMID:11430867

  8. Increased Oxidative Stress Impairs Adipose Tissue Function in Sphingomyelin Synthase 1 Null Mice

    OpenAIRE

    Masato Yano; Tadashi Yamamoto; Naotaka Nishimura; Tomomi Gotoh; Ken Watanabe; Kazutaka Ikeda; Yohei Garan; Ryo Taguchi; Koichi Node; Toshiro Okazaki; Yuichi Oike

    2013-01-01

    Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we found that SMS1 null mice showed lipodystrophic phenotype. Mutant mice showed up-regulation of plasma triglyceride concentrations accompanied by reduction of white adipose tissue (WAT) as they aged. Lipoprotein lipase (LPL) activity was severely reduced in mutant mice. In vivo analysis indicated that fatty acid uptake in WAT but not in liver decreased in SMS1 null compared to wild-type mice. In vit...

  9. Leucine supplementation via drinking water reduces atherosclerotic lesions in apoE null mice

    OpenAIRE

    Zhao, Yang; Dai, Xiao-Yan; Zhou, Zhou; Zhao, Ge-xin; Wang, Xian; Xu, Ming-Jiang

    2015-01-01

    Aim: Recent evidence suggests that the essential amino acid leucine may be involved in systemic cholesterol metabolism. In this study, we investigated the effects of leucine supplementation on the development of atherosclerosis in apoE null mice. Methods: ApoE null mice were fed with chow supplemented with leucine (1.5% w/v) in drinking water for 8 week. Aortic atherosclerotic lesions were examined using Oil Red O staining. Plasma lipoprotein-cholesterol levels were measured with fast protein...

  10. Organic anion transporting polypeptide 1a1 null mice are sensitive to cholestatic liver injury.

    Science.gov (United States)

    Zhang, Youcai; Csanaky, Iván L; Cheng, Xingguo; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2012-06-01

    Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na(+)-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance-associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis. PMID:22461449

  11. BALB/Mtv-Null Mice Responding to Strong Mouse Mammary Tumor Virus Superantigens Restrict Mammary Tumorigenesis▿

    OpenAIRE

    Bhadra, Sanchita; Lozano, Mary M.; Dudley, Jaquelin P.

    2008-01-01

    The absence of endogenous mouse mammary tumor viruses (MMTVs) in the congenic mouse strain, BALB/Mtv-null, restricts the early steps of exogenous C3H MMTV infection, preventing the superantigen (Sag) response and mammary tumorigenesis. Here we demonstrate that BALB/Mtv-null mice also resist tumor induction by FM MMTV, which encodes a stronger Sag compared to C3H MMTV. In contrast to infections with C3H MMTV, Mtv-null mice show FM-MMTV Sag-specific responses comparable to those observed in sus...

  12. Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent.

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    Jane Q Chen

    Full Text Available Female 129:Stat1-null mice (129S6/SvEvTac-Stat1(tm1Rds homozygous uniquely develop estrogen-receptor (ER-positive mammary tumors. Herein we report that the mammary glands (MG of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment.

  13. Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice.

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    Gerhard Sengle

    2015-06-01

    Full Text Available Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 null mice (on a 129/Sv background are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 null forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that

  14. Increased Fibronectin Deposition in Embryonic Hearts of Retinol-Binding Protein–Null Mice

    OpenAIRE

    Wendler, Christopher C.; Schmoldt, Angela; Flentke, George R.; Case, Lauren C.; Quadro, Loredana; Blaner, William S.; Lough, John; Susan M. Smith

    2003-01-01

    Precise regulation of retinoid levels is critical for normal heart development. Retinol-binding protein (RBP), an extracellular retinol transporter, is strongly secreted by cardiogenic endoderm. This study addresses whether RBP gene ablation affects heart development. Despite exhibiting an >85% decrease in serum retinol, adult RBP-null mice are viable, breed, and have normal vision when maintained on a vitamin A-sufficient diet. Comparison of RBP-null with wild-type (WT) hearts from embryos a...

  15. Human Cancer Growth and Therapy In NOD/SCID/IL2Rγnull (NSG) Mice

    OpenAIRE

    Shultz, Leonard D.; Goodwin, Neal; Ishikawa, Fumihiko; Hosur, Vishnu; Lyons, Bonnie L.; Greiner, Dale L.

    2014-01-01

    Since the discovery of the “nude” mouse over 40 years ago, investigators have attempted to model human tumor growth in immunodeficient mice. The field has advanced significantly over the ensuing years due to improvements in the murine recipient of human tumors. These improvements include the discovery of the scid mutation and development of targeted mutations in the recombination activating genes 1 and 2 (Rag1null, Rag2null) that severely cripple the adaptive immune response of the murine hos...

  16. Reduced infarct size in neuroglobin-null mice after experimental stroke in vivo

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    Raida Zindy

    2012-08-01

    Full Text Available Abstract Background Neuroglobin is considered to be a novel important pharmacological target in combating stroke and neurodegenerative disorders, although the mechanism by which this protection is accomplished remains an enigma. We hypothesized that if neuroglobin is directly involved in neuroprotection, then permanent cerebral ischemia would lead to larger infarct volumes in neuroglobin-null mice than in wild-type mice. Methods Using neuroglobin-null mice, we estimated the infarct volume 24 hours after permanent middle cerebral artery occlusion using Cavalieri’s Principle, and compared the infarct volume in neuroglobin-null and wild-type mice. Neuroglobin antibody staining was used to examine neuroglobin expression in the infarct area of wild-type mice. Results Infarct volumes 24 hours after permanent middle cerebral artery occlusion were significantly smaller in neuroglobin-null mice than in wild-types (p  Conclusions Neuroglobin-deficiency resulted in reduced tissue infarction, suggesting that, at least at endogenous expression levels, neuroglobin in itself is non-protective against ischemic injury.

  17. Inhibition of urethane-induced genotoxicity and cell proliferation in CYP2E1-null mice

    Energy Technology Data Exchange (ETDEWEB)

    Hoffler, Undi [Department of Pharmacology, Meharry Medical College, Nashville, TN (United States); Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 (United States); Dixon, Darlene [Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 (United States); Peddada, Shyamal [Biostatics Branch, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 (United States); Ghanayem, Burhan I. [Department of Pharmacology, Meharry Medical College, Nashville, TN (United States) and Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 (United States)]. E-mail: ghanayem@niehs.nih.gov

    2005-05-02

    Urethane is a multi-site animal carcinogen and was classified as 'reasonably anticipated to be a human carcinogen.' Urethane is a fermentation by-product and found at appreciable levels in alcoholic beverages and foods such as bread and cheese. Recent work in this laboratory demonstrated for the first time that CYP2E1 is the principal enzyme responsible for urethane metabolism. The current studies were undertaken to assess the relationships between CYP2E1-mediated metabolism and urethane-induced genotoxicity and cell proliferation as determined by induction of micronucleated erythrocytes (MN) and expression of Ki-67, respectively, using CYP2E1-null and wild-type mice. Urethane was administered at 0 (vehicle), 1, 10, or 100 mg/kg/day (p.o.), 5 days/week for 6 weeks. A significant dose-dependent increase in MN was observed in wild-type mice; however, a slight increase was measured in the MN-polychromatic erythrocytes in CYP2E1-null mice treated with 100 mg/kg. A significant increase in the expression of Ki-67 was detected in the livers and the lungs (terminal bronchioles, alveoli, and bronchi) of wild-type mice administered 100 mg urethane/kg in comparison to controls. In contrast, CYP2E1-null mice administered this dose exhibited negligible alterations in Ki-67 expression in the livers and lungs compared to controls. Interestingly, while Ki-67 expression in the forestomach decreased in wild-type mice, it increased in CYP2E1-null mice. Subsequent comparative metabolism studies demonstrated that total urethane-derived radioactivity in the plasma, liver, and lung was significantly higher in CYP2E1-null versus wild-type mice and un-metabolized urethane constituted greater than 83% of the radioactivity in CYP2E1-null mice. Un-metabolized urethane was not detectable in the plasma, liver, and lung of wild-type mice. In conclusion, these data demonstrated that CYP2E1-mediated metabolism of urethane, presumably via epoxide formation, is necessary for the induction

  18. Inhibition of urethane-induced genotoxicity and cell proliferation in CYP2E1-null mice

    International Nuclear Information System (INIS)

    Urethane is a multi-site animal carcinogen and was classified as 'reasonably anticipated to be a human carcinogen.' Urethane is a fermentation by-product and found at appreciable levels in alcoholic beverages and foods such as bread and cheese. Recent work in this laboratory demonstrated for the first time that CYP2E1 is the principal enzyme responsible for urethane metabolism. The current studies were undertaken to assess the relationships between CYP2E1-mediated metabolism and urethane-induced genotoxicity and cell proliferation as determined by induction of micronucleated erythrocytes (MN) and expression of Ki-67, respectively, using CYP2E1-null and wild-type mice. Urethane was administered at 0 (vehicle), 1, 10, or 100 mg/kg/day (p.o.), 5 days/week for 6 weeks. A significant dose-dependent increase in MN was observed in wild-type mice; however, a slight increase was measured in the MN-polychromatic erythrocytes in CYP2E1-null mice treated with 100 mg/kg. A significant increase in the expression of Ki-67 was detected in the livers and the lungs (terminal bronchioles, alveoli, and bronchi) of wild-type mice administered 100 mg urethane/kg in comparison to controls. In contrast, CYP2E1-null mice administered this dose exhibited negligible alterations in Ki-67 expression in the livers and lungs compared to controls. Interestingly, while Ki-67 expression in the forestomach decreased in wild-type mice, it increased in CYP2E1-null mice. Subsequent comparative metabolism studies demonstrated that total urethane-derived radioactivity in the plasma, liver, and lung was significantly higher in CYP2E1-null versus wild-type mice and un-metabolized urethane constituted greater than 83% of the radioactivity in CYP2E1-null mice. Un-metabolized urethane was not detectable in the plasma, liver, and lung of wild-type mice. In conclusion, these data demonstrated that CYP2E1-mediated metabolism of urethane, presumably via epoxide formation, is necessary for the induction of

  19. Glomerular injury is exacerbated in diabetic integrin alpha1-null mice.

    Science.gov (United States)

    Zent, R; Yan, X; Su, Y; Hudson, B G; Borza, D-B; Moeckel, G W; Qi, Z; Sado, Y; Breyer, M D; Voziyan, P; Pozzi, A

    2006-08-01

    Excessive glomerular collagen IV and reactive oxygen species (ROS) production are key factors in the development of diabetic nephropathy. Integrin alpha1beta1, the major collagen IV receptor, dowregulates collagen IV and ROS production, suggesting this integrin might determine the severity of diabetic nephropathy. To test this possibility, wild-type and integrin alpha1-null mice were rendered diabetic with streptozotocin (STZ) (100 mg/kg single intraperitoneal injection), after which glomerular filtration rate (GFR), glomerular collagen deposition, and glomerular basement membrane (GBM) thickening were evaluated. In addition, ROS and collagen IV production by mesangial cells as well as their proliferation was measured in vitro. Diabetic alpha1-null mice developed worse renal disease than diabetic wild-type mice. A significant increase in GFR was evident in the alpha1-null mice at 6 weeks after the STZ injection; it started to decrease by week 24 and reached levels of non-diabetic mice by week 36. In contrast, GFR only increased in wild-type mice at week 12 and its elevation persisted throughout the study. Diabetic mutant mice also showed increased glomerular deposition of collagen IV and GBM thickening compared to diabetic wild-type mice. Primary alpha1-null mesangial cells exposed to high glucose produced more ROS than wild-type cells, which led to decreased proliferation and increased collagen IV synthesis, thus mimicking the in vivo finding. In conclusion, this study suggests that lack of integrin alpha1beta1 exacerbates the glomerular injury in a mouse model of diabetes by modulating GFR, ROS production, cell proliferation, and collagen deposition. PMID:16775606

  20. Reversing hypomyelination in BACE1-null mice with Akt-DD overexpression

    OpenAIRE

    Hu, Xiangyou; Schlanger, Rita; He, Wanxia; Macklin, Wendy B.; Yan, Riqiang

    2013-01-01

    β-Site amyloid precursor protein convertase enzyme 1 (BACE1), a type I transmembrane aspartyl protease required to cleave amyloid precursor protein for releasing a toxic amyloid peptide, also cleaves type I and type III neuregulin-1 (Nrg-1). BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination if injured. In BACE1-null mice, the abolished cleavage of neuregulin-1 by BACE1 is speculated to cause reduced myelin sheath thickness in both the central nervous...

  1. SPARC-null mice exhibit increased adiposity without significant differences in overall body weight

    OpenAIRE

    Bradshaw, A. D.; Graves, D C; Motamed, K.; Sage, E H

    2003-01-01

    Secreted protein acidic and rich in cysteine/osteonectin/BM-40 (SPARC) is a matrix-associated protein that elicits changes in cell shape, inhibits cell-cycle progression, and influences the synthesis of extracellular matrix (ECM). The absence of SPARC in mice gives rise to aberrations in the structure and composition of the ECM that result in generation of cataracts, development of severe osteopenia, and accelerated closure of dermal wounds. In this report we show that SPARC-null mice have gr...

  2. Cell therapy of congenital corneal diseases with umbilical mesenchymal stem cells: lumican null mice.

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    Hongshan Liu

    Full Text Available BACKGROUND: Keratoplasty is the most effective treatment for corneal blindness, but suboptimal medical conditions and lack of qualified medical personnel and donated cornea often prevent the performance of corneal transplantation in developing countries. Our study aims to develop alternative treatment regimens for congenital corneal diseases of genetic mutation. METHODOLOGY/PRINCIPAL FINDINGS: Human mesenchymal stem cells isolated from neonatal umbilical cords were transplanted to treat thin and cloudy corneas of lumican null mice. Transplantation of umbilical mesenchymal stem cells significantly improved corneal transparency and increased stromal thickness of lumican null mice, but human umbilical hematopoietic stem cells failed to do the same. Further studies revealed that collagen lamellae were re-organized in corneal stroma of lumican null mice after mesenchymal stem cell transplantation. Transplanted umbilical mesenchymal stem cells survived in the mouse corneal stroma for more than 3 months with little or no graft rejection. In addition, these cells assumed a keratocyte phenotype, e.g., dendritic morphology, quiescence, expression of keratocyte unique keratan sulfated keratocan and lumican, and CD34. Moreover, umbilical mesenchymal stem cell transplantation improved host keratocyte functions, which was verified by enhanced expression of keratocan and aldehyde dehydrogenase class 3A1 in lumican null mice. CONCLUSIONS/SIGNIFICANCE: Umbilical mesenchymal stem cell transplantation is a promising treatment for congenital corneal diseases involving keratocyte dysfunction. Unlike donated corneas, umbilical mesenchymal stem cells are easily isolated, expanded, stored, and can be quickly recovered from liquid nitrogen when a patient is in urgent need.

  3. Altered lipid and salt taste responsivity in ghrelin and GOAT null mice.

    Directory of Open Access Journals (Sweden)

    Huan Cai

    Full Text Available Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT, ghrelin knockout (ghrelin(-/-, and GOAT knockout (GOAT(-/- mice. Ghrelin(-/- mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT(-/- mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin(-/- and GOAT(-/- mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin(-/- mice, yet potentiated in GOAT(-/- mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT(-/- mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin(-/- and GOAT(-/- mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities.

  4. Insulin resistance in skeletal muscles of caveolin-3-null mice

    OpenAIRE

    Oshikawa, Jin; Otsu, Koji; Toya, Yoshiyuki; Tsunematsu, Takashi; Hankins, Raleigh; Kawabe, Jun-ichi; Minamisawa, Susumu; Umemura, Satoshi; Hagiwara, Yasuko; Ishikawa, Yoshihiro

    2004-01-01

    Type 2 diabetes is preceded by the development of insulin resistance, in which the action of insulin is impaired, largely in skeletal muscles. Caveolin-3 (Cav3) is a muscle-specific subtype of caveolin, an example of a scaffolding protein found within membranes. Cav is also known as growth signal inhibitor, although it was recently demonstrated that the genetic disruption of Cav3 did not augment growth in mice. We found, however, that the lack of Cav3 led to the development of insulin resista...

  5. Altered astrocyte morphology and vascular development in dystrophin-Dp71-null mice.

    Science.gov (United States)

    Giocanti-Auregan, Audrey; Vacca, Ophélie; Bénard, Romain; Cao, Sijia; Siqueiros, Lourdes; Montañez, Cecilia; Paques, Michel; Sahel, José-Alain; Sennlaub, Florian; Guillonneau, Xavier; Rendon, Alvaro; Tadayoni, Ramin

    2016-05-01

    Understanding retinal vascular development is crucial because many retinal vascular diseases such as diabetic retinopathy (in adults) or retinopathy of prematurity (in children) are among the leading causes of blindness. Given the localization of the protein Dp71 around the retinal vessels in adult mice and its role in maintaining retinal homeostasis, the aim of this study was to determine if Dp71 was involved in astrocyte and vascular development regulation. An experimental study in mouse retinas was conducted. Using a dual immunolabeling with antibodies to Dp71 and anti-GFAP for astrocytes on retinal sections and isolated astrocytes, it was found that Dp71 was expressed in wild-type (WT) mouse astrocytes from early developmental stages to adult stage. In Dp71-null mice, a reduction in GFAP-immunopositive astrocytes was observed as early as postnatal day 6 (P6) compared with WT mice. Using real-time PCR, it was showed that Dp71 mRNA was stable between P1 and P6, in parallel with post-natal vascular development. Regarding morphology in Dp71-null and WT mice, a significant decrease in overall astrocyte process number in Dp71-null retinas at P6 to adult age was found. Using fluorescence-conjugated isolectin Griffonia simplicifolia on whole mount retinas, subsequent delay of developing vascular network at the same age in Dp71-null mice was found. An evidence that the Dystrophin Dp71, a membrane-associated cytoskeletal protein and one of the smaller Duchenne muscular dystrophy gene products, regulates astrocyte morphology and density and is associated with subsequent normal blood vessel development was provided. GLIA 2016;64:716-729. PMID:26711882

  6. Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact

    DEFF Research Database (Denmark)

    Mulder, Hindrik; Sörhede-Winzell, Maria; Contreras, Juan Antonio; Fex, Malin; Ström, Kristoffer; Ploug, Thorkil; Galbo, Henrik; Arner, Peter; Lundberg, Cecilia; Sundler, Frank; Ahrén, Bo; Holm, Cecilia

    2003-01-01

    HSL gene for glucose homeostasis were examined. HSL null mice were slightly hyperglycemic in the fasted, but not fed state, which was accompanied by moderate hyperinsulinemia. During glucose challenges, however, disposal of the sugar was not affected in HSL null mice, presumably because of release of......-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of beta-cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance...

  7. Comparative proteomics of skeletal muscle mitochondria from myostatin-null mice

    OpenAIRE

    Puddick, Jonathan; Martinus, Ryan D

    2011-01-01

    Myostatin, a secreted protein, is a negative regulator of skeletal muscle growth. Down-regulating its expression increases skeletal muscle mass that is accompanied by a marked change in the fibre composition from one reliant on mitochondrial oxidative metabolism to glycolysis. A comparative proteomic investigation of this altered metabolism was carried out on mitochondria from the gastrocnemius muscle of myostatin-null mice compared with wild-type. Most of the proteins identified showed no si...

  8. Premature aggregation of type IV collagen and early lethality in lysyl hydroxylase 3 null mice

    OpenAIRE

    Rautavuoma, Kati; Takaluoma, Kati; Sormunen, Raija; Myllyharju, Johanna; Kivirikko, Kari I.; Soininen, Raija

    2004-01-01

    Collagens carry hydroxylysine residues that act as attachment sites for carbohydrate units and are important for the stability of crosslinks but have been regarded as nonessential for vertebrate survival. We generated mice with targeted inactivation of the gene for one of the three lysyl hydroxylase isoenzymes, LH3. The null embryos developed seemingly normally until embryonic day 8.5, but development was then retarded, with death around embryonic day 9.5. Electron microscopy (EM) revealed fr...

  9. Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

    Directory of Open Access Journals (Sweden)

    Aunis Dominique

    2010-12-01

    Full Text Available Abstract Background- Mice deficient for the stable tubule only peptide (STOP display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p. produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

  10. Reduced wheel running and blunted effects of voluntary exercise in LPA1-null mice: The importance of assessing the amount of running in transgenic mice studies

    OpenAIRE

    Castilla-Ortega, Estela; Rosell-Valle, Cristina; Blanco, Eduardo; Pedraza, Carmen; Chun, Jerold; de Fonseca, Fernando Rodríguez; Estivill-Torrús, Guillermo; Santín, Luis J.

    2013-01-01

    This work was aimed to assess whether voluntary exercise rescued behavioral and hippocampal alterations in mice lacking the lysophosphatidic acid LPA1 receptor (LPA1-null mice), studying the potential relationship between the amount of exercise performed and its effects. Normal and LPA1-null mice underwent 23 days of free wheel running and were tested for open-field behavior and adult hippocampal neurogenesis (cell proliferation, immature neurons, cell survival). Running decreased anxiety-lik...

  11. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

    Directory of Open Access Journals (Sweden)

    Jeffrey B Eells

    Full Text Available Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%, genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/- mice and wild-type (+/+ mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  12. Joint dysfunction and functional decline in middle age myostatin null mice.

    Science.gov (United States)

    Guo, Wen; Miller, Andrew D; Pencina, Karol; Wong, Siu; Lee, Amanda; Yee, Michael; Toraldo, Gianluca; Jasuja, Ravi; Bhasin, Shalender

    2016-02-01

    Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn(-/-)), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn(-/-) mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn(-/-) mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn(-/-) mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway. PMID:26549246

  13. Impaired Thermogenesis and a Molecular Signature for Brown Adipose Tissue in Id2 Null Mice

    Directory of Open Access Journals (Sweden)

    Peng Zhou

    2016-01-01

    Full Text Available Inhibitor of DNA binding 2 (ID2 is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have sex-specific elevated glucose uptake in brown adipose tissue (BAT. Here we further explored the role of Id2 in the regulation of core body temperature over the circadian cycle and the impact of Id2 deficiency on genes involved in insulin signaling and adipogenesis in BAT. We discovered a reduced core body temperature in Id2−/− mice. Moreover, in Id2−/− BAT, 30 genes including Irs1, PPARs, and PGC-1s were identified as differentially expressed in a sex-specific pattern. These data provide valuable insights into the impact of Id2 deficiency on energy homeostasis of mice in a sex-specific manner.

  14. Impaired Thermogenesis and a Molecular Signature for Brown Adipose Tissue in Id2 Null Mice.

    Science.gov (United States)

    Zhou, Peng; Robles-Murguia, Maricela; Mathew, Deepa; Duffield, Giles E

    2016-01-01

    Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have sex-specific elevated glucose uptake in brown adipose tissue (BAT). Here we further explored the role of Id2 in the regulation of core body temperature over the circadian cycle and the impact of Id2 deficiency on genes involved in insulin signaling and adipogenesis in BAT. We discovered a reduced core body temperature in Id2-/- mice. Moreover, in Id2-/- BAT, 30 genes including Irs1, PPARs, and PGC-1s were identified as differentially expressed in a sex-specific pattern. These data provide valuable insights into the impact of Id2 deficiency on energy homeostasis of mice in a sex-specific manner. PMID:27144179

  15. Cdk2-Null Mice Are Resistant to ErbB-2-Induced Mammary Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Dipankar Ray

    2011-05-01

    Full Text Available The concept of targeting G1 cyclin-dependent kinases (CDKs in breast cancer treatments is supported by the fact that the genetic ablation of Cdk4 had minimal impacts on normal cell proliferation in majority of cell types, resulting in near-normal mouse development, whereas such loss of Cdk4 completely abrogated ErbB-2/neu-induced mammary tumorigenesis in mice. In most human breast cancer tissues, another G1-regulatory CDK, CDK2, is also hyperactivated by various mechanisms and is believed to be an important therapeutic target. In this report, we provide genetic evidence that CDK2 is essential for proliferation and oncogenesis of murine mammary epithelial cells. We observed that 87% of Cdk2-null mice were protected from ErbB-2-induced mammary tumorigenesis. Mouse embryonic fibroblasts isolated from Cdk2-null mouse showed resistance to various oncogene-induced transformation. Previously, we have reported that hemizygous loss of Cdc25A, the major activator of CDK2, can also protect mice from ErbB-2-induced mammary tumorigenesis [Cancer Res (2007 67(14: 6605–11]. Thus, we propose that CDC25A-CDK2 pathway is critical for the oncogenic action of ErbB-2 in mammary epithelial cells, in a manner similar to Cyclin D1/CDK4 pathway.

  16. Seizure phenotypes, periodicity, and sleep-wake pattern of seizures in Kcna-1 null mice.

    Science.gov (United States)

    Wright, Samantha; Wallace, Eli; Hwang, Youngdeok; Maganti, Rama

    2016-02-01

    This study was undertaken to describe seizure phenotypes, natural progression, sleep-wake patterns, as well as periodicity of seizures in Kcna-1 null mutant mice. These mice were implanted with epidural electroencephalography (EEG) and electromyography (EMG) electrodes, and simultaneous video-EEG recordings were obtained while animals were individually housed under either diurnal (LD) condition or constant darkness (DD) over ten days of recording. The video-EEG data were analyzed to identify electrographic and behavioral phenotypes and natural progression and to examine the periodicity of seizures. Sleep-wake patterns were analyzed to understand the distribution and onset of seizures across the sleep-wake cycle. Four electrographically and behaviorally distinct seizure types were observed. Regardless of lighting condition that animals were housed in, Kcna-1 null mice initially expressed only a few of the most severe seizure types that progressively increased in frequency and decreased in seizure severity. In addition, a circadian periodicity was noted, with seizures peaking in the first 12h of the Zeitgeber time (ZT) cycle, regardless of lighting conditions. Interestingly, seizure onset differed between lighting conditions where more seizures arose out of sleep in LD conditions, whereas under DD conditions, the majority occurred out of the wakeful state. We suggest that this model be used to understand the circadian pattern of seizures as well as the pathophysiological implications of sleep and circadian disturbances in limbic epilepsies. PMID:26724401

  17. Impaired Thermogenesis and a Molecular Signature for Brown Adipose Tissue in Id2 Null Mice

    OpenAIRE

    Peng Zhou; Maricela Robles-Murguia; Deepa Mathew; Duffield, Giles E.

    2016-01-01

    Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have sex-specific elevated glucose uptake in brown adipose tissue (BAT). Here we further explored the role of Id2 in the regulation of core body temperature over the circadian cycle and the impact of Id2 deficiency on genes involved in insulin signaling and adipogenesis in BAT. We discovered a reduced core body...

  18. Maturation stage enamel malformations in Amtn and Klk4 null mice.

    Science.gov (United States)

    Núñez, Stephanie M; Chun, Yong-Hee P; Ganss, Bernhard; Hu, Yuanyuan; Richardson, Amelia S; Schmitz, James E; Fajardo, Roberto; Yang, Jie; Hu, Jan C-C; Simmer, James P

    2016-01-01

    Amelotin (AMTN) and kallikrein-4 (KLK4) are secreted proteins specialized for enamel biomineralization. We characterized enamel from wild-type, Amtn(-/-), Klk4(-/-), Amtn(+/-)Klk4(+/-) and Amtn(-/-)Klk4(-/-) mice to gain insights into AMTN and KLK4 functions during amelogenesis. All of the null mice were healthy and fertile. The mandibular incisors in Amtn(-/-), Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice were chalky-white and chipped. No abnormalities except in enamel were observed, and no significant differences were detected in enamel thickness or volume, or in rod decussation. Micro-computed tomography (μCT) maximum intensity projections localized the onset of enamel maturation in wild-type incisors distal to the first molar, but mesial to this position in Amtn(-/-), Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice, demonstrating a delay in enamel maturation in Amtn(-/-) incisors. Micro-CT detected significantly reduced enamel mineral density (2.5 and 2.4gHA/cm(3)) in the Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice respectively, compared with wild-type enamel (3.1gHA/cm(3)). Backscatter scanning electron microscopy showed that mineral density progressively diminished with enamel depth in the Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice. The Knoop hardness of the Amtn(-/-) outer enamel was significantly reduced relative to the wild-type and was not as hard as the middle or inner enamel. Klk4(-/-) enamel hardness was significantly reduced at all levels, but the outer enamel was significantly harder than the inner and middle enamel. Thus the hardness patterns of the Amtn(-/-) and Klk4(-/-) mice were distinctly different, while the Amtn(-/-)Klk4(-/-) outer enamel was not as hard as in the Amtn(-/-) and Klk4(-/-) mice. We conclude that AMTN and KLK4 function independently, but are both necessary for proper enamel maturation. PMID:26620968

  19. Behavioral Disturbances in Estrogen-Related Receptor alpha-Null Mice

    Directory of Open Access Journals (Sweden)

    Huxing Cui

    2015-04-01

    Full Text Available Eating disorders, such as anorexia nervosa and bulimia nervosa, are common and severe mental illnesses of unknown etiology. Recently, we identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA that is associated with the development of eating disorders. However, little is known about ESRRA function in the brain. Here, we report that Esrra is expressed in the mouse brain and demonstrate that Esrra levels are regulated by energy reserves. Esrra-null female mice display a reduced operant response to a high-fat diet, compulsivity/behavioral rigidity, and social deficits. Selective Esrra knockdown in the prefrontal and orbitofrontal cortices of adult female mice recapitulates reduced operant response and increased compulsivity, respectively. These results indicate that Esrra deficiency in the mouse brain impairs behavioral responses in multiple functional domains.

  20. Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background

    Directory of Open Access Journals (Sweden)

    Sara N. Koenig

    2015-03-01

    Full Text Available Thoracic aortic aneurysms (TAA are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/− mice. Echocardiographic analysis of Notch1+/−; Nos3−/− mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.

  1. Neto2-null mice have impaired GABAergic inhibition and are susceptible to seizures

    Directory of Open Access Journals (Sweden)

    Vivek eMahadevan

    2015-09-01

    Full Text Available Neto2 is a transmembrane protein that interacts with the neuron-specific K+-Cl- cotransporter (KCC2 in the CNS. Efficient KCC2 transport is essential for setting the neuronal Cl- gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter. In the present study we characterized GABAergic inhibition and KCC2-mediated neuronal chloride homeostasis in pyramidal neurons from adult hippocampal slices. Using gramicidin perforated patch clamp recordings we found that the reversal potential for GABA (EGABA was significantly depolarized. We also observed that surface levels of KCC2 and phosphorylation of KCC2 serine 940 (Ser940 were reduced in Neto2-/- neurons compared to wild-type controls. To examine GABAergic inhibition we recorded spontaneous inhibitory postsynaptic currents (sIPSCs and found that Neto2-/- neurons had significant reductions in both their amplitude and frequency. Based on the critical role of Neto2 in regulating GABAergic inhibition we rationalized that Neto2-null mice would be prone to seizure activity. We found that Neto2-null mice demonstrated a decrease in the latency to pentylenetetrazole (PTZ-induced seizures and an increase in seizure severity.

  2. Thrombospondin 2-null mice display an altered brain foreign body response to polyvinyl alcohol sponge implants

    Energy Technology Data Exchange (ETDEWEB)

    Tian Weiming; Kyriakides, Themis R, E-mail: themis.kyriakides@yale.ed [Vascular Biology and Therapeutics Program, Departments of Pathology and Biomedical Engineering, Yale University, New Haven, CT 06519 (United States)

    2009-02-15

    Thrombospondin (TSP)-2 is a matricellular protein that participates in the processes of tissue repair and the foreign body response. In addition, TSP2 has been shown to influence synaptogenesis and recovery of the brain following stroke. In the present study we investigated the response following the implantation of polyvinyl alcohol (PVA) sponges in the brain. PVA sponges were implanted into the brain cortex of wild type and TSP2-null mice for a period of 4 and 8 weeks and the response was analyzed by histochemistry and quantitative immunohistochemistry. TSP2 expression was detected in the interstices of the sponge and co-localized with the extracellular matrix and astrocytes. PVA sponge invasion in TSP2-null mice was characterized by dense deposition of extracellular matrix and increased invasion of reactive astrocytes and macrophages/microglia. Furthermore, the angiogenic response was elevated and the detection of mouse serum albumin (MSA) in the brain cortex indicated excessive vessel leakage, suggesting that TSP2 plays a role in the repair/maintenance of the blood brain barrier. Finally, immunostaining demonstrated an increase in the levels of matrix metalloproteinase (MMP)-2 and MMP-9. Taken together, our observations support a role for TSP2 as critical determinant of the brain response to biomaterials.

  3. Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice

    Directory of Open Access Journals (Sweden)

    Boizot Alexia

    2011-04-01

    Full Text Available Abstract Background Giant Axonal Neuropathy (GAN is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and the sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting. Results We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology. Conclusions Together, our results show that gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the

  4. Carrageenan-Induced Colonic Inflammation Is Reduced in Bcl10 Null Mice and Increased in IL-10-Deficient Mice

    Science.gov (United States)

    Bhattacharyya, Sumit; Xue, Liquan; Devkota, Suzanne; Chang, Eugene; Morris, Stephan; Tobacman, Joanne K.

    2013-01-01

    The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF-κB activation. Exposure to low concentrations of carrageenan (10 μg/mL in the water supply) has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10) is a mediator of inflammatory signals from Toll-like receptor (TLR) 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC), nuclear RelA and RelB, phospho(Thr559)-NF-κB-inducing kinase (NIK), and phospho(Ser36)-IκBα in the colonic epithelial cells were significantly less (P < 0.001) in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF-κB (RelA) activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF-κB activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation. PMID:23766559

  5. Csf2 Null Mutation Alters Placental Gene Expression and Trophoblast Glycogen Cell and Giant Cell Abundance in Mice1

    OpenAIRE

    Sferruzzi-Perri, Amanda N.; Macpherson, Anne M.; Roberts, Claire T.; Robertson, Sarah A.

    2009-01-01

    Genetic deficiency in granulocyte-macrophage colony-stimulating factor (CSF2, GM-CSF) results in altered placental structure in mice. To investigate the mechanism of action of CSF2 in placental morphogenesis, the placental gene expression and cell composition were examined in Csf2 null mutant and wild-type mice. Microarray and quantitative RT-PCR analyses on Embryonic Day (E) 13 placentae revealed that the Csf2 null mutation caused altered expression of 17 genes not previously known to be ass...

  6. Reduced wheel running and blunted effects of voluntary exercise in LPA1-null mice: The importance of assessing the amount of running in transgenic mice studies

    Science.gov (United States)

    Castilla-Ortega, Estela; Rosell-Valle, Cristina; Blanco, Eduardo; Pedraza, Carmen; Chun, Jerold; de Fonseca, Fernando Rodríguez; Estivill-Torrús, Guillermo; Santín, Luis J.

    2014-01-01

    This work was aimed to assess whether voluntary exercise rescued behavioral and hippocampal alterations in mice lacking the lysophosphatidic acid LPA1 receptor (LPA1-null mice), studying the potential relationship between the amount of exercise performed and its effects. Normal and LPA1-null mice underwent 23 days of free wheel running and were tested for open-field behavior and adult hippocampal neurogenesis (cell proliferation, immature neurons, cell survival). Running decreased anxiety-like behavior in both genotypes but increased exploration only in the normal mice. While running affected all neurogenesis-related measures in normal mice (especially in the suprapyramidal blade of the dentate gyrus), only a moderate increase in cell survival was found in the mutants. Importantly, the LPA1-nulls showed notably reduced running. Analysis suggested that defective running in the LPA1-null mice could contribute to explain the scarce benefit of the voluntary exercise treatment. On the other hand, a literature review revealed that voluntary exercise is frequently used to modulate behavior and the hippocampus in transgenic mice, but half of the studies did not assess the quantity of running, overlooking any potential running impairments. This study adds evidence to the relevance of the quantity of exercise performed, emphasizing the importance of its assessment in transgenic mice research. PMID:24055600

  7. Enhanced Aortic Macrophage Lipid Accumulation and Inflammatory Response in LDL Receptor Null Mice Fed an Atherogenic Diet

    OpenAIRE

    Wang, Shu; Wu, Dayong; Matthan, Nirupa R.; Lamon-Fava, Stefania; Lecker, Jaime L; Lichtenstein, Alice H

    2010-01-01

    The effect of an atherogenic diet on inflammatory response and elicited peritoneal macrophage (Mφ) cholesterol accumulation in relation to aortic lesion formation was assessed in LDL receptor null (LDLr−/−) mice. Mice were fed an atherogenic or control diet for 32 weeks. The atherogenic relative to control diet resulted in significantly higher plasma monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) concentrations, more aortic wall Mφ depo...

  8. Calcium Homeostasis and Muscle Energy Metabolism Are Modified in HspB1-Null Mice

    Directory of Open Access Journals (Sweden)

    Brigitte Picard

    2016-05-01

    Full Text Available Hsp27—encoded by HspB1—is a member of the small heat shock proteins (sHsp, 12–43 kDa (kilodalton family. This protein is constitutively present in a wide variety of tissues and in many cell lines. The abundance of Hsp27 is highest in skeletal muscle, indicating a crucial role for muscle physiology. The protein identified as a beef tenderness biomarker was found at a crucial hub in a functional network involved in beef tenderness. The aim of this study was to analyze the proteins impacted by the targeted invalidation of HspB1 in the Tibialis anterior muscle of the mouse. Comparative proteomics using two-dimensional gel electrophoresis revealed 22 spots that were differentially abundant between HspB1-null mice and their controls that could be identified by mass spectrometry. Eighteen spots were more abundant in the muscle of the mutant mice, and four were less abundant. The proteins impacted by the absence of Hsp27 belonged mainly to calcium homeostasis (Srl and Calsq1, contraction (TnnT3, energy metabolism (Tpi1, Mdh1, PdhB, Ckm, Pygm, ApoA1 and the Hsp proteins family (HspA9. These data suggest a crucial role for these proteins in meat tenderization. The information gained by this study could also be helpful to predict the side effects of Hsp27 depletion in muscle development and pathologies linked to small Hsps.

  9. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.

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    Theresa Alexandra Mattioli

    Full Text Available The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4. Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (- naloxone, an opioid receptor antagonist, and (+ naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.

  10. Recovery and Biodistribution of Ex Vivo Expanded Human Erythroblasts Injected into NOD/SCID/IL2Rγnull mice

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    Barbara Ghinassi

    2011-01-01

    Full Text Available Ex vivo expanded erythroblasts (EBs may serve as advanced transfusion products provided that lodgment occurs in the macrophage-niche of the marrow permitting maturation. EBs expanded from adult and cord blood expressed the receptors (CXCR4, VLA-4, and P-selectin ligand 1 necessary for interaction with macrophages. However, 4-days following transfusion to intact NOD/SCID/IL2Rγnull mice, CD235apos EBs were observed inside CD235aneg splenic cells suggesting that they underwent phagocytosis. When splenectomized and intact NOD/SCID/IL2Rγnull mice were transfused using retrovirally labeled human EBs, human cells were visualized by bioluminescence imaging only in splenectomized animals. Four days after injection, human CD235apos cells were detected in marrow and liver of splenectomized mice but only in spleen of controls. Human CD235apos erythrocytes in blood remained low in all cases. These studies establish splenectomized NOD/SCID/IL2Rγnull mice as a suitable model for tracking and quantification of human EBs in vivo.

  11. Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice.

    Science.gov (United States)

    Markova, Dessislava Z; Pan, Te-Cheng; Zhang, Rui-Zhu; Zhang, Guiyun; Sasaki, Takako; Arita, Machiko; Birk, David E; Chu, Mon-Li

    2016-06-01

    Fibulin-4 is an extracellular matrix glycoprotein essential for elastic fiber formation. Mice deficient in fibulin-4 die perinatally because of severe pulmonary and vascular defects associated with the lack of intact elastic fibers. Patients with fibulin-4 mutations demonstrate similar defects, and a significant number die shortly after birth or in early childhood from cardiopulmonary failure. The patients also demonstrate skeletal and other systemic connective tissue abnormalities, including joint laxity and flexion contractures of the wrist. A fibulin-4 null mouse strain was generated and used to analyze the roles of fibulin-4 in tendon fibrillogenesis. This mouse model displayed bilateral forelimb contractures, in addition to pulmonary and cardiovascular defects. The forelimb and hindlimb tendons exhibited disruption in collagen fibrillogenesis in the absence of fibulin-4 as analyzed by transmission electron microscopy. Fewer fibrils were assembled, and fibrils were disorganized compared with wild-type controls. The organization of developing tenocytes and compartmentalization of the extracellular space was also disrupted. Fibulin-4 was co-localized with fibrillin-1 and fibrillin-2 in limb tendons by using immunofluorescence microscopy. Thus, fibulin-4 seems to play a role in regulating tendon collagen fibrillogenesis, in addition to its essential function in elastogenesis. PMID:26711913

  12. Maximal Oxygen Consumption Is Reduced in Aquaporin-1 Knockout Mice.

    Science.gov (United States)

    Al-Samir, Samer; Goossens, Dominique; Cartron, Jean-Pierre; Nielsen, Søren; Scherbarth, Frank; Steinlechner, Stephan; Gros, Gerolf; Endeward, Volker

    2016-01-01

    We have measured maximal oxygen consumption ([Formula: see text]O2,max) of mice lacking one or two of the established mouse red-cell CO2 channels AQP1, AQP9, and Rhag. We intended to study whether these proteins, by acting as channels for O2, determine O2 exchange in the lung and in the periphery. We found that [Formula: see text]O2,max as determined by the Helox technique is reduced by ~16%, when AQP1 is knocked out, but not when AQP9 or Rhag are lacking. This figure holds for animals respiring normoxic as well as hypoxic gas mixtures. To see whether the reduction of [Formula: see text]O2,max is due to impaired O2 uptake in the lung, we measured carotid arterial O2 saturation (SO2) by pulse oximetry. Neither under normoxic (inspiratory O2 21%) nor under hypoxic conditions (11% O2) is there a difference in SO2 between AQP1null and WT mice, suggesting that AQP1 is not critical for O2 uptake in the lung. The fact that the % reduction of [Formula: see text]O2,max is identical in normoxia and hypoxia indicates moreover that the limitation of [Formula: see text]O2,max is not due to an O2 diffusion problem, neither in the lung nor in the periphery. Instead, it appears likely that AQP1null animals exhibit a reduced [Formula: see text]O2,max due to the reduced wall thickness and muscle mass of the left ventricles of their hearts, as reported previously. We conclude that very likely the properties of the hearts of AQP1 knockout mice cause a reduced maximal cardiac output and thus cause a reduced [Formula: see text]O2,max, which constitutes a new phenotype of these mice. PMID:27559317

  13. Role of RANKL (TNFSF11)-Dependent Osteopetrosis in the Dental Phenotype of Msx2 Null Mutant Mice

    OpenAIRE

    Castaneda, Beatriz; Simon, Yohann; Ferbus, Didier; Robert, Benoit; Chesneau, Julie; Mueller, Christopher; Berdal, Ariane; Lézot, Frédéric

    2013-01-01

    The MSX2 homeoprotein is implicated in all aspects of craniofacial skeletal development. During postnatal growth, MSX2 is expressed in all cells involved in mineralized tissue formation and plays a role in their differentiation and function. Msx2 null (Msx2 −/−) mice display complex craniofacial skeleton abnormalities with bone and tooth defects. A moderate form osteopetrotic phenotype is observed, along with decreased expression of RANKL (TNFSF11), the main osteoclast-differentiating factor....

  14. Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

    OpenAIRE

    Mistlberger, Ralph; Hsu, Jennifer; Yu, Lisa; Bowman, Melody; Tecott, Laurence; Sullivan, Elinor

    2010-01-01

    The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanc...

  15. Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

    OpenAIRE

    Hsu, Jennifer L.; Lisa Yu; Elinor Sullivan; Melodi Bowman; Mistlberger, Ralph E.; Tecott, Laurence H.

    2010-01-01

    The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin(2C) receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enha...

  16. Natural suppressor (NS) cells found in the spleen of neonatal mice and adult mice given total lymphoid irradiation (TLI) express the null surface phenotype

    International Nuclear Information System (INIS)

    The authors studied the surface markers of suppressor cells of the mixed leukocyte reaction (MLR) that are transiently present in the spleens of neonatal mice after birth and of adult mice after total lymphoid irradiation (TLI). Approximately 80% of the mononuclear cells in the spleen, within the first few days after birth or after TLI, express neither the Thy-1 antigen nor surface immunoglobulin (Ig). After 30 days, less than 20% of mononuclear cells bear this null phenotype. With the use of the panning technique, they showed that the suppressors of the MLR are confined to the null cell population. The null suppressor cells are not macrophages because they did not carry macrophage markers identified by the monoclonal antibodies anti-MAC-1 and F4/80. In addition, the suppressor cells did not stain for nonspecific esterase and did not adhere firmly to plastic or glass. Spleen cells from TLI-treated mice maintained their suppressive capacity after culture in vitro for 6 to 8 wk. The cultured suppressor cells did not develop mature T cell, B cell, or macrophage markers during this time interval. Thus, the suppressor cells did not appear to be precursors of the latter cells. The suppressor cells are similar to NK cells in that both are found in the absence of antigenic challenge, lack antigen specificity, and bear the null surface phenotype. Thus, they have termed the former cells natural suppressor (NS) cells

  17. Lens transcriptome profile during cataract development in Mip-null mice.

    Science.gov (United States)

    Bennett, Thomas M; Zhou, Yuefang; Shiels, Alan

    2016-09-16

    Major intrinsic protein or aquaporin-0 (MIP/AQP0) functions as a water channel and a cell-junction molecule in the vertebrate eye lens. Loss of MIP function in the lens leads to degraded optical quality and cataract formation by pathogenic mechanisms that are unclear. Here we have used microarray-hybridization analysis to detect lens transcriptome changes during cataract formation in mice that are functionally null for MIP (Mip-/-). In newborn Mip-/- lenses (P1) 11 genes were up-regulated and 18 were down-regulated (>2-fold, p=6-fold) in the Mip-/- lens at P1 included those coding for a mitochondrial translocase (Timmdc1), a matrix metallopeptidase (Mmp2), a Rho GTPase-interacting protein (Ubxn11) and a transcription factor (Twist2). Apart from Mip, the most down-regulated genes (>4-fold) in the Mip-/- lens at P1 included those coding for a proteasome sub-unit (Psmd8), a ribonuclease (Pop4), and a heat-shock protein (Hspb1). Lens fiber cell degeneration in the Mip-/- lens was associated with increased numbers of TUNEL-positive cell nuclei and dramatically elevated levels of calpain-mediated proteolysis of αII-spectrin. However red-ox status, measured by glutathione and free-radical levels, was similar to that of wild-type. These data suggest that while relatively few genes (∼1.5% of the transcriptome) were differentially regulated >2-fold in the Mip-/- lens, calpain hyper-activation acts as a terminal pathogenic event during lens fiber cell death and cataract formation. PMID:27524245

  18. Sex-specific dysregulation of cysteine oxidation and the methionine and folate cycles in female cystathionine gamma-lyase null mice: a serendipitous model of the methylfolate trap

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    Hua Jiang

    2015-09-01

    Full Text Available In addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL is a major physiological source of the vasorelaxant hydrogen sulfide. Cgl null mice are potentially useful for studying the influence of this compound upon vascular tone and endothelial function. Here, we confirm a previous report that female Cgl null mice exhibit an approximate 45-fold increase in plasma total homocysteine compared to wild type controls. This level of homocysteine is approximately 3.5-fold higher than that observed in male Cgl null mice and is essentially equivalent to that observed in mouse models of cystathionine beta synthase deficient homocystinuria. Cgl null mice of both sexes exhibited decreased expression of methylenetetrahydrofolate reductase and cysteinesulfinate decarboxylase compared to WT controls. Female Cgl null mice exhibited a sex-specific induction of betaine homocysteine S-methyltransferase and methionine adenosyltransferase 1, alpha and a 70% decrease in methionine synthase expression accompanied by significantly decreased plasma methionine. Decreased plasma cysteine levels in female Cgl null mice were associated with sex-specific dysregulation of cysteine dioxygenase expression. Comparative histological assessment between cystathionine beta-synthase and Cgl null mice indicated that the therapeutic potential of cystathionine against liver injury merits possible further investigation. Collectively, our data demonstrates the importance of considering sex when investigating mouse models of inborn errors of metabolism and indicate that while female Cgl null mice are of questionable utility for studying the physiological role of hydrogen sulfide, they could serve as a useful model for studying the consequences of methionine synthase deficiency and the methylfolate trap.

  19. Influence of dietary iodine deficiency on the thyroid gland in Slc26a4-null mutant mice

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    Iwata Tomoyuki

    2011-06-01

    Full Text Available Abstract Background Pendred syndrome (PDS is an autosomal recessive disorder characterized by sensorineural hearing impairment and variable degree of goitrous enlargement of the thyroid gland with a partial defect in iodine organification. The thyroid function phenotype can range from normal function to overt hypothyroidism. It is caused by loss-of-function mutations in the SLC26A4 (PDS gene. The severity of the goiter has been postulated to depend on the amount of dietary iodine intake. However, direct evidence has not been shown to support this hypothesis. Because Slc26a4-null mice have deafness but do not develop goiter, we fed the mutant mice a control diet or an iodine-deficient diet to evaluate whether iodine deficiency is a causative environmental factor for goiter development in PDS. Methods We evaluated the thyroid volume in histological sections with the use of three-dimensional reconstitution software, we measured serum levels of total tri-iodothyronine (TT3 and total thyroxine (TT4 levels, and we studied the thyroid gland morphology by transmission electron microscopy. Results TT4 levels became low but TT3 levels did not change significantly after eight weeks of an iodine-deficient diet compared to levels in the control diet animals. Even in Slc26a4-null mice fed an iodine-deficient diet, the volume of the thyroid gland did not increase although the size of each epithelial cell increased with a concomitant decrease of thyroid colloidal area. Conclusions An iodine-deficient diet did not induce goiter in Slc26a4-null mice, suggesting that other environmental, epigenetic or genetic factors are involved in goiter development in PDS.

  20. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice.

    Science.gov (United States)

    Kishi, Noriyuki; MacDonald, Jessica L; Ye, Julia; Molyneaux, Bradley J; Azim, Eiman; Macklis, Jeffrey D

    2016-01-01

    Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

  1. Expression of aquaporin-9 in the brain tissue of rats with infectious brain edema%AQP-9在大鼠感染性脑水肿脑组织中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    田培超; 王怀立; 罗强; 禚志红

    2008-01-01

    Objective To investigate the expression of aquaporin-9(AQP-9)in the brain tissue of rats with infectious brain edema and explore the role of AQP-9 in the oecurrgnce and progression of the brain edema. Methods A total of 128 normal 1-month-old SD rats weighing 70-100 g of either sex were randomly divided into two equal groups, namely the normal saline(NS) group and lipopolysaecharide(LPS)group.Acute infectious brain edema was induced in rats in the LPS group by injecting LPS via the left internal carotid artery,and the rats in the NS groups received NS injection.At 6,12,24 and 48 h after the injection,the brain tissue was taken from the rats to observe the histopathology by Hernatoxylin-Eosin Stain and lneasure the brain water content(BWC).The permeability of the blood-brain barrier of the rats was tested using Evans blue(EB)method.The expressions of AQP-9 protein and mRNA in the brain tissue Were detected using immunohistochemistry and RT-PCR,respectively. Results InLPS group,the space around the blood vessels was obviously broadened in the brain tissue,where inflammatory cell infiltration,glioeyte swelling,vacuolar degeneration of the neurons and neuronal nuclear shrinkage were seen.At 6,12,24,and 48 h following LPS or NS injection,the BWC,EB content,and expressions of AQP-9 protein and mRNA in the LPS group were all significantly higher than those in the NS group(P<0.05),In the LPS group,positive correlations were found between BWC and EB content,AQP-9 protein expression and BWC,AQP一9 mRNA and BWC,AQP-9mR.NA and EBcontent,and between AQP-9 protein andmRNA.Conclusion AQP-9 might participate in occurrcnce and development of infectious brain edema in rats,it might be positive correlation.%目的 探讨水通道蛋白-9(AQP-9)在内毒素脂多糖(LPS)致大鼠感染性脑水肿脑组织中的表达及意义. 方法 1月龄普通级SD大鼠128只采用随机数字表法分为生理盐水(NS)组(64只)和LPS组(64只),采用颈内动脉注射LPS制作大鼠感染

  2. Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice

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    Chen Jianliang

    2007-04-01

    Full Text Available Abstract Background Targeted disruption of the murine 3β-hydroxysterol-Δ7-reductase gene (Dhcr7, an animal model of Smith-Lemli-Opitz syndrome, leads to loss of cholesterol synthesis and neonatal death that can be partially rescued by transgenic replacement of DHCR7 expression in brain during embryogenesis. To gain further insight into the role of non-brain tissue cholesterol deficiency in the pathophysiology, we tested whether the lethal phenotype could be abrogated by selective transgenic complementation with DHCR7 expression in the liver. Results We generated mice that carried a liver-specific human DHCR7 transgene whose expression was driven by the human apolipoprotein E (ApoE promoter and its associated liver-specific enhancer. These mice were then crossed with Dhcr7+/- mutants to generate Dhcr7-/- mice bearing a human DHCR7 transgene. Robust hepatic transgene expression resulted in significant improvement of cholesterol homeostasis with cholesterol concentrations increasing to 80~90 % of normal levels in liver and lung. Significantly, cholesterol deficiency in brain was not altered. Although late gestational lung sacculation defect reported previously was significantly improved, there was no parallel increase in postnatal survival in the transgenic mutant mice. Conclusion The reconstitution of DHCR7 function selectively in liver induced a significant improvement of cholesterol homeostasis in non-brain tissues, but failed to rescue the neonatal lethality of Dhcr7 null mice. These results provided further evidence that CNS defects caused by Dhcr7 null likely play a major role in the lethal pathogenesis of Dhcr7-/- mice, with the peripheral organs contributing the morbidity.

  3. Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice.

    Science.gov (United States)

    Tomasi, Mirta; Canato, Marta; Paolini, Cecilia; Dainese, Marco; Reggiani, Carlo; Volpe, Pompeo; Protasi, Feliciano; Nori, Alessandra

    2012-02-01

    Amplitude of Ca(2+) transients, ultrastructure of Ca(2+) release units, and molecular composition of sarcoplasmic reticulum (SR) are altered in fast-twitch skeletal muscles of calsequestrin-1 (CASQ1)-null mice. To determine whether such changes are directly caused by CASQ1 ablation or are instead the result of adaptive mechanisms, here we assessed ability of CASQ1 in rescuing the null phenotype. In vivo reintroduction of CASQ1 was carried out by cDNA electro transfer in flexor digitorum brevis muscle of the mouse. Exogenous CASQ1 was found to be correctly targeted to the junctional SR (jSR), as judged by immunofluorescence and confocal microscopy; terminal cisternae (TC) lumen was filled with electron dense material and its width was significantly increased, as judged by electron microscopy; peak amplitude of Ca(2+) transients was significantly increased compared with null muscle fibers transfected only with green fluorescent protein (control); and finally, transfected fibers were able to sustain cytosolic Ca(2+) concentration during prolonged tetanic stimulation. Only the expression of TC proteins, such as calsequestrin 2, sarcalumenin, and triadin, was not rescued as judged by Western blot. Thus our results support the view that CASQ1 plays a key role in both Ca(2+) homeostasis and TC structure. PMID:22049211

  4. Protective effect of naringenin against acetaminophen-induced acute liver injury in metallothionein (MT)-null mice.

    Science.gov (United States)

    Lv, Yingjian; Zhang, Baoxu; Xing, Guozhen; Wang, Fuqiang; Hu, Zhewen

    2013-02-01

    Naringenin is a natural flavonoid aglycone of naringin that has been reported to have a wide range of pharmacological properties, such as antioxidant activity and free radical scavenging capacity. This study was designed to examine the hepatoprotective effect of naringenin against acetaminophen (250 mg kg(-1), sc) in metallothionein (MT)-null mice. 42 SPF MT-knockout mice were used. Naringenin (200, 400, and 800 mg kg(-1), ig) was administered for 4 days before exposure to acetaminophen (250 mg kg(-1), sc). Liver injury was measured by serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as liver malondialdehyde (MDA). The glutathione-to-oxidized glutathione ratio (GSH/GSSG) was also assessed. The evidence of liver injury induced by acetaminophen included not only a significant increase in the levels of serum ALT, AST, LDH and liver MDA, and also a significant decrease in GSH/GSSG. Pretreatment of mice with naringenin at 400 and 800 mg kg(-1) reversed the altered parameters. Such reversal effects were dose-dependent: ALT decreased 78.62% and 98.03%, AST decreased 88.35% and 92.64%, LDH decreased 76.54% and 81.63%, MDA decreased 48.59% and 66.27% at a dose of 400 and 800 mg kg(-1) respectively; GSH/GSSG increased 22.57% and 16.93% at a dose of 400 and 800 mg kg(-1) respectively. Histopathological observation findings were also consistent with these effects. Together, this study suggests that naringenin can potentially reverse the hepatotoxic damage of acetaminophen intoxication in MT-null mice. PMID:23142768

  5. Renoprotective Effects of Vitex megapotamica (Spreng. Moldenke in C57BL/6 LDLr-Null Mice Undergoing High Fat Diet

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    Valdinei de Oliveira Araújo

    2015-01-01

    Full Text Available Although Vitex megapotamica (Spreng. Moldenke is used in Brazilian folk medicine as hypolipidemic drug no study has been conducted to evaluate the effects of this species in an experimental model of atherosclerosis. So, the aim of this study was to evaluate the possible renoprotective activity of methanolic extract obtained from Vitex megapotamica (MEVM using C57BL/6 LDLr-null mice submitted to high fat diet (HFD. MEVM was orally administered at doses of 30, 100, and 300 mg/kg, for three weeks, starting from the 2nd week of HFD. Systolic blood pressure (SBP and diuretic activity were measured weekly. At the end of experiments the serum lipids, atherogenic index serum (AIS, oxidative stress, and markers of renal function were determined. HFD induced a significant increase in the systolic blood pressure, dyslipidemia, increase in AIS, and lipid peroxidation accompanied by an important reduction in renal function. Treatment with MEVM was able to prevent increase in SBP, total cholesterol, triglycerides, AIS, urea, and creatinine levels in LDLr-null mice. These effects were accompanied by a significant reduction in oxidative stress and renal injury. The data reported here support the potential of Vitex megapotamica as candidate to be an herbal medicine used in cardiovascular or renal diseases.

  6. Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice.

    Science.gov (United States)

    Bittolo, Tamara; Raminelli, Carlo Antonio; Deiana, Chiara; Baj, Gabriele; Vaghi, Valentina; Ferrazzo, Sara; Bernareggi, Annalisa; Tongiorgi, Enrico

    2016-01-01

    Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome. PMID:26806603

  7. Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγnull mice is enhanced by transgenic expression of membrane-bound human SCF

    OpenAIRE

    Brehm, Michael A.; Racki, Waldemar J.; Leif, Jean; Burzenski, Lisa; Hosur, Vishnu; Wetmore, Amber; Gott, Bruce; Herlihy, Mary; Ignotz, Ronald; Dunn, Raymond; Shultz, Leonard D.; Greiner, Dale L.

    2012-01-01

    Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common γ chain (IL2rg) gene, including NOD-scid IL2rγnull (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of st...

  8. Mice Null for Sox18 Are Viable and Display a Mild Coat Defect

    OpenAIRE

    Pennisi, David; Bowles, Josephine; Nagy, Andras; Muscat, George; Koopman, Peter

    2000-01-01

    We have previously shown that Sox18 is expressed in developing vascular endothelium and hair follicles during mouse embryogenesis and that point mutations in Sox18 are the underlying cause of cardiovascular and hair follicle defects in ragged (Ra) mice. Here we describe the analysis of Sox18−/− mice produced by gene targeting. Despite the profound defects seen in Ra mice, Sox18−/− mice have no obvious cardiovascular defects and only a mild coat defect with a reduced proportion of zigzag hairs...

  9. MicroRNA Dysregulation in Liver and Pancreas of CMP-Neu5Ac Hydroxylase Null Mice Disrupts Insulin/PI3K-AKT Signaling

    Directory of Open Access Journals (Sweden)

    Deug-Nam Kwon

    2014-01-01

    Full Text Available CMP-Neu5Ac hydroxylase (Cmah-null mice fed with a high-fat diet develop fasting hyperglycemia, glucose intolerance, and pancreatic β-cell dysfunction and ultimately develop characteristics of type 2 diabetes. The precise metabolic role of the Cmah gene remains poorly understood. This study was designed to investigate the molecular mechanisms through which microRNAs (miRNAs regulate type 2 diabetes. Expression profiles of miRNAs in Cmah-null mouse livers were compared to those of control mouse livers. Liver miFinder miRNA PCR arrays (n=6 showed that eight miRNA genes were differentially expressed between the two groups. Compared with controls, seven miRNAs were upregulated and one miRNA was downregulated in Cmah-null mice. Specifically, miR-155-5p, miR-425-5p, miR-15a-5p, miR-503-5p, miR-16-5p, miR-29a-3p, and miR-29b-3p were significantly upregulated in the liver and pancreas of Cmah-null mice. These target miRNAs are closely associated with dysregulation of insulin/PI3K-AKT signaling, suggesting that the Cmah-null mice could be a useful model for studying diabetes.

  10. Cardiomyocyte-Restricted Deletion of PPARβ/δ in PPARα-Null Mice Causes Impaired Mitochondrial Biogenesis and Defense, but No Further Depression of Myocardial Fatty Acid Oxidation

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    Jian Liu

    2011-01-01

    Full Text Available It is well documented that PPARα and PPARβ/δ share overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPARβ/δ deficiency in mice leads to severe cardiac pathological development, whereas global PPARα knockout shows a benign cardiac phenotype. It is unknown whether a PPARα-null background would alter the pathological development in mice with cardiomyocyte-restricted PPARβ/δ deficiency. In the present study, a mouse model with long-term PPARβ/δ deficiency in PPARα-null background showed a comparably reduced cardiac expression of lipid metabolism to those of single PPAR-deficient mouse models. The PPARα-null background did not rescue or aggravate the cardiac pathological development linked to cardiomyocyte-restricted PPARβ/δ deficiency. Moreover, PPARα-null did not alter the phenotypic development in adult mice with the short-term deletion of PPARβ/δ in their hearts, which showed mitochondrial abnormalities, depressed cardiac performance, and cardiac hypertrophy with attenuated expression of key factors in mitochondrial biogenesis and defense. The present study demonstrates that cardiomyocyte-restricted deletion of PPARβ/δ in PPARα-null mice causes impaired mitochondrial biogenesis and defense, but no further depression of fatty acid oxidation. Therefore, PPARβ/δ is essential for maintaining mitochondrial biogenesis and defense in cardiomyocytes independent of PPARα.

  11. Prohormone convertase 2 (PC2) null mice have increased mu opioid receptor levels accompanied by altered morphine-induced antinociception, tolerance and dependence.

    Science.gov (United States)

    Lutfy, K; Parikh, D; Lee, D L; Liu, Y; Ferrini, M G; Hamid, A; Friedman, T C

    2016-08-01

    Chronic morphine treatment increases the levels of prohormone convertase 2 (PC2) in brain regions involved in nociception, tolerance and dependence. Thus, we tested if PC2 null mice exhibit altered morphine-induced antinociception, tolerance and dependence. PC2 null mice and their wild-type controls were tested for baseline hot plate latency, injected with morphine (1.25-10mg/kg) and tested for antinociception 30min later. For tolerance studies, mice were tested in the hot plate test before and 30min following morphine (5mg/kg) on day 1. Mice then received an additional dose so that the final dose of morphine was 10mg/kg on this day. On days 2-4, mice received additional doses of morphine (20, 40 and 80mg/kg on days 1, 2, 3, and 4, respectively). On day 5, mice were tested in the hot plate test before and 30min following morphine (5mg/kg). For withdrawal studies, mice were treated with the escalating doses of morphine (10, 20, 40 and 80mg/kg) for 4days, implanted with a morphine pellet on day 5 and 3 days later injected with naloxone (1mg/kg) and signs of withdrawal were recorded. Morphine dose-dependently induced antinociception and the magnitude of this response was greater in PC2 null mice. Tolerance to morphine was observed in wild-type mice and this phenomenon was blunted in PC2 null mice. Withdrawal signs were also reduced in PC2 null mice. Immunohistochemical studies showed up-regulation of the mu opioid receptor (MOP) protein expression in the periaqueductal gray area, ventral tegmental area, lateral hypothalamus, medial hypothalamus, nucleus accumbens, and somatosensory cortex in PC2 null mice. Likewise, naloxone specific binding was increased in the brains of these mice compared to their wild-type controls. The results suggest that the PC2-derived peptides may play a functional role in morphine-induced antinociception, tolerance and dependence. Alternatively, lack of opioid peptides led to up-regulation of the MOP and altered morphine

  12. Ciliary neurotrophic factor is not required for terminal sprouting and compensatory reinnervation of neuromuscular synapses: Re-evaluation of CNTF null mice

    OpenAIRE

    Wright, Megan C.; Son, Young-Jin

    2007-01-01

    Loss of synaptic activity or innervation induces sprouting of intact motor nerve terminals that adds or restores nerve-muscle connectivity. Ciliary neurotrophic factor (CNTF) and terminal Schwann cells (tSCs) have been implicated as molecular and cellular mediators of the compensatory process. We wondered if the previously reported lack of terminal sprouting in CNTF null mice was due to abnormal reactivity of tSCs. To this end, we examined nerve terminal and tSC responses in CNTF null mice us...

  13. Influence of genetic knockout of Pept2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice

    OpenAIRE

    Kamal, Mohamed A; Jiang, Huidi; Hu, Yongjun; Keep, Richard F; Smith, David E.

    2009-01-01

    Carnosine (β-alanyl-l-histidine), an endogenous dipeptide substrate of the proton-coupled oligopeptide transporter PEPT2, plays an important role in many physiological processes. This study examined the effect of PEPT2 on the disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice. After exogenous dosing of [3H]carnosine (1 nmol/g iv bolus), a marked increase was observed in its systemic clearance in Pept2 null mice (0.50 vs. 0.29 ml/min), resulting in a decreased s...

  14. Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice.

    Science.gov (United States)

    Sceniak, Michael P; Lang, Min; Enomoto, Addison C; James Howell, C; Hermes, Douglas J; Katz, David M

    2016-05-01

    Frontal cortical dysfunction is thought to contribute to cognitive and behavioral features of autism spectrum disorders; however, underlying mechanisms are poorly understood. The present study sought to define how loss ofMecp2, the gene mutated in Rett syndrome (RTT), disrupts function in the murine medial prefrontal cortex (mPFC) using acute brain slices and behavioral testing. Compared with wildtype, pyramidal neurons in theMecp2null mPFC exhibit significant reductions in excitatory postsynaptic currents, the duration of excitatory UP-states, evoked population activity, and the ratio of NMDA:AMPA currents, as well as an increase in the relative fraction of NR2B currents. These functional changes are associated with reductions in the density of excitatory dendritic spines, the ratio of vesicular glutamate to GABA transporters and GluN1 expression. In contrast to recent reports on circuit defects in other brain regions, we observed no effect ofMecp2loss on inhibitory synaptic currents or expression of the inhibitory marker parvalbumin. Consistent with mPFC hypofunction,Mecp2nulls exhibit respiratory dysregulation in response to behavioral arousal. Our data highlight functional hypoconnectivity in the mPFC as a potential substrate for behavioral disruption in RTT and other disorders associated with reduced expression ofMecp2in frontal cortical regions. PMID:25662825

  15. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression.

    Science.gov (United States)

    Schafer, Dorothy P; Heller, Christopher T; Gunner, Georgia; Heller, Molly; Gordon, Christopher; Hammond, Timothy; Wolf, Yochai; Jung, Steffen; Stevens, Beth

    2016-01-01

    Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2(tm1.1Bird/y)). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1(CreER);Mecp2(fl/y)or Cx3cr1(Cr)(eER); Mecp2(LSL/y)) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types. PMID:27458802

  16. Kharon1 null mutants of Leishmania mexicana are avirulent in mice and exhibit a cytokinesis defect within macrophages.

    Directory of Open Access Journals (Sweden)

    Khoa D Tran

    Full Text Available In a variety of eukaryotes, flagella play important roles both in motility and as sensory organelles that monitor the extracellular environment. In the parasitic protozoan Leishmania mexicana, one glucose transporter isoform, LmxGT1, is targeted selectively to the flagellar membrane where it appears to play a role in glucose sensing. Trafficking of LmxGT1 to the flagellar membrane is dependent upon interaction with the KHARON1 protein that is located at the base of the flagellar axoneme. Remarkably, while Δkharon1 null mutants are viable as insect stage promastigotes, they are unable to survive as amastigotes inside host macrophages. Although Δkharon1 promastigotes enter macrophages and transform into amastigotes, these intracellular parasites are unable to execute cytokinesis and form multinucleate cells before dying. Notably, extracellular axenic amastigotes of Δkharon1 mutants replicate and divide normally, indicating a defect in the mutants that is only exhibited in the intra-macrophage environment. Although the flagella of Δkharon1 amastigotes adhere to the phagolysomal membrane of host macrophages, the morphology of the mutant flagella is often distorted. Additionally, these null mutants are completely avirulent following injection into BALB/c mice, underscoring the critical role of the KHARON1 protein for viability of intracellular amastigotes and disease in the animal model of leishmaniasis.

  17. Nutritional intervention restores muscle but not kidney phenotypes in adult calcineurin aα null mice

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Reddy, Ramesh N; Price, S Russ;

    2013-01-01

    Mice lacking the α isoform of the catalytic subunit of calcineurin (CnAα) were first reported in 1996 and have been an important model to understand the role of calcineurin in the brain, immune system, bones, muscle, and kidney. Research using the mice has been limited, however, by failure to...... deprivation is known to significantly alter development, it is imperative that previous conclusions based on CnAα-/- mice are revisited to determine which aspects of the phenotype were attributable to caloric restriction versus a direct role for CnAα. In this study, we find that defects in renal development......, loss of CnAα likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAα-/- mice and the advances that are now possible with the use of adult, rescued knockout...

  18. Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice

    OpenAIRE

    Hu, Xiaoming; Roberts, Jenny R.; Apopa, Patrick L.; Kan, Yuet Wai; Ma, Qiang

    2006-01-01

    Genetic and biochemical analyses have uncovered an essential role for nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating phase II xenobiotic metabolism and antioxidant response. Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice. Nrf2−/− female mice exposed to VCD exhibit an age-dependent decline in reproduction leading to secondary infertility accompanied by hypergonadotropic hypogonadism after 30 weeks of age. VCD is show...

  19. Leptin Resistance Contributes to Obesity in Mice with Null Mutation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1.

    Science.gov (United States)

    Heinrich, Garrett; Russo, Lucia; Castaneda, Tamara R; Pfeiffer, Verena; Ghadieh, Hilda E; Ghanem, Simona S; Wu, Jieshen; Faulkner, Latrice D; Ergün, Süleyman; McInerney, Marcia F; Hill, Jennifer W; Najjar, Sonia M

    2016-05-20

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance. Consistently, mice with null mutation of Ceacam1 (Cc1(-/-)) exhibit impaired insulin clearance with increased lipid production in liver and redistribution to white adipose tissue, leading to visceral obesity at 2 months of age. When the mutation is propagated on the C57/BL6J genetic background, total fat mass rises significantly with age, and glucose intolerance and systemic insulin resistance develop at 6 months of age. This study was carried out to determine the mechanisms underlying the marked increase in total fat mass in 6-month-old mutants. Indirect calorimetry analysis showed that Cc1(-/-) mice develop hyperphagia and a significant reduction in physical activity, in particular in the early hours of the dark cycle, during which energy expenditure is only slightly lower than in wild-type mice. They also exhibit increased triglyceride accumulation in skeletal muscle, due in part to incomplete fatty acid β-oxidation. Mechanistically, hypothalamic leptin signaling is reduced, as demonstrated by blunted STAT3 phosphorylation in coronal sections in response to an intracerebral ventricular injection of leptin. Hypothalamic fatty-acid synthase activity is also elevated in the mutants. Together, the data show that the increase in total fat mass in Cc1(-/-) mice is mainly attributed to hyperphagia and reduced spontaneous physical activity. Although the contribution of the loss of CEACAM1 from anorexigenic proopiomelanocortin neurons in the arcuate nucleus is unclear, leptin resistance and elevated hypothalamic fatty-acid synthase activity could underlie altered energy balance in these mice. PMID:27002145

  20. Spontaneous hypertension occurs with adipose tissue dysfunction in perilipin-1 null mice.

    Science.gov (United States)

    Zou, Liangqiang; Wang, Weiyi; Liu, Shangxin; Zhao, Xiaojing; Lyv, Ying; Du, Congkuo; Su, Xueying; Geng, Bin; Xu, Guoheng

    2016-02-01

    Perilipin-1 (Plin1) coats lipid droplets exclusively in adipocytes and regulates two principle functions of adipose tissue, triglyceride storage and hydrolysis, which are disrupted upon Plin1 deficiency. In the present study, we investigated the alterations in systemic metabolites and hormones, vascular function and adipose function in spontaneous hypertensive mice lacking perilipin-1 (Plin1-/-). Plin1-/- mice developed spontaneous hypertension without obvious alterations in systemic metabolites and hormones. Plin1 expressed only in adipose cells but not in vascular cells, so its ablation would have no direct effect in situ on blood vessels. Instead, Plin1-/- mice showed dysfunctions of perivascular adipose tissue (PVAT), a fat depot that anatomically surrounds systemic arteries and has an anticontractile effect. In Plin1-/- mice, aortic and mesenteric PVAT were reduced in mass and adipocyte derived relaxing factor secretion, but increased in basal lipolysis, angiotensin II secretion, macrophage infiltration and oxidative stress. Such multiple culprits impaired the anticontractile effect of PVAT to promote vasoconstriction of aortic and mesenteric arteries of Plin1-/- mice. Furthermore, arterial vessels of Plin1-/- mice showed increasing angiotensin II receptor type 1, monocyte chemotactic protein-1 and interlukin-6 expression, structural damage of endothelial and smooth muscle cells, along with impaired endothelium-dependent relaxation. Hypertension in Plin1-/- mice might occur as a deleterious consequence of PVAT dysfunction. This finding provides the direct evidence that links dysfunctional PVAT to vascular dysfunction and hypertension, particularly in pathophysiological states. This hypertensive mouse model might mimic and explain the hypertension occurring in patients with adipose tissue dysfunction, particularly with Plin1 mutations. PMID:26521150

  1. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

    International Nuclear Information System (INIS)

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, β-myosin heavy chain (β-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and β-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice

  2. Gender-Specific Changes in Bone Turnover and Skeletal Architecture in Igfbp-2-Null Mice

    OpenAIRE

    DeMambro, V. E.; Clemmons, D R; Horton, L. G.; Bouxsein, M. L.; Wood, T. L.; Beamer, W. G.; Canalis, E; C. J. Rosen

    2008-01-01

    IGF-binding protein-2 (IGFBP-2) is a 36-kDa protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2−/− mice with Igfbp2+/+ colony controls. Igfbp2−/− males had shorter femurs and were heavier than controls but were not insulin resistant. Serum IGF-I levels in Igfbp2−/− mice were 10% higher than Igfbp2+/+ controls at 8 wk of age; in males, this was accompanied by a 3-fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared with ...

  3. Enhanced Susceptibility of Ago1/3 Double-Null Mice to Influenza A Virus Infection

    OpenAIRE

    Van Stry, Melanie; Oguin, Thomas H.; Cheloufi, Sihem; Vogel, Peter; Watanabe, Makiko; Pillai, Meenu R.; Dash, Pradyot; Thomas, Paul G.; Hannon, Gregory J.; Bix, Mark

    2012-01-01

    RNA interference (RNAi) is a critical component of many cellular antiviral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative-sense RNA virus influenza virus type A (flu) is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double-knockout mice deficient in components of the RNA-induced silencing complex. Compared to littermate controls, flu-infected double-knockout mice exhibited ...

  4. Enhanced hepatic apoA-I secretion and peripheral efflux of cholesterol and phospholipid in CD36 null mice.

    Directory of Open Access Journals (Sweden)

    Pin Yue

    Full Text Available CD36 facilitates oxidized low density lipoprotein uptake and is implicated in development of atherosclerotic lesions. CD36 also binds unmodified high and very low density lipoproteins (HDL, VLDL but its role in the metabolism of these particles is unclear. Several polymorphisms in the CD36 gene were recently shown to associate with serum HDL cholesterol. To gain insight into potential mechanisms for these associations we examined HDL metabolism in CD36 null (CD36(-/- mice. Feeding CD36(-/- mice a high cholesterol diet significantly increased serum HDL, cholesterol and phospholipids, as compared to wild type mice. HDL apolipoproteins apoA-I and apoA-IV were increased and shifted to higher density HDL fractions suggesting altered particle maturation. Clearance of dual-labeled HDL was unchanged in CD36(-/- mice and cholesterol uptake from HDL or LDL by isolated CD36(-/- hepatocytes was unaltered. However, CD36(-/- hepatocytes had higher cholesterol and phospholipid efflux rates. In addition, expression and secretion of apoA-I and apoA-IV were increased reflecting enhanced PXR. Similar to hepatocytes, cholesterol and phospholipid efflux were enhanced in CD36(-/- macrophages without changes in protein levels of ABCA1, ABCG1 or SR-B1. However, biotinylation assays showed increased surface ABCA1 localization in CD36(-/- cells. In conclusion, CD36 influences reverse cholesterol transport and hepatic ApoA-I production. Both pathways are enhanced in CD36 deficiency, increasing HDL concentrations, which suggests the potential benefit of CD36 inhibition.

  5. Ghrelin receptor deficiency does not affect diet-induced atherosclerosis in low-density lipoprotein receptor-null mice

    Directory of Open Access Journals (Sweden)

    Kirk M. Habegger

    2011-11-01

    Full Text Available Objective: Ghrelin, a stomach-derived, secreted peptide, and its receptor (growth hormone secretagogue receptor, GHSR are known to modulate food intake and energy homeostasis. The ghrelin system is also expressed broadly in cardiovascular tissues. Since ghrelin has been associated with anti-inflammatory and anti-atherogenic properties, but is also well known to promote obesity and impair glucose metabolism, we investigated whether ghrelin has any impact on the development of atherosclerosis. The hypothesis that endogenous ghrelin signaling may be involved in atherosclerosis has not been tested previously Methods and Results: We crossed ghrelin receptor knockout mice (GHSr-/- into a low-density lipoprotein receptor-null (Ldlr-/- mouse line. In this model, atherosclerotic lesions were promoted by feeding a high-fat, high-cholesterol Western-type diet for 13 months, following a standard protocol. Body composition and glucose homeostasis were similar between Ldlr-/- and Ldlr/GHSR -/- ko mice throughout the study. Absence or presence of GHSr did not alter the apolipoprotein profile changes in response to diet exposure on an LDLRko background. Atherosclerotic plaque volume in the aortic arch and thoracic aorta were also not affected differentially in mice without ghrelin signaling due to GHSR gene disruption as compared to control LDLRko littermates. In light of the associations reported for ghrelin with cardiovascular disease in humans, the lack of a phenotype in these loss-of- function studies in mice suggests no directly functional role for endogenous ghrelin in either the inhibition or the promotion of diet-induced atherosclerosis.Conclusions: These data indicate that, surprisingly, the complex and multifaceted actions of endogenous ghrelin signaling on the cardiovascular system have minimal direct impact on atherosclerotic plaque progression as based on loss-of-function in a mouse model of the disease.

  6. Cardiomyocyte-Restricted Deletion of PPAR β / δ in PPAR α -Null Mice Causes Impaired Mitochondrial Biogenesis and Defense, but No Further Depression of Myocardial Fatty Acid Oxidation

    OpenAIRE

    Jian Liu; Peiyong Wang; Lan He; Yuquan Li; Jinwen Luo; Lihong Cheng; Qianhong Qin; Brako, Lawrence A.; Woo-kuen Lo; William Lewis; Qinglin Yang

    2011-01-01

    It is well documented that PPAR α and PPAR β / δ share overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPAR β / δ deficiency in mice leads to severe cardiac pathological development, whereas global PPAR α knockout shows a benign cardiac phenotype. It is unknown whether a PPAR α -null background would alter the pathological development in mice with cardiomyocyte-restricted PPAR β / δ deficiency. In the presen...

  7. Selective Expression of Presenilin 1 in Neural Progenitor Cells Rescues the Cerebral Hemorrhages and Cortical Lamination Defects in Presenilin 1-Null Mutant Mice

    OpenAIRE

    Wen, Paul H.; De Gasperi, Rita; Sosa, Miguel A. Gama; Rocher, Anne B.; Friedrich, Victor L.; Hof, Patrick R; Elder, Gregory A.

    2005-01-01

    Mice with a null mutation of the presenilin 1 gene (Psen1-/-)die during late intrauterine life or shortly after birth and exhibit multiple CNS and non-CNS abnormalities, including cerebral hemorrhages and altered cortical development. The cellular and molecular basis for the developmental effects of Psen1 remain incompletely understood. Psen1 is expressed in neural progenitors in developing brai...

  8. Enhanced susceptibility of Ago1/3 double-null mice to influenza A virus infection.

    Science.gov (United States)

    Van Stry, Melanie; Oguin, Thomas H; Cheloufi, Sihem; Vogel, Peter; Watanabe, Makiko; Pillai, Meenu R; Dash, Pradyot; Thomas, Paul G; Hannon, Gregory J; Bix, Mark

    2012-04-01

    RNA interference (RNAi) is a critical component of many cellular antiviral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative-sense RNA virus influenza virus type A (flu) is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double-knockout mice deficient in components of the RNA-induced silencing complex. Compared to littermate controls, flu-infected double-knockout mice exhibited increased mortality, consistent with more severe alveolitis and pneumonitis. These data indicate that optimal resistance to flu requires Argonaute 1 and/or 3. Enhanced mortality of double-knockout mice was not associated either with increased viral replication or with differential pulmonary recruitment or function of innate and adaptive immune cells. Given the absence of detectable immune defects, our results support the notion that the enhanced flu susceptibility of double-knockout mice arises from an intrinsic impairment in the ability of lung cells to tolerate flu-elicited inflammation. PMID:22318144

  9. Ectopic cerebellar cell migration causes maldevelopment of Purkinje cells and abnormal motor behaviour in Cxcr4 null mice.

    Science.gov (United States)

    Huang, Guo-Jen; Edwards, Andrew; Tsai, Cheng-Yu; Lee, Yi-Shin; Peng, Lei; Era, Takumi; Hirabayashi, Yoshio; Tsai, Ching-Yen; Nishikawa, Shin-Ichi; Iwakura, Yoichiro; Chen, Shu-Jen; Flint, Jonathan

    2014-01-01

    SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice. PMID:24516532

  10. Ectopic cerebellar cell migration causes maldevelopment of Purkinje cells and abnormal motor behaviour in Cxcr4 null mice.

    Directory of Open Access Journals (Sweden)

    Guo-Jen Huang

    Full Text Available SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice.

  11. Comparative metabolism of methacrylonitrile and acrylonitrile to cyanide using cytochrome P4502E1 and microsomal epoxide hydrolase-null mice

    International Nuclear Information System (INIS)

    Methacrylonitrile (MAN) and acrylonitrile (AN) are metabolized via glutathione (GSH) conjugation or epoxide formation. We have recently shown that CYP2E1 is essential for AN epoxidation and subsequent cyanide liberation. Current studies were designed to compare the enzymatic basis of MAN vs. AN metabolism to cyanide using wild-type (WT), CYP2E1-, and mEH-null mice. Mice received a single gavage dose of 0.047, 0.095, 0.19, or 0.38 mmol/kg of MAN or AN, and blood cyanide was measured at 1 or 3 h later. Blood cyanide levels in WT mice treated with AN or MAN were dose and time dependent. At equimolar doses, significantly higher levels of cyanide were detected in the blood of MAN- vs. AN-treated mice. Further, while significant reduction in blood cyanide levels occurred in MAN-treated CYP2E1-null vs. WT mice, AN metabolism to cyanide was largely abolished in CYP2E1-null mice. Pretreatment of mice with 1-aminobenzotriazole (ABT, CYP inhibitor) demonstrated that CYPs other than CYP2E1 also contribute to MAN metabolism to cyanide. Blood cyanide levels in mEH-null mice treated with aliphatic nitriles are generally lower than levels in similarly treated WT mice. Western blot analysis showed that expression of sEH was greater in male vs. female mice. The role of various epoxide hydrolases (EHs) in the production of cyanide from aliphatic nitriles is apparently structure and dose dependent. Regardless of genotype, significantly higher levels of cyanide were measured in the blood of male vs. female mice treated with MAN or AN. In conclusion, these data showed that (1) at equimolar doses, higher blood cyanide levels were detected in mice treated with MAN vs. AN; (2) while CYP2E1 is the only enzyme responsible for AN metabolism to cyanide, other CYPs also contribute to MAN metabolism; and (3) significantly higher levels of cyanide were measured in the blood of male vs. female treated with either nitrile. Higher blood cyanide levels in male vs. female mice and in MAN- vs. AN

  12. Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections

    OpenAIRE

    Liu, Zhuoming; Petersen, Robert; Devireddy, L.

    2013-01-01

    Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens whose siderophores would normally be chelated by 24p3. Specific granule deficiency (...

  13. Dopamine and α-synuclein dysfunction in Smad3 null mice

    OpenAIRE

    Casarejos M José; Cuartero M Isabel; Giráldez-Pérez Rosa M; Tapia-González Silvia; Mena M Ángeles; Wang Xiao-Fan; Sánchez-Capelo Amelia

    2011-01-01

    Abstract Background Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Transforming growth factor-β1 (TGF-β1) levels increase in patients with PD, although the effects of this increment remain unclear. We have examined the mesostriatal system in adult mice deficient in Smad3, a molecule involved in the intracellular TGF-β1 signalling cascade. Results Striatal monoamine oxidase (MAO)-mediated dopamine (DA) catabolism to 3,4-dihydroxyphenyl...

  14. Abnormal placental development and early embryonic lethality in EpCAM-null mice.

    Directory of Open Access Journals (Sweden)

    Keisuke Nagao

    Full Text Available BACKGROUND: EpCAM (CD326 is encoded by the tacstd1 gene and expressed by a variety of normal and malignant epithelial cells and some leukocytes. Results of previous in vitro experiments suggested that EpCAM is an intercellular adhesion molecule. EpCAM has been extensively studied as a potential tumor marker and immunotherapy target, and more recent studies suggest that EpCAM expression may be characteristic of cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: To gain insights into EpCAM function in vivo, we generated EpCAM -/- mice utilizing an embryonic stem cell line with a tacstd1 allele that had been disrupted. Gene trapping resulted in a protein comprised of the N-terminus of EpCAM encoded by 2 exons of the tacstd1 gene fused in frame to betageo. EpCAM +/- mice were viable and fertile and exhibited no obvious abnormalities. Examination of EpCAM +/- embryos revealed that betageo was expressed in several epithelial structures including developing ears (otocysts, eyes, branchial arches, gut, apical ectodermal ridges, lungs, pancreas, hair follicles and others. All EpCAM -/- mice died in utero by E12.5, and were small, developmentally delayed, and displayed prominent placental abnormalities. In developing placentas, EpCAM was expressed throughout the labyrinthine layer and by spongiotrophoblasts as well. Placentas of EpCAM -/- embryos were compact, with thin labyrinthine layers lacking prominent vascularity. Parietal trophoblast giant cells were also dramatically reduced in EpCAM -/- placentas. CONCLUSION: EpCAM was required for differentiation or survival of parietal trophoblast giant cells, normal development of the placental labyrinth and establishment of a competent maternal-fetal circulation. The findings in EpCAM-reporter mice suggest involvement of this molecule in development of vital organs including the gut, kidneys, pancreas, lungs, eyes, and limbs.

  15. GDF9 Modulates the Reproductive and Tumor Phenotype of Female Inha-Null Mice1

    OpenAIRE

    Myers, Michelle; Mansouri-Attia, Nadera; James, Rebecca; Peng, Jia; Pangas, Stephanie A.

    2013-01-01

    Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha−/−), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors charact...

  16. Mice null for NEDD9 (HEF1) display extensive hippocampal dendritic spine loss and cognitive impairment.

    Science.gov (United States)

    Knutson, D C; Mitzey, A M; Talton, L E; Clagett-Dame, M

    2016-02-01

    NEDD9 (neural precursor cell expressed, developmentally down-regulated 9) is a member of the CAS (Crk-associated substrate) family of scaffolding proteins that regulate cell adhesion and migration. A Nedd9 knock-out/lacZ knock-in mouse (Nedd9(-/)(-)) was developed in order to study Nedd9 expression and function in the nervous system. Herein we show that NEDD9 is expressed in the adult brain and is prominently expressed in the hippocampus. Behavioral testing uncovered functional deficits in Nedd9(-)(/)(-) mice. In the Morris water maze test, Nedd9(-)(/)(-) mice showed deficits in both the ability to learn the task as well as in their ability to recall the platform location. There was no change in the gross morphology of the hippocampus, and stereological analysis of BrdU-labeled newly formed hippocampal cells suggested that this defect is not secondary to altered neurogenesis. However, analysis of the hippocampus revealed extensive loss of dendritic spine density in both the dentate gyrus (DG) and CA1 regions. Spine loss occurred equally across all branch orders and regions of the dendrite. Analysis of spine density in Nedd9(-)(/)(-) mice at 1.5, 6 and 10 months revealed an age-dependent spine loss. This work shows that NEDD9 is required for the maintenance of dendritic spines in the hippocampus, and suggests it could play a role in learning and memory. PMID:26683084

  17. Micronuclei induced by low dose rate irradiation in early spermatids of p53 null and wild mice

    Energy Technology Data Exchange (ETDEWEB)

    Kunugita, Naoki; Kakihara, Hiroyo; Kawamoto, Toshihiro; Norimura, Toshiyuki [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan)

    2002-12-01

    To obtain evidence of the dose-rate effect on induction of micronuclei in early spermatids, we observed frequencies in wild-type p53(+/+), heterozygous p53(+/-) and null p53(-/-) mice 14 days after gamma rays irradiation at a high (1,020 mGy/min) or a low (1.2 mGy/min) dose-rate. A dose- and dose-rate-related increase in micronuclei was seen in early spermatids with no difference between the different p53 status. These data were found to be best fitted by a linear-quadratic dose-response model at a high dose-rate, and by a linear dose-response model at a low dose-rate. The yields at 1.2 mGy/min were significantly lower than those at 1,020 mGy/min in the same manner, independent of p53 status. Testis weight declined significantly after 3 Gy irradiation, but did not depend on dose-rates. In our other studies, we observed the complete elimination both of malformation in fetuses and CD3{sup -}4{sup +} mutant T-lymphocytes in p53(+/+) mice, but not in p53(-/-) mice after irradiation. This indicates that concerted DNA repair and p53-dependent apoptosis are likely to completely eliminate mutagenic damage from the irradiated tissues at low doses or dose-rates in teratogenesis and lymphocytes. In the germ cell, however, irradiation at 1.2 mGy/min was mutagenic, independent of p53 status. (author)

  18. Micronuclei induced by low dose rate irradiation in early spermatids of p53 null and wild mice

    International Nuclear Information System (INIS)

    To obtain evidence of the dose-rate effect on induction of micronuclei in early spermatids, we observed frequencies in wild-type p53(+/+), heterozygous p53(+/-) and null p53(-/-) mice 14 days after gamma rays irradiation at a high (1,020 mGy/min) or a low (1.2 mGy/min) dose-rate. A dose- and dose-rate-related increase in micronuclei was seen in early spermatids with no difference between the different p53 status. These data were found to be best fitted by a linear-quadratic dose-response model at a high dose-rate, and by a linear dose-response model at a low dose-rate. The yields at 1.2 mGy/min were significantly lower than those at 1,020 mGy/min in the same manner, independent of p53 status. Testis weight declined significantly after 3 Gy irradiation, but did not depend on dose-rates. In our other studies, we observed the complete elimination both of malformation in fetuses and CD3-4+ mutant T-lymphocytes in p53(+/+) mice, but not in p53(-/-) mice after irradiation. This indicates that concerted DNA repair and p53-dependent apoptosis are likely to completely eliminate mutagenic damage from the irradiated tissues at low doses or dose-rates in teratogenesis and lymphocytes. In the germ cell, however, irradiation at 1.2 mGy/min was mutagenic, independent of p53 status. (author)

  19. Hyperactivity of the Dopaminergic System in NTS1 and NTS2 Null Mice

    OpenAIRE

    Liang, Yanqi; Boules, Mona; Li, Zhimin; Williams, Katrina; Miura, Tomofumi; Oliveros, Alfredo; Richelson, Elliott

    2010-01-01

    Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors, NTS1 and NTS2. The functional-anatomical interactions between NT, the mesotelencephalic dopamine system, and structures targeted by dopaminergic projections have been studied. The present study was conducted to determine the effects of NT receptor subtypes on dopaminergic function with the use of mice lacking either NTS1 (NTS1−/−) or NTS2 (NTS2−/−). Basal and amphe...

  20. Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis.

    Science.gov (United States)

    Wu, Fenfen; Mi, Wentao; Fu, Yu; Struyk, Arie; Cannon, Stephen C

    2016-06-01

    Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na(+) current density to support sustained high-frequency action potentials in muscle. PMID:27048647

  1. Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice*

    OpenAIRE

    Molotkov, Andrei; Deltour, Louise; Foglio, Mario H.; Cuenca, Arnold E.; Duester, Gregg

    2002-01-01

    The ability of class I alcohol dehydrogenase (ADH1) and class IV alcohol dehydrogenase (ADH4) to metabolize retinol to retinoic acid is supported by genetic studies in mice carrying Adh1 or Adh4 gene disruptions. To differentiate the physiological roles of ADH1 and ADH4 in retinoid metabolism we report here the generation of an Adh1/4 double null mutant mouse and its comparison to single null mutants. We demonstrate that loss of both ADH1 and ADH4 does not have additive effects, either for pr...

  2. Decreased sensory responses in osteocalcin null mutant mice imply neuropeptide function.

    Science.gov (United States)

    Patterson-Buckendahl, Patricia; Sowinska, Agnieszka; Yee, Stephanie; Patel, Dhara; Pagkalinawan, Stephen; Shahid, Muhammad; Shah, Ankit; Franz, Christopher; Benjamin, Daniel E; Pohorecky, Larissa A

    2012-07-01

    Osteocalcin, the most abundant member of the family of extracellular mineral binding gamma-carboxyglutamic acid proteins is synthesized primarily by osteoblasts. Its affinity for calcium ions is believed to limit bone mineralization. Several of the numerous hormones that regulate synthesis of osteocalcin, including glucocorticoids and parathyroid hormone, are also affected by stressful stimuli that require energy for an appropriate response. Based on our observations of OC responding to stressful sensory stimuli, the expression of OC in mouse and rat sensory ganglia was confirmed. It was thus hypothesized that the behavioral responses of the OC knockout mouse to stressful sensory stimuli would be abnormal. To test this hypothesis, behaviors related to sensory aspects of the stress response were quantified in nine groups of mice, aged 4-14 months, comparing knockout with their wild-type counterparts in six distinctly different behavioral tests. Resulting data indicated the following statistically significant differences: open field grooming frequency following saline injection, wild-type > knockout; paw stimulation with Von Frey fibers, knockout wire test indicate that these responses are unrelated to reduced muscle strength. Each of these disparate environmental stimuli provided data indicating alterations of responses in knockout mice that suggest participation of osteocalcin in transmission of information about those sensory stimuli. PMID:22350212

  3. Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice.

    Directory of Open Access Journals (Sweden)

    Suh Young Jeong

    Full Text Available Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2, which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

  4. Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice

    KAUST Repository

    Jeong, Suh Young

    2011-10-07

    Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.

  5. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.

    Directory of Open Access Journals (Sweden)

    Marcella Funicello

    Full Text Available Growing evidences indicate that proteases are implicated in adipogenesis and in the onset of obesity. We previously reported that the cysteine protease cathepsin K (ctsk is overexpressed in the white adipose tissue (WAT of obese individuals. We herein characterized the WAT and the metabolic phenotype of ctsk deficient animals (ctsk-/-. When the growth rate of ctsk-/- was compared to that of the wild type animals (WT, we could establish a time window (5-8 weeks of age within which ctsk-/-display significantly lower body weight and WAT size as compared to WT. Such a difference was not observable in older mice. Upon treatment with high fat diet (HFD for 12 weeks ctsk-/- gained significantly less weight than WT and showed reduced brown adipose tissue, liver mass and a lower percentage of body fat. Plasma triglycerides, cholesterol and leptin were significantly lower in HFD-fed-ctsk-/- as compared to HFD-fed WT animals. Adipocyte lipolysis rates were increased in both young and HFD-fed-ctsk-/-, as compared to WT. Carnitine palmitoyl transferase-1 activity, was higher in mitochondria isolated from the WAT of HFD treated ctsk-/- as compared to WT. Together, these data indicate that ctsk ablation in mice results in reduced body fat content under conditions requiring a rapid accumulation of fat stores. This observation could be partly explained by an increased release and/or utilization of FFA and by an augmented ratio of lipolysis/lipogenesis. These results also demonstrate that under a HFD, ctsk deficiency confers a partial resistance to the development of dyslipidemia.

  6. Dopamine and α-synuclein dysfunction in Smad3 null mice

    Directory of Open Access Journals (Sweden)

    Casarejos M José

    2011-10-01

    Full Text Available Abstract Background Parkinson's disease (PD is characterized by dopaminergic neurodegeneration in the substantia nigra (SN. Transforming growth factor-β1 (TGF-β1 levels increase in patients with PD, although the effects of this increment remain unclear. We have examined the mesostriatal system in adult mice deficient in Smad3, a molecule involved in the intracellular TGF-β1 signalling cascade. Results Striatal monoamine oxidase (MAO-mediated dopamine (DA catabolism to 3,4-dihydroxyphenylacetic acid (DOPAC is strongly increased, promoting oxidative stress that is reflected by an increase in glutathione levels. Fewer astrocytes are detected in the ventral midbrain (VM and striatal matrix, suggesting decreased trophic support to dopaminergic neurons. The SN of these mice has dopaminergic neuronal degeneration in its rostral portion, and the pro-survival Erk1/2 signalling is diminished in nigra dopaminergic neurons, not associated with alterations to p-JNK or p-p38. Furthermore, inclusions of α-synuclein are evident in selected brain areas, both in the perikaryon (SN and paralemniscal nucleus or neurites (motor and cingulate cortices, striatum and spinal cord. Interestingly, these α-synuclein deposits are detected with ubiquitin and PS129-α-synuclein in a core/halo cellular distribution, which resemble those observed in human Lewy bodies (LB. Conclusions Smad3 deficiency promotes strong catabolism of DA in the striatum (ST, decrease trophic and astrocytic support to dopaminergic neurons and may induce α-synuclein aggregation, which may be related to early parkinsonism. These data underline a role for Smad3 in α-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents.

  7. Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice.

    Science.gov (United States)

    Frullanti, Elisa; Amabile, Sonia; Lolli, Maria Grazia; Bartolini, Anna; Livide, Gabriella; Landucci, Elisa; Mari, Francesca; Vaccarino, Flora M; Ariani, Francesca; Massimino, Luca; Renieri, Alessandra; Meloni, Ilaria

    2016-02-01

    Foxg1 gene encodes for a transcription factor essential for telencephalon development in the embryonic mammalian forebrain. Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies. In order to evaluate the effects of Foxg1 alteration in adult brain, we performed expression profiling in total brains from Foxg1+/- heterozygous mutants and wild-type littermates. We identified statistically significant differences in expression levels for 466 transcripts (Pgenes was found a group of genes expressed in the basal ganglia and involved in the control of movements. A relevant (three to sevenfold changes) and statistically significant increase of expression, confirmed by qRT-PCR, was found in two highly correlated genes with expression restricted to the hypothalamus: Oxytocin (Oxt) and Arginine vasopressin (Avp). These neuropeptides have an important role in maternal and social behavior, and their alteration is associated with impaired social interaction and autistic behavior. In addition, Neuronatin (Nnat) levels appear significantly higher both in Foxg1+/- whole brain and in hippocampal neurons after silencing Foxg1, strongly suggesting that it is directly or indirectly repressed by Foxg1. During fetal and neonatal brain development, Nnat may regulate neuronal excitability, receptor trafficking and calcium-dependent signaling and, in the adult brain, it is predominantly expressed in parvalbumin-positive GABAergic interneurons. Overall, these results implicate the overexpression of a group of neuropeptides in the basal ganglia, hypothalamus, cortex and hippocampus in the pathogenesis FOXG1 behavioral impairments. PMID:25966633

  8. Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype

    OpenAIRE

    Niwa Ali; Barry Flutter; Robert Sanchez Rodriguez; Ehsan Sharif-Paghaleh; Barber, Linda D.; Giovanna Lombardi; Nestle, Frank O

    2012-01-01

    The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the N...

  9. Spectratyping analysis of the islet-reactive T cell repertoire in diabetic NOD Igμnull mice after polyclonal B cell reconstitution

    Directory of Open Access Journals (Sweden)

    Sercarz Eli E

    2011-07-01

    Full Text Available Abstract Background Non Obese Diabetic mice lacking B cells (NOD.Igμnull mice do not develop diabetes despite their susceptible background. Upon reconstitution of B cells using a chimera approach, animals start developing diabetes at 20 weeks of age. Methods We have used the spectratyping technique to follow the T cell receptor (TCR V beta repertoire of NOD.Igμnull mice following B cell reconstitution. This technique provides an unbiased approach to understand the kinetics of TCR expansion. We have also analyzed the TCR repertoire of reconstituted animals receiving cyclophosphamide treatment and following tissue transplants to identify common aggressive clonotypes. Results We found that B cell reconstitution of NOD.Igμnull mice induces a polyclonal TCR repertoire in the pancreas 10 weeks later, gradually diversifying to encompass most BV families. Interestingly, these clonotypic BV expansions are mainly confined to the pancreas and are absent from pancreatic lymph nodes or spleens. Cyclophosphamide-induced diabetes at 10 weeks post-B cell reconstitution reorganized the predominant TCR repertoires by removing potential regulatory clonotypes (BV1, BV8 and BV11 and increasing the frequency of others (BV4, BV5S2, BV9, BV16-20. These same clonotypes are more frequently present in neonatal pancreatic transplants under the kidney capsule of B-cell reconstituted diabetic NOD.Igμnull mice, suggesting their higher invasiveness. Phenotypic analysis of the pancreas-infiltrating lymphocytes during diabetes onset in B cell reconstituted animals show a predominance of CD19+ B cells with a B:T lymphocyte ratio of 4:1. In contrast, in other lymphoid organs (pancreatic lymph nodes and spleens analyzed by FACS, the B:T ratio was 1:1. Lymphocytes infiltrating the pancreas secrete large amounts of IL-6 and are of Th1 phenotype after CD3-CD28 stimulation in vitro. Conclusions Diabetes in NOD.Igμnull mice appears to be caused by a polyclonal repertoire of T cell

  10. Normalizing Dopamine D2 Receptor-Mediated Responses in D2 Null Mutant Mice by Virus-Mediated Receptor Restoration: Comparing D2L and D2S

    OpenAIRE

    Neve, Kim A.; Ford, Christopher P.; Buck, David C; Grandy, David K; Neve, Rachael L.; Phillips, Tamara J.

    2013-01-01

    D2 receptor null mutant (Drd2−/−) mice have altered responses to the rewarding and locomotor effects of psychostimulant drugs, which is evidence of a necessary role for D2 receptors in these behaviors. Furthermore, work with mice that constitutively express only the D2 receptor short form (D2S), as a result of genetic deletion of the long form (D2L), provides the basis for a current model in which D2L is thought to be the postsynaptic D2 receptor on medium spiny neurons in the basal forebrain...

  11. Molecular profiles of Quadriceps muscle in myostatin-null mice reveal PI3K and apoptotic pathways as myostatin targets

    Directory of Open Access Journals (Sweden)

    Hocquette Jean-François

    2009-04-01

    Full Text Available Abstract Background Myostatin (MSTN, a member of the TGF-β superfamily, has been identified as a negative regulator of skeletal muscle mass. Inactivating mutations in the MSTN gene are responsible for the development of a hypermuscular phenotype. In this study, we performed transcriptomic and proteomic analyses to detect altered expression/abundance of genes and proteins. These differentially expressed genes and proteins may represent new molecular targets of MSTN and could be involved in the regulation of skeletal muscle mass. Results Transcriptomic analysis of the Quadriceps muscles of 5-week-old MSTN-null mice (n = 4 and their controls (n = 4 was carried out using microarray (human and murine oligonucleotide sequences of 6,473 genes expressed in muscle. Proteomic profiles were analysed using two-dimensional gel electrophoresis coupled with mass spectrometry. Comparison of the transcriptomic profiles revealed 192 up- and 245 down- regulated genes. Genes involved in the PI3K pathway, insulin/IGF pathway, carbohydrate metabolism and apoptosis regulation were up-regulated. Genes belonging to canonical Wnt, calcium signalling pathways and cytokine-receptor cytokine interaction were down-regulated. Comparison of the protein profiles revealed 20 up- and 18 down-regulated proteins spots. Knockout of the MSTN gene was associated with up-regulation of proteins involved in glycolytic shift of the muscles and down-regulation of proteins involved in oxidative energy metabolism. In addition, an increased abundance of survival/anti-apoptotic factors were observed. Conclusion All together, these results showed a differential expression of genes and proteins related to the muscle energy metabolism and cell survival/anti-apoptotic pathway (e.g. DJ-1, PINK1, 14-3-3ε protein, TCTP/GSK-3β. They revealed the PI3K and apoptotic pathways as MSTN targets and are in favour of a role of MSTN as a modulator of cell survival in vivo.

  12. An improved protocol for efficient engraftment in NOD/LTSZ-SCIDIL-2Rγnull mice allows HIV replication and development of anti-HIV immune responses.

    Directory of Open Access Journals (Sweden)

    Maneesh Singh

    Full Text Available Cord blood hematopoietic progenitor cells (CB-HPCs transplanted immunodeficient NOD/LtsZ-scidIL2Rγ(null (NSG and NOD/SCID/IL2Rγ(null (NOG mice need efficient human cell engraftment for long-term HIV-1 replication studies. Total body irradiation (TBI is a classical myeloablation regimen used to improve engraftment levels of human cells in these humanized mice. Some recent reports suggest the use of busulfan as a myeloablation regimen to transplant HPCs in neonatal and adult NSG mice. In the present study, we further ameliorated the busulfan myeloablation regimen with fresh CB-CD34+cell transplantation in 3-4 week old NSG mice. In this CB-CD34+transplanted NSG mice engraftment efficiency of human CD45+cell is over 90% in peripheral blood. Optimal engraftment promoted early and increased CD3+T cell levels, with better lymphoid tissue development and prolonged human cell chimerism over 300 days. These humanized NSG mice have shown long-lasting viremia after HIV-1JRCSF and HIV-1Bal inoculation through intravenous and rectal routes. We also saw a gradual decline of the CD4+T cell count, widespread immune activation, up-regulation of inflammation marker and microbial translocation after HIV-1 infection. Humanized NSG mice reconstituted according to our new protocol produced, moderate cellular and humoral immune responses to HIV-1 postinfection. We believe that NSG mice reconstituted according to our easy to use protocol will provide a better in vivo model for HIV-1 replication and anti-HIV-1 therapy trials.

  13. Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state.

    Science.gov (United States)

    Allen, Susan J; Garcia-Galiano, David; Borges, Beatriz C; Burger, Laura L; Boehm, Ulrich; Elias, Carol F

    2016-06-01

    Leptin signals energy sufficiency to the reproductive hypothalamic-pituitary-gonadal (HPG) axis. Studies using genetic models have demonstrated that hypothalamic neurons are major players mediating these effects. Leptin receptor (LepR) is also expressed in the pituitary gland and in the gonads, but the physiological effects of leptin in these sites are still unclear. Female mice with selective deletion of LepR in a subset of gonadotropes show normal pubertal development but impaired fertility. Conditional deletion approaches, however, often result in redundancy or developmental adaptations, which may compromise the assessment of leptin's action in gonadotropes for pubertal maturation. To circumvent these issues, we adopted a complementary genetic approach and assessed if selective reexpression of LepR only in gonadotropes is sufficient to enable puberty and improve fertility of LepR null female mice. We initially assessed the colocalization of gonadotropin-releasing hormone receptor (GnRHR) and LepR in the HPG axis using GnRHR-IRES-Cre (GRIC) and LepR-Cre reporter (tdTomato or enhanced green fluorescent protein) mice. We found that GRIC and leptin-induced phosphorylation of STAT3 are expressed in distinct hypothalamic neurons. Whereas LepR-Cre was observed in theca cells, GRIC expression was rarely found in the ovarian parenchyma. In contrast, a subpopulation of gonadotropes expressed the LepR-Cre reporter gene (tdTomato). We then crossed the GRIC mice with the LepR null reactivable (LepR(loxTB)) mice. These mice showed an increase in FSH levels, but they remained in a prepubertal state. Together with previous findings, our data indicate that leptin-selective action in gonadotropes serves a role in adult reproductive physiology but is not sufficient to allow pubertal maturation in mice. PMID:27101301

  14. Prevention of the disrupted enamel phenotype in Slc4a4-null mice using explant organ culture maintained in a living host kidney capsule.

    Directory of Open Access Journals (Sweden)

    Xin Wen

    Full Text Available Slc4a4-null mice are a model of proximal renal tubular acidosis (pRTA. Slc4a4 encodes the electrogenic sodium base transporter NBCe1 that is involved in transcellular base transport and pH regulation during amelogenesis. Patients with mutations in the SLC4A4 gene and Slc4a4-null mice present with dysplastic enamel, amongst other pathologies. Loss of NBCe1 function leads to local abnormalities in enamel matrix pH regulation. Loss of NBCe1 function also results in systemic acidemic blood pH. Whether local changes in enamel pH and/or a decrease in systemic pH are the cause of the abnormal enamel phenotype is currently unknown. In the present study we addressed this question by explanting fetal wild-type and Slc4a4-null mandibles into healthy host kidney capsules to study enamel formation in the absence of systemic acidemia. Mandibular E11.5 explants from NBCe1-/- mice, maintained in host kidney capsules for 70 days, resulted in teeth with enamel and dentin with morphological and mineralization properties similar to cultured NBCe1+/+ mandibles grown under identical conditions. Ameloblasts express a number of proteins involved in dynamic changes in H+/base transport during amelogenesis. Despite the capacity of ameloblasts to dynamically modulate the local pH of the enamel matrix, at least in the NBCe1-/- mice, the systemic pH also appears to contribute to the enamel phenotype. Extrapolating these data to humans, our findings suggest that in patients with NBCe1 mutations, correction of the systemic metabolic acidosis at a sufficiently early time point may lead to amelioration of enamel abnormalities.

  15. Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice.

    Science.gov (United States)

    Akingbasote, James A; Foster, Alison J; Wilson, Ian; Sarda, Sunil; Jones, Huw B; Kenna, J Gerry

    2016-04-01

    Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [(14)C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [(14)C]-diclofenac was incubated with HRN™ mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN™ mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN™ mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN™ mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN™ mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN™ mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment. PMID:25820915

  16. Calcium receptor expression and function in oligodendrocyte commitment and lineage progression: potential impact on reduced myelin basic protein in CaR-null mice

    DEFF Research Database (Denmark)

    Chattopadhyay, N.; Espinosa-Jeffrey, A.; Yano, S.; Bandyopadhyay, S.; Brown, E.M.; Vellis, J. de; Tfelt, Jacob

    2008-01-01

    oligodendrocyte > neuron > astrocyte. We next determined the rank order of CaR expression on inducing specification of neural stem cells to the neuronal, oligodendroglial, or astrocytic lineages and found that the relative levels of CaR mRNA expression are OPC > neuron > astrocytes. CaR mRNA expression in cells......R promotes cellular proliferation. We further observed that high Ca(2+) stimulates the mRNA levels of myelin basic protein in preoligodendrocytes, which is also CaR mediated. Finally, myelin basic protein levels were significantly reduced in the cerebellum of CaR-null mice during development. Our results...

  17. Upregulated Expression of AQP 7 in the Skeletal Muscles of Obese ob/ob Mice

    International Nuclear Information System (INIS)

    Aquaporin (AQP) is suggested to be regulated by leptin through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. AQP7 and AQP9 are membrane proteins with water and glycerol channels, the latter of which is essential for triglyceride synthesis. We conjectured that the expression of AQP7 and AQP9 would be altered in the skeletal myofibers in obese leptin deficient ob/ob mice as compared with that of wild mice. RNA and protein levels were studied in the quadriceps femoris muscles of ob/ob and wild mice. Real time quantitative RT-PCR analysis showed that mouse AQP7 mRNA levels in skeletal muscles were significantly higher in ob/ob mice than in wild mice (P<0.01), whereas mouse AQP9 mRNA level was not different between the two groups (P>0.05). Histologically the type 1 myofibers of ob/ob mice contained numerous lipid droplets in oil red O stain samples. Immunohistochemical staining of ob/ob mouse muscles revealed enhanced expression of AQP7 at myofiber surface membranes, while AQP9 expression appeared to be similar to that of wild mice. The findings suggest that the upregulated expression of AQP7 in ob/ob mouse muscles facilitates the secretion of glycerol from myocytes

  18. Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Noriko; Yonemoto, Junzo [National Institute for Environmental Studies, Endocrine Disruptors and Dioxin Research Project, Tsukuba (Japan); Miyabara, Yuichi [Shinshu University, Research and Education Center for Inlandwater Environment, Nagano (Japan); Fujii-Kuriyama, Yoshiaki [University of Tsukuba, Center for Tsukuba Advanced Research Alliance, Tsukuba (Japan); Tohyama, Chiharu [National Institute for Environmental Studies, Environmental Health Sciences Division, Tsukuba (Japan)

    2005-05-01

    To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/-) mice were administered a single oral dose of 10 {mu}g kg{sup -1} TCDD at gestation day 12.5. Serum and liver were collected on postnatal day 21 from vehicle-treated control or TCDD-treated AhR+/- and AhR-null (AhR-/-) mouse pups. Whereas TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum of AhR+/- mice, TCDD had no effects on AhR-/- mice. Gene expression of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP)1A1, and CYP1A2 in the liver was induced markedly by TCDD in AhR+/- but not AhR-/- mice. Induction of CYP1A1 in response to TCDD was confirmed by immunohistochemical evidence in that CYP1A1 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region. Levels of retinyl palmitate were greatly reduced in the liver of TCDD-exposed AhR+/- mice, but not in vehicle-treated AhR+/- mice. No effects of TCDD on retinoid levels in the liver were found in AhR-/- mice. We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via AhR. Induction of UGT1A6 is thought to be responsible at least partly for reduced serum thyroid hormone levels in TCDD-exposed mice. (orig.)

  19. Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlβ (RELMβ) Null Mice: A Model of Intestinal Immune System Dysfunction in Disease Susceptibility.

    Science.gov (United States)

    Wernstedt Asterholm, Ingrid; Kim-Muller, Ja Young; Rutkowski, Joseph M; Crewe, Clair; Tao, Caroline; Scherer, Philipp E

    2016-09-01

    Resistin, and its closely related homologs, the resistin-like molecules (RELMs) have been implicated in metabolic dysregulation, inflammation, and cancer. Specifically, RELMβ, expressed predominantly in the goblet cells in the colon, is released both apically and basolaterally, and is hence found in both the intestinal lumen in the mucosal layer as well as in the circulation. RELMβ has been linked to both the pathogenesis of colon cancer and type 2 diabetes. RELMβ plays a complex role in immune system regulation, and the impact of loss of function of RELMβ on colon cancer and metabolic regulation has not been fully elucidated. We therefore tested whether Retnlβ (mouse ortholog of human RETNLβ) null mice have an enhanced or reduced susceptibility for colon cancer as well as metabolic dysfunction. We found that the lack of RELMβ leads to increased colonic expression of T helper cell type-2 cytokines and IL-17, associated with a reduced ability to maintain intestinal homeostasis. This defect leads to an enhanced susceptibility to the development of inflammation, colorectal cancer, and glucose intolerance. In conclusion, the phenotype of the Retnlβ null mice unravels new aspects of inflammation-mediated diseases and strengthens the notion that a proper intestinal barrier function is essential to sustain a healthy phenotype. PMID:27397737

  20. Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl and sour (citric acid tastants.

    Directory of Open Access Journals (Sweden)

    Yu-Kyong Shin

    Full Text Available BACKGROUND: The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3, ghrelin, its cognate receptor (GHSR, and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid and salty (sodium chloride tastants. CONCLUSIONS/SIGNIFICANCE: These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.

  1. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rγnull mice treated with alogliptin

    Directory of Open Access Journals (Sweden)

    Jurczyk A

    2013-12-01

    Full Text Available Agata Jurczyk,1 Philip diIorio,1 Dean Brostowin,1 Linda Leehy,1 Chaoxing Yang,1 Fumihiko Urano,2 David M Harlan,3 Leonard D Shultz,4 Dale L Greiner,1 Rita Bortell1 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 2Department of Medicine, Washington University School of Medicine, St Louis, MO, 3Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 4The Jackson Laboratory, Bar Harbor, ME, USA Purpose: Dipeptidyl-peptidase-4 (DPP-4 inhibitors are known to increase insulin secretion and beta cell proliferation in rodents. To investigate the effects on human beta cells in vivo, we utilize immunodeficient mice transplanted with human islets. The study goal was to determine the efficacy of alogliptin, a DPP-4 inhibitor, to enhance human beta cell function and proliferation in an in vivo context using diabetic immunodeficient mice engrafted with human pancreatic islets. Methods: Streptozotocin-induced diabetic NOD-scid IL2rγnull (NSG mice were transplanted with adult human islets in three separate trials. Transplanted mice were treated daily by gavage with alogliptin (30 mg/kg/day or vehicle control. Islet graft function was compared using glucose tolerance tests and non-fasting plasma levels of human insulin and C-peptide; beta cell proliferation was determined by bromodeoxyuridine (BrdU incorporation. Results: Glucose tolerance tests were significantly improved by alogliptin treatment for mice transplanted with islets from two of the three human islet donors. Islet-engrafted mice treated with alogliptin also had significantly higher plasma levels of human insulin and C-peptide compared to vehicle controls. The percentage of insulin+BrdU+ cells in human islet grafts from alogliptin-treated mice was approximately 10-fold more than from vehicle control mice, consistent with a significant increase in human beta cell proliferation. Conclusion: Human islet-engrafted immunodeficient mice

  2. Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy.

    OpenAIRE

    Moffett R.C.; Vasu S; Thorens B.; Drucker D.J.; Flatt P.R.

    2014-01-01

    Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 a...

  3. Incretin Receptor Null Mice Reveal Key Role of GLP-1 but Not GIP in Pancreatic Beta Cell Adaptation to Pregnancy

    OpenAIRE

    Moffett, R. Charlotte; Vasu, Srividya; Thorens, Bernard; Drucker, Daniel J.; Peter R. Flatt

    2014-01-01

    Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 a...

  4. Minocycline attenuates HIV-1 infection and suppresses chronic immune activation in humanized NOD/LtsZ-scidIL-2Rγnull mice

    Science.gov (United States)

    Singh, Maneesh; Singh, Pratibha; Vaira, Dolores; Amand, Mathieu; Rahmouni, Souad; Moutschen, Michel

    2014-01-01

    More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T-cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB-HPCs) -transplanted humanized NOD/LtsZ-scidIL-2Rγnull mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up-regulation of several T-cell immune activation markers such as CD38, HLA-DR, CD69 and co-receptor CCR5. T-cell exhaustion markers PD-1 and CTLA-4 were found to be significantly up-regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin-10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T-cell counts in HIV-infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low-cost adjunctive treatment to regulate chronic immune activation and replication of HIV. PMID:24409837

  5. ZnT4 (SLC30A4)-null ("lethal milk") mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation.

    Science.gov (United States)

    McCormick, Nicholas H; Lee, Sooyeon; Hennigar, Stephen R; Kelleher, Shannon L

    2016-01-01

    During lactation, highly specialized secretory mammary epithelial cells (MECs) produce and secrete huge quantities of nutrients and nonnutritive factors into breast milk. The zinc (Zn) transporter ZnT4 (SLC30A4) transports Zn into the trans-Golgi apparatus for lactose synthesis, and across the apical cell membrane for efflux from MECs into milk. This is consistent with observations in "lethal milk" (lm/lm) mice, which have a truncation mutation in SLC30A4, and present with not only low milk Zn concentration, but also smaller mammary glands, decreased milk volume, and lactation failure by lactation day 2. However, the molecular underpinnings of these defects are not understood. Here, we used lactating C57BL/6J(lm/lm) (ZnT4-null) mice to explore the consequences of a ZnT4-null phenotype on mammary gland function during early lactation. Lactating C57BL/6J(lm/lm) mice had significantly fewer, smaller, and collapsed alveoli comprising swollen, lipid-filled MECs during early lactation. These defects were associated with decreased Akt expression and STAT5 activation, indicative of defects in MEC secretion. In addition, increased expression of ZnT2, TNF-α, and cleaved e-cadherin concomitant with increased activation of STAT3 implicated the loss of ZnT4 in precocious activation of involution. Collectively, our study indicates that the loss of ZnT4 has profound consequences on MEC secretion and may promote tissue remodeling in the mammary gland during early lactation. PMID:26538236

  6. Acute intermittent hypoxia-induced expression of Brain-Derived Neurotrophic Factor is disrupted in the brainstem of mecp2 null mice

    Science.gov (United States)

    Vermehren-Schmaedick, Anke; Jenkins, Victoria K.; Knopp, Sharon J.; Balkowiec, Agnieszka; Bissonnette, John M.

    2012-01-01

    Rett syndrome is a neurodevelopmental disorder caused by loss of function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2−/y) mice were subjected to three 5-min episodes of exposure to 8% O2/4% CO2/88% N2, delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, i.e. 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking Mecp2. The results indicate that Mecp2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo. PMID:22297041

  7. Acute intermittent hypoxia-induced expression of brain-derived neurotrophic factor is disrupted in the brainstem of methyl-CpG-binding protein 2 null mice.

    Science.gov (United States)

    Vermehren-Schmaedick, A; Jenkins, V K; Knopp, S J; Balkowiec, A; Bissonnette, J M

    2012-03-29

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2(-/y)) mice were subjected to three 5-min episodes of exposure to 8% O(2)/4% CO(2)/88% N(2), delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, that is, 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking MeCP2. The results indicate that MeCP2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo. PMID:22297041

  8. Antioxidant/oxidant status and cardiac function in bradykinin B(1)- and B(2)-receptor null mice.

    Science.gov (United States)

    Delemasure, S; Blaes, N; Richard, C; Couture, R; Bader, M; Dutartre, P; Girolami, J-P; Connat, J-L; Rochette, L

    2013-01-01

    Kinin-vasoactive peptides activate two G-protein-coupled receptors (R), B(1)R (inducible) and B(2)R (constitutive). Their complex role in cardiovascular diseases could be related to differential actions on oxidative stress. This study investigated impacts of B(1)R or B(2)R gene deletion in mice on the cardiac function and plasma antioxidant and oxidant status. Echocardiography-Doppler was performed in B(1)R (B(1)R(-/-)) and B(2)R (B(2)R(-/-)) deficient and wild type (WT) adult male mice. No functional alteration was observed in B(2)R(-/-) hearts. B(1)R(-/-) mice had significantly lowered fractional shortening and increased isovolumetric contraction time. The diastolic E and A waves velocity ratio was similar in all mice groups. Thus B(1)R(-/-) mice provide a model of moderate systolic dysfunction, whereas B(2)R(-/-) mice displayed a normal cardiac phenotype. Plasma antioxidant capacity (ORAC) was significantly decreased in both B(1)R(-/-) and B(2)R(-/-) mice whereas the vitamin C levels were decreased in B(2)R(-/-) mice only. Plasma ascorbyl free radical was significantly higher in B(1)R(-/-) compared to WT and B(2)R(-/-) mice. Therefore, the oxidative stress index, ascorbyl free radical to vitamin C ratio, was increased in both B(1)R(-/-) and B(2)R(-/-) mice. Hence, B(1)R and B(2)R deficiency are associated with increased oxidative stress, but there is a differential imbalance between free radical production and antioxidant defense. The interrelationship between the differential B(1)R and B(2)R roles in oxidative stress and cardiovascular diseases remain to be investigated. PMID:24020815

  9. Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

    DEFF Research Database (Denmark)

    Larsen, Peter Hjørringgaard; DaSilva, Angelika G.; Conant, Kathrine; Young, V. Wee

    2006-01-01

    around a demyelinating lesion of the spinal cord of adult mice facilitated remyelination. In the current study, we have addressed whether and how MMPs might be required for myelin formation in normal ontogeny. Using a probe for multiple MMPs and the developing mouse optic nerve, we found two members, MMP...... to remain high in MMP-deficient mice. These results reveal a novel function for MMP-9 and -12 in developmental myelination likely through regulating IGF-1 bioavailability....

  10. Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice

    Science.gov (United States)

    Veron, Delma; Aggarwal, Pardeep K.; Velazquez, Heino; Kashgarian, Michael; Moeckel, Gilbert

    2014-01-01

    VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess podocyte VEGF-A on the renal phenotype of endothelial nitric oxide synthase (eNOS) knockout mice. Podocyte-specific VEGF164 gain of function in eNOS−/− mice resulted in nodular glomerulosclerosis, mesangiolysis, microaneurysms, and arteriolar hyalinosis associated with massive proteinuria and renal failure in the absence of diabetic milieu or hypertension. In contrast, podocyte-specific VEGF164 gain of function in wild-type mice resulted in less pronounced albuminuria and increased creatinine clearance. Transmission electron microscopy revealed glomerular basement membrane thickening and podocyte effacement in eNOS−/− mice with podocyte-specific VEGF164 gain of function. Furthermore, glomerular nodules overexpressed collagen IV and laminin extensively. Biotin-switch and proximity ligation assays demonstrated that podocyte-specific VEGF164 gain of function decreased glomerular S-nitrosylation of laminin in eNOS−/− mice. In addition, treatment with VEGF-A decreased S-nitrosylated laminin in cultured podocytes. Collectively, these data indicate that excess glomerular VEGF-A and eNOS deficiency is necessary and sufficient to induce Kimmelstiel-Wilson–like nodular glomerulosclerosis in mice through a process that involves deposition of laminin and collagen IV and de-nitrosylation of laminin. PMID:24578128

  11. Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice.

    Science.gov (United States)

    Verpeut, Jessica L; DiCicco-Bloom, Emanuel; Bello, Nicholas T

    2016-07-01

    Prolonged consumption of ketogenic diets (KD) has reported neuroprotective benefits. Several studies suggest KD interventions could be useful in the management of neurological and developmental disorders. Alterations in the Engrailed (En) genes, specifically Engrailed 2 (En2), have neurodevelopmental consequences and produce autism-related behaviors. The following studies used En2 knockout (KO; En2(-/-)), and wild-type (WT; En2(+/+)), male mice fed either KD (80% fat, 0.1% carbohydrates) or control diet (CD; 10% fat, 70% carbohydrates). The objective was to determine whether a KD fed from weaning at postnatal day (PND) 21 to adulthood (PND 60) would alter brain monoamines concentrations, previously found dysregulated, and improve social outcomes. In WT animals, there was an increase in hypothalamic norepinephrine content in the KD-fed group. However, regional monoamines were not altered in KO mice in KD-fed compared with CD-fed group. In order to determine the effects of juvenile exposure to KD in mice with normal blood ketone levels, separate experiments were conducted in mice removed from the KD or CD and fed standard chow for 2days (PND 62). In a three-chamber social test with a novel mouse, KO mice previously exposed to the KD displayed similar social and self-grooming behaviors compared with the WT group. Groups previously exposed to a KD, regardless of genotype, had more c-Fos-positive cells in the cingulate cortex, lateral septal nuclei, and anterior bed nucleus of the stria terminalis. In the novel object condition, KO mice previously exposed to KD had similar behavioral responses and pattern of c-Fos immunoreactivity compared with the WT group. Thus, juvenile exposure to KD resulted in short-term consequences of improving social interactions and appropriate exploratory behaviors in a mouse model that displays autism-related behaviors. Such findings further our understanding of metabolic-based therapies for neurological and developmental disorders. PMID

  12. Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing

    OpenAIRE

    Ruggiu, Matteo; Herbst, Ruth; Kim, Natalie; Jevsek, Marko; Fak, John J.; Mann, Mary Anne; Fischbach, Gerald; Burden, Steven J.; Darnell, Robert B.

    2009-01-01

    Synapse formation at the neuromuscular junction (NMJ) requires an alternatively spliced variant of agrin (Z+ agrin) that is produced only by neurons. Here, we show that Nova1 and Nova2, neuron-specific splicing factors identified as targets in autoimmune motor disease, are essential regulators of Z+ agrin. Nova1/Nova2 double knockout mice are paralyzed and fail to cluster AChRs at the NMJ, and breeding them with transgenic mice constitutively expressing Z+ agrin in motor neurons rescued AChR ...

  13. Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice.

    Science.gov (United States)

    Iwanishi, Hiroki; Fujita, Norihito; Tomoyose, Katsuo; Okada, Yuka; Yamanaka, Osamu; Flanders, Kathleen C; Saika, Shizuya

    2016-06-01

    We evaluated the effects of the loss of Smad3 on the development of experimental argon laser-induced choroidal neovascularization (CNV) in mice. An in vitro angiogenesis model was also used to examine the role of transforming growth factor-β1 (TGFβ1)/Smad3 signaling in vessel-like tube formation by human umbilical vein endothelial cells (HUVECs). CNV was induced in eyes of 8-12-week-old B6.129-background Smad3-deficient (KO) mice (n=47) and wild-type (WT) mice (n=47) by argon laser irradiation. Results showed that the size of the CNV induced was significantly smaller in KO mice as compared with WT mice at day 14 as revealed by high-resolution angiography with fluorescein isothiocyanate-dextran. Immunohistochemistry and real-time reverse transcription-polymerase chain reaction of RNA extracted from laser-irradiated choroidal tissues were conducted on specimens at specific timepoints. Invasion of macrophages (F4/80+), but not neutrophils (myeloperoxidase+), and appearance of myofibroblasts (α-smooth muscle actin+) were suppressed in laser-irradiated KO tissues. mRNA expression of inflammation-related factors, that is, vascular endothelial growth factor (VEGF), macrophage-chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and TGFβ1 in choroidal tissues was suppressed by the loss of Smad3. We then examined the effects of adding a Smad3 inhibitor, SIS3, or an ALK5 inhibitor, SB431542, on tube formation promoted by TGFβ1 or VEGF in HUVECs cocultured with fibroblast feeder. Further addition of SIS3 or SB431542 augmented vessel-like tube formation by HUVECs in the presence of TGFβ1 or VEGF. In conclusion, lack of Smad3 attenuated the growth of laser-induced CNV with suppression of inflammation by macrophages in mice. Because blocking TGFβ1/Smad3 signal stimulated the activity of angiogenesis of HUVECs in vitro, the reduction of CNV in vivo in KO mice is attributed to a decrease in growth factor levels in the tissue by the loss of Smad3. PMID:26950486

  14. Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4

    International Nuclear Information System (INIS)

    Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease. Here we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4. Human MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45. We developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies

  15. Autistic-Like Syndrome in Mu Opioid Receptor Null Mice is Relieved by Facilitated mGluR4 Activity

    OpenAIRE

    Becker, Jérôme AJ; Clesse, Daniel; Spiegelhalter, Coralie; Schwab, Yannick; Le Merrer, Julie; Kieffer, Brigitte L.

    2014-01-01

    The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1−/−) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1−/− animals recapitulate core...

  16. Null mutation for Macrophage Migration Inhibitory Factor (MIF) is associated with less aggressive bladder cancer in mice

    International Nuclear Information System (INIS)

    Inflammatory cytokines may promote tumorigenesis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We studied the development of bladder cancer in wild type (WT) and MIF knockout (KO) mice given N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression. 5-month old male C57Bl/6 MIF WT and KO mice were treated with and without BBN. Animals were sacrificed at intervals up to 23 weeks of treatment. Bladder tumor stage and grade were evaluated by H&E. Immunohistochemical (IHC) analysis was performed for MIF and platelet/endothelial cell adhesion molecule 1 (PECAM-1), a measure of vascularization. MIF mRNA was analyzed by quantitative real-time polymerase chain reaction. Poorly differentiated carcinoma developed in all BBN treated mice by week 20. MIF WT animals developed T2 disease, while KO animals developed only T1 disease. MIF IHC revealed predominantly urothelial cytoplasmic staining in the WT control animals and a shift toward nuclear staining in WT BBN treated animals. MIF mRNA levels were 3-fold higher in BBN treated animals relative to controls when invasive cancer was present. PECAM-1 staining revealed significantly more stromal vessels in the tumors in WT animals when compared to KOs. Muscle invasive bladder cancer with increased stromal vascularity was associated with increased MIF mRNA levels and nuclear redistribution. Consistently lower stage tumors were seen in MIF KO compared to WT mice. These data suggest that MIF may play a role in the progression to invasive bladder cancer

  17. Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

    OpenAIRE

    Bruscia, Emanuela M.; Price, Joanna E.; Cheng, Ee-chun; Weiner, Scott; Caputo, Christina; Ferreira, Elisa C.; Egan, Marie E.; Krause, Diane S.

    2006-01-01

    Several studies have demonstrated that bone marrow (BM)-derived cells give rise to rare epithelial cells in the gastrointestinal (GI) and respiratory tracts after BM transplantation into myeloablated recipients. We investigate whether, after transplantation of cystic fibrosis transmembrane conductance regulator (CFTR)-positive BM-derived cells, BM-derived GI and airway epithelial cells can provide CFTR activity in the GI tract and nasal epithelium of recipient cystic fibrosis mice. CFTR−/− mi...

  18. Null mutation for Macrophage Migration Inhibitory Factor (MIF is associated with less aggressive bladder cancer in mice

    Directory of Open Access Journals (Sweden)

    Tsimikas John

    2007-07-01

    Full Text Available Abstract Background Inflammatory cytokines may promote tumorigenesis. Macrophage migration inhibitory factor (MIF is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We studied the development of bladder cancer in wild type (WT and MIF knockout (KO mice given N-butyl-N-(4-hydroxybutyl-nitrosamine (BBN, a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression. Methods 5-month old male C57Bl/6 MIF WT and KO mice were treated with and without BBN. Animals were sacrificed at intervals up to 23 weeks of treatment. Bladder tumor stage and grade were evaluated by H&E. Immunohistochemical (IHC analysis was performed for MIF and platelet/endothelial cell adhesion molecule 1 (PECAM-1, a measure of vascularization. MIF mRNA was analyzed by quantitative real-time polymerase chain reaction. Results Poorly differentiated carcinoma developed in all BBN treated mice by week 20. MIF WT animals developed T2 disease, while KO animals developed only T1 disease. MIF IHC revealed predominantly urothelial cytoplasmic staining in the WT control animals and a shift toward nuclear staining in WT BBN treated animals. MIF mRNA levels were 3-fold higher in BBN treated animals relative to controls when invasive cancer was present. PECAM-1 staining revealed significantly more stromal vessels in the tumors in WT animals when compared to KOs. Conclusion Muscle invasive bladder cancer with increased stromal vascularity was associated with increased MIF mRNA levels and nuclear redistribution. Consistently lower stage tumors were seen in MIF KO compared to WT mice. These data suggest that MIF may play a role in the progression to invasive bladder cancer.

  19. Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy.

    Directory of Open Access Journals (Sweden)

    R Charlotte Moffett

    Full Text Available Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1 and gastric inhibitory polypeptide (GIP. Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 and PC1/3 together with significant amounts of GLP-1 and GIP were detected in alpha cells. Knockout of GLP-1R abolished these islet adaptations and paradoxically decreased pancreatic insulin, GLP-1 and GIP. This was associated with abolition of normal pregnancy-induced increases in plasma GIP, L-cell numbers, and intestinal GIP and GLP-1 stores. These data indicate that GLP-1 but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-1.

  20. Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice.

    Science.gov (United States)

    Sorokin, Alexander V; Yang, Zhi-Hong; Vaisman, Boris L; Thacker, Seth; Yu, Zu-Xi; Sampson, Maureen; Serhan, Charles N; Remaley, Alan T

    2016-09-01

    Aspirin (ASA) is known to alter the production of potent inflammatory lipid mediators, but whether it interacts with omega-3 fatty acids (FAs) from fish oil to affect atherosclerosis has not been determined. The goal was to investigate the impact of a fish oil-enriched diet alone and in combination with ASA on the production of lipid mediators and atherosclerosis. ApoE(-/-) female mice were fed for 13weeks one of the four following diets: omega-3 FA deficient (OD), omega-3 FA rich (OR) (1.8g omega-3 FAs/kg·diet per day), omega-3 FA rich plus ASA (ORA) (0.1g ASA/kg·diet per day) or an omega-3 FA deficient plus ASA (ODA) with supplement levels equivalent to human doses. Plasma lipids, atherosclerosis, markers of inflammation, hepatic gene expression and aortic lipid mediators were determined. Hepatic omega-3 FAs were markedly higher in OR (9.9-fold) and ORA (7-fold) groups. Mice in both OR and ORA groups had 40% less plasma cholesterol in very low-density lipoprotein-cholesterol and low-density lipoprotein fractions, but aortic plaque area formation was only significantly lower in the ORA group (5.5%) compared to the OD group (2.5%). Plasma PCSK9 protein levels were approximately 70% lower in the OR and ORA groups. Proinflammatory aortic lipid mediators were 50%-70% lower in the ODA group than in the OD group and more than 50% lower in the ORA group. In summary, less aortic plaque lesions and aortic proinflammatory lipid mediators were observed in mice on the fish oil diet plus ASA vs. just the fish oil diet. PMID:27394692

  1. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

    Energy Technology Data Exchange (ETDEWEB)

    Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao; Nagasawa, Hatsumi; Little, John B.; Oshimura, Mitsuo; Li, Gloria C.; Chen, David J.

    2002-04-15

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.

  2. Hyper-Variability in Circulating Insulin, High Fat Feeding Outcomes, and Effects of Reducing Ins2 Dosage in Male Ins1-Null Mice in a Specific Pathogen-Free Facility

    OpenAIRE

    Templeman, Nicole M.; Mehran, Arya E.; Johnson, James D.

    2016-01-01

    Insulin is an essential hormone with key roles in energy homeostasis and body composition. Mice and rats, unlike other mammals, have two insulin genes: the rodent-specific Ins1 gene and the ancestral Ins2 gene. The relationships between insulin gene dosage and obesity has previously been explored in male and female Ins2 -/- mice with full or reduced Ins1 dosage, as well as in female Ins1 -/- mice with full or partial Ins2 dosage. We report herein unexpected hyper-variability in Ins1-null male...

  3. Post-translationally Abnormal Collagens of Prolyl 3-Hydroxylase-2 Null Mice Offer a Pathobiological Mechanism for the High Myopia Linked to Human LEPREL1 Mutations*

    Science.gov (United States)

    Hudson, David M.; Joeng, Kyu Sang; Werther, Rachel; Rajagopal, Abbhirami; Weis, MaryAnn; Lee, Brendan H.; Eyre, David R.

    2015-01-01

    Myopia, the leading cause of visual impairment worldwide, results from an increase in the axial length of the eyeball. Mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), have recently been identified in individuals with recessively inherited nonsyndromic severe myopia. P3H2 is a member of a family of genes that includes three isoenzymes of prolyl 3-hydroxylase (P3H), P3H1, P3H2, and P3H3. Fundamentally, it is understood that P3H1 is responsible for converting proline to 3-hydroxyproline. This limited additional knowledge also suggests that each isoenzyme has evolved different collagen sequence-preferred substrate specificities. In this study, differences in prolyl 3-hydroxylation were screened in eye tissues from P3h2-null (P3h2n/n) and wild-type mice to seek tissue-specific effects due the lack of P3H2 activity on post-translational collagen chemistry that could explain myopia. The mice were viable and had no gross musculoskeletal phenotypes. Tissues from sclera and cornea (type I collagen) and lens capsule (type IV collagen) were dissected from mouse eyes, and multiple sites of prolyl 3-hydroxylation were identified by mass spectrometry. The level of prolyl 3-hydroxylation at multiple substrate sites from type I collagen chains was high in sclera, similar to tendon. Almost every known site of prolyl 3-hydroxylation in types I and IV collagen from P3h2n/n mouse eye tissues was significantly under-hydroxylated compared with their wild-type littermates. We conclude that altered collagen prolyl 3-hydroxylation is caused by loss of P3H2. We hypothesize that this leads to structural abnormalities in multiple eye tissues, but particularly sclera, causing progressive myopia. PMID:25645914

  4. Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations.

    Science.gov (United States)

    Hudson, David M; Joeng, Kyu Sang; Werther, Rachel; Rajagopal, Abbhirami; Weis, MaryAnn; Lee, Brendan H; Eyre, David R

    2015-03-27

    Myopia, the leading cause of visual impairment worldwide, results from an increase in the axial length of the eyeball. Mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), have recently been identified in individuals with recessively inherited nonsyndromic severe myopia. P3H2 is a member of a family of genes that includes three isoenzymes of prolyl 3-hydroxylase (P3H), P3H1, P3H2, and P3H3. Fundamentally, it is understood that P3H1 is responsible for converting proline to 3-hydroxyproline. This limited additional knowledge also suggests that each isoenzyme has evolved different collagen sequence-preferred substrate specificities. In this study, differences in prolyl 3-hydroxylation were screened in eye tissues from P3h2-null (P3h2(n/n)) and wild-type mice to seek tissue-specific effects due the lack of P3H2 activity on post-translational collagen chemistry that could explain myopia. The mice were viable and had no gross musculoskeletal phenotypes. Tissues from sclera and cornea (type I collagen) and lens capsule (type IV collagen) were dissected from mouse eyes, and multiple sites of prolyl 3-hydroxylation were identified by mass spectrometry. The level of prolyl 3-hydroxylation at multiple substrate sites from type I collagen chains was high in sclera, similar to tendon. Almost every known site of prolyl 3-hydroxylation in types I and IV collagen from P3h2(n/n) mouse eye tissues was significantly under-hydroxylated compared with their wild-type littermates. We conclude that altered collagen prolyl 3-hydroxylation is caused by loss of P3H2. We hypothesize that this leads to structural abnormalities in multiple eye tissues, but particularly sclera, causing progressive myopia. PMID:25645914

  5. Metal components analysis of metallothionein-III in the brain sections of metallothionein-I and metallothionein-II null mice exposed to mercury vapor with HPLC/ICP-MS

    Energy Technology Data Exchange (ETDEWEB)

    Kameo, Satomi; Nakai, Kunihiko; Kurokawa, Naoyuki; Satoh, Hiroshi [Tohoku University, Graduate School of Medicine, Aoba-ku, Sendai (Japan); Kanehisa, Tomokazu; Naganuma, Akira [Tohoku University, Graduate School of Pharmaceutical Sciences, Sendai (Japan)

    2005-04-01

    Mercury vapor is effectively absorbed via inhalation and easily passes through the blood-brain barrier; therefore, mercury poisoning with primarily central nervous system symptoms occurs. Metallothionein (MT) is a cysteine-rich metal-binding protein and plays a protective role in heavy-metal poisoning and it is associated with the metabolism of trace elements. Two MT isoforms, MT-I and MT-II, are expressed coordinately in all mammalian tissues, whereas MT-III is a brain-specific member of the MT family. MT-III binds zinc and copper physiologically and is seemed to have important neurophysiological and neuromodulatory functions. The MT functions and metal components of MTs in the brain after mercury vapor exposure are of much interest; however, until now they have not been fully examined. In this study, the influences of the lack of MT-I and MT-II on mercury accumulation in the brain and the changes of zinc and copper concentrations and metal components of MTs were examined after mercury vapor exposure by using MT-I, II null mice and 129/Sv (wild-type) mice as experimental animals. MT-I, II null mice and wild-type mice were exposed to mercury vapor or an air stream for 2 h and were killed 24 h later. The brain was dissected into the cerebral cortex, the cerebellum, and the hippocampus. The concentrations of mercury in each brain section were determined by cold vapor atomic absorption spectrometry. The concentrations of mercury, copper, and zinc in each brain section were determined by inductively coupled plasma mass spectrometry (ICP-MS). The mercury accumulated in brains after mercury vapor exposure for MT-I, II null mice and wild-type mice. The mercury levels of MT-I, II null mice in each brain section were significantly higher than those of wild-type mice after mercury vapor exposure. A significant change of zinc concentrations with the following mercury vapor exposure for MT-I, II null mice was observed only in the cerebellum analyzed by two-way analysis of

  6. Sensitization to autoimmune hepatitis in group VIA calcium-independent phospholipase A2-null mice led to duodenal villous atrophy with apoptosis, goblet cell hyperplasia and leaked bile acids.

    Science.gov (United States)

    Jiao, Li; Gan-Schreier, Hongying; Tuma-Kellner, Sabine; Stremmel, Wolfgang; Chamulitrat, Walee

    2015-08-01

    Chronic bowel disease can co-exist with severe autoimmune hepatitis (AIH) in an absence of primary sclerosing cholangitis. Genetic background may contribute to this overlap syndrome. We previously have shown that the deficiency of iPLA2β causes an accumulation of hepatocyte apoptosis, and renders susceptibility for acute liver injury. We here tested whether AIH induction in iPLA2β-null mice could result in intestinal injury, and whether bile acid metabolism was altered. Control wild-type (WT) and female iPLA2β-null (iPLA2β(-/-)) mice were intravenously injected with 10mg/kg concanavalinA (ConA) or saline for 24h. ConA treatment of iPLA2β(-/-) mice caused massive liver injury with increased liver enzymes, fibrosis, and necrosis. While not affecting WT mice, ConA treatment of iPLA2β(-/-) mice caused severe duodenal villous atrophy concomitant with increased apoptosis, cell proliferation, globlet cell hyperplasia, and endotoxin leakage into portal vein indicating a disruption of intestinal barrier. With the greater extent than in WT mice, ConA treatment of iPLA2β(-/-) mice increased jejunal expression of innate response cytokines CD14, TNF-α, IL-6, and SOCS3 as well as chemokines CCL2 and the CCL3 receptor CCR5. iPLA2β deficiency in response to ConA-induced AIH caused a significant decrease in hepatic and biliary bile acids, and this was associated with suppression of hepatic Cyp7A1, Ntcp and ABCB11/Bsep and upregulation of intestinal FXR/FGF15 mRNA expression. The suppression of hepatic Ntcp expression together with the loss of intestinal barrier could account for the observed bile acid leakage into peripheral blood. Thus, enteropathy may result from acute AIH in a susceptible host such as iPLA2β deficiency. PMID:25957555

  7. Application of Osmotic Pumps for Sustained Release of 1-Aminobenzotriazole and Inhibition of Cytochrome P450 Enzymes in Mice: Model Comparison with the Hepatic P450 Reductase Null Mouse.

    Science.gov (United States)

    Stringer, Rowan A; Ferreira, Suzie; Rose, Jonathan; Ronseaux, Sebastien

    2016-08-01

    The effectiveness of controlled release 1-aminobenzotriazole (ABT) administration to inhibit cytochrome P450 (P450) enzymes has been evaluated in mice. To maximize the duration of P450 inhibition in vivo, ABT was administered via an osmotic pump. The degree of P450 inhibition was compared with that achieved with a single bolus dose of ABT. Two-hour prior subcutaneous treatment of mice with ABT (50 mg/kg) inhibited antipyrine clearance by 88%. A less pronounced inhibitory effect (29% reduction in clearance) was observed when ABT was administered 24-hours before antipyrine administration, indicating partial restoration of P450 activity during this longer pretreatment time. The duration of ABT in mice was very short (mean residence time = 1.7 hours) after subcutaneous bolus administration. When the inhibitor was delivered by an osmotic pump, maximum blood concentrations of the inhibitor were observed 24 hours after device implantation and were maintained at steady state for 6 days. Inhibition of P450 activity, as measured by antipyrine clearance, was confirmed at 24 hours and 120 hours after pump implantation, highlighting the utility of this method as a longer-term model for P450 inhibition in mice. The magnitude of P450 inhibition in ABT-treated mice was compared with that in hepatic P450 reductase null mice and both models were comparable. In vivo ABT administration by an osmotic pump offers an effective approach for longer-term P450 inhibition in mice and avoids the necessity for multiple dosing of the inhibitor. PMID:27271368

  8. Apolipoprotein A-I Mimetic Peptide D-4F Reduces Cardiac Hypertrophy and Improves Apolipoprotein A-I-Mediated Reverse Cholesterol Transport From Cardiac Tissue in LDL Receptor-null Mice Fed a Western Diet.

    Science.gov (United States)

    Han, Jie; Zhang, Song; Ye, Ping; Liu, Yong-Xue; Qin, Yan-Wen; Miao, Dong-Mei

    2016-05-01

    Epidemiological studies have suggested that hypercholesterolemia is an independent determinant of increased left ventricular (LV) mass. Because high-density lipoprotein and its major protein apolipoprotein A-I (apoA-I) mediate reverse cholesterol transport (RCT) and have cardiac protective effects, we hypothesized that the apoA-I mimetic peptide D-4F could promote RCT in cardiac tissue and decrease cardiac hypertrophy induced by hypercholesterolemia. Low-density lipoprotein receptor-null mice were fed by a Western diet for 18 weeks and then randomized to receive water, or D-4F 0.3 mg/mL, or D-4F 0.5 mg/mL added to drinking water for 6 weeks. After D-4F administration, an increase in high-density lipoprotein cholesterol and a decrease in low-density lipoprotein cholesterol, total cholesterol, and triglyceride in a trend toward dose-responsivity were found in cardiac tissue. Ultrasound biomicroscopy revealed a reduction in LV posterior wall end-diastolic dimension, and an increase in mitral valve E/A ratio and LV ejection fraction. Hematoxylin-eosin staining showed reduced LV wall thickness and myocardial cell diameter. The protein levels of ABCA1 and LXRα were elevated in cardiac tissue of D-4F treated mice compared with the controls (P < 0.05). These results demonstrated that D-4F treatment reduced cardiac hypertrophy, and improved cardiac performance in low-density lipoprotein receptor-null mice fed a Western diet, presumably through the LXRα-ABCA1 pathway associated with enhanced myocardial RCT. PMID:26828321

  9. Direct comparison of mice null for liver or intestinal fatty acid-binding proteins reveals highly divergent phenotypic responses to high fat feeding.

    Science.gov (United States)

    Gajda, Angela M; Zhou, Yin Xiu; Agellon, Luis B; Fried, Susan K; Kodukula, Sarala; Fortson, Walter; Patel, Khamoshi; Storch, Judith

    2013-10-18

    The enterocyte expresses two fatty acid-binding proteins (FABP), intestinal FABP (IFABP; FABP2) and liver FABP (LFABP; FABP1). LFABP is also expressed in liver. Despite ligand transport and binding differences, it has remained uncertain whether these intestinally coexpressed proteins, which both bind long chain fatty acids (FA), are functionally distinct. Here, we directly compared IFABP(-/-) and LFABP(-/-) mice fed high fat diets containing long chain saturated or unsaturated fatty acids, reasoning that providing an abundance of dietary lipid would reveal unique functional properties. The results showed that mucosal lipid metabolism was indeed differentially modified, with significant decreases in FA incorporation into triacylglycerol (TG) relative to phospholipid (PL) in IFABP(-/-) mice, whereas LFABP(-/-) mice had reduced monoacylglycerol incorporation in TG relative to PL, as well as reduced FA oxidation. Interestingly, striking differences were found in whole body energy homeostasis; LFABP(-/-) mice fed high fat diets became obese relative to WT, whereas IFABP(-/-) mice displayed an opposite, lean phenotype. Fuel utilization followed adiposity, with LFABP(-/-) mice preferentially utilizing lipids, and IFABP(-/-) mice preferentially metabolizing carbohydrate for energy production. Changes in body weight and fat may arise, in part, from altered food intake; mucosal levels of the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamine were elevated in LFABP(-/-), perhaps contributing to increased energy intake. This direct comparison provides evidence that LFABP and IFABP have distinct roles in intestinal lipid metabolism; differential intracellular functions in intestine and in liver, for LFABP(-/-) mice, result in divergent downstream effects at the systemic level. PMID:23990461

  10. Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling.

    Directory of Open Access Journals (Sweden)

    Christopher S Potter

    Full Text Available SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM, typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(-/- mice, which lack mature B and T cells, were crossed with Sharpin(-/- mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(-/- mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(-/- mice. Double homozygous Sharpin(-/- , Il4ra(-/- mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(-/- , Il4ra(-/- double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(-/- , Il4ra(-/- mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(-/- mice and this was maintained in Sharpin(-/- , Il4ra(-/- mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling

  11. Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L

    OpenAIRE

    Oliveros, Alfredo; Michael G. Heckman; del Pilar Corena-McLeod, Maria; Williams, Katrina; Boules, Mona; Richelson, Elliott

    2010-01-01

    Pre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) recept...

  12. Direct Comparison of Mice Null for Liver or Intestinal Fatty Acid-binding Proteins Reveals Highly Divergent Phenotypic Responses to High Fat Feeding*

    Science.gov (United States)

    Gajda, Angela M.; Zhou, Yin Xiu; Agellon, Luis B.; Fried, Susan K.; Kodukula, Sarala; Fortson, Walter; Patel, Khamoshi; Storch, Judith

    2013-01-01

    The enterocyte expresses two fatty acid-binding proteins (FABP), intestinal FABP (IFABP; FABP2) and liver FABP (LFABP; FABP1). LFABP is also expressed in liver. Despite ligand transport and binding differences, it has remained uncertain whether these intestinally coexpressed proteins, which both bind long chain fatty acids (FA), are functionally distinct. Here, we directly compared IFABP−/− and LFABP−/− mice fed high fat diets containing long chain saturated or unsaturated fatty acids, reasoning that providing an abundance of dietary lipid would reveal unique functional properties. The results showed that mucosal lipid metabolism was indeed differentially modified, with significant decreases in FA incorporation into triacylglycerol (TG) relative to phospholipid (PL) in IFABP−/− mice, whereas LFABP−/− mice had reduced monoacylglycerol incorporation in TG relative to PL, as well as reduced FA oxidation. Interestingly, striking differences were found in whole body energy homeostasis; LFABP−/− mice fed high fat diets became obese relative to WT, whereas IFABP−/− mice displayed an opposite, lean phenotype. Fuel utilization followed adiposity, with LFABP−/− mice preferentially utilizing lipids, and IFABP−/− mice preferentially metabolizing carbohydrate for energy production. Changes in body weight and fat may arise, in part, from altered food intake; mucosal levels of the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamine were elevated in LFABP−/−, perhaps contributing to increased energy intake. This direct comparison provides evidence that LFABP and IFABP have distinct roles in intestinal lipid metabolism; differential intracellular functions in intestine and in liver, for LFABP−/− mice, result in divergent downstream effects at the systemic level. PMID:23990461

  13. Structural observation of the anterior chamber angle in CYP1B1-null mice%CYP1B1基因缺失小鼠眼前房角组织结构的观察

    Institute of Scientific and Technical Information of China (English)

    姜发纲; 崔凌; 刘晓文

    2008-01-01

    Objective To determine the effects of CYP1B1 gene on the structure of anterior chamber angle in mice. Methods It is experimental study. Adult CYP1BI-null mice were used, in comparison C57BL/6J mice was used as control. The mice eyes were enueleated and plastic-embedded and the anterior chamber angle were sagittally sectioned in 3 μm thickness. The morphology and structure of the eye tissues was studied by light microscopy and transmission electron microscopy. Results The anterior chamber angle in C57BL/6J mice were well developed. But in CYPIBI-null mice, a variety of anomalies were found in the these tissues, including hypoplastic and compressed trabecular meshwork, abnormal structure of trabecular cells, a basal lamina extending from cornea over the meshwork, small or absent Schlemm's canal, and long iris process extending from the iris root to the trabecular meshwork. These pathological changes was demonstrated focally and the rest of the angle in CYP1BI-null were normal.Conclusions CYP1B1 gene plays an important role in the development of the anterior chamber angle.Deletion of this gene leads to the abnormalities in trabecular meshwork, Schlemm's canal and iris process,which may have some influence on the metabolism and function of the outflow facilities.%目的 研究细胞色素P450 181(CYP1B1)基因对小鼠眼前房角组织结构的影响.方法 实验研究.采用成年CYP1B1基因缺失小鼠模型,以同龄C57BL/6J小鼠为对照.通过塑料包埋切片技术,用光学显微镜和透射电子显微镜观察两组小鼠眼前房角组织的形态和超微结构.结果 C57BL/6J小鼠眼前房角组织发育正常;CYP1B1因缺失小鼠存在不同程度的房水引流系统发育畸形,表现为小梁网发育不良,网眼狭窄,小梁细胞结构变异,有时可见小梁柱间有异常存在的均质膜,Schlemm管狭窄或缺失,虹膜突从虹膜根直达全部小梁网.这些异常改变在CYP1B1基因缺失小鼠眼前房角

  14. AMP-activated protein kinase (AMPK) {beta}1{beta}2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

    DEFF Research Database (Denmark)

    O'Neill, Hayley M; Maarbjerg, Stine Just; Crane, Justin D;

    2011-01-01

    . Interestingly, young ß1ß2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings...

  15. Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

    International Nuclear Information System (INIS)

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE−/− mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE−/− mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies. - Highlights: • Augmented atherogenesis was found in ApoE−/− mice co-exposed to Aroclor1254 and TCDD. • Enhanced expression of PF4, MCP-1 and RIG-I correlated with augmented lesions. • POPs combination may be a greater cardiovascular health risk than individual POPs

  16. Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Qiuli [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Wang, Jing, E-mail: avaecn@gmail.com [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Huang, Fengchen [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Lv, Xiaowen [Feed Safety Reference Laboratory of Ministry of Agriculture, Feed Research Institute, Chinese Academy of Agricultural Sciences, Zhongguancun South Street 12, Beijing 100081 (China); Ma, Min [Laboratory of Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Du, Yuguo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China)

    2014-04-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE{sup −/−} mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several pro-atherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE{sup −/−} mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies. - Highlights: • Augmented atherogenesis was found in ApoE{sup −/−} mice co-exposed to Aroclor1254 and TCDD. • Enhanced expression of PF4, MCP-1 and RIG-I correlated with augmented lesions. • POPs combination may be a greater cardiovascular health risk than individual POPs.

  17. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.

    Science.gov (United States)

    Savonenko, A V; Melnikova, T; Laird, F M; Stewart, K-A; Price, D L; Wong, P C

    2008-04-01

    beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders. PMID:18385378

  18. Network models predict that reduced excitatory fluctuations can give rise to hippocampal network hyper-excitability in MeCP2-null mice.

    Directory of Open Access Journals (Sweden)

    Ernest C Y Ho

    Full Text Available Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2. Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.

  19. Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc-null mice: evidence for a critical role of the central nervous system

    Directory of Open Access Journals (Sweden)

    Gourdain Pauline

    2012-01-01

    Full Text Available Abstract Background The cellular prion protein (PrPc is a host-encoded glycoprotein whose transconformation into PrP scrapie (PrPSc initiates prion diseases. The role of PrPc in health is still obscure, but many candidate functions have been attributed to the protein, both in the immune and the nervous systems. Recent data show that experimental autoimmune encephalomyelitis (EAE is worsened in mice lacking PrPc. Disease exacerbation has been attributed to T cells that would differentiate into more aggressive effectors when deprived of PrPc. However, alternative interpretations such as reduced resistance of neurons to autoimmune insult and exacerbated gliosis leading to neuronal deficits were not considered. Method To better discriminate the contribution of immune cells versus neural cells, reciprocal bone marrow chimeras with differential expression of PrPc in the lymphoid or in the central nervous system (CNS were generated. Mice were subsequently challenged with MOG35-55 peptide and clinical disease as well as histopathology were compared in both groups. Furthermore, to test directly the T cell hypothesis, we compared the encephalitogenicity of adoptively transferred PrPc-deficient versus PrPc-sufficient, anti-MOG T cells. Results First, EAE exacerbation in PrPc-deficient mice was confirmed. Irradiation exacerbated EAE in all the chimeras and controls, but disease was more severe in mice with a PrPc-deleted CNS and a normal immune system than in the reciprocal construction. Moreover, there was no indication that anti-MOG responses were different in PrPc-sufficient and PrPc-deficient mice. Paradoxically, PrPc-deficient anti-MOG 2D2 T cells were less pathogenic than PrPc-expressing 2D2 T cells. Conclusions In view of the present data, it can be concluded that the origin of EAE exacerbation in PrPc-ablated mice resides in the absence of the prion protein in the CNS. Furthermore, the absence of PrPc on both neural and immune cells does not

  20. Plaque Size Is Decreased but M1 Macrophage Polarization and Rupture Related Metalloproteinase Expression Are Maintained after Deleting T-Bet in ApoE Null Mice

    OpenAIRE

    Tsaousi, Aikaterini; Hayes, Elaine M.; Di Gregoli, Karina; Bond, Andrew R.; Bevan, Laura; Thomas, Anita C.; Newby, Andrew C.

    2016-01-01

    Background Thelper1 (Th1) lymphocytes have been previously implicated in atherosclerotic plaque growth but their role in plaque vulnerability to rupture is less clear. We investigated whether T-bet knockout that prevents Th1 lymphocyte differentiation modulates classical (M1) macrophage activation or production of matrix degrading metalloproteinases (MMPs) and their tissue inhibitors, TIMPs. Methods & Results We studied the effect of T-bet deletion in apolipoproteinE (ApoE) knockout mice fed ...

  1. 5-HT1A Receptor Null Mutant Mice Responding Under a Differential-Reinforcement-of-Low-Rate 72-Second Schedule of Reinforcement

    OpenAIRE

    Scott-McKean, Jonah J.; Wenger, Galen R.; Tecott, Laurence H.; Costa, Alberto C.S.

    2008-01-01

    Over the last two decades, our ever-increasing ability to manipulate the mouse genome has resulted in a variety of genetically defined mouse models of depression and other psychiatric and neurological disorders. However, it is still the case that some relevant rodent models for depression and antidepressant action have been validated experimentally in rats only and not in mice. An important example of such models is the operant model of antidepressant action known as differential-reinforcemen...

  2. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Directory of Open Access Journals (Sweden)

    Fang Xiao

    Full Text Available Type 1 diabetes mellitus (T1DM is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  3. Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rg(null) mice.

    Science.gov (United States)

    Cany, Jeannette; van der Waart, Anniek B; Tordoir, Marleen; Franssen, Gerben M; Hangalapura, Basav N; de Vries, Jolanda; Boerman, Otto; Schaap, Nicolaas; van der Voort, Robbert; Spanholtz, Jan; Dolstra, Harry

    2013-01-01

    Natural killer (NK) cell-based adoptive immunotherapy is an attractive adjuvant treatment option for patients with acute myeloid leukemia. Recently, we reported a clinical-grade, cytokine-based culture method for the generation of NK cells from umbilical cord blood (UCB) CD34⁺ hematopoietic progenitor cells with high yield, purity and in vitro functionality. The present study was designed to evaluate the in vivo anti-leukemic potential of UCB-NK cells generated with our GMP-compliant culture system in terms of biodistribution, survival and cytolytic activity following adoptive transfer in immunodeficient NOD/SCID/IL2Rg(null) mice. Using single photon emission computed tomography, we first demonstrated active migration of UCB-NK cells to bone marrow, spleen and liver within 24 h after infusion. Analysis of the chemokine receptor expression profile of UCB-NK cells matched in vivo findings. Particularly, a firm proportion of UCB-NK cells functionally expressed CXCR4, what could trigger BM homing in response to its ligand CXCL12. In addition, high expression of CXCR3 and CCR6 supported the capacity of UCB-NK cells to migrate to inflamed tissues via the CXCR3/CXCL10-11 and CCR6/CCL20 axis. Thereafter, we showed that low dose IL-15 mediates efficient survival, expansion and maturation of UCB-NK cells in vivo. Most importantly, we demonstrate that a single UCB-NK cell infusion combined with supportive IL-15 administration efficiently inhibited growth of human leukemia cells implanted in the femur of mice, resulting in significant prolongation of mice survival. These preclinical studies strongly support the therapeutic potential of ex vivo-generated UCB-NK cells in the treatment of myeloid leukemia after immunosuppressive chemotherapy. PMID:23755121

  4. Intratibial injection of human multiple myeloma cells in NOD/SCID IL-2Rγ(null mice mimics human myeloma and serves as a valuable tool for the development of anticancer strategies.

    Directory of Open Access Journals (Sweden)

    Julia Schueler

    Full Text Available BACKGROUND: We systematically analyzed multiple myeloma (MM cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents. DESIGN AND METHODS: Using flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null mice (NSG. RESULTS: Myeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID. Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses. CONCLUSIONS: Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies.

  5. Supersymmetric null-surfaces

    OpenAIRE

    Mikhailov, Andrei

    2004-01-01

    Single trace operators with the large R-charge in supersymmetric Yang-Mills theory correspond to the null-surfaces in $AdS_5\\times S^5$. We argue that the moduli space of the null-surfaces is the space of contours in the super-Grassmanian parametrizing the complex $(2|2)$-dimensional subspaces of the complex $(4|4)$-dimensional space. The odd coordinates on this super-Grassmanian correspond to the fermionic degrees of freedom of the superstring.

  6. Plaque Size Is Decreased but M1 Macrophage Polarization and Rupture Related Metalloproteinase Expression Are Maintained after Deleting T-Bet in ApoE Null Mice

    Science.gov (United States)

    Tsaousi, Aikaterini; Hayes, Elaine M.; Di Gregoli, Karina; Bond, Andrew R.; Bevan, Laura

    2016-01-01

    Background Thelper1 (Th1) lymphocytes have been previously implicated in atherosclerotic plaque growth but their role in plaque vulnerability to rupture is less clear. We investigated whether T-bet knockout that prevents Th1 lymphocyte differentiation modulates classical (M1) macrophage activation or production of matrix degrading metalloproteinases (MMPs) and their tissue inhibitors, TIMPs. Methods & Results We studied the effect of T-bet deletion in apolipoproteinE (ApoE) knockout mice fed a high fat diet (HFD) or normal chow diet (ND). Transcript levels of M1/M2 macrophage polarization markers, selected MMPs and TIMPs were measured by RT-qPCR in macrophages isolated from subcutaneous granulomas or in whole aortae. Immunohistochemistry of aortic sinus (AS) and brachiocephalic artery (BCA) plaques was conducted to quantify protein expression of the same factors. Deletion of T-bet decreased mRNA for the M1 marker NOS-2 in granuloma macrophages but levels of M2 markers (CD206, arginase-1 and Ym-1), MMPs-2, -9, -12, -13, -14 and -19 or TIMPs-1 to -3 were unchanged. No mRNA differences were observed in aortic extracts from mice fed a HFD for 12 weeks. Moreover, AS and BCA plaques were similarly sized between genotypes, and had similar areas stained for NOS-2, COX-2, MMP-12 and MMP-14 proteins. T-bet deletion increased MMP-13, MMP-14 and arginase-1 in AS plaques. After 35 weeks of ND, T-bet deletion reduced the size of AS and BCA plaques but there were no differences in the percentage areas stained for M1 or M2 markers, MMPs-12, -13, -14, or TIMP-3. Conclusions Absence of Th1 lymphocytes is associated with reduced plaque size in ApoE knockout mice fed a normal but not high fat diet. In either case, M1 macrophage polarization and expression of several MMPs related to plaque instability are either maintained or increased. PMID:26886778

  7. Plaque Size Is Decreased but M1 Macrophage Polarization and Rupture Related Metalloproteinase Expression Are Maintained after Deleting T-Bet in ApoE Null Mice.

    Directory of Open Access Journals (Sweden)

    Aikaterini Tsaousi

    Full Text Available Thelper1 (Th1 lymphocytes have been previously implicated in atherosclerotic plaque growth but their role in plaque vulnerability to rupture is less clear. We investigated whether T-bet knockout that prevents Th1 lymphocyte differentiation modulates classical (M1 macrophage activation or production of matrix degrading metalloproteinases (MMPs and their tissue inhibitors, TIMPs.We studied the effect of T-bet deletion in apolipoproteinE (ApoE knockout mice fed a high fat diet (HFD or normal chow diet (ND. Transcript levels of M1/M2 macrophage polarization markers, selected MMPs and TIMPs were measured by RT-qPCR in macrophages isolated from subcutaneous granulomas or in whole aortae. Immunohistochemistry of aortic sinus (AS and brachiocephalic artery (BCA plaques was conducted to quantify protein expression of the same factors. Deletion of T-bet decreased mRNA for the M1 marker NOS-2 in granuloma macrophages but levels of M2 markers (CD206, arginase-1 and Ym-1, MMPs-2, -9, -12, -13, -14 and -19 or TIMPs-1 to -3 were unchanged. No mRNA differences were observed in aortic extracts from mice fed a HFD for 12 weeks. Moreover, AS and BCA plaques were similarly sized between genotypes, and had similar areas stained for NOS-2, COX-2, MMP-12 and MMP-14 proteins. T-bet deletion increased MMP-13, MMP-14 and arginase-1 in AS plaques. After 35 weeks of ND, T-bet deletion reduced the size of AS and BCA plaques but there were no differences in the percentage areas stained for M1 or M2 markers, MMPs-12, -13, -14, or TIMP-3.Absence of Th1 lymphocytes is associated with reduced plaque size in ApoE knockout mice fed a normal but not high fat diet. In either case, M1 macrophage polarization and expression of several MMPs related to plaque instability are either maintained or increased.

  8. Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.

    Directory of Open Access Journals (Sweden)

    Min Jung Park

    Full Text Available Rett syndrome (RTT is an autism spectrum disorder (ASD caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2. Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.

  9. Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase

    OpenAIRE

    Palmer, Lisa A.; May, Walter J.; deRonde, Kimberly; Brown-Steinke, Kathleen; Bates, James N; Gaston, Benjamin; Lewis, Stephen J.

    2012-01-01

    Exposure to a hypoxic challenge increases ventilation in wild-type (WT) mice that diminish during the challenge (roll-off) whereas return to room air causes an increase in ventilation (short-term facilitation, STF). Since plasma and tissue levels of ventilatory excitant S-nitrosothiols such as S-nitrosoglutathione (GSNO) increase during hypoxia, this study examined whether (1) the initial increase in ventilation is due to generation of GSNO, (2) roll-off is due to increased activity of the GS...

  10. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion

    OpenAIRE

    Martin, Gregory G.; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Storey, Stephen M.; HOWLES, PHILIP N.; Kier, Ann B.; Schroeder, Friedhelm

    2014-01-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In cont...

  11. Increased Lung Ischemia-Reperfusion Injury in Aquaporin 1-Null Mice Is Mediated via Decreased Hypoxia-Inducible Factor 2α Stability.

    Science.gov (United States)

    Ge, Haiyan; Zhu, Huili; Xu, Nuo; Zhang, Dan; Ou, Jiaxian; Wang, Guifang; Fang, Xiaocong; Zhou, Jian; Song, Yuanlin; Bai, Chunxue

    2016-06-01

    Aquaporin (AQP) 1, a water channel protein expressed widely in vascular endothelia, has been shown to regulate cell migration, angiogenesis, and organ regeneration. Even though its role in the pathogenesis of lung ischemia-reperfusion (IR) injury has been defined, the functional role of AQP1 during long-term IR resolution remains to be clarified. Here, we found that AQP1 expression was increased at late time points (7-14 d) after IR and colocalized with endothelial cell (EC) marker CD31. Compared with IR in wild-type mice, IR in Aqp1(-/-) mice had significantly enhanced leukocyte infiltration, collagen deposition, and microvascular permeability, as well as inhibited angiogenic factor expression. AQP1 knockdown repressed hypoxia-inducible factor (HIF)-2α protein stability. HIF-2α overexpression rescued the angiogenic factor expression in pulmonary microvascular ECs with AQP1 knockdown exposed to hypoxia-reoxygenation. Furthermore, AQP1 knockdown suppressed cellular viability and capillary tube formation, and enhanced permeability in pulmonary microvascular ECs, which were partly rescued by HIF-2α overexpression. Thus, this study demonstrates that AQP1 deficiency delays long-term IR resolution, partly through repressing angiogenesis mediated by destabilizing HIF-2α. These results suggest that AQP1 participates in long-term IR resolution, at least in part by promoting angiogenesis. PMID:26649797

  12. Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice.

    Science.gov (United States)

    Helwig, Michael; Klinkenberg, Michael; Rusconi, Raffaella; Musgrove, Ruth E; Majbour, Nour K; El-Agnaf, Omar M A; Ulusoy, Ayse; Di Monte, Donato A

    2016-03-01

    Aggregation and neuron-to-neuron transmission are attributes of α-synuclein relevant to its pathogenetic role in human synucleinopathies such as Parkinson's disease. Intraparenchymal injections of fibrillar α-synuclein trigger widespread propagation of amyloidogenic protein species via mechanisms that require expression of endogenous α-synuclein and, possibly, its structural corruption by misfolded conformers acting as pathological seeds. Here we describe another paradigm of long-distance brain diffusion of α-synuclein that involves inter-neuronal transfer of monomeric and/or oligomeric species and is independent of recruitment of the endogenous protein. Targeted expression of human α-synuclein was induced in the mouse medulla oblongata through an injection of viral vectors into the vagus nerve. Enhanced levels of intra-neuronal α-synuclein were sufficient to initiate its caudo-rostral diffusion that likely involved at least one synaptic transfer and progressively reached specific brain regions such as the locus coeruleus, dorsal raphae and amygdala in the pons, midbrain and forebrain. Transfer of human α-synuclein was compared in two separate lines of α-synuclein-deficient mice versus their respective wild-type controls and, interestingly, lack of endogenous α-synuclein expression did not counteract diffusion but actually resulted in a more pronounced and advanced propagation of exogenous α-synuclein. Self-interaction of adjacent molecules of human α-synuclein was detected in both wild-type and mutant mice. In the former, interaction of human α-synuclein with mouse α-synuclein was also observed and might have contributed to differences in protein transmission. In wild-type and α-synuclein-deficient mice, accumulation of human α-synuclein within recipient axons in the pons, midbrain and forebrain caused morphological evidence of neuritic pathology. Tissue sections from the medulla oblongata and pons were stained with different antibodies recognizing

  13. The apolipoprotein-AI mimetic peptide L4F at a modest dose does not attenuate weight gain, inflammation, or atherosclerosis in LDLR-null mice.

    Directory of Open Access Journals (Sweden)

    Michelle M Averill

    Full Text Available High density lipoprotein (HDL cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/- model fed a high fat high sucrose with cholesterol (HFHSC diet.Studies in differentiated 3T3-L1 adipocytes tested whether L4F could inhibit palmitate-induced adipocyte inflammation. In vivo studies used male Ldlr-/- mice fed a HFHSC diet for 12 weeks and were injected daily with L4F (100 µg/mouse subcutaneously during the last 8 weeks. Wild-type and apoA-I overexpressing Ldlr-/- mice were fed HFHSC diet for 16 weeks.Neither L4F administration nor apoA-I overexpression affected weight gain, total plasma cholesterol or triglycerides in our studies. While pre-treatment of 3T3-L1 adipocytes with either L4F or HDL abolished palmitate-induced cytokine expression in vitro, L4F treatment did not affect circulating or adipose tissue inflammatory markers in vivo. Neither L4F administration nor apoA-I overexpression affected glucose tolerance. ApoA-I overexpression significantly reduced atherosclerotic lesion size, yet L4F treatment did not affect atherosclerosis.Our results suggest that neither L4F (100 µg/day/mouse nor apoA-I overexpression affects adiposity or insulin resistance in this model. We also were unable to confirm a reduction in atherosclerosis with L4F in our particular model. Further studies on the effect of apoA-I mimetics on atherosclerosis and insulin resistance in a variety of dietary contexts are warranted.

  14. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion.

    Science.gov (United States)

    Martin, Gregory G; Atshaves, Barbara P; Landrock, Kerstin K; Landrock, Danilo; Storey, Stephen M; Howles, Philip N; Kier, Ann B; Schroeder, Friedhelm

    2014-12-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  15. Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice.

    Directory of Open Access Journals (Sweden)

    Wendy W J Unger

    Full Text Available Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP. HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγ(null mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies.

  16. Gravitational action with null boundaries

    CERN Document Server

    Lehner, Luis; Poisson, Eric; Sorkin, Rafael D

    2016-01-01

    We present a complete discussion of the boundary term in the action functional of general relativity when the boundary includes null segments in addition to the more usual timelike and spacelike segments. We confirm that ambiguities appear in the contribution from a null segment, because it depends on an arbitrary choice of parametrization for the generators. We also show that similar ambiguities appear in the contribution from a codimension-two surface at which a null segment is joined to another (spacelike, timelike, or null) segment. The parametrization ambiguity can be tamed by insisting that the null generators be affinely parametrized; this forces each null contribution to the boundary action to vanish, but leaves intact the fredom to rescale the affine parameter by a constant factor on each generator. Once a choice of parametrization is made, the ambiguity in the joint contributions can be eliminated by formulating well-motivated rules that ensure the additivity of the gravitational action. Enforcing t...

  17. Partial Rescue of the Amelogenin Null Dental Enamel Phenotype*

    OpenAIRE

    LI, YONG; Suggs, Cynthia; Wright, J. Timothy; Yuan, Zhi-An; Aragon, Melissa; Fong, Hanson; Simmons, Darrin; Daly, Bill; Golub, Ellis E.; Harrison, Gerald; Kulkarni, Ashok B.; Gibson, Carolyn W.

    2008-01-01

    The amelogenins are the most abundant secreted proteins in developing dental enamel. Enamel from amelogenin (Amelx) null mice is hypoplastic and disorganized, similar to that observed in X-linked forms of the human enamel defect amelogenesis imperfecta resulting from amelogenin gene mutations. Both transgenic strains that express the most abundant amelogenin (TgM180) have relatively normal enamel, but strains of mice that express a mutated amelogenin (TgP70T), which leads to amelogenesis impe...

  18. On Spinors and Null Vectors

    CERN Document Server

    Budinich, Marco

    2014-01-01

    We investigate the relations between spinors and null vectors in Clifford algebra with particular emphasis on the conditions that a spinor must satisfy to be simple (also: pure). In particular we prove: i) a new property for null vectors: each of them bisects spinor space into two parts of equal size; ii) that simple spinors form one-dimensional subspaces of spinor space; iii) a necessary and sufficient condition for a spinor to be simple that generalizes a theorem of Cartan and Chevalley that appears now as a corollary of this result. We also show how to write down easily the most general spinor with a given associated totally null plane.

  19. Null distance on a spacetime

    CERN Document Server

    Sormani, Christina

    2015-01-01

    Given a time function $\\tau$ on a spacetime $M$, we define a `null distance function', $\\hat{d}_\\tau$, built from and closely related to the causal structure of $M$. In basic models with timelike $\

  20. Null lifts and projective dynamics

    CERN Document Server

    Cariglia, Marco

    2015-01-01

    We describe natural Hamiltonian systems using projective geometry. The null lift procedure endows the tangent bundle with a projective structure where the null Hamiltonian is identified with a projective conic and induces a Weyl geometry. Projective transformations generate a set of known and new dualities between Hamiltonian systems, as for example the phenomenon of coupling-constant metamorphosis. We conclude outlining how this construction can be extended to the quantum case for Eisenhart-Duval lifts.

  1. HLA-A*01:03, HLA-A*24:02, HLA-B*08:01, HLA-B*27:05, HLA-B*35:01, HLA-B*44:02, and HLA-C*07:01 Monochain Transgenic/H-2 Class I Null Mice

    DEFF Research Database (Denmark)

    Boucherma, Rachid; Kridane-Miledi, Hédia; Bouziat, Romain;

    2013-01-01

    We have generated a panel of transgenic mice expressing HLA-A*01:03, -A*24:02, -B*08:01, -B*27:05, -B*35:01, -B*44:02, or -C*07:01 as chimeric monochain molecules (i.e., appropriate HLA α1α2 H chain domains fused with a mouse α3 domain and covalently linked to human β2-microglobulin). Whereas...... surface expression of several transgenes was markedly reduced in recipient mice that coexpressed endogenous H-2 class I molecules, substantial surface expression of all human transgenes was observed in mice lacking H-2 class I molecules. In these HLA monochain transgenic/H-2 class I null mice, we observed...... a quantitative and qualitative restoration of the peripheral CD8(+) T cell repertoire, which exhibited a TCR diversity comparable with C57BL/6 WT mice. Potent epitope-specific, HLA-restricted, IFN-γ-producing CD8(+) T cell responses were generated against known reference T cell epitopes after either...

  2. Phase-Occultation Nulling Coronagraphy

    CERN Document Server

    Lyon, Richard G; Clampin, Mark; Petrone, Peter

    2015-01-01

    The search for life via characterization of earth-like planets in the habitable zone is one of the key scientific objectives in Astronomy. We describe a new phase-occulting (PO) interferometric nulling coronagraphy (NC) approach. The PO-NC approach employs beamwalk and freeform optical surfaces internal to the interferometer cavity to introduce a radially dependent plate scale difference between each interferometer arm (optical path) that nulls the central star at high contrast while transmitting the off-axis field. The design is readily implemented on segmented-mirror telescope architectures, utilizing a single nulling interferometer to achieve high throughput, a small inner working angle (IWA), sixth-order or higher starlight suppression, and full off-axis discovery space, a combination of features that other coronagraph designs generally must trade. Unlike previous NC approaches, the PO-NC approach does not require pupil shearing; this increases throughput and renders it less sensitive to on-axis common-mo...

  3. On spinors and null vectors

    Science.gov (United States)

    Budinich, Marco

    2014-03-01

    We investigate the relations between spinors and null vectors in Clifford algebra of any dimension with particular emphasis on the conditions that a spinor must satisfy to be simple (also: pure). In particular, we prove: (i) a new property for null vectors: each of them bisects spinor space into two subspaces of equal size; (ii) that simple spinors form one-dimensional subspaces of spinor space; (iii) a necessary and sufficient condition for a spinor to be simple that generalizes a theorem of Cartan and Chevalley which becomes a corollary of this result. We also show how to write down easily the most general spinor with a given associated totally null plane. This paper is dedicated to the memory of my father Paolo Budinich who passed away in November 2013 not before transferring to me his enthusiasm for simple spinors.

  4. Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: a possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia

    OpenAIRE

    Li, Zhimin; Liang, Yanqi; Boules, Mona; Gordillo, Andres; Richelson, Elliott

    2010-01-01

    Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors: NTS1 and NTS2. The present study was done to determine the roles of NTS1 and NTS2 on amino acid release in striatum with the use of NTS1 or NTS2 knock-out (-/-) mice given d-amphetamine. Both NTS1-/- and NTS2-/- mice had lower extracellular concentrations of D-serine in striatum than did wild type (WT) mice. NTS2-/- but not NTS1-/- mice also had significantly lower...

  5. Bootstrapping Null Polygon Wilson Loops

    OpenAIRE

    Gaiotto, Davide; Maldacena, Juan; Sever, Amit; Vieira, Pedro

    2010-01-01

    We derive the two loop expressions for polygonal Wilson loops by starting from the one loop expressions and applying an operator product expansion. We do this for polygonal Wilson loops in R^{1,1} and find a result in agreement with previous computations. We also discuss the spectrum of excitations around flux tube that connects two null Wilson lines.

  6. Parasitic interference in nulling interferometry

    CERN Document Server

    Matter, Alexis; Danchi, William C; Lopez, Bruno; Absil, Olivier

    2013-01-01

    Nulling interferometry aims to detect faint objects close to bright stars. Its principle is to produce a destructive interference along the line-of-sight so that the stellar flux is rejected, while the flux of the off-axis source can be transmitted. In practice, various instrumental perturbations can degrade the nulling performance. Any imperfection in phase, amplitude, or polarization produces a spurious flux that leaks to the interferometer output and corrupts the transmitted off-axis flux. One of these instrumental pertubations is the crosstalk phenomenon, which occurs because of multiple parasitic reflections inside transmitting optics, and/or diffraction effects related to beam propagation along finite size optics. It can include a crosstalk of a beam with itself, and a mutual crosstalk between different beams. This can create a parasitic interference pattern, which degrades the intrinsic transmission map - or intensity response - of the interferometer. In this context, we describe how this instrumental ...

  7. Balloon Exoplanet Nulling Interferometer (BENI)

    Science.gov (United States)

    Lyon, Richard G.; Clampin, Mark; Woodruff, Robert A.; Vasudevan, Gopal; Ford, Holland; Petro, Larry; Herman, Jay; Rinehart, Stephen; Carpenter, Kenneth; Marzouk, Joe

    2009-01-01

    We evaluate the feasibility of using a balloon-borne nulling interferometer to detect and characterize exosolar planets and debris disks. The existing instrument consists of a 3-telescope Fizeau imaging interferometer with 3 fast steering mirrors and 3 delay lines operating at 800 Hz for closed-loop control of wavefront errors and fine pointing. A compact visible nulling interferometer is under development which when coupled to the imaging interferometer would in-principle allow deep suppression of starlight. We have conducted atmospheric simulations of the environment above 100,000 feet and believe balloons are a feasible path forward towards detection and characterization of a limited set of exoplanets and their debris disks. Herein we will discuss the BENI instrument, the balloon environment and the feasibility of such as mission.

  8. Standard and Null Weak Values

    OpenAIRE

    Zilberberg, Oded; Romito, Alessandro; Gefen, Yuval

    2013-01-01

    Weak value (WV) is a quantum mechanical measurement protocol, proposed by Aharonov, Albert, and Vaidman. It consists of a weak measurement, which is weighed in, conditional on the outcome of a later, strong measurement. Here we define another two-step measurement protocol, null weak value (NVW), and point out its advantages as compared to WV. We present two alternative derivations of NWVs and compare them to the corresponding derivations of WVs.

  9. Visualization of the human CD4{sup +} T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/γc{sup null} (NOG) mice by retrogenic expression of the human TCR gene

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Takeshi, E-mail: takeshi-takahashi@ciea.or.jp; Katano, Ikumi; Ito, Ryoji; Ito, Mamoru

    2015-01-02

    Highlights: • β-Lactoglobulin (BLG) specific TCR genes were introduced to human HSC by retrovirus. • Human HSC with BLG-specific TCR were transplanted into NOG-HLA-DR4 I-A{sup −/−} mice. • BLG-specific TCR induced positive selection of thymocytes. • BLG-specific TCR positive CD4{sup +} T cells mediated immune responses in humanized mice. - Abstract: The development of severe immunodeficient mouse strains containing various human genes, including cytokines or HLA, has enabled the reconstitution of functional human immune systems after transplantation of human hematopoietic stem cells (HSC). Accumulating evidence has suggested that HLA-restricted antigen-specific human T-cell responses can be generated in these humanized mice. To directly monitor immune responses of human CD4{sup +} T cells, we introduced β-lactoglobulin (BLG)-specific T cell receptor (TCR) genes derived from CD4{sup +} T-cell clones of cow-milk allergy patients into HSCs, and subsequently transplanted them into NOG-HLA-DR4 transgenic/I-Aβ deficient mice (NOG-DR4/I-A{sup o}). In the thymus, thymocytes with BLG-specific TCR preferentially differentiated into CD4{sup +}CD8{sup −} single-positive cells. Adoptive transfer of mature CD4{sup +} T cells expressing the TCR into recipient NOG-DR4/I-A{sup o} mice demonstrated that human CD4{sup +} T cells proliferated in response to antigenic stimulation and produced IFN-γ in vivo, suggesting that functional T-cell reactions (especially Th1-skewed responses) were induced in humanized mice.

  10. On the Penrose inequality along null hypersurfaces

    CERN Document Server

    Mars, Marc

    2015-01-01

    The null Penrose inequality, i.e. the Penrose inequality in terms of the Bondi energy, is studied by introducing a funtional on surfaces and studying its properties along a null hypersurface $\\Omega$ extending to past null infinity. We prove a general Penrose-type inequality which involves the limit at infinity of the Hawking energy along a specific class of geodesic foliations called Geodesic Asymptotic Bondi (GAB), which are shown to always exist. Whenever, this foliation approaches large spheres, this inequality becomes the null Penrose inequality and we recover the results of Ludvigsen-Vickers and Bergqvist. By exploiting further properties of the functional along general geodesic foliations, we introduce an approach to the null Penrose inequality called Renormalized Area Method and find a set of two conditions which implies the validity of the null Penrose inequality. One of the conditions involves a limit at infinity and the other a condition on the spacetime curvature along the flow. We investigate the...

  11. Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice

    International Nuclear Information System (INIS)

    Background and purpose: We previously showed that irradiating the carotid arteries of ApoE−/− mice accelerated the development of macrophage-rich, inflammatory and thrombotic atherosclerotic lesions. In this study we investigated the potential of anti-inflammatory (atorvastatin, CD40L knockout) and anti-thrombotic (clopidogrel) intervention strategies to inhibit radiation-induced atherosclerosis. Material and methods: ApoE−/− mice were given 0 or 14 Gy to the neck and the carotid arteries were harvested at 4 or 28 weeks after irradiation. Atorvastatin (15 mg/kg/day) or clopidogrel (20 mg/kg/day) was given in the chow; control groups received regular chow. Clopidogrel inhibited platelet aggregation by 50%. CD40L−/−/ApoE−/− and ApoE−/− littermates were also given 0 or 14 Gy to the neck and the carotid arteries were harvested after 30 weeks. Results: Clopidogrel decreased MCP-1 expression in the carotid artery at 4 weeks after irradiation. Expression of VCAM-1, ICAM-1, thrombomodulin, tissue factor and eNOS was unchanged in atorvastatin and clopidogrel-treated mice. Neither drug inhibited either age-related or radiation-induced atherosclerosis. Furthermore, loss of the inflammatory mediator CD40L did not influence the development of age-related and radiation-induced atherosclerosis. Conclusions: The effects of radiation-induced atherosclerosis could not be circumvented by these specific anti-inflammatory and anti-coagulant therapies. This suggests that more effective drug combinations may be required to overcome the radiation stimulus, or that other underlying mechanistic pathways are involved compared to age-related atherosclerosis.

  12. Parasitic interference in nulling interferometry

    Science.gov (United States)

    Matter, A.; Defrère, D.; Danchi, W. C.; Lopez, B.; Absil, O.

    2013-05-01

    Nulling interferometry aims to detect faint objects close to bright stars. Its principle is to produce a destructive interference along the line of sight so that the stellar flux is rejected, while the flux of the off-axis source can be transmitted. In practice, various instrumental perturbations can degrade the nulling performance. Any imperfection in phase, amplitude or polarization produces a spurious flux that leaks to the interferometer output and corrupts the transmitted off-axis flux. One of these instrumental perturbations is the crosstalk phenomenon, which occurs because of multiple parasitic reflections inside transmitting optics, and/or diffraction effects related to beam propagation along finite size optics. It can include a crosstalk of a beam with itself, and a mutual crosstalk between different beams. This can create a parasitic interference pattern, which degrades the intrinsic transmission map - or intensity response - of the interferometer. In this context, we describe how this instrumental effect impairs the performance of a Bracewell interferometer. A simple formalism is developed to derive the corresponding modified intensity response of the interferometer, as a function of the two parameters of interest: the crosstalk level (or contamination rate) and the phase shift between the primary and secondary - parasitic - beams. We then apply our mathematical approach to a few scientific cases, both analytically and using the GENIESIM simulation software, adapted to handle coherent crosstalk. Our results show that a coherent crosstalk level of about 1 per cent implies a 20 per cent drop of the signal-to-noise ratio at most. Careful attention should thus be paid to reduce the crosstalk level inside an interferometric instrument and ensure an instrumental stability that provides the necessary sensitivity through calibration procedures.

  13. Thermodynamic origin of the null energy condition

    OpenAIRE

    Parikh, Maulik; Svesko, Andrew

    2016-01-01

    We derive the classical null energy condition, understood as a constraint on the Ricci tensor, from the second law of thermodynamics applied to Bekenstein-Hawking entropy. The derivation provides evidence that the null energy condition, which has usually been regarded as a condition on matter, is fundamentally a property of gravity.

  14. Thermodynamic Origin of the Null Energy Condition

    CERN Document Server

    Parikh, Maulik

    2015-01-01

    We derive the classical null energy condition, understood as a constraint on the Ricci tensor, from the second law of thermodynamics applied to Bekenstein-Hawking entropy. The derivation provides evidence that the null energy condition, which has usually been regarded as a condition on matter, is fundamentally a property of gravity.

  15. Causal cells: spacetime polytopes with null hyperfaces

    CERN Document Server

    Neiman, Yasha

    2012-01-01

    We consider polyhedra and 4-polytopes in Minkowski spacetime - in particular, null polyhedra with zero volume, and 4-polytopes that have such polyhedra as their hyperfaces. We present the basic properties of several classes of null-faced 4-polytopes: 4-simplices, "tetrahedral diamonds" and 4-parallelotopes. We propose a "most regular" representative of each class. The most-regular parallelotope is of particular interest: its edges, faces and hyperfaces are all congruent, and it features both null hyperplanes and null segments. A tiling of spacetime with copies of this polytope can be viewed alternatively as a lattice with null edges, such that each point is at the intersection of four lightrays in a tetrahedral pattern. We speculate on the relevance of this construct for discretizations of curved spacetime and for quantum gravity.

  16. Null Subjects in European and Brazilian Portuguese

    OpenAIRE

    Barbosa, Pilar; Duarte, Maria Eugênia L.; Kato, Mary Aizawa

    2005-01-01

    The goals of this paper are twofold: a) to provide a structural account of the effects of the informal ‘Avoid Pronoun Principle’, proposed in Chomsky (1981: 65) for the Null Subject Languages (NSLs), and b) to compare, in European and Brazilian Portuguese (EP and BP), the distribution of the third person pronouns in its full and null forms, to check whether in written corpora BP incorporates signs of the ongoing loss of the null subject, largely attested in its contemporary spoken language. T...

  17. Real null coframes in general relativity and GPS type coordinates

    International Nuclear Information System (INIS)

    Some time ago, Finkelstein defined a 'symmetric' null frame with four real null vectors. We discuss this Finkelstein frame and show that a similarly defined real null coframe is closely related to the GPS type coordinates recently introduced by Rovelli

  18. High-contrast Nulling Interferometry Techniques Project

    Data.gov (United States)

    National Aeronautics and Space Administration — "We are developing rotating-baseline nulling-interferometry techniques and algorithms on the single-aperture Hale and Keck telescopes at near-infrared wavelengths,...

  19. Null geodesics in brane world universe

    International Nuclear Information System (INIS)

    We study null bulk geodesic motion in the brane world cosmology in the RS2 scenario and in the static universe in the bulk of the charged topological AdS black hole. We obtain equations describing the null bulk geodesic motion as observed in one lower dimensions. We find that the null geodesic motion in the bulk of the brane world cosmology in the RS2 scenario is observed to be under the additional influence of extra non-gravitational force by the observer on the three-brane, if the brane universe does not possess the Z2 symmetry. As for the null geodesic motion in the static universe in the bulk of the charged AdS black hole, the extra force is realized even when the brane universe has the Z2 symmetry. (author)

  20. Latex allergy and filaggrin null mutations

    DEFF Research Database (Denmark)

    Carlsen, Berit C; Meldgaard, Michael; Hamann, Dathan;

    2011-01-01

    Objectives Natural rubber latex (NRL) contains over 200 proteins of which 13 have been identified as allergens and the cause of type I latex allergy. Health care workers share a high occupational risk for developing latex allergy. Filaggrin null mutations increase the risk of type I sensitizations...... to aeroallergens and it is possible that filaggrin null mutations also increase the risk of latex allergy. The aim of this paper was to examine the association between filaggrin null mutations and type I latex allergy. Methods Twenty latex allergic and 24 non-latex allergic dentists and dental...... assistants, occupationally exposed to latex, were genotyped for filaggrin null mutations R501X and 2282del4. Latex allergy was determined by a positive reaction or a historical positive reaction to a skin prick test with NRL. Results 41 individuals were successfully genotyped. Three individuals were...

  1. Null-sissemakse - eraisikule riskantne / Tõnu Tramm

    Index Scriptorium Estoniae

    Tramm, Tõnu, 1968-

    2005-01-01

    Ilmunud ka: Delovõje Vedomosti 20. apr. lk. 26. Hansaliising ja Ühisliising käivitasid kampaania, mille käigus pakutakse uusi kuni 250 000 krooni maksvaid autosid null-sissemaksega. Kommenteerib ASi SEB Ühisliising arendusdirektor Ove Muuk. Tabel: Null-sissemaksega auto tuleb kallim. Lisad: Kuidas saavutada võimalikult väike kuumakse?; Kuidas maksta võimalikult vähe intressi? Vt. samas: Argo Rebane: Liisingufirmast saab parema hinna

  2. Computing extinction maps of star nulling interferometers

    OpenAIRE

    Henault, Francois

    2008-01-01

    Herein is discussed the performance of spaceborne nulling interferometers searching for extra-solar planets, in terms of their extinction maps projected on-sky. In particular, it is shown that the designs of Spatial Filtering (SF) and Achromatic Phase Shifter (APS) subsystems, both required to achieve planet detection and characterization, can sensibly affect the nulling maps produced by a simple Bracewell interferometer. Analytical relationships involving cross correlation products are provi...

  3. Computing extinction maps of star nulling interferometers.

    Science.gov (United States)

    Hénault, Francois

    2008-03-31

    Herein is discussed the performance of spaceborne nulling interferometers searching for extra-solar planets, in terms of their extinction maps projected on-sky. In particular, it is shown that the designs of Spatial Filtering (SF) and Achromatic Phase Shifter (APS) subsystems, both required to achieve planet detection and characterization, can sensibly affect the nulling maps produced by a simple Bracewell interferometer. Analytical relationships involving cross correlation products are provided and numerical simulations are performed, demonstrating marked differences in the aspect of extinction maps and the values of attained fringes contrasts. It is concluded that depending on their basic principles and designs, FS and APS will result in variable capacities for serendipitous discoveries of planets orbiting around their parent star. The mathematical relationships presented in this paper are assumed to be general, i.e. they should apply to other types of multi-apertures nulling interferometers. PMID:18542551

  4. Two roads to the null energy condition

    Science.gov (United States)

    Parikh, Maulik

    2015-11-01

    The null energy condition has sweeping consequences in general relativity. I argue here that it has been misunderstood as a property exclusively of matter, when in fact it arises only in a theory of both matter and gravity. I then derive an equivalent geometric formulation of the null energy condition from worldsheet string theory, where it arises beautifully as simple Einstein’s equations in two dimensions. But further, I show that this condition also has a thermodynamic origin, following from a local version of the second law of thermodynamics, applied to gravitational entropy. Thus, far from being an incidental property of matter, the validity of the null energy condition hints at the deep dual origins of gravity.

  5. Two Roads to the Null Energy Condition

    CERN Document Server

    Parikh, Maulik

    2015-01-01

    The null energy condition has sweeping consequences in general relativity. I argue here that it has been misunderstood as a property exclusively of matter, when in fact it arises only in a theory of both matter and gravity. I then derive an equivalent geometric formulation of the null energy condition from worldsheet string theory, where it arises beautifully as simply Einstein's equations in two dimensions. But further, I show that this condition also has a thermodynamic origin, following from a local version of the second law of thermodynamics, applied to gravitational entropy. Thus, far from being an incidental property of matter, the validity of the null energy condition hints at the deep dual origins of gravity.

  6. Supersymmteric Null-like Holographic Cosmologies

    OpenAIRE

    Lin, Feng-Li; Wen, Wen-Yu

    2006-01-01

    We construct a new class of 1/4-BPS time dependent domain-wall solutions with null-like metric and dilaton in type II supergravities, which admit a null-like big bang singularity. Based on the domain-wall/QFT correspondence, these solutions are dual to 1/4-supersymmetric quantum field theories living on a boundary cosmological background with time dependent coupling constant and UV cutoff. In particular we evaluate the holographic $c$ function for the 2-dimensional dual field theory living on...

  7. Molecular bass for a malic enzyme null mutation

    International Nuclear Information System (INIS)

    Many tissues from normal (wt) mice have cytosolic malic enzyme (ME) activity and express two mRNAs (2 and 3.1 kb) that code for a single ME polypeptide. Mod-1 null (M-n) mice lack cytosolic ME activity, but express 2.5 and 3.6 kb mRNAs that hybridize with wt ME cDNAs. To investigate the basis for the ME deficiency cDNAs corresponding to M-n ME RNA were cloned. A λgt11 library was prepared using M-n liver mRNA as a template. Wt ME cDNA probes hybridized with several recombinant phages and a 2kb insert with an atypical (non-wt) restriction pattern was subcloned in pGEM 1 and sequenced. The M-n ME cDNA contains an internal directly repeated sequence that corresponds to nts 1109-1617 in the coding region of wt ME cDNA. A restriction fragment from M-n ME cDNA that includes the first 204 bp of repeated sequence and 306 bp of contiguous 5' sequence was subcloned into pGEM 1 and used as a template for synthesizing 32P-labeled anti-sense RNA. After hybridization with M-n liver RNA the 510 nt transcript was resistant to RNA digestion; after hybridization with wt RNA only fragments corresponding to the normally non-contiguous 204 bp and 306 bp segments of the insert were protected. Thus the partial duplication of coding sequence in M-n ME mRNA is confirmed. Analyses of intron-exon organization in the relevant regions of the wt and M-n ME genes will provide further insights into the mechanism underlying the ME null mutation

  8. The Null Energy Condition and its violation

    OpenAIRE

    Rubakov, V. A.

    2014-01-01

    We give a mini-review of scalar field theories with second-derivative Lagrangians, whose field equations are second order. Some of these theories admit solutions violating the Null Energy Condition and having no obvious pathologies. We give a few examples of using these theories in cosmological setting and also in the context of the creation of a universe in the laboratory.

  9. A Philosophical Critique of Null Hypothesis Testing.

    Science.gov (United States)

    Orey III, Michael A.; And Others

    1989-01-01

    An attempt is made to clarify the philosophical foundations of the debate over research methodology appropriate for psychology in particular and the utility of null hypothesis testing in general. The article also relates the debate to education and suggests that the debate is far from settled. (IAH)

  10. Gravitational collapse of a cylindrical null shell in vacuum

    Directory of Open Access Journals (Sweden)

    S. Khakshournia

    2008-03-01

    Full Text Available   Barrabès-Israel null shell formalism is used to study the gravitational collapse of a thin cylindrical null shell in vacuum. In general the lightlike matter shell whose history coincides with a null hypersurface is characterized by a surface energy density. In addition, a gravitational impulsive wave is present on this null hypersurface whose generators admit both the shear and expansion. In the case of imposing the cylindrical flatness the surface energy-momentum tensor of the matter shell on the null hypersurface vanishes and the null hyper- surface is just the history of the gravitational wave .

  11. Vascular Response to Intra-arterial Injury in the Thrombospondin-1 Null Mouse

    OpenAIRE

    Budhani, Faisal; Leonard, Katherine A.; Bergdahl, Andreas; Gao, Jimin; Lawler, Jack; Davis, Elaine C.

    2007-01-01

    Thrombospondin-1 (TSP-1) is a multifunctional, extracellular matrix protein that has been implicated in the regulation of smooth muscle cell proliferation, migration and differentiation during vascular development and injury. Vascular injury in wildtype and TSP-1 null mice was carried out by insertion of a straight spring guidewire into the femoral artery via a muscular arterial branch. Blood flow was restored after the muscular branch was ligated. The injury completely denuded the endotheliu...

  12. Broadband nulling behaviour of PSR B2319+60

    CERN Document Server

    Gajjar, Vishal; Kramer, M

    2012-01-01

    Pulse nulling is one of many single pulse phenomena exhibited by radio pulsars. The broadband nature of this phenomena remained unexplained due to lack of coordinated observations. We are reporting broadband nulling behaviour of a well known nulling pulsar PSR B2319+60. The simultaneous observations were carried out at four different frequencies using the Giant Meterwave Radio telescope (325 and 610 MHz), the Westerbork Synthesis Radio Telescope (1420 MHz) and the Effelsberg radio telescope (5100 MHz). The nulling fractions were estimated at all four observed frequencies, which suggest similar degree of nulling across these frequencies. To comment on the broadband behaviour of pulse nulling, we calculated the Pearson cross-correlation coefficients for the occurrence of null and burst pulses between all four frequencies. We conclude that nulling is largely a broadband phenomenon for this pulsar and it points towards a global failure of the magnetospheric currents which produces radio emission at these frequenc...

  13. The spacetime geometry of a null electromagnetic field

    International Nuclear Information System (INIS)

    We give a set of local geometric conditions on a spacetime metric which are necessary and sufficient for it to be a null electrovacuum, that is, the metric is part of a solution to the Einstein–Maxwell equations with a null electromagnetic field. These conditions are restrictions on a null congruence canonically constructed from the spacetime metric, and can involve up to five derivatives of the metric. The null electrovacuum conditions are counterparts of the Rainich conditions, which geometrically characterize non-null electrovacua. Given a spacetime satisfying the conditions for a null electrovacuum, a straightforward procedure builds the null electromagnetic field from the metric. Null electrovacuum geometry is illustrated using some pure radiation spacetimes taken from the literature. (paper)

  14. N-ethyl-N-nitrosourea-induced null mutation at the mouse Car-2 locus: An animal model for human carbonic anhydrase II deficiency syndrome

    International Nuclear Information System (INIS)

    Electrophoretic screening of (C57BL/6J x DBA/2J)F1 progeny of male mice treated with N-ethyl-N-nitrosourea revealed a mouse that lacked the paternal carbonic anhydrase II (Ca II). Breeding tests showed that this trait was heritable and due to a null mutation at the Car-2 locus on chromosome 3. Like humans with the same inherited enzyme defect, animals homozygous for the new null allele are runted and have renal tubular acidosis. However, the prominent osteopetrosis found in humans with CA II deficiency could be detected even in very old homozygous null mice. A molecular analysis of the deficient mice shows that the mutant gene is not deleted and is transcribed. The CA II protein, which is normally expressed in most tissues, could not be detected by immunodiffusion analysis in any tissues of the CA II-deficient mice, suggesting a nonsense or a missense mutation at the Car-2 locus

  15. Motion Behavior of Null Space in Redundant Robotic Manipulators

    OpenAIRE

    Shibata, Tsuyoshi; Murakami, Toshiyuki

    2008-01-01

    This chapter shows the control design of null space motion by PID controller. When the work space observer is emplyed in work space controller, work space and null space motion are determined independently. Then the PD based work space controller makes work space motion stable, but global stability of null space motion is not always guranteed. To improve the stability and the robustness of null space motion, PID controller considering passivity is useful and the design strategy of PID control...

  16. On the null origin of the ambitwistor string

    OpenAIRE

    Casali, Eduardo; Tourkine, Piotr

    2016-01-01

    In this paper we present the null string origin of the ambitwistor string. Classically, the null string is the tensionless limit of string theory, and so too is the Ambitwistor string. Both have as constraint algebra the Galilean Conformal Algebra in two dimensions. But something interesting happens in the quantum theory since there is an ambiguity in quantizing the null string. We show that, given a particular choice of quantization scheme and a particular gauge, the null string coincides wi...

  17. String spectra near some null cosmological singularities

    OpenAIRE

    Madhu, Kallingalthodi; Narayan, K.

    2009-01-01

    We construct cosmological spacetimes with null Kasner-like singularities as purely gravitational solutions with no other background fields turned on. These can be recast as anisotropic plane-wave spacetimes by coordinate transformations. We analyse string quantization to find the spectrum of string modes in these backgrounds. The classical string modes can be solved for exactly in these time-dependent backgrounds, which enables a detailed study of the near singularity string spectrum, (time-d...

  18. Renormalization of null Wilson lines in EQCD

    International Nuclear Information System (INIS)

    Radiation and energy loss of a light, high-energy parton in a perturbative Quark-Gluon Plasma is controlled by transverse momentum exchange. The troublesome infrared contributions to transverse momentum exchange can be computed on the lattice using dimensional reduction to EQCD. However a novel extended operator, the Null Wilson Line of EQCD, is involved. We compute the renormalization properties of this object’s lattice implementation to next-to-leading order, which should facilitate its efficient calculation on the lattice

  19. PHASE CLOSURE NULLING: THEORY AND PRACTICE

    Directory of Open Access Journals (Sweden)

    A. Chelli

    2009-01-01

    Full Text Available We provide a complete theory of the phase closure of a binary system in which a small, feeble, and unresolved companion acts as a perturbing parameter on the spatial frequency spectrum of a dominant, bright, resolved source. We demonstrate that the in uence of the companion can be measured with precision by measuring the phase closure of the system near the nulls of the primary visibility function. In these regions of phase closure nulling, frequency intervals always exist where the phase closure signature of the companion is larger than any systematic error and can thus be measured. We show that this technique allows retrieval of many astrophysically relevant properties of faint and close companions such as ux, position, and in favorable cases, spectrum. As a proof of concept, using the AMBER/VLTI instrument with 3 auxiliary telescopes of 1.8 m and only 15 minutes of on-sky integration, we detected the ve magnitudes fainter companion of HD 59717 at only 3.5 stellar radii distance from the primary. This is one of the highest contrast detected by interferometry between a companion and its parent star. We conclude by a rapid study of the potentialities of phase closure nulling observations with current interferometers and explore the requirements for a new type of dedicated instrument.

  20. Real null coframes in general relativity and GPS type coordinates

    CERN Document Server

    Blagojevic, M; Hehl, F W; Obukhov, Yu N; Obukhov, Yu.N.

    2002-01-01

    Some time ago, D. Finkelstein defined a `symmetric' null frame with {\\it four real null vectors}. We discuss this Finkelstein frame and show that a similarly defined real null coframe is closely related to the GPS type coordinates recently introduced by Rovelli.

  1. A Conformal Extension Theorem based on Null Conformal Geodesics

    CERN Document Server

    Lübbe, Christian

    2008-01-01

    In this article we describe the formulation of null geodesics as null conformal geodesics and their description in the tractor formalism. A conformal extension theorem through an isotropic singularity is proven by requiring the boundedness of the tractor curvature and its derivatives to sufficient order along a congruence of null conformal geodesic. This article extends earlier work by Tod and Luebbe.

  2. Null conformal Killing-Yano tensors and Birkhoff theorem

    CERN Document Server

    Ferrando, Joan Josep

    2015-01-01

    We study the space-times admitting a null conformal Killing-Yano tensor whose divergence defines a Killing vector. We analyze the similitudes and differences with the recently studied non null case (Gen. Relativ. Grav. (2015) {\\bf 47} 1911). The results by Barnes concerning the Birkhoff theorem for the case of null orbits are analyzed and generalized.

  3. Null conformal Killing-Yano tensors and Birkhoff theorem

    Science.gov (United States)

    Ferrando, Joan Josep; Sáez, Juan Antonio

    2016-04-01

    We study the space-times admitting a null conformal Killing-Yano tensor whose divergence defines a Killing vector. We analyze the similarities and differences with the recently studied non null case (Ferrando and Sáez in Gen Relativ Gravit 47:1911, 2015). The results by Barnes concerning the Birkhoff theorem for the case of null orbits are analyzed and generalized.

  4. Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

    Directory of Open Access Journals (Sweden)

    Daniela Brunner

    Full Text Available Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept14Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of

  5. Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

    Science.gov (United States)

    Brunner, Daniela; Kabitzke, Patricia; He, Dansha; Cox, Kimberly; Thiede, Lucinda; Hanania, Taleen; Sabath, Emily; Alexandrov, Vadim; Saxe, Michael; Peles, Elior; Mills, Alea; Spooren, Will; Ghosh, Anirvan; Feliciano, Pamela; Benedetti, Marta; Luo Clayton, Alice; Biemans, Barbara

    2015-01-01

    Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we

  6. A Nulling Coronagraph for TPF-C

    Science.gov (United States)

    Shao, Michael; Levine, Bruce Martin; Wallace, James Kent; Orton, Glenn S.; Schmidtlin, Edouard; Lane, Benjamin F.; Seager, Sara; Tolls, Volker; Lyon, Richard G.; Samuele, Rocco; Tenerelli, Domenick J.; Woodruff, Robert; Ge, Jian

    2006-01-01

    The nulling coronagraph is one of 5 instrument concepts selected by NASA for study for potential use in the TPF-C mission. This concept for extreme starlight suppression has two major components, a nulling interferometer to suppress the starlight to 10(sup -10) per airy spot within 2 (lamda)/D of the star, and a calibration interferometer to measure the residual scattered starlight. The ability to work at 2 (lamda)/D dramatically improves the science throughput of a space based coronagraph like TPF-C. The calibration interferometer is an equally important part of the starlight suppression system. It measures the measures the wavefront of the scattered starlight with very high SNR, to 0.05nm in less than 5 minutes on a 5mag star. In addition, the post coronagraph wavefront sensor will be used to measure the residual scattered light after the coronagraph and subtract it in post processing to 12x10(sup -11) to enable detection of an Earthlike planet with a SNR of 510.

  7. Null Geodesics in Five Dimensional Manifolds

    CERN Document Server

    Seahra, S S; Seahra, Sanjeev S.; Wesson, Paul S.

    2001-01-01

    We analyze a class of 5D non-compact warped-product spaces characterized by metrics that depend on the extra coordinate via a conformal factor. Our model is closely related to the so-called canonical coordinate gauge of Mashhoon et al. We confirm that if the 5D manifold in our model is Ricci-flat, then there is an induced cosmological constant in the 4D sub-manifold. We derive the general form of the 5D Killing vectors and relate them to the 4D Killing vectors of the embedded spacetime. We then study the 5D null geodesic paths and show that the 4D part of the motion can be timelike --- that is, massless particles in 5D can be massive in 4D. We find that if the null trajectories are affinely parameterized in 5D, then the particle is subject to an anomalous acceleration or fifth force. However, this force may be removed by reparameterization, which brings the correct definition of the proper time into question. Physical properties of the geodesics --- such as rest mass variations induced by a variable cosmologi...

  8. Quasilocal energy exchange and the null cone

    CERN Document Server

    Uzun, Nezihe

    2016-01-01

    Energy is at best defined quasilocally in general relativity. Quasilocal energy definitions depend on the conditions one imposes on the boundary Hamiltonian, i.e., how a finite region of spacetime is "isolated". Here, we propose a method to define and investigate systems in terms of their matter plus gravitational energy content. We adopt a generic construction, that involves embedding of an arbitrary dimensional worldsheet into an arbitrary dimensional spacetime, to a 2 + 2 picture. In our case, the closed 2-dimensional spacelike surface $\\mathbb{S}$, that is orthogonal to the 2-dimensional timelike worldsheet $\\mathbb{T}$ at every point, encloses the system in question. The integrability conditions of $\\mathbb{T}$ and $\\mathbb{S}$ correspond to three null tetrad gauge conditions once we transform our notation to the one of the null cone observables. We interpret the Raychaudhuri equation of $\\mathbb{T}$ as a work-energy relation for systems that are not in equilibrium with their surroundings. We achieve thi...

  9. Peculiar nulling in PSR J1738-2330

    CERN Document Server

    Gajjar, Vishal; Krämer, M

    2009-01-01

    Several pulsars show sudden cessation of pulsed emission, which is known as nulling. The number of known nulling pulsars has not been significantly enhanced in the last decade, although the pulsar population has more than doubled following the Parkes multi-beam pulsar survey. A systematic follow-up study of the new pulsars, discovered in this survey, is being carried out by us at 325-MHz with GMRT. The peculiar nulling behaviour of PSR J1738-2330, observed as a part of this 325-MHz GMRT survey, is reported in this paper. The pulsar appears to show a periodic null-burst cycle with an upper limit to nulling fraction, of about 90 percent. The pulsed flux density declines by a factor 94 during the nulled pulses in this pulsar.

  10. On the null origin of the ambitwistor string

    CERN Document Server

    Casali, Eduardo

    2016-01-01

    In this paper we present the null string origin of the ambitwistor string. Classically, the null string is the tensionless limit of string theory, and so too is the Ambitwistor string. Both have as constraint algebra the Galilean Conformal Algebra in two dimensions. But something interesting happens in the quantum theory since there is an ambiguity in quantizing the null string. We show that, given a particular choice of quantization scheme and a particular gauge, the null string coincides with the ambitwistor string both classically and quantum mechanically. We also show that the same holds for the spinning versions of the null string and Ambitwistor string. With these results we clarify the relationship between the Ambitwistor string, the null string, the usual string and the Hohm-Siegel-Zwiebach theory.

  11. On the Local Extension of the Future Null Infinity

    OpenAIRE

    Li, Junbin; Zhu, Xi-Ping

    2014-01-01

    We consider a characteristic problem of the vacuum Einstein equations with part of the initial data given on a future complete null cone with suitable decay, and show that the solution exists uniformly around the null cone for general such initial data. We can then define a segment of the future null infinity. The initial data are not required to be small and the decaying condition inherits from the works of \\cite{Ch-K} and \\cite{K-N}.

  12. Null subjects and agreement marks in European and Brazilian Portuguese

    OpenAIRE

    Duarte, Maria Eugênia Lammoglia; Varejão, Filomena

    2013-01-01

    The purpose of this article is to discuss the relation between the presence of agreement marks and null subjects in contemporary European and Brazilian Portuguese based on very recent samples of speech collected in Lisbon and Rio de Janeiro. In order to bring additional evidence to support the analysis, we will briefly review the issues involving the Null Subject in Romance Languages and some diachronic and synchronic analyses which distinguish Brazilian and European Portuguese as far as null...

  13. Are Null Results Becoming an Endangered Species in Marketing?

    OpenAIRE

    Raymond Hubbard; JS Armstrong

    1992-01-01

    Editorial procedures in the social and biomedical sciences are said to promote studies that falsely reject the null hypothesis. This problem may also exist in major marketing journals. Of 692 papers using statistical significance tests sampled from the Journal of Marketing, Journal of Marketing Research, and Journal of Consumer Research between 1974 and 1989, only 7.8% failed to reject the null hypothesis. The percentage of null results declined by one-half from the 1970s to the 1980s. The...

  14. String spectra near some null cosmological singularities

    International Nuclear Information System (INIS)

    We construct cosmological spacetimes with null Kasner-like singularities as purely gravitational solutions with no other background fields turned on. These can be recast as anisotropic plane-wave spacetimes by coordinate transformations. We analyze string quantization to find the spectrum of string modes in these backgrounds. The classical string modes can be solved for exactly in these time-dependent backgrounds, which enables a detailed study of the near-singularity string spectrum, (time-dependent) oscillator masses, and wave functions. We find that for low-lying string modes (finite oscillation number), the classical near-singularity string mode functions are nondivergent for various families of singularities. Furthermore, for any infinitesimal regularization of the vicinity of the singularity, we find a tower of string modes of ultrahigh oscillation number which propagate essentially freely in the background. The resulting picture suggests that string interactions are non-negligible near the singularity.

  15. Null radiation zone at the LHC

    CERN Document Server

    Hagiwara, Kaoru

    2012-01-01

    The null radiation zone theorem states that, when special kinematical conditions are satisfied, all the helicity amplitudes of a parton-level subprocess where a vector current is emitted vanish due to destructive interference among different diagrams. We study the manifestation of the theorem in $pp$ collisions at the $\\sqrt{s}=8$ TeV LHC. The theorem predicts that the cross section for $p p \\rightarrow j j \\gamma$ events is suppressed when the transverse momenta of the two jets are similar and when the rapidity difference between the photon and the cluster of the jets is nearly zero, because the $u u \\rightarrow u u \\gamma$ subprocess, which dominates in events with large $j j \\gamma$ invaraint mass, has strong destructive interference in this region. We confirm this prediction by the calculation with MadGraph 5, and show that the suppression on the $p p \\rightarrow j j \\gamma$ cross section is observable at the LHC.

  16. Blob dynamics in TORPEX poloidal null configurations

    CERN Document Server

    Shanahan, Brendan

    2016-01-01

    Three dimensional blob dynamics are simulated in X-point magnetic configurations in the TORPEX device via a non-field-aligned coordinate system, using an isothermal model which evolves density, vorticity, parallel velocity and parallel current density. By modifying the parallel gradient operator to include perpendicular perturbations from poloidal field coils, numerical singularities associated with field aligned coordinates are avoided. Blobs are found to propagate according to the sheath-connected scaling, and a validation with experiment is performed. It is determined that the null region can cause an acceleration of filaments due to increasing connection length, but this accleration is small relative to other effects, which we quantify. A comparison with a previously developed analytical model is performed and an agreement is found with minimal modification. Experimental measurements are reproduced, and the dominant acceleration mechanism is identified as that of a developing dipole in a moving background...

  17. Wormholes minimally violating the null energy condition

    CERN Document Server

    Bouhmadi-Lopez, Mariam; Martin-Moruno, Prado

    2014-01-01

    We consider novel wormhole solutions supported by a matter content that minimally violates the null energy condition. More specifically, we consider an equation of state in which the sum of the energy density and radial pressure is proportional to a constant with a value smaller than that of the inverse area characterising the system, i.e., the area of the wormhole mouth. This approach is motivated by a recently proposed cosmological event, denoted "the little sibling of the big rip", where the Hubble rate and the scale factor blow up but the cosmic derivative of the Hubble rate does not [1]. By using the cut-and-paste approach, we match interior spherically symmetric wormhole solutions to an exterior Schwarzschild geometry, and analyze the stability of the thin-shell to linearized spherically symmetric perturbations around static solutions, by choosing suitable properties for the exotic material residing on the junction interface radius. Furthermore, we also consider an inhomogeneous generalisation of the eq...

  18. Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice.

    Science.gov (United States)

    Ryder, J W; Kawano, Y; Galuska, D; Fahlman, R; Wallberg-Henriksson, H; Charron, M J; Zierath, J R

    1999-12-01

    To determine the role of GLUT4 on postexercise glucose transport and glycogen resynthesis in skeletal muscle, GLUT4-deficient and wild-type mice were studied after a 3 h swim exercise. In wild-type mice, insulin and swimming each increased 2-deoxyglucose uptake by twofold in extensor digitorum longus muscle. In contrast, insulin did not increase 2-deoxyglucose glucose uptake in muscle from GLUT4-null mice. Swimming increased glucose transport twofold in muscle from fed GLUT4-null mice, with no effect noted in fasted GLUT4-null mice. This exercise-associated 2-deoxyglucose glucose uptake was not accompanied by increased cell surface GLUT1 content. Glucose transport in GLUT4-null muscle was increased 1.6-fold over basal levels after electrical stimulation. Contraction-induced glucose transport activity was fourfold greater in wild-type vs. GLUT4-null muscle. Glycogen content in gastrocnemius muscle was similar between wild-type and GLUT4-null mice and was reduced approximately 50% after exercise. After 5 h carbohydrate refeeding, muscle glycogen content was fully restored in wild-type, with no change in GLUT4-null mice. After 24 h carbohydrate refeeding, muscle glycogen in GLUT4-null mice was restored to fed levels. In conclusion, GLUT4 is the major transporter responsible for exercise-induced glucose transport. Also, postexercise glycogen resynthesis in muscle was greatly delayed; unlike wild-type mice, glycogen supercompensation was not found. GLUT4 it is not essential for glycogen repletion since muscle glycogen levels in previously exercised GLUT4-null mice were totally restored after 24 h carbohydrate refeeding.-Ryder, J. W., Kawano, Y., Galuska, D., Fahlman, R., Wallberg-Henriksson, H., Charron, M. J., Zierath, J. R. Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice. PMID:10593872

  19. Visual and Plastic Arts in Teaching Literacy: Null Curricula?

    Science.gov (United States)

    Wakeland, Robin Gay

    2010-01-01

    Visual and plastic arts in contemporary literacy instruction equal null curricula. Studies show that painting and sculpture facilitate teaching reading and writing (literacy), yet such pedagogy has not been formally adopted into USA curriculum. An example of null curriculum can be found in late 19th - early 20th century education the USA…

  20. Magnetic null points in kinetic simulations of space plasmas

    CERN Document Server

    Olshevsky, Vyacheslav; Divin, Andrey; Peng, Ivy Bo; Markidis, Stefano; Innocenti, Maria Elena; Cazzola, Emanuele; Lapenta, Giovanni

    2015-01-01

    We present a systematic attempt to study magnetic null points and the associated magnetic energy conversion in kinetic Particle-in-Cell simulations of various plasma configurations. We address three-dimensional simulations performed with the semi-implicit kinetic electromagnetic code iPic3D in different setups: variations of a Harris current sheet, dipolar and quadrupolar magnetospheres interacting with the solar wind; and a relaxing turbulent configuration with multiple null points. Spiral nulls are more likely created in space plasmas: in all our simulations except lunar magnetic anomaly and quadrupolar mini-magnetosphere the number of spiral nulls prevails over the number of radial nulls by a factor of 3-9. We show that often magnetic nulls do not indicate the regions of intensive energy dissipation. Energy dissipation events caused by topological bifurcations at radial nulls are rather rare and short-lived. The so-called X-lines formed by the radial nulls in the Harris current sheet and lunar magnetic ano...

  1. Null Arguments in the Yoruba Child’s Early Speech

    Directory of Open Access Journals (Sweden)

    Bolanle Elizabeth Arokoyo

    2012-09-01

    Full Text Available This paper studied null arguments in the early speech of the Yoruba child. We examined whether null subjects are more prominent than null objects and whether the usage of null subjects decreases with language development in the early utterance of the Yoruba child. We also examined the relationship between argument ellipses and finiteness. Minimalist Programme was adopted as the theoretical framework because of its provision for minimality in the processes of language acquisition.  The database was made up of longitudinal naturalistic speech output of three Yoruba-speaking children between 15and 36 months of age. We discovered the preponderance of null argument-NPs at the initial stage; subjects-NPs were easily omitted while object-NPs were hardly omitted; the three Yoruba-speaking children began to make use of overt argument-NPs from fifteen months and gradually, null argument-NPs gave way. We found no direct relationship between the acquisition of finiteness and the end of null arguments.Keywords: arguments, null, object, subject, finiteness, ellipses

  2. Energy dissipation in magnetic null points at kinetic scales

    CERN Document Server

    Olshevsky, Vyacheslav; Eriksson, Elin; Markidis, Stefano; Lapenta, Giovanni

    2015-01-01

    We use kinetic particle-in-cell and magnetohydrodynamic simulations supported by an observational dataset to investigate magnetic reconnection in clusters of null points in space plasma. The magnetic configuration under investigation is driven by fast adiabatic flux rope compression that dissipates almost half of the initial magnetic field energy. In this phase powerful currents are excited producing secondary instabilities, and the system is brought into a state of `intermittent turbulence' within a few ion gyro-periods. Reconnection events are distributed all over the simulation domain and energy dissipation is rather volume-filling. Numerous spiral null points interconnected via their spines form null lines embedded into magnetic flux ropes; null point pairs demonstrate the signatures of torsional spine reconnection. However, energy dissipation mainly happens in the shear layers formed by adjacent flux ropes with oppositely directed currents. In these regions radial null pairs are spontaneously emerging an...

  3. Sidelobe Suppression with Null Steering by Independent Weight Control

    Directory of Open Access Journals (Sweden)

    Zafar-Ullah Khan

    2015-01-01

    Full Text Available A uniform linear array of n antenna elements can steer up to n-1 nulls. In situations where less than n-1 nulls are required to be steered, the existing algorithms have no criterion to utilize the remaining weights for sidelobe suppression. This work combines sidelobe suppression capability with null steering by independent weight control. For this purpose, the array factor is transformed as the product of two polynomials. One of the polynomials is used for null steering by independent weight control, while the second one is for sidelobe suppression whose coefficients or weights are determined by using convex optimization. Finally, a new structure is proposed to incorporate the product of two polynomials such that sidelobe suppression weights are decoupled from those of null steering weights. Simulation results validate the effectiveness of the proposed scheme.

  4. The first mecp2-null zebrafish model shows altered motor behaviors.

    Directory of Open Access Journals (Sweden)

    Thomas Pietri

    2013-07-01

    Full Text Available Rett syndrome is an X-linked neurodevelopmental disorder and one of the most common causes of mental retardation in affected girls. Other symptoms include a rapid regression of motor and cognitive skills after an apparently early normal development. Sporadic mutations in the transcription factor MECP2 has been shown to be present in more than 90% of the patients and several models of MeCP2-deficient mice have been created to understand the role of this gene. These models have pointed toward alterations in the maintenance of the central nervous system rather than its development, in line with the late onset of the disease in humans. However, the exact functions of MeCP2 remain difficult to delineate and the animal models have yielded contradictory results. Here, we present the first mecp2-null allele mutation zebrafish model. Surprisingly and in contrast to MeCP2-null mouse models, mecp2-null zebrafish are viable and fertile. They present nonetheless clear behavioral alterations during their early development, including spontaneous and sensory-evoked motor anomalies, as well as defective thigmotaxis.

  5. Wormholes minimally violating the null energy condition

    Energy Technology Data Exchange (ETDEWEB)

    Bouhmadi-López, Mariam [Departamento de Física, Universidade da Beira Interior, 6200 Covilhã (Portugal); Lobo, Francisco S N; Martín-Moruno, Prado, E-mail: mariam.bouhmadi@ehu.es, E-mail: fslobo@fc.ul.pt, E-mail: pmmoruno@fc.ul.pt [Centro de Astronomia e Astrofísica da Universidade de Lisboa, Campo Grande, Edifício C8, 1749-016 Lisboa (Portugal)

    2014-11-01

    We consider novel wormhole solutions supported by a matter content that minimally violates the null energy condition. More specifically, we consider an equation of state in which the sum of the energy density and radial pressure is proportional to a constant with a value smaller than that of the inverse area characterising the system, i.e., the area of the wormhole mouth. This approach is motivated by a recently proposed cosmological event, denoted {sup t}he little sibling of the big rip{sup ,} where the Hubble rate and the scale factor blow up but the cosmic derivative of the Hubble rate does not [1]. By using the cut-and-paste approach, we match interior spherically symmetric wormhole solutions to an exterior Schwarzschild geometry, and analyse the stability of the thin-shell to linearized spherically symmetric perturbations around static solutions, by choosing suitable properties for the exotic material residing on the junction interface radius. Furthermore, we also consider an inhomogeneous generalization of the equation of state considered above and analyse the respective stability regions. In particular, we obtain a specific wormhole solution with an asymptotic behaviour corresponding to a global monopole.

  6. The curious case of null warped space

    Science.gov (United States)

    Anninos, Dionysios; Compère, Geoffrey; de Buyl, Sophie; Detournay, Stéphane; Guica, Monica

    2010-11-01

    We initiate a comprehensive study of a set of solutions of topologically massive gravity known as null warped anti-de Sitter spacetimes. These are pp-wave extensions of three-dimensional anti-de Sitter space. We first perform a careful analysis of the linearized stability of black holes in these spacetimes. We find two qualitatively different types of solutions to the linearized equations of motion: the first set has an exponential time dependence, the second — a polynomial time dependence. The solutions polynomial in time induce severe pathologies and moreover survive at the non-linear level. In order to make sense of these geometries, it is thus crucial to impose appropriate boundary conditions. We argue that there exists a consistent set of boundary conditions that allows us to reject the above pathological modes from the physical spectrum. The asymptotic symmetry group associated to these boundary conditions consists of a centrally-extended Virasoro algebra. Using this central charge we can account for the entropy of the black holes via Cardy's formula. Finally, we note that the black hole spectrum is chiral and prove a Birkoff theorem showing that there are no other stationary axisymmetric black holes with the specified asymptotics. We extend most of the analysis to a larger family of pp-wave black holes which are related to Schrödinger spacetimes with critical exponent z.

  7. The Curious Case of Null Warped Space

    CERN Document Server

    Anninos, Dionysios; de Buyl, Sophie; Detournay, Stéphane; Guica, Monica

    2010-01-01

    We initiate a comprehensive study of a set of solutions of topologically massive gravity known as null warped anti-de Sitter spacetimes. These are pp-wave extensions of three-dimensional anti-de Sitter space. We first perform a careful analysis of the linearized stability of black holes in these spacetimes. We find two qualitatively different types of solutions to the linearized equations of motion: the first set has an exponential time dependence, the second - a polynomial time dependence. The solutions polynomial in time induce severe pathologies and moreover survive at the non-linear level. In order to make sense of these geometries, it is thus crucial to impose appropriate boundary conditions. We argue that there exists a consistent set of boundary conditions that allows us to reject the above pathological modes from the physical spectrum. The asymptotic symmetry group associated to these boundary conditions consists of a centrally-extended Virasoro algebra. Using this central charge we can account for th...

  8. BAX and tumor suppressor TRP53 are important in regulating mutagenesis in spermatogenic cells in mice.

    Science.gov (United States)

    Xu, Guogang; Vogel, Kristine S; McMahan, C Alex; Herbert, Damon C; Walter, Christi A

    2010-12-01

    During the first wave of spermatogenesis, and in response to ionizing radiation, elevated mutant frequencies are reduced to a low level by unidentified mechanisms. Apoptosis is occurring in the same time frame that the mutant frequency declines. We examined the role of apoptosis in regulating mutant frequency during spermatogenesis. Apoptosis and mutant frequencies were determined in spermatogenic cells obtained from Bax-null or Trp53-null mice. The results showed that spermatogenic lineage apoptosis was markedly decreased in Bax-null mice and was accompanied by a significantly increased spontaneous mutant frequency in seminiferous tubule cells compared to that of wild-type mice. Apoptosis profiles in the seminiferous tubules for Trp53-null were similar to control mice. Spontaneous mutant frequencies in pachytene spermatocytes and in round spermatids from Trp53-null mice were not significantly different from those of wild-type mice. However, epididymal spermatozoa from Trp53-null mice displayed a greater spontaneous mutant frequency compared to that from wild-type mice. A greater proportion of spontaneous transversions and a greater proportion of insertions/deletions 15 days after ionizing radiation were observed in Trp53-null mice compared to wild-type mice. Base excision repair activity in mixed germ cell nuclear extracts prepared from Trp53-null mice was significantly lower than that for wild-type controls. These data indicate that BAX-mediated apoptosis plays a significant role in regulating spontaneous mutagenesis in seminiferous tubule cells obtained from neonatal mice, whereas tumor suppressor TRP53 plays a significant role in regulating spontaneous mutagenesis between postmeiotic round spermatid and epididymal spermatozoon stages of spermiogenesis. PMID:20739667

  9. Null weak singularities in plane-symmetric spacetimes

    CERN Document Server

    Ori, A

    1998-01-01

    We construct a new class of plane-symmetric solutions possessing a curvature singularity which is null and weak, like the spacetime singularity at the Cauchy horizon of spinning (or charged) black holes. We then analyse the stability of this singularity using a rigorous non-perturbative method. We find that within the framework of (linearly-polarized) plane-symmetric spacetimes this type of null weak singularity is locally stable. Generically, the singularity is also scalar-curvature. These observations support the new picture of the null weak singularity inside spinning (or charged) black holes, which is so far established primarily on the perturbative approach.

  10. The Density of Coronal Null Points from Hinode and MDI

    CERN Document Server

    Longcope, Dana; DeForest, Craig

    2009-01-01

    Magnetic null points can be located numerically in a potential field extrapolation or their average density can be estimated from the Fourier spectrum of a magnetogram. We use both methods to compute the null point density from a quiet Sun magnetogram made with Hinode's NFI and from magnetograms from SOHO's MDI in both its high-resolution and low-resolution modes. All estimates of the super-chromospheric column density (z>1.5 Mm) agree with one another and with the previous measurements: 0.003 null points per square Mm of solar surface.

  11. Molecular basis for the CAT-2 null phenotype in maize

    International Nuclear Information System (INIS)

    Previous reports have described several maize lines whose developmental patterns of catalase gene expression vary from the typical maize line, W64A. Among these variants are the lines A16 and A338, both found to be null for the CAT-2 protein. Identification of a third CAT-2 null line, designated A340, is described. RNA blots and S1 nuclease protection analysis, using [32P]-labeled dCTP, indicate that all three CAT-2 null lines produce a similarly shortened Cat2 transcript. The molecular basis for this aberrant Cat2 transcript is discussed

  12. Performance Analysis of the Different Null Steering Techniques in the Field of Adaptive Beamforming

    OpenAIRE

    Fawad Zaman; Bilal Shoaib; Zafar Ullah Khan; Shahid Mehmood

    2013-01-01

    In this study, we compare the performance of three null steering techniques using uniform linear array. These techniques include Null Steering without using Phase Shifters, Null Steering by Decoupling the Real Weights and Null Steering by Decoupling the Complex Weights. The evaluation criteria of these techniques is based on the bases of different parameters i.e., null depth, main beam width, side lobe levels, number of steerable nulls, computational complexity and number of sensors used in t...

  13. Young Little Mice Express a Premature Cardiovascular Aging Phenotype

    OpenAIRE

    Reddy, Anilkumar K.; Hartley, Craig J.; Pham, Thuy T.; Darlington, Gretchen; Entman, Mark L.; Taffet, George E.

    2013-01-01

    To investigate the effect of growth hormone and insulin-like growth factor 1 deficiency on the aging mouse arterial system, we compared the hemodynamics in young (4 months) and old (30 months) growth hormone–releasing hormone receptor null dwarf (Little) mice and their wild-type littermates. Young Little mice had significantly lower peak and mean aortic velocity and significantly higher aortic impedance than young wild-type mice. However, unlike the wild-type mice, there were no significant c...

  14. Waves and null congruences in a draining bathtub

    CERN Document Server

    Dempsey, David

    2016-01-01

    We study wave propagation in a draining bathtub: a fluid-mechanical black hole analogue in which perturbations are governed by a Klein-Gordon equation on an effective Lorentzian geometry. Like the Kerr spacetime, the draining bathtub geometry possesses an (effective) horizon, an ergosphere and null circular orbits. We propose that a `pulse' disturbance may be used to map out the light-cone of the effective geometry. First, we apply the eikonal approximation to elucidate the link between wavefronts, null geodesic congruences and the Raychaudhuri equation. Next, we solve the wave equation numerically in the time domain using the method of lines. Starting with Gaussian initial data, we demonstrate that a pulse will propagate along a null congruence and thus trace out the light-cone of the effective geometry. Our numerical results reveal features, such as wavefront intersections, frame-dragging, winding and interference effects, that are closely associated with the presence of null circular orbits and the ergosph...

  15. A null-steering viewpoint of interferometric SAR

    Energy Technology Data Exchange (ETDEWEB)

    BICKEL,DOUGLAS L.

    2000-05-02

    Interferometric synthetic aperture radar (IFSAR) extends the two-dimensional imaging capability of traditional synthetic aperture radar to three-dimensions by using an aperture in the elevation plane to estimate the 3-D structure of the target. The operation of this additional aperture can be viewed from a null-steering point of view, rather than the traditional phase determination point of view. Knowing that IFSAR can be viewed from the null-steering perspective allows one to take advantage of the mathematical foundation developed for null-steering arrays. In addition, in some problems of interest in IFSAR the null-steering perspective provides better intuition and suggests alternative solutions. One example is the problem of estimating building height where layover is present.

  16. Worldtube conservation laws for the null-timelike evolution problem

    CERN Document Server

    Winicour, Jeffrey

    2011-01-01

    I treat the worldtube constraints which arise in the null-timelike initial-boundary value problem for the Bondi-Sachs formulation of Einstein's equations. Boundary data on a worldtube and initial data on an outgoing null hypersurface determine the exterior spacetime by integration along the outgoing null geodsics. The worldtube constraints are a set of conservation laws which impose conditions on the integration constants. I show how these constraints lead to a well-posed initial value problem governing the extrinsic curvature of the worldtube, whose components are related to the integration constants. Possible applications to gravitational waveform extraction and to the well-posedness of the null-timelike initial-boundary value problem are discussed.

  17. A Non-Null Annotation Inferencer for Java Bytecode

    OpenAIRE

    Hubert, Laurent

    2008-01-01

    We present a non-null annotations inferencer for the Java bytecode language. We previously proposed an analysis to infer non-null annotations and proved it soundness and completeness with respect to a state of the art type system. This paper proposes extensions to our former analysis in order to deal with the Java bytecode language. We have implemented both analyses and compared their behaviour on several benchmarks. The results show a substantial improvement in the precision and, despite bei...

  18. Overt and Null Subject Pronouns in Jordanian Arabic

    Directory of Open Access Journals (Sweden)

    Islam M. Al-Momani

    2015-08-01

    Full Text Available The paper aims at examining the role that morphology plays in allowing and/or motivating sentences in Jordanian Arabic (hereafter JA to be formed with or without subject pronouns. It also aims at giving a comprehensive and descriptive presentation of the distribution of overt and null subject pronouns in JA, and tries to determine to what extent there is optionality in its system.Keywords: null subject pronouns, overt subjects, pro-drop languages, verbal inflectional morphology

  19. On the failures of the null-hypothesis test

    OpenAIRE

    Longford, Nicholas

    2015-01-01

    This report comprises four reactions to the recent policy statement in Basic and Applied Social Psychology that announced a ban on null-hypothesis testing in that journal. A personal perspective is presented which agrees with the editors that null-hypothesis testing has become dysfunctional, but proposes a solution different from the editors'. In particular, application of formal statistical methods is defended, but they have to be tailored much more closely to the specifics of...

  20. Another Nulling Hall-Effect Current-Measuring Circuit

    Science.gov (United States)

    Thibodeau, Phillip E.; Sullender, Craig C.

    1993-01-01

    Lightweight, low-power circuit provides noncontact measurement of alternating or direct current of many ampheres in main conductor. Advantages of circuit over other nulling Hall-effect current-measuring circuits is stability and accuracy increased by putting both analog-to-digital and digital-to-analog converters in nulling feedback loop. Converters and rest of circuit designed for operation at sampling rate of 100 kHz, but rate changed to alter time or frequency response of circuit.

  1. Sequential weak continuity of null Lagrangians at the boundary

    Czech Academy of Sciences Publication Activity Database

    Kalamajska, A.; Kraemer, S.; Kružík, Martin

    2014-01-01

    Roč. 49, 3/4 (2014), s. 1263-1278. ISSN 0944-2669 R&D Projects: GA ČR GAP201/10/0357 Institutional support: RVO:67985556 Keywords : null Lagrangians * nonhomogeneous nonlinear mappings * sequential weak/in measure continuity Subject RIV: BA - General Math ematics Impact factor: 1.518, year: 2014 http://library.utia.cas.cz/separaty/2013/MTR/kruzik-sequential weak continuity of null lagrangians at the boundary.pdf

  2. Designing asynchronous circuits using NULL convention logic (NCL)

    CERN Document Server

    Smith, Scott

    2009-01-01

    Designing Asynchronous Circuits using NULL Convention Logic (NCL) begins with an introduction to asynchronous (clockless) logic in general, and then focuses on delay-insensitive asynchronous logic design using the NCL paradigm. The book details design of input-complete and observable dual-rail and quad-rail combinational circuits, and then discusses implementation of sequential circuits, which require datapath feedback. Next, throughput optimization techniques are presented, including pipelining, embedding registration, early completion, and NULL cycle reduction. Subsequently, low-power design

  3. Accelerated atherogenesis and neointima formation in heparin cofactor II–deficient mice

    OpenAIRE

    Vicente, Cristina P; Li HE; Tollefsen, Douglas M.

    2007-01-01

    Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin when bound to dermatan sulfate or heparin. HCII-deficient mice are viable and fertile but rapidly develop thrombosis of the carotid artery after endothelial injury. We now report the effects of HCII deficiency on atherogenesis and neointima formation. HCII-null or wild-type mice, both on an apolipoprotein E–null background, were fed an atherogenic diet for 12 weeks. HCII-null mice developed plaque areas in the aortic arch a...

  4. Juvenile manifestation of ultrasound communication deficits in the neuroligin-4 null mutant mouse model of autism.

    Science.gov (United States)

    Ju, Anes; Hammerschmidt, Kurt; Tantra, Martesa; Krueger, Dilja; Brose, Nils; Ehrenreich, Hannelore

    2014-08-15

    Neuroligin-4 (Nlgn4) is a member of the neuroligin family of postsynaptic cell adhesion molecules. Loss-of-function mutations of NLGN4 are among the most frequent, known genetic causes of heritable autism. Adult Nlgn4 null mutant (Nlgn4(-/-)) mice are a construct valid model of human autism, with both genders displaying a remarkable autistic phenotype, including deficits in social interaction and communication as well as restricted and repetitive behaviors. In contrast to adults, autism-related abnormalities in neonatal and juvenile Nlgn4(-/-) mice have not been reported yet. The present study has been designed to systematically investigate in male and female Nlgn4(-/-) pups versus wildtype littermates (WT, Nlgn4(+/+)) developmental milestones and stimulus-induced ultrasound vocalization (USV). Neonatal development, followed daily from postnatal days (PND) 4 to 21, including physical development, neurological reflexes and neuromotor coordination, did not yield any differences between Nlgn4(-/-) and their WT littermates. USV in pups (PND8-9) in response to brief separation from their mothers revealed remarkable gender effects, and a genotype influence in females regarding latency to first call. In juveniles (PND22-23), USV monitoring upon exposure to an anesthetized female intruder mouse uncovered a clear genotype effect with reduced USV in Nlgn4(-/-) mice, and again a more prominent phenotype in females. Together, these data support an early manifestation of communication deficits in Nlgn4(-/-) mice that appear more pronounced in immature females with their overall stronger USV as compared to males. PMID:24855039

  5. Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice

    Science.gov (United States)

    Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong; Lesburguères, Edith; Wallace, Emma Jane Claire; Tcherepanov, Andrew; Jothianandan, Desingarao; Hartley, Benjamin Rush; Pan, Ling; Rivard, Bruno; Farese, Robert V; Sajan, Mini P; Bergold, Peter John; Hernández, Alejandro Iván; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

    2016-01-01

    PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice. DOI: http://dx.doi.org/10.7554/eLife.14846.001 PMID:27187150

  6. Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

    OpenAIRE

    Ohbuchi, Masato; Yoshinari, Kouichi; Kaneko, Hayato; Matsumoto, Satoru; Inoue, Akiko; Kawamura, Akio; Usui, Takashi; Yamazoe, Yasushi

    2013-01-01

    The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr- and Car-null (Pxr/Car-null) mice for 7 d...

  7. Three-dimensional magnetic reconnection through a moving magnetic null

    Directory of Open Access Journals (Sweden)

    V. S. Lukin

    2011-11-01

    Full Text Available A computational study of three-dimensional magnetic reconnection between two flux ropes through a moving reconnection site is presented. The configuration is considered in the context of two interacting spheromaks constrained by a perfectly conducting cylindrical boundary and oriented to form a single magnetic field null at its center. The initial magnetic field configuration is embedded into a uniform thermal plasma and is unstable to tilting. As the spheromaks tilt, their magnetic fields begin to reconnect at the null, subsequently displacing both the null and the reconnection site. The motion of the reconnection region and the magnetic null are shown to be correlated, with stronger correlation and faster reconnection observed in plasmas with lower thermal to magnetic pressure ratio. It is also shown that ion inertial effects allow for yet faster reconnection, but do not qualitatively change the dynamics of the process. Implications of the coupling between moving magnetic nulls and reconnection sites, as well as of possible mechanisms for fast reconnection through a moving reconnection region, are discussed. The simulations are conducted using both single-fluid and Hall MHD plasma models within the HiFi multi-fluid modeling framework.

  8. The causal topology of neutral 4-manifolds with null boundary

    CERN Document Server

    Georgiou, Nikos

    2016-01-01

    This paper considers aspects of 4-manifold topology from the point of view of a neutral metric, a point of view we call neutral causal topology. In particular, we construct and investigate neutral 4-manifolds with null boundary that arise from canonical 3- and 4-dimensional settings. A null hypersurface is foliated by its normal and, in the neutral case, inherits a pair of totally null planes at each point. This paper focuses on this structure in a number of classical settings The first construction is the conformal compactification of flat neutral 4-space into the 4-ball. The null foliation on the boundary in this case is the Hopf fibration on the 3-sphere and the totally null planes in the boundary are integrable. The metric on the 4-ball is a conformally flat, scalar-flat, positive Ricci curvature neutral metric. The second constructions are subsets of the 4-dimensional space of oriented geodesics in a 3-dimensional space-form, equipped with its canonical neutral metric. We consider all oriented geodesics ...

  9. Resistivity at the field null of the FRC plasma

    International Nuclear Information System (INIS)

    In the absence of the major destructive instabilities, the configuration time is ultimately determined by particle and flux containment. If the profiles are ''gentle,'' then the anomalous flux-loss rate depends essentially on the anomalous resistivity at the field null. Conventional electrostatic quasi-linear models of anomalous cross-field resistive diffusivity are based upon the use of rvec E x rvec B drift velocities, and hence break down at the magnetic field null. In this paper, an electromagnetic treatment valid at the field null is developed, based upon the presence of flute-parity perturbations. An expression for anomalous resistivity at the field null in the quasi-linear approximation is derived by averaging in the ignorable direction over the random phases of the perturbations. The expression is valid for arbitrary (non-local) radial shapes of the perturbing modes (for example, the eigenfunctions need not be centered at the field null), and for an arbitrary ratio of real frequency to growth rate. The effective resistivity due to flute perturbations of the MHD type will be considered. 1 ref

  10. Long-term Observations of Three Nulling Pulsars

    CERN Document Server

    Young, N J; Stappers, B W; Lyne, A G; Kramer, M

    2015-01-01

    We present an analysis of approximately 200 hours of observations of the pulsars J1634$-$5107, J1717$-$4054 and J1853$+$0505, taken over the course of 14.7 yr. We show that all of these objects exhibit long term nulls and radio-emitting phases (i.e. minutes to many hours), as well as considerable nulling fractions (NFs) in the range $\\sim67\\,\\% - 90\\,\\%$. PSR J1717$-$4054 is also found to exhibit short timescale nulls ($1 - 40~P$) and burst phases ($\\lesssim 200~P$) during its radio-emitting phases. This behaviour acts to modulate the NF, and therefore the detection rate of the source, over timescales of minutes. Furthermore, PSR J1853$+$0505 is shown to exhibit a weak emission state, in addition to its strong and null states, after sufficient pulse integration. This further indicates that nulls may often only represent transitions to weaker emission states which are below the sensitivity thresholds of particular observing systems. In addition, we detected a peak-to-peak variation of $33\\pm1\\,\\%$ in the spin-...

  11. Pedestal and ELM characterisation of highly shaped single null and quasi double null plasmas in JET

    Energy Technology Data Exchange (ETDEWEB)

    Saibene, G.; Sartori, R.; Ingesson, L.C.; Loarte, A. [European Fusion Development Agreement Close Support Unit - Garching (Germany); Lomas, P.J.; Andrew, P.; Andrew, Y.; Guenther, K.; Korothov, A.; McDonald, D.; Meigs, A.G.; Parail, V.V.; Sharapov, S. [Euratom/Ukaea Association, Culham Science Centre, Abingdon, OX (United Kingdom); Becoulet, M.; Monier Garbet, P.; Rimini, F.G.; Thomas, P.R. [Association Euratom-CEA Cadarache, 13 - Saint-Paul-lez-Durance (France); Conway, G.D.; Stober, J. [Association Euratom-IPP, MPI fur Plasmophysik, Garching (Germany); Kempenaars, M. [Association Euratom-FOM, Rijnhuizen (Netherlands); Koslowski, H.R.; Perez, C.P. [Forschungszentrum Juelich GmbH, Inst. fuer Plasmaphysik, Euratom Association, Trilateral Euregio Cluster, Julich (Germany); Lonnroth, J.S.; Saarelma, S. [Association Euratom-Tekes, Helsinki Univ. of Techn., Hut (Finland); Nave, M.F. [Association Euratom/IST, Centro de Fusao Nuclear, Lisbon (Portugal); Ongena, J. [ECOLE ROYALE MILITAIRE (ERM-KMS), Lab. Plasma Physics, Bruxelles (Belgium)

    2003-07-01

    This paper presents the results of experiments carried out in JET to study the plasma pedestal and ELM (edge localized modes) behaviour of high density/high confinement ELMy H-modes, focusing on the exploration of the effects of the plasma boundary magnetic geometry (triangularity {delta}, as well as proximity to Double-Null (DN)) and of q{sub 95} on the pedestal parameters, edge stability and ELM losses. These experiments were aimed at the study of Type-I ELMs at high density and of the access to steady-state Type-II ELM regime for JET plasma conditions, comparing pedestal and ELM characteristics in high {delta} SN (single-null) and QDN (quasi double-null) plasmas, in similar experimental conditions. To date, complete Type-I ELM suppression has not been achieved in JET in steady state conditions, although at high shaping and density mixed phases of Type-I and Type-II ELMs are observed, both for SN and QDN plasmas. Long periods of Type II ELMs (up to 150 ms in QDN) are obtained at high n(pedestal), associated with an increase of magnetic and density fluctuations, compared to levels in pure Type-I ELMy H-modes. The location of these enhanced fluctuation region is likely to be near the pedestal top. Increasing q{sub 95} from {approx} 3 to {approx} 4.5 (by varying either Ip or Bt), does not facilitate the access to the Type-II ELM regime, in contrast to indications from other experiments. In general, at high q{sub 95}, the Type-I ELMs frequency is much higher than at q{sub 95} {approx} 3 (typical for JET ELMy H-modes), the plasma global confinement is reduced, the Type II activity weakens, with the Type I-III transition occurring at lower pedestal density than at lower q{sub 95}. The enhanced {approx} 20 kHz magnetic fluctuations with Type-II ELMs are identified with strong washboard modes, possible responsible for the increased inter-ELM transport. Power balance calculations do indeed show that the power carried by ELMs is reduced by more than a factor of two in the

  12. The appearance, motion, and disappearance of three-dimensional magnetic null points

    CERN Document Server

    Murphy, Nicholas A; Haynes, Andrew L

    2015-01-01

    While theoretical models and simulations of magnetic reconnection often assume symmetry such that the magnetic null point when present is co-located with a flow stagnation point, the introduction of asymmetry typically leads to non-ideal flows across the null point. To understand this behavior, we present exact expressions for the motion of three-dimensional linear null points. The most general expression shows that linear null points move in the direction along which the vector field and its time derivative are antiparallel. Null point motion in resistive magnetohydrodynamics results from advection by the bulk plasma flow and resistive diffusion of the magnetic field, which allows non-ideal flows across topological boundaries. Null point motion is described intrinsically by parameters evaluated locally; however, global dynamics help set the local conditions at the null point. During a bifurcation of a degenerate null point into a null-null pair or the reverse, the instantaneous velocity of separation or conv...

  13. Data volume and power of multiple tests with small sample size per null

    OpenAIRE

    Chi, Zhiyi

    2008-01-01

    In multiple hypothesis testing, the volume of data, defined as the number of replications per null times the total number of nulls, usually defines the amount of resource required. On the other hand, power is an important measure of performance for multiple testing. Due to practical constraints, the number of replications per null may not be large enough in terms of the difference between false and true nulls. For the case where the population fraction of false nulls is constant, we show that...

  14. Stabilising a nulling interferometer using optical path difference dithering

    CERN Document Server

    Gabor, Pavel; Brachet, Frank; Ollivier, Marc; Decaudin, Michel; Jacquinod, Sophie; Labèque, Alain; Léger, Alain

    2008-01-01

    Context. Nulling interferometry has been suggested as the underlying principle for the Darwin and TPF-I exoplanet research missions. Aims. There are constraints both on the mean value of the nulling ratio, and on its stability. Instrument instability noise is most detrimental to the stability of the nulling performance. Methods. We applied a modified version of the classical dithering technique to the optical path difference in the scientific beam. Results. Using only this method, we repeatedly stabilised the dark fringe for several hours. This method alone sufficed to remove the 1/ f component of the noise in our setup for periods of 10 minutes, typically. These results indicate that performance stability may be maintained throughout the long-duration data acquisitions typical of exoplanet spectroscopy. Conclusions. We suggest that further study of possible stabilisation strategies should be an integral part of Darwin/TPF-I research and development

  15. Null but not void: considerations for hypothesis testing.

    Science.gov (United States)

    Shaw, Pamela A; Proschan, Michael A

    2013-01-30

    Standard statistical theory teaches us that once the null and alternative hypotheses have been defined for a parameter, the choice of the statistical test is clear. Standard theory does not teach us how to choose the null or alternative hypothesis appropriate to the scientific question of interest. Neither does it tell us that in some cases, depending on which alternatives are realistic, we may want to define our null hypothesis differently. Problems in statistical practice are frequently not as pristinely summarized as the classic theory in our textbooks. In this article, we present examples in statistical hypothesis testing in which seemingly simple choices are in fact rich with nuance that, when given full consideration, make the choice of the right hypothesis test much less straightforward. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID:22807023

  16. Fully achromatic nulling interferometer (FANI) for high SNR exoplanet characterization

    CERN Document Server

    Henault, Francois

    2015-01-01

    Space-borne nulling interferometers have long been considered as the best option for searching and characterizing extra-solar planets located in the habitable zone of their parent stars. Solutions for achieving deep starlight extinction are now numerous and well demonstrated. However they essentially aim at realizing an achromatic central null in order to extinguish the star. In this communication is described a major improvement of the technique, where the achromatization process is extended to the entire fringe pattern. Therefore higher Signal-to-noise ratios (SNR) and appreciable simplification of the detection system should result. The basic principle of this Fully achromatic nulling interferometer (FANI) consists in inserting dispersive elements along the arms of the interferometer. Herein this principle is explained and illustrated by a preliminary optical system design. The typical achievable performance and limitations are discussed and some initial tolerance requirements are also provided

  17. Biological and genetic properties of the p53 null preneoplastic mammary epithelium

    Science.gov (United States)

    Medina, Daniel; Kittrell, Frances S.; Shepard, Anne; Stephens, L. Clifton; Jiang, Cheng; Lu, Junxuan; Allred, D. Craig; McCarthy, Maureen; Ullrich, Robert L.

    2002-01-01

    The absence of the tumor suppressor gene p53 confers an increased tumorigenic risk for mammary epithelial cells. In this report, we describe the biological and genetic properties of the p53 null preneoplastic mouse mammary epithelium in a p53 wild-type environment. Mammary epithelium from p53 null mice was transplanted serially into the cleared mammary fat pads of p53 wild-type BALB/c female to develop stable outgrowth lines. The outgrowth lines were transplanted for 10 generations. The outgrowths were ductal in morphology and progressed through ductal hyperplasia and ductal carcinoma in situ before invasive cancer. The preneoplastic outgrowth lines were immortal and exhibited activated telomerase activity. They are estrogen and progesterone receptor-positive, and aneuploid, and had various levels of tumorigenic potential. The biological and genetic properties of these lines are distinct from those found in most hyperplastic alveolar outgrowth lines, the form of mammary preneoplasia occurring in most traditional models of murine mammary tumorigenesis. These results indicate that the preneoplastic cell populations found in this genetically engineered model are similar in biological properties to a subset of precurser lesions found in human breast cancer and provide a unique model to identify secondary events critical for tumorigenicity and invasiveness.

  18. P63 null mutation protects mouse oocytes from radio-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Livera, G.; Petre-Lazar, B.; Guerquin, M.J.; Trautmann, E.; Coffigny, H.; Habert, R. [CEA, DSV/DRR/SEGG/LDRG, Unit Gametogenesis et Genotoxic, F-92265 Fontenay Aux Roses (France); Univ Paris 07 Denis Diderot, UFR Biol, UMR S 566, F-92265 Fontenay Aux Roses (France); INSERM, U566, F-92265 Fontenay Aux Roses (France)

    2008-07-01

    Female fertility in mammals is determined by the pool of primordial follicles and low doses of radiation induce a major loss of primordial follicles in the ovary. We investigated the expression of p53 and its homologues, p63 and p73, in the normal and irradiated neonatal ovary. p63 was the only member of the p53 family detected in oocyte nucleus. No p63 transcripts or protein were detected in the early foetal ovary. p63 production began in late pachytene-stage oocytes and peaked in diplotene oocytes in mice and humans. The production of p63 was correlated with meiotic DNA double-strand break repair. Only trans-activation (TA) isoforms were present in the ovary, with TAp63 alpha by far the most abundant in terms of mRNA and protein levels. Complete p63 null mutation did not affect normal ovary development. Irradiation rapidly triggered p63 phosphorylation. p63 null mutation prevented the cleavage of caspases-9 and -3 and the follicle loss induced by ionizing radiation. Thus, our results evidence that irradiation-induced depletion of the primordial follicle pool results from the activation of p63 in quiescent oocytes. (authors)

  19. Optimization of myocardial nulling in pediatric cardiac MRI

    Energy Technology Data Exchange (ETDEWEB)

    Tham, Edythe B. [Stollery Children' s Hospital, University of Alberta, Department of Pediatrics, Division of Pediatric Cardiology, Edmonton, Alberta (Canada); Hung, Ryan W.; Crawley, Cinzia; Noga, Michelle L. [University of Alberta, Pediatric Radiology, Stollery Children' s Hospital, Edmonton (Canada); Myers, Kimberley A. [Alberta Children' s Hospital, Calgary (Canada)

    2012-04-15

    Current protocols to determine optimal nulling time in late enhancement imaging using adult techniques may not apply to children. To determine the optimal nulling time in anesthetised children, with the hypothesis that this occurs earlier than in adults. Sedated cardiac MRI was performed in 12 children (median age: 12 months, range: 1-60 months). After gadolinium administration, scout images at 2, 3, 4 and 10 min and phase sensitive inversion recovery (PSIR) images from 5 to 10 min were obtained. Signal-to-noise ratio (SNR) and inversion time (TI) were determined. Quality of nulling was assessed according to a grading score by three observers. Data was analysed using linear regression, Kruskal-Wallis and quadratic-weighted kappa statistics. One child with a cardiomyopathy had late enhancement. Good agreement in nulling occurred for scout images at 2 ({kappa} = 0.69) and 3 ({kappa} = 0.66) min and moderate agreement at 4 min ({kappa} = 0.57). Agreement of PSIR images was moderate at 7 min ({kappa} = 0.44) and poor-fair at other times. There were significant correlations between TI and scout time (r = 0.61, P < 0.0001), and SNR and kappa (r = 0.22, P = 0.017). Scout images at 2-4 min can be used to determine the TI with little variability. Image quality for PSIR images was highest at 7 min and SNR optimal at 7-9 min. TI increases with time and should be adjusted frequently during imaging. Thus, nulling times in children differ from nulling times in adults when using standard adult techniques. (orig.)

  20. Magnetoacoustic Waves in Stratified Atmospheres with a Magnetic Null Point

    Science.gov (United States)

    Tarr, Lucas A.; Linton, Mark; Leake, James E.

    2016-05-01

    Magnetic fields strongly modify the propagation of MHD waves from the photosphere to the low corona, as can be shown exactly for the most simple case of a uniform magnetic field and isothermally stratrified atmosphere. For slightly more realistic scenarios, where both the atmospheric parameters and the magnetic field vary spatially, the linear MHD equations typically cannot be solved analytically. We use the Lagrangian Remap code--a nonlinear, shock-capturing MHD code--to study the propagation of initially acoustic wavepackets through a model 2D atmosphere that includes a gravitationally stratified chromosphere, transition region, and low corona. The magnetic field is formed by three photospheric concentrations and includes a single magnetic null point, resulting in an inhomogeneous system with a magnetic dome topology. A portion of an introduced wavepacket will refract toward the null due to the varying Alfven speed. Waves incident on the equipartition contour surrounding the null, where the sound and Alfven speeds coincide, partially transmit, reflect, and mode convert between branches of the local dispersion relation. Outward propagating slow modes generated during conversion become strongly concentrated along the set of field lines passing near the null. Acoustic energy is beamed back downwards towards each photospheric foot point, and upwards along one separatrix that exits the top of the numerical domain. Changes in the dominant restoring force for the wavepacket, between the Lorentz and pressure gradient forces, lead to a buildup of current density along topologically important features of the system (the null point and its four separatrices) and can drive reconnection at the null point itself. Ohmic dissipation of the currents locally heats the plasma. We find that the amount of current accumulation depends on where the centroid of a wavepacket initial crosses the photosphere, but does not simply coincide with regions of open versus closed magnetic field or

  1. A Matrix Model for the Null-Brane

    OpenAIRE

    Robbins, Daniel; Sethi, Savdeep

    2005-01-01

    The null-brane background is a simple smooth 1/2 BPS solution of string theory. By tuning a parameter, this background develops a big crunch/big bang type singularity. We construct the DLCQ description of this space-time in terms of a Yang-Mills theory on a time-dependent space-time. Our dual Matrix description provides a non-perturbative framework in which the fate of both (null) time, and the string S-matrix can be studied.

  2. Effect of residual phase gradients in optical null interference.

    Science.gov (United States)

    Naik, Dinesh N; Pradeep Chakravarthy, T; Viswanathan, Nirmal K

    2016-01-01

    A scheme to study the effect of residual phase gradients in an optical interference between two out-of-phase Gaussian beams is proposed. In a Sagnac interferometer configured to provide a null output, a variable linear phase swept across the null point unfolds an optical field rotation due to an apparently negligible residual phase gradient present orthogonal to the linear phase sweep. As the optical beam that rotates around its propagation axis carries orbital angular momentum, the experimental results presented in this Letter could provide an insight into the momentum change associated with the energy redistribution in the fundamental phenomenon of optical interference. PMID:26696166

  3. Quantization in Spacetime from Null Paths in Higher Dimensions

    OpenAIRE

    Wesson, Paul S.

    2008-01-01

    Massive particles on timelike paths in spacetime can be viewed as moving on null paths in a higher-dimensional manifold. This and other consequences follow from the use of Campbell's theorem to embed 4D general relativity in non-compactified 5D Kaluza-Klein theory. We now show that it is possible in principle to obtain the standard rule for quantization in 4D from the canonical metric with null paths in 5D. Particle mass can be wavelike, as suggested originally by Dirac, and other 4D/5D conse...

  4. A Matrix Model for the Null-Brane

    CERN Document Server

    Robbins, D; Robbins, Daniel; Sethi, Savdeep

    2006-01-01

    The null-brane background is a simple smooth 1/2 BPS solution of string theory. By tuning a parameter, this background develops a big crunch/big bang type singularity. We construct the DLCQ description of this space-time in terms of a Yang-Mills theory on a time-dependent space-time. Our dual Matrix description provides a non-perturbative framework in which the fate of both (null) time, and the string S-matrix can be studied.

  5. A matrix model for the null-brane

    International Nuclear Information System (INIS)

    The null-brane background is a simple smooth 1/2 BPS solution of string theory. By tuning a parameter, this background develops a big crunch/big bang type singularity. We construct the DLCQ description of this space-time in terms of a Yang-Mills theory on a time-dependent space-time. Our dual Matrix description provides a non-perturbative framework in which the fate of both (null) time, and the string S-matrix can be studied

  6. Null geodesics in a magnetically charged stringy black hole spacetime

    Science.gov (United States)

    Kuniyal, Ravi Shankar; Uniyal, Rashmi; Nandan, Hemwati; Purohit, K. D.

    2016-04-01

    We study the null geodesics of a four-dimensional magnetic charged black hole spacetime arising in string theory. The behaviour of effective potential in view of the different values of black hole parameters are analysed in the equatorial plane. The possible orbits for null geodesics are also discussed in view of the different values of the impact parameter. We have also calculated the frequency shift of photons in this spacetime. The results are compared to those obtained for the electrically charged stringy black hole spacetime and the Schwarzschild black hole spacetime in general relativity.

  7. Quantization in Spacetime from Null Paths in Higher Dimensions

    CERN Document Server

    Wesson, Paul S

    2008-01-01

    Massive particles in spacetime can be viewed as moving on null paths in a higher-dimensional manifold. Using a novel gauge, we show that geometric structure in 5D can lead to the standard rule for quantization in 4D. Particle mass can be wavelike, as suggested originally by Dirac, and other 5D/4D consequences are outlined.

  8. Progress in broadband infrared nulling technology for TPF

    Science.gov (United States)

    Wallace, J. Kent; Brown, Ken; Bartos, Randall; Gappinger, Robert; Loya, Frank; Macdonald, Dan; Moser, Steve; Negron, John

    2005-01-01

    TPF-I has set for itself a host of challenging technical milestones along its path to demonstrating the feasibility of infrared nulling for planet detection Progress in each of these areas of technical development will be reviewed as well as progress in meeting the overarching technical milestones.

  9. Circumpulsar Asteroids: Inferences from Nulling Statistics and High Energy Correlations

    Science.gov (United States)

    Shannon, Ryan; Cordes, J. M.

    2006-12-01

    We have proposed that some classes of radio pulsar variability are associated with the entry of neutral asteroidal material into the pulsar magnetosphere. The region surrounding neutron stars is polluted with supernova fall-back material, which collapses and condenses into an asteroid-bearing disk that is stable for millions of years. Over time, collisional and radiative processes cause the asteroids to migrate inward until they are heated to the point of ionization. For older and cooler pulsars, asteroids ionize within the large magnetospheres and inject a sufficient amount of charged particles to alter the electrodynamics of the gap regions and modulate emission processes. This extrinsic model unifies many observed phenomena of variability that occur on time scales that are disparate with the much shorter time scales associated with pulsars and their magnetospheres. One such type of variability is nulling, in which certain pulsars exhibit episodes of quiescence that for some objects may be as short as a few pulse periods, but, for others, is longer than days. Here, in the context of this model, we examine the nulling phenomenon. We analyze the relationship between in-falling material and the statistics of nulling. In addition, as motivation for further high energy observations, we consider the relationship between the nulling and other magnetospheric processes.

  10. The appearance, motion, and disappearance of three-dimensional magnetic null points

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Nicholas A., E-mail: namurphy@cfa.harvard.edu [Harvard-Smithsonian Center for Astrophysics, Cambridge, Massachusetts 02138 (United States); Parnell, Clare E.; Haynes, Andrew L. [School of Mathematics and Statistics, University of St Andrews, North Haugh, St Andrews, Fife KY16 9SS (United Kingdom)

    2015-10-15

    While theoretical models and simulations of magnetic reconnection often assume symmetry such that the magnetic null point when present is co-located with a flow stagnation point, the introduction of asymmetry typically leads to non-ideal flows across the null point. To understand this behavior, we present exact expressions for the motion of three-dimensional linear null points. The most general expression shows that linear null points move in the direction along which the magnetic field and its time derivative are antiparallel. Null point motion in resistive magnetohydrodynamics results from advection by the bulk plasma flow and resistive diffusion of the magnetic field, which allows non-ideal flows across topological boundaries. Null point motion is described intrinsically by parameters evaluated locally; however, global dynamics help set the local conditions at the null point. During a bifurcation of a degenerate null point into a null-null pair or the reverse, the instantaneous velocity of separation or convergence of the null-null pair will typically be infinite along the null space of the Jacobian matrix of the magnetic field, but with finite components in the directions orthogonal to the null space. Not all bifurcating null-null pairs are connected by a separator. Furthermore, except under special circumstances, there will not exist a straight line separator connecting a bifurcating null-null pair. The motion of separators cannot be described using solely local parameters because the identification of a particular field line as a separator may change as a result of non-ideal behavior elsewhere along the field line.

  11. Performance Analysis of the Different Null Steering Techniques in the Field of Adaptive Beamforming

    Directory of Open Access Journals (Sweden)

    Fawad Zaman

    2013-04-01

    Full Text Available In this study, we compare the performance of three null steering techniques using uniform linear array. These techniques include Null Steering without using Phase Shifters, Null Steering by Decoupling the Real Weights and Null Steering by Decoupling the Complex Weights. The evaluation criteria of these techniques is based on the bases of different parameters i.e., null depth, main beam width, side lobe levels, number of steerable nulls, computational complexity and number of sensors used in the array. The validity and effectiveness of these techniques is reflected by the resultant radiation pattern of the array.

  12. Serum metabolite profiles are altered by erlotinib treatment and the integrin α1-null genotype, but not by post traumatic osteoarthritis

    Science.gov (United States)

    Mickiewicz, Beata; Shin, Sung Y.; Pozzi, Ambra; Vogel, Hans J.; Clark, Andrea L.

    2016-01-01

    The risk of developing post traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA, however the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following 1H nuclear magnetic resonance spectroscopy we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice, and the integrin α1-null versus wild type mouse genotype. Our results show the sex dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site specific factors such as surgery. PMID:26784366

  13. Serum Metabolite Profiles Are Altered by Erlotinib Treatment and the Integrin α1-Null Genotype but Not by Post-Traumatic Osteoarthritis.

    Science.gov (United States)

    Mickiewicz, Beata; Shin, Sung Y; Pozzi, Ambra; Vogel, Hans J; Clark, Andrea L

    2016-03-01

    The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following (1)H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery. PMID:26784366

  14. The effect of Clostridium perfringens type C strain CN3685 and its isogenic beta toxin null mutant in goats.

    Science.gov (United States)

    Garcia, J P; Beingesser, J; Fisher, D J; Sayeed, S; McClane, B A; Posthaus, H; Uzal, F A

    2012-06-15

    Clostridium perfringens type C is an important cause of enteritis and/or enterocolitis in several animal species, including pigs, sheep, goats, horses and humans. The disease is a classic enterotoxemia and the enteric lesions and associated systemic effects are thought to be caused primarily by beta toxin (CPB), one of two typing toxins produced by C. perfringens type C. This has been demonstrated recently by fulfilling molecular Koch's postulates in rabbits and mice. We present here an experimental study to fulfill these postulates in goats, a natural host of C. perfringens type C disease. Nine healthy male or female Anglo Nubian goat kids were inoculated with the virulent C. perfringens type C wild-type strain CN3685, an isogenic CPB null mutant or a strain where the cpb null mutation had been reversed. Three goats inoculated with the wild-type strain presented abdominal pain, hemorrhagic diarrhea, necrotizing enterocolitis, pulmonary edema, hydropericardium and death within 24h of inoculation. Two goats inoculated with the CPB null mutant and two goats inoculated with sterile culture media (negative controls) remained clinically healthy during 24h after inoculation and no gross or histological abnormalities were observed in the tissues of any of them. Reversal of the null mutation to partially restore CPB production also increased virulence; 2 goats inoculated with this reversed mutant presented clinical and pathological changes similar to those observed in goats inoculated with the wild-type strain, except that spontaneous death was not observed. These results indicate that CPB is required for C. perfringens type C to induce disease in goats, supporting a key role for this toxin in natural C. perfringens type C disease pathogenesis. PMID:22296994

  15. Proof of a Null Penrose Conjecture using a new Quasi-local Mass

    CERN Document Server

    Roesch, Henri

    2016-01-01

    We define an explicit quasi-local mass functional which is non-decreasing along all foliations (satisfying a convexity assumption) of null cones. We use this new functional to prove the null Penrose conjecture under fairly generic conditions.

  16. Cortical Development in the Presenilin-1 Null Mutant Mouse Fails After Splitting of the Preplate and is Not Due to a Failure of Reelin-Dependent Signaling

    OpenAIRE

    De Gasperi, Rita; Gama Sosa, Miguel A.; Wen, Paul H.; Li, Jingjun; Perez, Gissel M.; Curran, Tom; Elder, Gregory A.

    2008-01-01

    Cortical development is disrupted in presenilin-1 null mutant (Psen1−/−) mice. Prior studies have commented on similarities between Psen1−/− and reeler mice. Reelin induces phosphorylation of Dab1 and activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Psen1 is known to modulate PI3K/Akt signaling and both known reelin receptors (apoER2 and VLDLR) are substrates for Psen1 associated γ-secretase activity. The purpose of this study was to determine whether reelin signaling is disrup...

  17. Conserved quantities at spatial and null infinity: The Penrose potential

    International Nuclear Information System (INIS)

    We define a superpotential for energy-momentum and rotation momentum which is built out of the conformal tensor and a bivector. This superpotential is identified with that used by Penrose in his definition of quasilocal energy. It is applied to the definition of energy-momentum and rotation momentum at spatial and at null infinities. At spatial infinity the results are in agreement with those of Ashtekar and Hansen. At null infinity the results are unsatisfactory; they are tied to a specific Bondi frame. Thus, they are not in agreement with the results of Tamburino and Winicour, Geroch and Winicour, nor with those of Dray and Streubel. Some reasons for this failure are discussed

  18. Null Cones and Einstein's Equations in Minkowski Spacetime

    CERN Document Server

    Pitts, J B

    2004-01-01

    If Einstein's equations are to describe a field theory of gravity in Minkowski spacetime, then causality requires that the effective curved metric must respect the flat background metric's null cone. The kinematical problem is solved using a generalized eigenvector formalism based on the Segr\\'{e} classification of symmetric rank 2 tensors with respect to a Lorentzian metric. Securing the correct relationship between the two null cones dynamically plausibly is achieved using the naive gauge freedom. New variables tied to the generalized eigenvector formalism reduce the configuration space to the causality-respecting part. In this smaller space, gauge transformations do not form a group, but only a groupoid. The flat metric removes the difficulty of defining equal-time commutation relations in quantum gravity and guarantees global hyperbolicity.

  19. Null warped AdS in higher spin gravity

    CERN Document Server

    Breunhoelder, Veronika; Grumiller, Daniel; Prohazka, Stefan

    2015-01-01

    We equip three-dimensional spin-3 gravity in the principal embedding with a new set of boundary conditions that we call "asymptotically null warped AdS". We find a chiral copy of the Polyakov-Bershadsky algebra as asymptotic symmetry algebra, reminiscent of the situation in topologically massive gravity with strict null warped AdS boundary conditions. We prove the invertibility of the map between zuvielbein and metric variables and construct a global gauge transformation to half of AdS spin-3 gravity in the diagonal embedding. This explains why the theory is chiral and why the Polyakov-Bershadsky algebra arises. We then introduce chemical potentials, derive the entropy, free energy, and the holographic response functions, and conclude with a discussion.

  20. Nonparametric Regression Estimation for Multivariate Null Recurrent Processes

    Directory of Open Access Journals (Sweden)

    Biqing Cai

    2015-04-01

    Full Text Available This paper discusses nonparametric kernel regression with the regressor being a \\(d\\-dimensional \\(\\beta\\-null recurrent process in presence of conditional heteroscedasticity. We show that the mean function estimator is consistent with convergence rate \\(\\sqrt{n(Th^{d}}\\, where \\(n(T\\ is the number of regenerations for a \\(\\beta\\-null recurrent process and the limiting distribution (with proper normalization is normal. Furthermore, we show that the two-step estimator for the volatility function is consistent. The finite sample performance of the estimate is quite reasonable when the leave-one-out cross validation method is used for bandwidth selection. We apply the proposed method to study the relationship of Federal funds rate with 3-month and 5-year T-bill rates and discover the existence of nonlinearity of the relationship. Furthermore, the in-sample and out-of-sample performance of the nonparametric model is far better than the linear model.

  1. MHD Mode Conversion around a 2D Magnetic Null Point

    CERN Document Server

    McDougall, A M D; 10.1063/1.3099224

    2009-01-01

    Mode conversion occurs when a wave passes through a region where the sound and Alfven speeds are equal. At this point there is a resonance, which allows some of the incident wave to be converted into a different mode. We study this phenomenon in the vicinity of a two-dimensional, coronal null point. As a wave approaches the null it passes from low- to high-beta plasma, allowing conversion to take place. We simulate this numerically by sending in a slow magnetoacoustic wave from the upper boundary; as this passes through the conversion layer a fast wave can clearly be seen propagating ahead. Numerical simulations combined with an analytical WKB investigation allow us to determine and track both the incident and converted waves throughout the domain.

  2. Analysis of nulling phase functions suitable to image plane coronagraphy

    CERN Document Server

    Henault, Francois; Verinaud, Christophe

    2016-01-01

    Coronagraphy is a very efficient technique for identifying and characterizing extra-solar planets orbiting in the habitable zone of their parent star, especially when used in a space environment. An important family of coronagraphs is based on phase plates located at an intermediate image plane of the optical system, that spread the starlight outside the "Lyot" exit pupil plane of the instrument. In this communication we present a set of candidate phase functions generating a central null at the Lyot plane, and study how it propagates to the image plane of the coronagraph. These functions include linear azimuthal phase ramps (the well-known optical vortex), azimuthally cosine-modulated phase profiles, and circular phase gratings. Numerical simulations of the expected null depth, inner working angle, sensitivity to pointing errors, effect of central obscuration located at the pupil or image planes, and effective throughput including image mask and Lyot stop transmissions are presented and discussed. The prelim...

  3. Holographic proof of the quantum null energy condition

    Science.gov (United States)

    Koeller, Jason; Leichenauer, Stefan

    2016-07-01

    We use holography to prove the quantum null energy condition (QNEC) at leading order in large N for CFTs and relevant deformations of CFTs in Minkowski space which have Einstein gravity duals. Given any codimension-two surface Σ which is locally stationary under a null deformation in the direction k at the point p , the QNEC is a lower bound on the energy-momentum tensor at p in terms of the second variation of the entropy to one side of Σ : ⟨Tk k⟩≥S''/2 π √{h } . In a CFT, conformal transformations of this inequality give results which apply when Σ is not locally stationary. The QNEC was proven previously for free theories, and taken together with our result this provides strong evidence that the QNEC is a true statement about quantum field theory in general.

  4. Quantization of black hole entropy from unstable circular null geodesics

    Science.gov (United States)

    Wei, Shao-Wen; Liu, Yu-Xiao; Fu, Chun-E.

    2016-04-01

    The quasinormal mode frequencies can be understood from the massless particles trapped at the unstable circular null geodesics and slowly leaking out to infinity. Based on this viewpoint, in this paper, we semiclassically construct the entropy spectrum of the static and stationary black holes from the null geodesics. The result shows that the spacing of the entropy spectrum only depends on the property of the black hole in the eikonal limit. Moreover, for a black hole far from the extremal case, the spacing is found to be smaller than 2πħ for any dimension, which is very different from the result of the previous work by using the usual quasinormal mode frequencies.

  5. Magnetic Reconnection at a Three-dimensional Solar Null Point

    DEFF Research Database (Denmark)

    Frederiksen, Jacob Trier; Baumann, Gisela; Galsgaard, Klaus;

    2012-01-01

    Using a specific solar null point reconnection case studied by Masson et al (2009; ApJ 700, 559) we investigate the dependence of the reconnection rate on boundary driving speed, numerical resolution, type of resistivity (constant or numerical), and assumed stratification (constant density or solar......-like). The MHD simulations start out from a potential magnetic field containing a null-point, obtained from a SOHO magnetogram extrapolation approximately 8 hours before a C-class flare was observed. The magnetic field is stressed with a boundary motion pattern similar to the horizontal motions observed by SOHO...... during the period preceding the flare. The general behavior is nearly independent of driving speed and numerical resolution, and is also very similar in stratified and unstratified models, provided only that the boundary motions are slow enough....

  6. Improving Null Depth Measurement with statistics : theory and first results with the Palomar Fiber Nuller

    OpenAIRE

    Hanot, Charles

    2010-01-01

    A unique statistical data analysis method has been developed for reducing nulling interferometry data. The idea is to make use of the statistical distributions of the fluctuating null depths and beam intensities to retrieve the astrophysical null depth in the presence of fluctuations. The approach yields an accuracy much better than is possible with standard data reduction methods, because the accuracy of the null depth is not limited by the sizes of the phase and intensity errors but by the ...

  7. Oscillatory null singularity inside realistic spinning black holes

    OpenAIRE

    Ori, Amos

    2001-01-01

    We calculate the asymptotic behavior of the curvature scalar $(Riemann)^2$ near the null weak singularity at the inner horizon of a generic spinning black hole, and show that this scalar oscillates infinite number of times while diverging. The dominant parallelly-propagated Riemann components oscillate in a similar manner. This oscillatory behavior, which is in a remarkable contrast to the monotonic mass-inflation singularity in spherical charged black holes, is caused by the dragging of iner...

  8. The Tolman VII solution, trapped null orbits and w - modes

    CERN Document Server

    Neary, N J; Lake, K; Neary, Nicholas; Ishak, Mustapha; Lake, Kayll

    2001-01-01

    The Tolman VII solution is an exact static spherically symmetric perfect fluid solution of Einstein's equations that exhibits a surprisingly good approximation to a neutron star. We show that this solution exhibits trapped null orbits in a causal region even for a tenuity (total radius to mass ratio) $> 3$. In this region the dynamical part of the potential for axial w - modes dominates over the centrifugal part.

  9. Do electromagnetic waves always propagate along null geodesics?

    CERN Document Server

    Asenjo, Felipe A

    2016-01-01

    We find exact solutions to Maxwell equations written in terms of four-vector potentials in non--rotating, as well as in G\\"odel and Kerr spacetimes. Exact electromagnetic waves solutions are written on given gravitational field backgrounds where they evolve. We find that in non--rotating spherical symmetric spacetimes, electromagnetic plane waves travel along null geodesics. However, electromagnetic plane waves on G\\"odel and Kerr spacetimes do not exhibit that behavior.

  10. Nulling Hall-Effect Current-Measuring Circuit

    Science.gov (United States)

    Sullender, Craig C.; Vazquez, Juan M.; Berru, Robert I.

    1993-01-01

    Circuit measures electrical current via combination of Hall-effect-sensing and magnetic-field-nulling techniques. Known current generated by feedback circuit adjusted until it causes cancellation or near cancellation of magnetic field produced in toroidal ferrite core by current measured. Remaining magnetic field measured by Hall-effect sensor. Circuit puts out analog signal and digital signal proportional to current measured. Accuracy of measurement does not depend on linearity of sensing components.

  11. Null distribution of multiple correlation coefficient under mixture normal model

    OpenAIRE

    Hydar Ali; Nagar, Daya K.

    2002-01-01

    The multiple correlation coefficient is used in a large variety of statistical tests and regression problems. In this article, we derive the null distribution of the square of the sample multiple correlation coefficient, R2, when a sample is drawn from a mixture of two multivariate Gaussian populations. The moments of 1−R2 and inverse Mellin transform have been used to derive the density of R2.

  12. Atoms of weakly null-additive monotone measures and integrals

    Czech Academy of Sciences Publication Activity Database

    Li, J.; Mesiar, Radko; Pap, E.

    2014-01-01

    Roč. 257, č. 1 (2014), s. 183-192. ISSN 0020-0255 R&D Projects: GA ČR GAP402/11/0378 Institutional support: RVO:67985556 Keywords : atom of a measure * weak null-additivty * monotone measure Subject RIV: BA - General Mathematics Impact factor: 4.038, year: 2014 http://library.utia.cas.cz/separaty/2014/E/mesiar-0432227.pdf

  13. A null model for testing thermodynamic optimization in ecological systems

    OpenAIRE

    Doyle, Santiago R.; Carusela, Florencia; Guala, Sebastián; Momo, Fernando

    2011-01-01

    Several authors have hypothesized that ecological systems are subject to thermodynamic optimization, which, if proven correct, could represent a long sought general principle of organization in ecology. Although there have been recent advances, this still remains as an unresolved topic, and ecologists lack a general method to test thermodynamic optimization hypotheses in specific systems. Here we present a general, novel approach that allows generating a null model for testing thermodynamic o...

  14. A semilinear hyperbolic system violating the null condition

    CERN Document Server

    Katayama, Soichiro; Sunagawa, Hideaki

    2012-01-01

    We consider a two-component system of semilinear wave equations in three space dimensions with quadratic nonlinear terms not satisfying the null condition. We prove small data global existence of the classical solution if some quantity defined from the nonlinearities is positive. It is also shown that only one component is dissipated and the other one behaves like a (non-trivial) free solution in the large time.

  15. Metabolism and pharmacokinetics of the anti-tuberculosis drug ethionamide in a flavin-containing monooxygenase null mouse.

    Science.gov (United States)

    Palmer, Amy L; Leykam, Virginia L; Larkin, Andrew; Krueger, Sharon K; Phillips, Ian R; Shephard, Elizabeth A; Williams, David E

    2012-01-01

    Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA. PMID:23580869

  16. Hepatic phenotype of liver fatty acid binding protein gene-ablated mice

    OpenAIRE

    Martin, Gregory G.; Atshaves, Barbara P.; Huang, Huan; McIntosh, Avery L.; Williams, Brad J.; Pai, Pei-Jing; Russell, David H.; Kier, Ann B.; Schroeder, Friedhelm

    2009-01-01

    Although the function of liver fatty acid binding protein in hepatic fatty acid metabolism has been extensively studied, its potential role in hepatic cholesterol homeostasis is less clear. Although hepatic cholesterol accumulation was initially reported in L-FABP-null female mice, that study was performed with early N2 backcross generation mice. To resolve whether the hepatic cholesterol phenotype in these L-FABP−/− mice was attributable to genetic inhomogeneity, these L-FABP−/− mice were fu...

  17. Enterocolitis causes profound lymphoid depletion in endothelin receptor B- and endothelin 3-null mouse models of Hirschsprung-associated enterocolitis

    Science.gov (United States)

    Frykman, Philip K.; Cheng, Zhi; Wang, Xiao; Dhall, Deepti

    2015-01-01

    Potentially life-threatening enterocolitis is the most frequent complication in children with colonic aganglionosis (Hirschsprung disease, HSCR), and little is known about the mechanisms leading to enterocolitis. Splenic lymphopenia has been reported in the Endothelin Receptor B (Ednrb)-null mouse model of HSCR that develops enterocolitis. In this study, we sought to identify molecular mechanisms underlying this immune phenotype. We employed the Ednrb−/− mouse, and the knockout of its ligand, Edn3 (Edn3−/−). The major finding is that enterocolitis in the Ednrb−/− and Edn3−/− mice lead to thymic involution, splenic lymphopenia, and suppression of B lymphopoiesis as a consequence of colonic aganglionosis, not an intrinsic Edn3-Ednrb signaling defect directly affecting the lymphoid organs. We showed that adoptive transfer of Ednrb−/− marrow repopulated the RAG2-null mice marrow, thymus and spleen without development of enterocolitis. We identified the glucocorticoid corticosterone, as a potential mediator of the immune phenotype. This previously unrecognized pattern of immune abnormalities in mouse is nearly identical to lymphoid depletion in neonatal sepsis during severe physiological stress, suggesting that the mouse model used here could be also used for sepsis studies. PMID:25487064

  18. Zero emission city. Preliminary study; Null-Emissions-Stadt. Sondierungsstudie

    Energy Technology Data Exchange (ETDEWEB)

    Diefenbach, N.; Enseling, A.; Werner, P.; Flade, A.; Greiff, R.; Hennings, D.; Muehlich, E.; Wullkopf, U.; Sturm, P.; Kieslich, W.; Born, R.; Grossklos, M.; Hatteh, R.; Mueller, K.; Ratschow, A.; Valouch-Fornoff, C.

    2002-10-01

    The idea of a 'zero emission city' is investigated by the Institut Wohnen und Umwelt on behalf of the Federal Minister of Education and Research. After describing the current situation and defining the key parameters of a 'zero emission city', settlement structures, power supply, production processes and transportation are analyzed and linked with the communal action level to obtain a framework for research, activities and actions. The study ends with recommendations for a research programme 'zero emission city'. (orig.) [German] Die von den Staedten der Industrielaender ausgehenden Emissionen stellen im Hinblick auf die globalen Belastungen wie z.B. Treibhauseffekt, Ozonabbau und Versauerung das Hauptproblem dar. Aus diesem Grunde bietet es sich an, den Gedanken der 'Null-Emissions-Stadt', der Vision einer moeglichst emissionsfreien Stadt, aufzugreifen und auf seine Tragfaehigkeit fuer innovative Handlungsmodelle forschungsstrategisch zu ueberpruefen. Das Bundesministerium fuer Bildung und Forschung hat das Institut Wohnen und Umwelt beauftragt, in einer Sondierungsstudie dieser Fragestellung nachzugehen. Nach der Festlegung der Ausgangsbedingungen und Eckpunkte der Vision 'Null-Emissions-Stadt' und der Analyse der vier Handlungsfelder Siedlungsstrukturen, Energieversorgung, Produktionsprozesse (Kreislaufwirtschaft) und Verkehr werden diese aufgegriffen und mit der kommunalen Handlungsebene verknuepft und zu einem Forschungs-, Handlungs- und moeglichen Aktionsrahmen zusammengefuegt. Die Studie schliesst mit Hinweisen fuer die Gestaltung eines Forschungsprogramms 'Null-Emissions-Stadt'. (orig.)

  19. Mice lacking sulfonylurea receptor 2 (SUR2) ATP sensitive potassium channels are resistant to acute cardiovascular stress

    OpenAIRE

    Stoller, Douglas; Kakkar, Rahul; Smelley, Matthew; Chalupsky, Karel; Earley, Judy U.; Shi, Nian-Qing; Makielski, Jonathan C.; McNally, Elizabeth M.

    2007-01-01

    Adenosine triphosphate sensitive potassium (KATP) channels are thought to mediate stress response by sensing intracellular ATP concentration. Cardiomyocyte KATP channels are composed of the pore-forming Kir6.2 subunit and the regulatory sulfonylurea receptor 2 (SUR2). We studied the response to acute isoproterenol in SUR2 null mice as a model of acute adrenergic stress and found that the episodic coronary vasospasm observed at baseline in SUR2 null mice was alleviated. Similar results were ob...

  20. Variational principle for gravity with null and non-null boundaries: a unified boundary counter-term

    Energy Technology Data Exchange (ETDEWEB)

    Parattu, Krishnamohan; Chakraborty, Sumanta; Padmanabhan, T. [IUCAA, Post Bag 4, Pune (India)

    2016-03-15

    It is common knowledge that the Einstein-Hilbert action does not furnish a well-posed variational principle. The usual solution to this problem is to add an extra boundary term to the action, called a counter-term, so that the variational principle becomes well-posed. When the boundary is spacelike or timelike, the Gibbons-Hawking-York counter-term is the most widely used. For null boundaries, we had proposed a counter-term in a previous paper. In this paper, we extend the previous analysis and propose a counter-term that can be used to eliminate variations of the ''off-the-surface'' derivatives of the metric on any boundary, regardless of its spacelike, timelike or null nature. (orig.)

  1. Variational Principle for Gravity with Null and Non-null boundaries: A Unified Boundary Counter-term

    CERN Document Server

    Parattu, Krishnamohan; Padmanabhan, T

    2016-01-01

    It is common knowledge that the Einstein-Hilbert action does not furnish a well-posed variational principle. The usual solution to this problem is to add an extra boundary term to the action, called a counter-term, so that the variational principle becomes well-posed. When the boundary is spacelike or timelike, the Gibbons-Hawking-York counter-term is the most widely used. For null boundaries, we had proposed a counter-term in a previous paper. In this paper, we extend the previous analysis and propose a counter-term that can be used to eliminate variations of the "off-the-surface" derivatives of the metric on any boundary, regardless of its spacelike, timelike or null nature.

  2. Null controllable region of delta operator systems subject to actuator saturation

    Science.gov (United States)

    Yang, Hongjiu; Yan, Ce; Xia, Yuanqing; Zhang, Jinhui

    2016-07-01

    In this paper, we give exact description of null controllable regions for delta operator systems subject to actuator saturation. The null controllable region is in terms of a set of extremal trajectories of anti-stable subsystems. For the delta operator system with real eigenvalues or complex eigenvalues, the description is simplified to an explicit formula which is used to characterise the boundary of a null controllable region. The relations of null controllable regions are shown separately for continuous-time systems, discrete-time systems and delta operator systems. Two numerical examples are given to illustrate the effectiveness of the proposed techniques on null controllable regions.

  3. Predisposition to apoptosis in keratin 8-null liver is related to inactivation of NF-κB and SAPKs but not decreased c-Flip

    Directory of Open Access Journals (Sweden)

    Jongeun Lee

    2013-05-01

    Keratin 8 and 18 (K8/K18 are major intermediate filament proteins of liver hepatocytes. They provide mechanical and nonmechanical stability, thereby protecting cells from stress. Hence, K8-null mice are highly sensitive to Fas-mediated liver cell apoptosis. However, the role of c-Flip protein in K8-null related susceptibility to liver injury is controversial. Here we analyzed c-Flip protein expression in various K8 or K18 null/mutant transgenic livers and show that they are similar in all analyzed transgenic livers and that previously reported c-Flip protein changes are due to antibody cross-reaction with mouse K18. Furthermore, analysis of various apoptosis- or cell survival-related proteins demonstrated that inhibition of phosphorylation of NF-κB and various stress activated protein kinases (SAPKs, such as p38 MAPK, p44/42 MAPK and JNK1/2, is related to the higher sensitivity of K8-null hepatocytes whose nuclear NF-κB is rapidly depleted through Fas-mediated apoptosis. Notably, we found that NF-κB and the studied protein kinases are associated with the K8/K18 complex and are released upon phosphorylation. Therefore, interaction of keratins with cell survival-related protein kinases and transcription factors is another important factor for hepatocyte survival.

  4. Broadband Achromatic Phase Shifter for a Nulling Interferometer

    Science.gov (United States)

    Bolcar, Matthew R.; Lyon, Richard G.

    2011-01-01

    Nulling interferometry is a technique for imaging exoplanets in which light from the parent star is suppressed using destructive interference. Light from the star is divided into two beams and a phase shift of radians is introduced into one of the beams. When the beams are recombined, they destructively interfere to produce a deep null. For monochromatic light, this is implemented by introducing an optical path difference (OPD) between the two beams equal to lambda/2, where lambda is the wavelength of the light. For broadband light, however, a different phase shift will be introduced at each wavelength and the two beams will not effectively null when recombined. Various techniques have been devised to introduce an achromatic phase shift a phase shift that is uniform across a particular bandwidth. One popular technique is to use a series of dispersive elements to introduce a wavelength-dependent optical path in one or both of the arms of the interferometer. By intelligently choosing the number, material and thickness of a series of glass plates, a nearly uniform, arbitrary phase shift can be introduced between two arms of an interferometer. There are several constraints that make choosing the number, type, and thickness of materials a difficult problem, such as the size of the bandwidth to be nulled. Several solutions have been found for bandwidths on the order of 20 to 30 percent (Delta(lambda)/lambda(sub c)) in the mid-infrared region. However, uniform phase shifts over a larger bandwidth in the visible regime between 480 to 960 nm (67 percent) remain difficult to obtain at the tolerances necessary for exoplanet detection. A configuration of 10 dispersive glass plates was developed to be used as an achromatic phase shifter in nulling interferometry. Five glass plates were placed in each arm of the interferometer and an additional vacuum distance was also included in the second arm of the interferometer. This configuration creates a phase shift of pi radians with

  5. DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents.

    NARCIS (Netherlands)

    B.J. Glassner (Brian); G. Weeda (Geert); J.M. Allan (James); J.L.M. Broekhof (Jose'); N.H.E. Carls (Nick); I. Donker (Ingrid); B.P. Engelward (Bevin); R.J. Hampson (Richard); R. Hersmus (Remko); M.J. Hickman (Mark); R.B. Roth (Richard); H.B. Warren (Henry); M.M. Wu (Mavis); J.H.J. Hoeijmakers (Jan); L.D. Samson (Leona)

    1999-01-01

    textabstractWe have generated mice deficient in O6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine. Tissues from Mgmt null mice displayed very low O6-methylguanine DNA methyltransf

  6. CNS wound healing is severely depressed in metallothionein I- and II-deficient mice

    DEFF Research Database (Denmark)

    Penkowa, M; Carrasco, J; Giralt, M; Moos, T; Hidalgo, J

    1999-01-01

    dpl. In contrast to normal mice, at 20 dpl no wound healing had occurred. The rate of apoptosis, as determined by using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, was drastically increased in neurons of ipsilateral cortex of the MT-I+II null mice. Our results...

  7. Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol

    OpenAIRE

    Blednov, Y.A.; Harris, R. A.

    2009-01-01

    The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of ri...

  8. Burn injury reveals altered phenotype in mannan-binding lectin-deficient mice

    DEFF Research Database (Denmark)

    Møller-Kristensen, Mette; Hamblin, MR; Thiel, Steffen; Jensenius, Jens Christian; Takahashi, K

    2007-01-01

    lectin complement pathway and acts as an opsonin. Recent studies suggest that MBL also modulates inflammatory responses. We report that local responses after burn in MBL null mice differ from those found in wild-type (WT) mice in the following important biological markers: spontaneous eschar separation......, thinned epidermis and dermis, upregulation of soluble factors including cytokines, chemokines, cell adhesion molecules, a growth factor-binding protein, and matrix metalloproteinases. Mice lacking C1q, C4, or C3 did not show the lack of eschar separation seen in MBL null-burn phenotype. These findings...

  9. FAK Mediates a Compensatory Survival Signal Parallel to PI3K-AKT in PTEN-Null T-ALL Cells

    Directory of Open Access Journals (Sweden)

    Dewen You

    2015-03-01

    Full Text Available Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN are observed in 15%–25% of cases of human T cell acute lymphoblastic leukemia (T-ALL. Pten deletion induces myeloproliferative disorders (MPDs, acute myeloid leukemia (AML, and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak, a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo.

  10. FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-null T-ALL cells.

    Science.gov (United States)

    You, Dewen; Xin, Junping; Volk, Andrew; Wei, Wei; Schmidt, Rachel; Scurti, Gina; Nand, Sucha; Breuer, Eun-Kyoung; Kuo, Paul C; Breslin, Peter; Kini, Ameet R; Nishimura, Michael I; Zeleznik-Le, Nancy J; Zhang, Jiwang

    2015-03-31

    Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%-25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo. PMID:25801032

  11. A Visualization of Null Geodesics for the Bonnor Massive Dipole

    CERN Document Server

    Oliva-Mercado, Guillermo Andree; Cordero-García, Iván; Frutos-Alfaro, Francisco

    2015-01-01

    In this work we simulate null geodesics for the Bonnor massive dipole metric by implementing a symbolic-numerical algorithm in Sage and Python. This program is also capable of visualizing in 3D, in principle, the geodesics for any given metric. Geodesics are launched from a common point, collectively forming a cone of light beams, simulating a solid-angle section of a point source in front of a massive object with a magnetic field. Parallel light beams also were considered, and their bending due to the curvature of the space-time was simulated.

  12. Trapping of waves and null geodesics for rotating black holes

    OpenAIRE

    Dyatlov, Semyon; Zworski, Maciej

    2013-01-01

    We present dynamical properties of linear waves and null geodesics valid for Kerr and Kerr-de Sitter black holes and their stationary perturbations. The two are intimately linked by the geometric optics approximation. For the nullgeodesic flow the key property is the r-normal hyperbolicity of the trapped set and for linear waves it is the distribution of quasi-normal modes: the exact quantization conditions do not hold for perturbations but the bounds on decay rates and the statistics of freq...

  13. Why is the null HBT result at RHIC so interesting?

    CERN Document Server

    Gyulassy, M

    2003-01-01

    Pion interferometry (HBT of A+A) data have posed a thorn in the theoretical interpretation of AA collisions at RHIC (sq root s = 130 AGeV). How can R sub o sub u sub t approx R sub s sub i sub d sub e approx R sub l sub o sub n sub g and remain so between AGS and RHIC? Where is the QGP Stall? Can elephants hide along the x sub 0 sup + dimension? We rummage old hydrodynamic scenarios and uncover some previously ignored NULL solutions. (author)

  14. Null controllability in a fluid-solid structure model

    Science.gov (United States)

    Raymond, J.-P.; Vanninathan, M.

    We consider a system coupling the Stokes equations in a two-dimensional domain with a structure equation which is a system of ordinary differential equations corresponding to a finite dimensional approximation of equations modeling deformations of an elastic body or vibrations of a rigid body. For that system we establish a null controllability result for localized distributed controls acting only in the fluid equations and there is no control in the solid part. This controllability result follows from a Carleman inequality that we prove for the adjoint system.

  15. Scale anomalies imply violation of the averaged null energy condition

    CERN Document Server

    Visser, M

    1994-01-01

    Considerable interest has recently been expressed regarding the issue of whether or not quantum field theory on a fixed but curved background spacetime satisfies the averaged null energy condition (ANEC). A comment by Wald and Yurtsever [Phys. Rev. D43, 403 (1991)] indicates that in general the answer is no. In this note I explore this issue in more detail, and succeed in characterizing a broad class of spacetimes in which the ANEC is guaranteed to be violated. Finally, I add some comments regarding ANEC violation in Schwarzschild spacetime.

  16. Conformal symmetry wormholes and the null energy condition

    CERN Document Server

    Kuhfittig, Peter K F

    2016-01-01

    In this paper we seek a relationship between the assumption of conformal symmetry and the exotic matter needed to hold a wormhole open. By starting with a Morris-Thorne wormhole having a constant energy density, it is shown that the conformal factor provides the extra degree of freedom sufficient to account for the exotic matter. The same holds for Morris-Thorne wormholes in a noncommutative-geometry setting. Applied to thin shells, there would exist a radius that results in a wormhole with positive surface density and negative surface pressure and which violates the null energy condition on the thin shell.

  17. Five-dimensional null & time-like supersymmetric geometries

    CERN Document Server

    Pasini, Giulio

    2015-01-01

    We show that there exist supersymmetric solutions of five-dimensional, pure, $\\mathcal{N}=1$ Supergravity whose supersymmetric Killing vector, built out of the Killing spinor, is null on an open set of the underlying space-time manifold and generically time-like on the complementary set. We explicitly construct such solutions by using a multi-center Gibbons-Hawking base. Although many of these solutions have infinite charges, we find explicit examples with finite charges that asymptote to $AdS_3\\times S_2$ and discuss their physical interpretation.

  18. Null weak values in multi-level systems

    OpenAIRE

    Zilberberg, Oded; Romito, Alessandro; Gefen, Yuval

    2013-01-01

    A two-step measurement protocol of a quantum system, known as weak value (WV), has been introduced more than two decades ago by Aharonov et al. [1], and has since been studied in various contexts. Here we discuss another two-step measurement protocol which we dub null weak value (NWV). The protocol consists of a partial-collapse measurement followed by quantum manipulation on the system and finally a strong measurement. The first step is a strong measurement which takes place with small proba...

  19. Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice

    OpenAIRE

    Lin, Shu-Xian; Zhang, Qi; Hua ZHANG; Yan, Kevin; Ward, Leanne; Lu, Yong-Bo; Feng, Jian-Quan

    2014-01-01

    Dentin matrix protein 1 (DMP1) is essential to odontogenesis. Its mutations in human subjects lead to dental problems such as dental deformities, hypomineralization and periodontal impairment. Primarily, DMP1 is considered as an extracellular matrix protein that promotes hydroxyapatite formation and activates intracellular signaling pathway via interacting with αvβ3 integrin. Recent in vitro studies suggested that DMP1 might also act as a transcription factor. In this study, we examined wheth...

  20. Calcium Homeostasis and Muscle Energy Metabolism Are Modified in HspB1-Null Mice

    OpenAIRE

    Brigitte Picard; Malek Kammoun; Mohammed Gagaoua; Christiane Barboiron; Bruno Meunier; Christophe Chambon; Isabelle Cassar-Malek

    2016-01-01

    Hsp27—encoded by HspB1—is a member of the small heat shock proteins (sHsp, 12–43 kDa (kilodalton)) family. This protein is constitutively present in a wide variety of tissues and in many cell lines. The abundance of Hsp27 is highest in skeletal muscle, indicating a crucial role for muscle physiology. The protein identified as a beef tenderness biomarker was found at a crucial hub in a functional network involved in beef tenderness. The aim of this study was to analyze the proteins impacted by...

  1. Deficiency of Glycine N-Methyltransferase Aggravates Atherosclerosis in Apolipoprotein E–Null Mice

    OpenAIRE

    Chen, Chien-Yu; Ching, Li-Chieh; Liao, Yi-Jen; Yu, Yuan-Bin; Tsou, Chia-Yuan; Shyue, Song-Kun; Chen, Yi-Ming Arthur; Lee, Tzong-Shyuan

    2012-01-01

    The mechanism underlying the dysregulation of cholesterol metabolism and inflammation in atherogenesis is not understood fully. Glycine N-methyltransferase (GNMT) has been implicated in hepatic lipid metabolism and the pathogenesis of liver diseases. However, little is known about the significance of GNMT in atherosclerosis. We showed the predominant expression of GNMT in foamy macrophages of mouse atherosclerotic aortas. Genetic deletion of GNMT exacerbated the hyperlipidemia, inflammation a...

  2. Severe Defects in Proliferation and Differentiation of Lens Cells in Foxe3 Null Mice

    OpenAIRE

    Medina-Martinez, Olga; Brownell, Isaac; Amaya-Manzanares, Felipe; Hu, Qiyong; Behringer, Richard R.; Jamrich, Milan

    2005-01-01

    During mouse eye development, the correct formation of the lens occurs as a result of reciprocal interactions between the neuroectoderm that forms the retina and surface ectoderm that forms the lens. Although many transcription factors required for early lens development have been identified, the mechanism and genetic interactions mediated by them remain poorly understood. Foxe3 encodes a winged helix-forkhead transcription factor that is initially expressed in the developing brain and in the...

  3. Altered Morphine-Induced Analgesia in Neurotensin Type 1 Receptor Null Mice

    OpenAIRE

    Roussy, Geneviève; Beaudry, Hélène; Lafrance, Mylène; Belleville, Karine; Beaudet, Nicolas; Wada, Keiji; Gendron, Louis; Sarret, Philippe

    2010-01-01

    Both neurotensin (NT) and opioid agonists have been shown to induce antinociception in rodents after central administration. Besides, previous studies have revealed the existence of functional interactions between NT and opioid systems in the regulation of pain processing. We recently demonstrated that NTS1 receptors play a key role in the mediation of the analgesic effects of NT in long-lasting pain. In the present study, we therefore investigated whether NTS1 gene deletion affected the anti...

  4. Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B–null mice

    OpenAIRE

    Choi, Young Hun; Park, Sunhee; Hockman, Steven; Zmuda-Trzebiatowska, Emilia; Svennelid, Fredrik; Haluzik, Martin; Gavrilova, Oksana; Ahmad, Faiyaz; Pepin, Laurent; Napolitano, Maria; Taira, Masato; Sundler, Frank; Stenson Holst, Lena; Degerman, Eva; Manganiello, Vincent C.

    2006-01-01

    Cyclic nucleotide phosphodiesterase 3B (PDE3B) has been suggested to be critical for mediating insulin/IGF-1 inhibition of cAMP signaling in adipocytes, liver, and pancreatic β cells. In Pde3b-KO adipocytes we found decreased adipocyte size, unchanged insulin-stimulated phosphorylation of protein kinase B and activation of glucose uptake, enhanced catecholamine-stimulated lipolysis and insulin-stimulated lipogenesis, and blocked insulin inhibition of catecholamine-stimulated lipolysis. Glucos...

  5. Reduced infarct size in neuroglobin-null mice after experimental stroke in vivo

    DEFF Research Database (Denmark)

    Raida, Zindy; Hundahl, Christian Ansgar; Kelsen, Jesper; Nyengaard, Jens Randel; Hay-Schmidt, Anders

    2012-01-01

    BACKGROUND: Neuroglobin is considered to be a novel important pharmacological target in combating stroke and neurodegenerative disorders, although the mechanism by which this protection is accomplished remains an enigma. We hypothesized that if neuroglobin is directly involved in neuroprotection...

  6. Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation

    Science.gov (United States)

    Weis, MaryAnn; Rai, Jyoti; Hudson, David M.; Dimori, Milena; Zimmerman, Sarah M.; Hogue, William R.; Swain, Frances L.; Burdine, Marie S.; Mackintosh, Samuel G.; Tackett, Alan J.; Suva, Larry J.; Eyre, David R.

    2016-01-01

    Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis. PMID:27119146

  7. Perilipin overexpression in mice protects against diet-induced obesity

    OpenAIRE

    Miyoshi, Hideaki; Souza, Sandra C.; Endo, Mikiko; Sawada, Takashi; Perfield, James W.; Shimizu, Chikara; Stancheva, Zlatina; Nagai, So; Strissel, Katherine J.; Yoshioka, Narihito; Obin, Martin S.; Koike, Takao; Greenberg, Andrew S.

    2010-01-01

    Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/en...

  8. Perilipin overexpression in mice protects against diet-induced obesity

    Science.gov (United States)

    Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand t...

  9. Holographic Description of Negative Null Energy in Squeezed Vacuum States

    CERN Document Server

    Lee, Da-Shin

    2016-01-01

    Using the AdS/CFT duality, we study the expectation value of stress tensor in squeezed vacuum states of $2+1$-dimensional quantum critical theories with a general dynamical scaling $z$. The holographic dual theory is the theory of gravity in 3+1-dimensional Lifshitz backgrounds. We then adopt a consistent approach to obtain the boundary stress tensor from bulk construction, which satisfies the trace Ward identity associated with Lifshitz scaling symmetry. The scheme for holographic dual of squeezed vacuum states is found to be the gravity theory in the geometry perturbed by gravitational wave. For small squeezing parameters, the expectation value of stress tensor in squeezed vacuum states is obtained for both strongly coupled quantum critical fields and free relativistic fields. We find that, in both cases with $z=1$, the stress tensor satisfies the averaged null energy condition and is consistent with the quantum interest conjecture. In particular, the negative lower bound on null-contracted stress tensor, w...

  10. Conceptual design of the ALADDIN Antarctic nulling interferometer

    Science.gov (United States)

    Barillot, Marc; Courteau, Pascal; Absil, Olivier; Coudé du Foresto, Vincent; Swain, Mark

    2006-06-01

    It is commonly accepted that highly challenging planet finding missions such as Darwin and TPF need precursors on the ground, for both technological demonstration and study of the exozodiacal clouds around potential targets. A first instrument, GENIE, designed to be implemented in the interferometric laboratory of the VLTI, was studied by ESA and scientific/industrial teams. In this paper we present a concept for ALADDIN, an operational nulling instrument to be implemented at Dome C in Antarctica, and discuss the comparison with GENIE from the instrumental point of view. Our preliminary design involves moderate ~1m size telescopes mounted on a 40m long rotating beam allowing baselines up to 30m and feeding a 2-arm nulling beam combiner. When compared to GENIE, the rotating beam design has the advantage of removing the need for both long-stroke delay line and dispersion control equipments. As a side effect, the instrumental arrangement of ALADDIN finds itself more representative of what Darwin will be. Furthermore, critical issues like phase control, photometric balance and instrumental background suppression are expected to be relaxed by the improved atmospheric conditions, lower temperature, and simpler optical trains. Calibration of geometrical stellar leakage will make advantage of the continuously adjustable baseline. As results, a simpler instrument showing improved performance is expected. In conclusion, we see our ALADDIN concept as a valuable alternative to GENIE, with a quite stronger scientific potential and a considerably simplified instrumental design.

  11. Adding light to the gravitational waves on the null cone

    Science.gov (United States)

    Babiuc, Maria

    2014-03-01

    Recent interesting astrophysical observations point towards a multi-messenger, multi-wavelength approach to understanding strong gravitational sources, like compact stars or black hole collisions, supernovae explosions, or even the big bang. Gravitational radiation is properly defined only at future null infinity, but usually is estimated at a finite radius, and then extrapolated. Our group developed a characteristic waveform extraction tool, implemented in an open source code, which computes the gravitational waves infinitely far from their source, in terms of compactified null cones, by numerically solving Einstein equation in Bondi space-time coordinates. The goal is extend the capabilities of the code, by solving Einstein-Maxwell's equations together with the Maxwell's equations, to obtain the energy radiated asymptotically at infinity, both in gravitational and electromagnetic waves. The purpose is to analytically derive and numerically calculate both the gravitational waves and the electromagnetic counterparts at infinity, in this characteristic framework. The method is to treat the source of gravitational and electromagnetic radiation as a black box, and therefore the code will be very flexible, with potentially large applicability.

  12. Does horizon entropy satisfy a Quantum Null Energy Conjecture?

    CERN Document Server

    Fu, Zicao

    2016-01-01

    A modern version of the idea that the area of event horizons gives $4G$ times an entropy is the Hubeny-Rangamani Causal Holographic Information (CHI) proposal for holographic field theories. Given a region $R$ of a holographic QFTs, CHI computes $A/4G$ on a certain cut of an event horizon in the gravitational dual. The result is naturally interpreted as a coarse-grained entropy. CHI is known to be finitely greater than the fine-grained Hubeny-Rangamani-Takayanagi (HRT) entropy when $\\partial R$ lies on a Killing horizon of the QFT spacetime, and in this context satisfies other non-trivial properties expected of an entropy. Here we present evidence that it also satisfies the quantum null energy condition (QNEC), which bounds the second derivative of the entropy of a quantum field theory on one side of a non-expanding null surface by the flux of stress-energy across the surface. In particular, we show CHI to satisfy the QNEC in 1+1 holographic CFTs when evaluated in states dual to conical defects in AdS$_3$. Th...

  13. Null weak values in multi-level systems

    International Nuclear Information System (INIS)

    A two-step measurement protocol of a quantum system, known as the weak value (WV), was introduced more than two decades ago by Aharonov et al (1988 Phys. Rev. Lett. 60 1351) and has since then been studied in various contexts. In this paper, we discuss another two-step measurement protocol that we dub the null weak value (NWV). The protocol consists of a partial-collapse measurement followed by quantum manipulation on the system and finally a strong measurement. The first step is a strong measurement which takes place with a small probability. The second strong measurement is used as a postselection on the outcome of the earlier step. Not being measured in the partial-collapse stage (null outcome) leads to a nontrivial correlation between the two measurements. The NVW protocol, first defined for a two-level system (Zilberberg et al 2012 arXiv:1205.3877), is then generalized to a multi-level system and compared with the standard-WV protocol.

  14. Non-dissipative electromagnetic media with two Lorentz null cones

    International Nuclear Information System (INIS)

    We study Maxwell’s equations on a 4-manifold where the electromagnetic medium is modeled by an antisymmetric (2/2 )-tensor with 21 real coefficients. In this setting the Fresnel surface is a fourth-order polynomial surface that describes the dynamical response of the medium in the geometric optics limit. For example, in an isotropic medium the Fresnel surface is a Lorentz null cone. The contribution of this paper is the pointwise description of all electromagnetic medium tensors κ with real coefficients that satisfy the following three conditions: (i)medium κ is invertible, (ii)medium κ is skewon-free, or non-dissipative, (iii)the Fresnel surface of κ is the union of two distinct Lorentz null cones. We show that there are only three classes of media with these properties and give explicit expressions in local coordinates for each class. - Highlights: ► We find two new electromagnetic media classes for which the Fresnel surface decomposes into two light cones. ► In a suitable setting we classify all electromagnetic media where this is the case. ► We find an electromagnetic medium tensor with three different signal speeds in one direction. ► The work is related to [5], which classifies all media with one light cone (in a suitable setting).

  15. Exoplanet detection and characterization via parallel broadband nulling coronagraphy

    Science.gov (United States)

    Hicks, Brian A.

    2016-01-01

    The contrast and angular resolution required to directly image and characterize mature exoplanetary systems place stringent requirements on the space-based telescopes and starlight suppression systems needed to study spatial distributions of debris disks, exozodiacal dust, and individual planets at multiple epochs in their orbits. A nulling interferometer (nuller) is a coronagraphic suppression system that can be used with all telescope types, including those with obscured and segmented apertures envisioned for upcoming and future observatories. One of the challenges for detection and characterization of exoplanetary signals is achieving high contrast with broad spectral coverage. This work presents design concepts for broadband nulling over four parallel ˜20% bandpasses spanning the visible spectrum. Contrast-limiting effects of stellar angular extent, residual chromaticity of broadband phase shifters, and aperture diffraction are considered to reach simultaneous ≲2×10-8 contrast over separations spanning 0.2 to 0.9 arc sec for a 2.4-m telescope observing a Sun-like star at 10 pc. With added dark hole wavefront control and postprocessing point spread function subtraction techniques to further reduce scattered starlight, such a system could be capable of detecting the very the nearest Earth-like exoplanets and spectral characterization of several nearby extrasolar gas giants.

  16. Quantification of Pelvic Organ Prolapse in Mice: Vaginal Protease Activity Precedes Increased MOPQ Scores in Fibulin 5 Knockout Mice1

    OpenAIRE

    Wieslander, Cecilia K.; Rahn, David D.; Donald D. Mcintire; Acevedo, Jesús F.; Peter G. Drewes; Yanagisawa, Hiromi; Word, R. Ann

    2009-01-01

    Two mouse models of pelvic organ prolapse have been generated recently, both of which have null mutations in genes involved in elastic fiber synthesis and assembly (fibulin 5 and lysyl oxidase-like 1). Interestingly, although these mice exhibit elastinopathies early in life, pelvic organ prolapse does not develop until later in life. In this investigation we developed and validated a tool to quantify the severity of pelvic organ prolapse in mice, and we used this tool prospectively to study t...

  17. Greatly attenuated experimental autoimmune encephalomyelitis in aquaporin-4 knockout mice

    Directory of Open Access Journals (Sweden)

    Verkman AS

    2009-08-01

    Full Text Available Abstract Background The involvement of astrocyte water channel aquaporin-4 (AQP4 in autoimmune diseases of the central nervous system has been suggested following the identification of AQP4 autoantibodies in neuromyelitis optica, an inflammatory demyelinating disease. Results We investigated the involvement of AQP4 in disease severity in an established mouse model of experimental autoimmune encephalomyelitis (EAE produced by immunization with myelin oligodendrocyte glycoprotein (MOG35–55 peptide. EAE was remarkably attenuated in AQP4 null mice compared to identically treated wildtype mice. Whereas most wildtype mice developed progressive tail and hindlimb paralysis, clinical signs were virtually absent in AQP4 null mice. Brain and spinal cords from AQP1 null mice showed greatly reduced mononuclear cell infiltration compared to wildtype mice, with relatively little myelin loss and axonal degeneration. Conclusion The reduced severity of autoimmune encephalomyelitis in AQP4 deficiency suggests AQP4 as a novel determinant in autoimmune inflammatory diseases of the central nervous system and hence a potential drug target.

  18. Quantification of adsorbed human serum albumin : a comparison between radioimmunoassay and simple null ellipsometry

    OpenAIRE

    Benesch, Johan; Askendal, A.; Tengvall, P.

    2000-01-01

    Radioimmunoassay (RIA) and null ellipsometry are two common methods to quantify adsorbed proteins. However, the accuracy of null ellipsometry with a constant protein refractive index (n 1.465, k 0) at l 632.8 nm has this far not been explored. The present study compared the methods, and the degree of agreement between the simplified single wavelength null ellipsometry and RIA to quantify adsorbed proteins was explored on different surfaces. The quantification methods agreed well w...

  19. Does anomalous violation of null energy condition invalidate holographic c-theorem?

    International Nuclear Information System (INIS)

    Null energy condition plays a crucial role in holographic renormalization group flow, leading to the holographic c-theorem. Unfortunately, the null energy condition is quantum mechanically violated. Even the averaged version can be violated. We discuss how the anomalous violation of the null energy condition affects the holographic renormalization group flow in (1+3)-dimensional bulk gravity. We show that despite the violation of the null energy condition, a suitably modified holographic c-function with a peculiar log correction is still monotonically decreasing in so far as we add the counterterm that removes a ghost mode of gravity

  20. Principles: when there should be no difference--how to fail to reject the null hypothesis.

    Science.gov (United States)

    Lew, Michael J

    2006-05-01

    It is common to perform experiments in which a 'success' is claimed when the null hypothesis is discarded. However, there is a category of experiment that has become important in which a success is when the null hypothesis is not rejected. Failing to discard the null hypothesis is different from proving it to be valid, a distinction that is particularly important in experiments in which any inadequacy of experimental design or implementation enhances the likelihood of a success. The appropriate analysis of such experiments tests for evidence of the validity of the null hypothesis rather than simply failing to find evidence against it. PMID:16595154

  1. Review of OCA activities on nulling testbench PERSEE

    Science.gov (United States)

    Hénault, François; Girard, Paul; Marcotto, Aurélie; Mauclert, Nicolas; Bailet, Christophe; Clausse, Jean-Michel; Mourard, Denis; Rabbia, Yves; Roussel, Alain; Barillot, Marc; Cassaing, Frédéric; Le Duigou, Jean-Michel

    2010-07-01

    We present a review of our activities on PERSEE (Pégase Experiment for Research and Stabilization of Extreme Extinction) at Observatoire de la Côte d'Azur (OCA). PERSEE is a laboratory testbench aiming at achieving a stabilized nulling ratio better than 10-4 in the astronomical bands K and M, in presence of flight-representative spacecraft perturbations. The bench has been jointly developed by a Consortium of six French institutes and companies, among which OCA was responsible for the star simulator and of the opto-mechanical studies, procurement and manufacturing of the optical train. In this communication are presented the alignment and image quality requirements and the optomechanical design of the illumination module and main optical train, including a periscope Achromatic Phase Shifter (APS), tip-tilt mirrors used to introduce and then compensate for dynamic disturbances, delay lines, beam compressors and fiber injection optics. Preliminary test results of the star simulator are also provided.

  2. 'Peeling property' for linearized gravity in null coordinates

    International Nuclear Information System (INIS)

    A complete description of the linearized gravitational field on a flat background is given in terms of gauge-independent quasilocal quantities. This is an extension of the results from [16]. Asymptotic spherical quasilocal parameterization of the Weyl field and its relation with Einstein equations is presented. The field equations are equivalent to the wave equation. A generalization for the Schwarzschild background is developed and the axial part of the gravitational field is fully analysed. In the case of axial degrees of freedom for the linearized gravitational field the corresponding generalization of the d'Alembert operator is a Regge-Wheeler equation. Finally, the asymptotics at null infinity are investigated and the strong peeling property for axial waves is proved

  3. Radiation Hardened NULL Convention Logic Asynchronous Circuit Design

    Directory of Open Access Journals (Sweden)

    Liang Zhou

    2015-10-01

    Full Text Available This paper proposes a radiation hardened NULL Convention Logic (NCL architecture that can recover from a single event latchup (SEL or single event upset (SEU fault without deadlock or any data loss. The proposed architecture is analytically proved to be SEL resistant, and by extension, proved to be SEU resistant. The SEL/SEU resistant version of a 3-stage full-word pipelined NCL 4 × 4 unsigned multiplier was implemented using the IBM cmrf8sf 130 nm 1.2 V process at the transistor level and simulated exhaustively with SEL fault injection to validate the proposed architectures. Compared with the original version, the SEL/SEU resilient version has 1.31× speed overhead, 2.74× area overhead, and 2.79× energy per operation overhead.

  4. Horizons in matter: black hole hair vs. Null Big Bang

    CERN Document Server

    Bronnikov, K A

    2009-01-01

    It is shown that only particular kinds of matter (in terms of the "radial" pressure to density ratio $w$) can coexist with Killing horizons in black-hole or cosmological space-times. Thus, for arbitrary (not necessarily spherically symmetric) static black holes, admissible are vacuum matter ($w=-1$, i.e., the cosmological constant or some its generalization) and matter with certain values of $w$ between 0 and -1, in particular, a gas of disordered cosmic strings ($w=-1/3$). If the cosmological evolution starts from a horizon (the so-called Null Big Bang scenarios), this horizon can co-exist with vacuum matter and certain kinds of phantom matter with $w\\geq -3$. It is concluded that normal matter in such scenarios is entirely created from vacuum.

  5. Linearized gravitational waves near space-like and null infinity

    CERN Document Server

    Beyer, Florian; Frauendiener, Jörg; Whale, Ben

    2013-01-01

    Linear perturbations on Minkowski space are used to probe numerically the remote region of an asymptotically flat space-time close to spatial infinity. The study is undertaken within the framework of Friedrich's conformal field equations and the corresponding conformal representation of spatial infinity as a cylinder. The system under consideration is the (linear) zero-rest-mass equation for a spin-2 field. The spherical symmetry of the underlying background is used to decompose the field into separate non-interacting multipoles. It is demonstrated that it is possible to reach null-infinity from initial data on an asymptotically Euclidean hyper-surface and that the physically important radiation field can be extracted accurately on $\\scri^+$.

  6. A new interferometer architecture combining nulling with phase closure measurements

    CERN Document Server

    Lacour, S; Monnier, J D; Kotani, T; Gauchet, L; Labeye, P

    2013-01-01

    Imaging the direct light signal from a faint exoplanet against the overwhelming glare of its host star presents one of the fundamental challenges to modern astronomical instrumentation. Achieving sufficient signal-to-noise for detection by direct imaging is limited by three basic physical processes: aberration of the wavefronts (both instrumental and atmospheric), photon noise, and detector noise. In this paper, we advance a novel optical setup which synthesizes the advantages of two different techniques: nulling interferometry to mitigate photon noise, and closure phase to combat optical aberrations. Our design, which employs technology from integrated optics and photonics, is intended to combine the advantageous aspects of both a coronagraph and a non-redundant interferometer. We show that such an instrument would allow readout noise limited detection of exoplanets, even in the presence of residual co-phasing errors. As a result, this concept would be ideal for space interferometry and for ground based obse...

  7. Area, Entanglement Entropy and Supertranslations at Null Infinity

    CERN Document Server

    Kapec, Daniel; Strominger, Andrew

    2016-01-01

    The area of a cross-sectional cut $\\Sigma$ of future null infinity ($\\mathcal{I}^+$) is infinite. We define a finite, renormalized area by subtracting the area of the same cut in any one of the infinite number of BMS-degenerate classical vacua. The renormalized area acquires an anomalous dependence on the choice of vacuum. We relate it to the modular energy, including a soft graviton contribution, of the region of $\\mathcal{I}^+$ to the future of $\\Sigma$. Under supertranslations, the renormalized area shifts by the supertranslation charge of $\\Sigma$. In quantum gravity, we conjecture a bound relating the renormalized area to the entanglement entropy across $\\Sigma$ of the outgoing quantum state on $\\mathcal{I}^+$.

  8. Power spectrum nulls due to nonstandard inflationary evolution

    Science.gov (United States)

    Goswami, Gaurav; Souradeep, Tarun

    2011-01-01

    The simplest models of inflation based on slow roll produce nearly scale invariant primordial power spectra (PPS). But there are also numerous models that predict radically broken scale invariant PPS. In particular, markedly cuspy dips in the PPS correspond to nulls where the perturbation amplitude, hence PPS, goes through a zero at a specific wave number. Near this wave number, the true quantum nature of the generation mechanism of the primordial fluctuations may be revealed. Naively these features may appear to arise from fine-tuned initial conditions. However, we show that this behavior arises under fairly generic set of conditions involving super-Hubble scale evolution of perturbation modes during inflation. We illustrate this with the well-studied examples of punctuated inflation and the Starobinsky-break model.

  9. Power spectrum nulls due to non-standard inflationary evolution

    CERN Document Server

    Goswami, Gaurav

    2010-01-01

    The simplest models of inflation based on slow roll produce nearly scale invariant primordial power spectra (PPS). But there are also numerous models that predict radically broken scale invariant PPS. In particular, markedly cuspy dips in the PPS correspond to nulls where the perturbation amplitude, hence PPS, goes through a zero at a specific wavenumber. Near this wavenumber, the true quantum nature of the generation mechanism of the primordial fluctuations may be revealed. Naively these features may appear to arise from fine tuned initial conditions. However, we show that this behavior arises under fairly generic set of conditions involving super-Hubble scale evolution of perturbation modes during inflation. We illustrate this with the well-studied examples of punctuated inflation and the Starobinsky-break model.

  10. From Satisfying to Violating the Null Energy Condition

    CERN Document Server

    Elder, Benjamin; Khoury, Justin

    2013-01-01

    We construct a theory which admits a time-dependent solution smoothly interpolating between a null energy condition (NEC)-satisfying phase at early times and a NEC-violating phase at late times. We first review earlier attempts to violate the NEC and an argument of Rubakov, presented in 1305.2614, which forbids the existence of such interpolating solutions in a single-field dilation-invariant theory. We then construct a theory which, in addition to possessing a Poincar\\'e-invariant vacuum, does admit such a solution. For a wide range of parameters, perturbations around this solution are at all times stable, comfortably subluminal and weakly-coupled. The theory requires us to explicitly break dilation-invariance, so it is unlikely that the theory is fully stable under quantum corrections, but we argue that the existence of a healthy interpolating solution is quantum-mechanically robust.

  11. Null-stream pointing with pulsar timing arrays

    CERN Document Server

    Hazboun, Jeffrey S

    2016-01-01

    Locating sources on the sky is one of the largest challenges in gravitational wave astronomy, owing to the omni-directional nature of gravitational wave detection techniques, and the often intrinsically weak signals being observed. Ground-based detectors can address the pointing problem by observing with a network of detectors, effectively triangulating signal locations by observing the arrival times across the network. Space-based detectors will observe long-lived sources that persist while the detector moves relative to their location on the sky, using Doppler shifts of the signal to locate the sky position. While these methods improve the pointing capability of a detector or network, the angular resolution is still coarse compared to the standards one expects from electromagnetic astronomy. Another technique that can be used for sky localization is null-stream pointing. In the case where multiple independent data streams exist, a single astrophysical source of gravitational waves will appear in each of the...

  12. Null polarimetry near shot noise limit at 1 Hz

    Science.gov (United States)

    He, Dechao; Xie, Boya; Feng, Sheng

    2016-04-01

    We describe the principle and report on the realization of a null polarimeter with two demonstrated features: (1) the sensitivity of the system is near shot noise limit and (2) quasi-stationary signals at 1 Hz can be measured without signal modulation. The achieved single-pass sensitivity is 7 × 10-9 rad/ √{ Hz } with a pair of Glan-Taylor polarizers, which should be of great interest for experiments such as observation of vacuum magnetic birefringence and search for new particles. The system is brought near its shot noise limit by appropriate polarization control and coherent heterodyne detection of light, resulting in a sensitivity improvement by two orders of magnitude in comparison with the case of no control on light polarization.

  13. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yu-Kun Jennifer; Wu, Kai Connie; Liu, Jie; Klaassen, Curtis D., E-mail: cklaasse@kumc.edu

    2012-11-01

    Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulating glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling. -- Highlights: ► Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. ► The anti-diabetic hormone, Fgf21, is highly expressed in livers of Nrf2-null mice. ► The absence of Nrf2 increases the insulin-regulated Igfbp-1 mRNA in liver.

  14. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet

    International Nuclear Information System (INIS)

    Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulating glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling. -- Highlights: ► Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. ► The anti-diabetic hormone, Fgf21, is highly expressed in livers of Nrf2-null mice. ► The absence of Nrf2 increases the insulin-regulated Igfbp-1 mRNA in liver.

  15. DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents.

    OpenAIRE

    Glassner, Brian; Weeda, Geert; Allan, James; Broekhof, Jose'; Carls, Nick; Donker, Ingrid; Engelward, Bevin; Hampson, Richard; Hersmus, Remko; Hickman, Mark; Roth, Richard; Warren, Henry; Wu, Mavis; Hoeijmakers, Jan; Samson, Leona

    1999-01-01

    textabstractWe have generated mice deficient in O6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine. Tissues from Mgmt null mice displayed very low O6-methylguanine DNA methyltransferase activity, suggesting that Mgmt constitutes the major, if not the only, O6-methylguanine DNA methyltransferase. Primary mouse embryo fibroblasts and bone marrow cells from Mgmt -/- mice were s...

  16. Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid

    OpenAIRE

    Harrison, Fiona E.; Yu, S Sarah; Van Den Bossche, Kristen L; Li, Liying; May, James M.; McDonald, Michael P.

    2008-01-01

    Oxidative stress is implicated in the cognitive deterioration associated with normal aging as well as neurodegenerative disorders such as Alzheimer’s and Parkinson's diseases. We investigated the effect of ascorbic acid (vitamin C) on oxidative stress, cognition and motor abilities in mice null for gulono-γ-lactone oxidase (Gulo). Gulo−/− mice are unable to synthesize ascorbic acid and depend on dietary ascorbic acid for survival. Gulo−/− mice were given supplements that provided them either ...

  17. Sleep and Sleep Homeostasis in Mice Lacking the 5-HT2c Receptor

    OpenAIRE

    Frank, Marcos G.; Stryker, Michael P.; Tecott, Laurence H.

    2002-01-01

    Studies in humans and rats indicate that serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in mammalian sleep expression. We investigated the contribution of the 5-HT2c receptor to sleep expression by examining sleep patterns in mice bearing a targeted null mutation of this receptor. 5-HT2c receptor knock-out mice had more wakefulness, several abnormalities in rapid eye movement sleep expression and an enhanced response to sleep deprivation compared with wild-type control mice. The...

  18. Coordinated roles of pregnane X receptor and constitutive androstane receptor in autoinduction of voriconazole metabolism in mice.

    Science.gov (United States)

    Ohbuchi, Masato; Yoshinari, Kouichi; Kaneko, Hayato; Matsumoto, Satoru; Inoue, Akiko; Kawamura, Akio; Usui, Takashi; Yamazoe, Yasushi

    2013-03-01

    The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr- and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR- and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species. PMID:23274663

  19. (−)-EPICATECHIN IMPROVES MITOCHONDRIAL RELATED PROTEIN LEVELS AND AMELIORATES OXIDATIVE STRESS IN DYSTROPHIC DELTA SARCOGLYCAN NULL MOUSE STRIATED MUSCLE

    Science.gov (United States)

    Ramirez-Sanchez, Israel; De los Santos, Sergio; Gonzalez-Basurto, Silvia; Canto, Patricia; Mendoza-Lorenzo, Patricia; Palma-Flores, Carlos; Ceballos-Reyes, Guillermo; Villarreal, Francisco; Zentella-Dehesa, Alejandro; Coral-Vazquez, Ramon

    2014-01-01

    Muscular dystrophies (MD) are a group of heterogeneous genetic disorders characterized by progressive striated muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for disease pathogenesis remains unclear. The presence of oxidative stress (OS) is known to contribute to the pathophysiology and severity of the MD. Mitochondrial dysfunction is observed in MD and likely represents an important determinant of increased OS. Experimental antioxidant therapies have been implemented with the aim of protecting against disease progression, but results from clinical trials have been disappointing. In this study, we explored the capacity of the cacao flavonoid (−)-epicatechin (Epi) to mitigate OS by acting as a positive regulator of mitochondrial structure/function endpoints and redox balance control systems in skeletal and cardiac muscles of dystrophic, δ-sarcoglycan (δ-SG) null mice. Wild type or δ-SG null 2.5 month old male mice were treated via oral gavage with either water (control animals) or Epi (1 mg/kg, twice/day) for 2 weeks. Results evidence a significant normalization of total protein carbonylation, recovery of reduced/oxidized glutathione (GSH/GSSG ratio) and enhanced superoxide dismutase 2, catalase and citrate synthase activities with Epi treatment. These effects were accompanied by increases in protein levels for thiolredoxin, glutathione peroxidase, superoxide dismutase 2, catalase and mitochondrial endpoints. Furthermore, we evidence decreases in heart and skeletal muscle fibrosis, accompanied with an improvement in skeletal muscle function with treatment. These results warrant the further investigation of Epi as a potential therapeutic agent to mitigate MD associated muscle degeneration. PMID:25284161

  20. null Faults, null Images

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Through the study of faults and their effects, much can be learned about the size and recurrence intervals of earthquakes. Faults also teach us about crustal...

  1. Secretoglobin 3A2 Exhibits Anti-Fibrotic Activity in Bleomycin-Induced Pulmonary Fibrosis Model Mice.

    Directory of Open Access Journals (Sweden)

    Yan Cai

    Full Text Available Secretoglobin (SCGB 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.Mice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.BLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFβ were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.The role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2

  2. Agreement and Null Subjects in German L2 Development: New Evidence from Reaction-Time Experiments.

    Science.gov (United States)

    Clahsen, Harald; Hong, Upyong

    1995-01-01

    Reports on reaction time experiments investigating subject-verb agreement and null subjects in 33 Korean learners of German and a control group of 20 German native speakers. Results found that the two phenomena do not covary in the Korean learners, indicating that properties of agreement and null subjects are acquired separately from one another.…

  3. Exact null-controllability of interconnected abstract evolution systems by scalar force motion

    OpenAIRE

    Shklyar, B.

    2013-01-01

    The paper deals with exact null-controllability problem for a linear control system consisting of two serially connected abstract control systems. Controllability conditions are obtained. Applications to the exact null-controllability for interconnected control system of heat and wave equations are considered.

  4. Alpha-null defocus: An optimum defocus condition with relevance for focal-series reconstruction

    Energy Technology Data Exchange (ETDEWEB)

    O' Keefe, Michael A.

    2001-02-14

    Two optimum defocus conditions are used in high-resolution transmission electron microscopy. Scherzer defocus produces an image of the specimen ''projected potential'' to the resolution of the microscope, and Lichte defocus minimizes dispersion. A third optimum defocus is best for focal-series reconstruction; alpha-null defocus maximizes transfer of high-frequency diffracted beam amplitudes into the microscope image. Beam transfer is confined by incident-beam convergence to a Gaussian ''packet'' of defocus values centered on the alpha-null defocus. For a diffracted beam hkl, with a spatial frequency of u, the envelope for incident beam convergence has null damping effect when defocus is set to -Cs. (wavelength.u)**2. On either side of this alpha-null defocus value, the damping effect of incident-beam convergence reduces diffracted-beam transfer. The position of alpha-null defocus for any spatial frequency depends only on the value of Cs, but defocus-packet width around the alpha-null defocus depends only on the convergence semi-angle. Under NCEM OAM (one-Angstrom microscope) conditions, a [110] diamond image with the correct 0.89A spacing appears when the Si (004) alpha-null defocus is selected. The alpha-null defocus should be included as the (furthest underfocus) limit for all high-resolution focal series reconstruction.

  5. Symbolic computation of polyhomogeneous asymptotic solutions of Einstein's equations in null characteristic transport form

    International Nuclear Information System (INIS)

    Full text: Calculational methods and Reduce software are described for determining polyhomogeneous asymptotic expansions of solutions of Einstein's equations in null characteristic transport form. As an example, results concerning peeling of gravitational radiation in Null Quasi-Spherical (NQS) spacetimes are presented

  6. Null controllability of the viscous Camassa–Holm equation with moving control

    Indian Academy of Sciences (India)

    Peng Gao

    2016-02-01

    In this paper, we study the null controllability of the viscous Camassa–Holm equation on the one-dimensional torus. By using a moving distributed control, we obtain that the system is null controllable for a given data with certain regularity.

  7. A trilinear method for finding null points in a three-dimensional vector space

    International Nuclear Information System (INIS)

    Null points are important locations in vector fields, such as a magnetic field. A new technique (a trilinear method for finding null points) is presented for finding null points over a large grid of points, such as those derived from a numerical experiment. The method was designed so that the null points found would agree with any field lines traced using the commonly used trilinear interpolation. It is split into three parts: reduction, analysis, and positioning, which, when combined, provide an efficient means of locating null points to a user-defined subgrid accuracy. We compare the results of the trilinear method with that of a method based on the Poincare index, and discuss the accuracy and limitations of both methods

  8. Spacetime characterizations of $\\Lambda$-vacuum metrics with a null Killing 2-form

    CERN Document Server

    Mars, Marc

    2016-01-01

    An exhaustive list of four-dimensional $\\Lambda$-vacuum spacetimes admitting a Killing vector whose self-dual Killing two-form ${\\cal F}$ is null is obtained assuming that the self-dual Weyl tensor is proportional to the tensor product of ${\\cal F}$ by itself. Our analysis complements previous results concerning the case with non-null ${\\cal F}$. We analyze both cases with $\\Lambda$ vanishing or not. In the latter case we prove that $\\Lambda< 0$ must hold necessarily, and we find a characterization of the Einstein spacetimes conformal to pp-waves. In the former case we obtain spacetime characterizations of vacuum plane waves and of the stationary vacuum Brinkmann spacetimes. At the light of the full set of results, old and new, we reformulate the case with non-null ${\\cal F}$ and $\\Lambda= 0$. We finally present a table collecting the results for both null, and non-null, ${\\cal F}$.

  9. Why Are Flare Ribbons Associated with the Spines of Magnetic Null Points Generically Elongated?

    Science.gov (United States)

    Pontin, David; Galsgaard, Klaus; Démoulin, Pascal

    2016-08-01

    Coronal magnetic null points exist in abundance, as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, which can be analysed using the "squashing factor", Q. In this article we analyse in detail the distribution of Q in the presence of magnetic nulls. While Q is formally infinite on both the spine and fan of the null, the decay of Q away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, Q decays most slowly away from the spine or fan in the direction in which |{B}| increases most slowly. In particular, this demonstrates that the extended elliptical high-Q halo around the spine footpoints observed by Masson et al. ( Astrophys. J. 700, 559, 2009) is a generic feature. This extension of the Q halos around the spine or fan footpoints is important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss how our results can be used to interpret the geometry of observed flare ribbons in circular ribbon flares, in which typically a coronal null is implicated. We conclude that both the physics in the vicinity of the null and how this is related to the extension of Q away from the spine or fan can be used in tandem to understand observational signatures of reconnection at coronal null points.

  10. Why Are Flare Ribbons Associated with the Spines of Magnetic Null Points Generically Elongated?

    Science.gov (United States)

    Pontin, David; Galsgaard, Klaus; Démoulin, Pascal

    2016-06-01

    Coronal magnetic null points exist in abundance, as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, which can be analysed using the "squashing factor", Q. In this article we analyse in detail the distribution of Q in the presence of magnetic nulls. While Q is formally infinite on both the spine and fan of the null, the decay of Q away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, Q decays most slowly away from the spine or fan in the direction in which |{B}| increases most slowly. In particular, this demonstrates that the extended elliptical high- Q halo around the spine footpoints observed by Masson et al. (Astrophys. J. 700, 559, 2009) is a generic feature. This extension of the Q halos around the spine or fan footpoints is important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss how our results can be used to interpret the geometry of observed flare ribbons in circular ribbon flares, in which typically a coronal null is implicated. We conclude that both the physics in the vicinity of the null and how this is related to the extension of Q away from the spine or fan can be used in tandem to understand observational signatures of reconnection at coronal null points.

  11. Strong subadditivity, null energy condition and charged black holes

    International Nuclear Information System (INIS)

    Using the Hubeny-Rangamani-Takayanagi (HRT) conjectured formula for entanglement entropy in the context of the AdS/CFT correspondence with time-dependent backgrounds, we investigate the relation between the bulk null energy condition (NEC) of the stress-energy tensor with the strong sub-additivity (SSA) property of entanglement entropy in the boundary theory. In a background that interpolates between an AdS to an AdS-Reissner-Nordstrom-type geometry, we find that generically there always exists a critical surface beyond which the violation of NEC would naively occur. However, the extremal area surfaces that determine the entanglement entropy for the boundary theory, can penetrate into this forbidden region only for certain choices for the mass and the charge functions in the background. This penetration is then perceived as the violation of SSA in the boundary theory. We also find that this happens only when the critical surface lies above the apparent horizon, but not otherwise. We conjecture that SSA, which is thus non-trivially related to NEC, also characterizes the entire time-evolution process along which the dual field theory may thermalize

  12. On the Null Energy Condition and Causality in Lifshitz Holography

    CERN Document Server

    Hoyos, Carlos

    2010-01-01

    We use a WKB approximation to establish a relation between the wavefront velocity in a strongly coupled theory and the local speed of light in a holographic dual, with our main focus put on systems with Lifshitz scaling with dynamical exponent z. We then use Einstein equations to relate the behavior of the local speed of light in the bulk with the null energy condition (NEC) for bulk matter, and we show that it is violated for Lifshitz backgrounds with z<1. We study signal propagation in the gravity dual and show that violations of the NEC are incompatible with causality in the strongly coupled theory, ruling out as holographic models Lifshitz backgrounds with z<1. We argue that causality violations in z<1 theories will show up in correlators as superluminal modes and confirm this for a particular example with z=1/2. Finally, as an application, we use z<1 solutions to uncover regions of the parameter space of curvature squared corrections to gravity where the NEC can be violated.

  13. Aspects of QCD Current Algebra on a Null Plane

    CERN Document Server

    Beane, Silas R

    2015-01-01

    Consequences of QCD current algebra formulated on a light-like hyperplane are derived for the forward scattering of vector and axial-vector currents on an arbitrary hadronic target. It is shown that current algebra gives rise to a special class of sum rules that are direct consequences of the independent chiral symmetry that exists at every point on the two-dimensional transverse plane orthogonal to the lightlike direction. These sum rules are obtained by exploiting the closed, infinite-dimensional algebra satisfied by the transverse moments of null-plane axial-vector and vector charge distributions. In the special case of a nucleon target, this procedure leads to the Adler-Weisberger, Gerasimov-Drell-Hearn, Cabbibo-Radicatti and Fubini-Furlan-Rossetti sum rules. Matching to the dispersion-theoretic language which is usually invoked in deriving these sum rules, the moment sum rules are shown to be equivalent to algebraic constraints on forward S-matrix elements in the Regge limit.

  14. Strong Subadditivity, Null Energy Condition and Charged Black Holes

    CERN Document Server

    Caceres, Elena; Pedraza, Juan F; Tangarife, Walter

    2014-01-01

    Using the Hubeny-Rangamani-Takayanagi (HRT) conjectured formula for entanglement entropy in the context of the AdS/CFT correspondence with time-dependent backgrounds, we investigate the relation between the bulk null energy condition (NEC) of the stress-energy tensor with the strong sub-additivity (SSA) property of entanglement entropy in the boundary theory. In a background that interpolates between an AdS to an AdS-Reissner-Nordstrom-type geometry, we find that generically there always exists a critical surface beyond which the violation of NEC would naively occur. However, the extremal area surfaces that determine the entanglement entropy for the boundary theory, can penetrate into this forbidden region only for certain choices for the mass and the charge functions in the background. This penetration is then perceived as the violation of SSA in the boundary theory. We also find that this happens only when the critical surface lies above the apparent horizon, but not otherwise. We conjecture that SSA, which...

  15. Aspects of QCD current algebra on a null plane

    Science.gov (United States)

    Beane, S. R.; Hobbs, T. J.

    2016-09-01

    Consequences of QCD current algebra formulated on a light-like hyperplane are derived for the forward scattering of vector and axial-vector currents on an arbitrary hadronic target. It is shown that current algebra gives rise to a special class of sum rules that are direct consequences of the independent chiral symmetry that exists at every point on the two-dimensional transverse plane orthogonal to the lightlike direction. These sum rules are obtained by exploiting the closed, infinite-dimensional algebra satisfied by the transverse moments of null-plane axial-vector and vector charge distributions. In the special case of a nucleon target, this procedure leads to the Adler-Weisberger, Gerasimov-Drell-Hearn, Cabibbo-Radicati and Fubini-Furlan-Rossetti sum rules. Matching to the dispersion-theoretic language which is usually invoked in deriving these sum rules, the moment sum rules are shown to be equivalent to algebraic constraints on forward S-matrix elements in the Regge limit.

  16. Initial Study Comparing the Radiating Divertor Behavior in Single-Null and Double-Null Plasmas in DIII-D

    International Nuclear Information System (INIS)

    'Puff and pump' radiating divertor scenarios [1,2] were applied to upper SN and DN H-mode plasmas. Under similar operating conditions, argon (Ar) accumulated in the main plasma of single-null (SN) plasmas more rapidly and reached a higher steady-state concentration when the B x (del)B ion drift direction was toward the divertor than when the B x (del)B ion drift direction was out of the divertor. The initial rate that Ar accumulated inside double-null (DN) plasmas was more than twice that of comparably-prepared SNs with the same B x (del)B direction. One way to reduce power loading at the divertor targets is to 'seed' the divertor plasma with impurities that radiatively reduce the conducted power. Studies have shown that the concentration of impurities in the divertor are increased by raising the flow of deuterium ions (D+) into the divertor by a combination of upstream deuterium gas puffing and active particle exhaust at the divertor targets, i.e., puff-and-pump. An enhanced D+ particle flow toward the divertor targets exerts a frictional drag on impurities, and inhibits their escape from the divertor. A puff-and-pump approach using Ar as the impurity was successfully applied in recent DIII-D experiments to SN plasmas [3] while maintaining good H-mode performance. Studies on DIII-D and other tokamaks have shown that both the direction of the toroidal magnetic field BT and the degree of magnetic balance between divertors [i.e., the degree to which the plasma shape is considered SN or DN] are important factors in determining recycling and particle pumping [4,5]. It is unclear whether the favorable results of Ref. [3] can be extended to cases with different magnetic balance and/or BT direction. We show in this paper that reversing the direction of BT or altering the divertor magnetic balance does have an impact on how plasmas behave under puff-and-pump conditions. Our study takes advantage of DIII-D's capabilities to actively pump SN and DN shapes with high

  17. Oculomotor deficits in aryl hydrocarbon receptor null mouse.

    Directory of Open Access Journals (Sweden)

    Aline Chevallier

    Full Text Available The Aryl hydrocarbon Receptor or AhR, a ligand-activated transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD. Recent studies in Caenorhabditis elegans and Drosophila melanogaster show that the orthologs of the AhR are expressed exclusively in certain types of neurons and are implicated in the development and the homeostasis of the central nervous system. While physiological roles of the AhR were demonstrated in the mammalian heart, liver and gametogenesis, its ontogenic expression and putative neural functions remain elusive. Here, we report that the constitutive absence of the AhR in adult mice (AhR-/- leads to abnormal eye movements in the form of a spontaneous pendular horizontal nystagmus. To determine if the nystagmus is of vestibular, visual, or cerebellar origin, gaze stabilizing reflexes, namely vestibulo-ocular and optokinetic reflexes (VOR and OKR, were investigated. The OKR is less effective in the AhR-/- mice suggesting a deficit in the visuo-motor circuitry, while the VOR is mildly affected. Furthermore, the AhR is expressed in the retinal ganglion cells during the development, however electroretinograms revealed no impairment of retinal cell function. The structure of the cerebellum of the AhR-/- mice is normal which is compatible with the preserved VOR adaptation, a plastic process dependent on cerebellar integrity. Finally, intoxication with TCDD of control adults did not lead to any abnormality of the oculomotor control. These results demonstrate that the absence of the AhR leads to acquired central nervous system deficits in the adults. Given the many common features between both AhR mouse and human infantile nystagmus syndromes, the AhR-/- mice might give insights into the developmental mechanisms which lead to congenital eye disorders.

  18. BAX and Tumor Suppressor TRP53 Are Important in Regulating Mutagenesis in Spermatogenic Cells in Mice1

    OpenAIRE

    Xu, Guogang; Vogel, Kristine S.; McMahan, C. Alex; Herbert, Damon C.; Walter, Christi A.

    2010-01-01

    During the first wave of spermatogenesis, and in response to ionizing radiation, elevated mutant frequencies are reduced to a low level by unidentified mechanisms. Apoptosis is occurring in the same time frame that the mutant frequency declines. We examined the role of apoptosis in regulating mutant frequency during spermatogenesis. Apoptosis and mutant frequencies were determined in spermatogenic cells obtained from Bax-null or Trp53-null mice. The results showed that spermatogenic lineage a...

  19. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2−/− mice

    OpenAIRE

    Gil-Henn, Hava; Destaing, Olivier; Sims, Natalie A.; Aoki, Kazuhiro; Alles, Neil; Neff, Lynn; Sanjay, Archana; Bruzzaniti, Angela; De Camilli, Pietro; Baron, Roland; Schlessinger, Joseph

    2007-01-01

    The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microt...

  20. Aggravation of Chronic Stress Effects on Hippocampal Neurogenesis and Spatial Memory in LPA1 Receptor Knockout Mice

    OpenAIRE

    Castilla-Ortega, Estela; Hoyo-Becerra, Carolina; Pedraza, Carmen; Chun, Jerold; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo; Santín, Luis J.

    2011-01-01

    Background The lysophosphatidic acid LPA1 receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA1 receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory. Methodology/Principal Findings Male LPA1-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous marker...

  1. Why are flare ribbons generically elongated in configurations with magnetic null points?

    Science.gov (United States)

    Pontin, David Iain; Galsgaard, Klaus; Demoulin, Pascal

    2016-05-01

    Coronal magnetic null points exist in abundance as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection in the corona. In addition, the field line mapping in the vicinity of these null points exhibits strong gradients as measured by the “squashing factor”, Q. We demonstrate that the extension of the Q halos around the spine/fan footpoints is in general important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss the extent to which our results can be used to interpret the geometry of observed flare ribbons in events in which a coronal null is implicated. We conclude that together the physics in the vicinity of the null and how this is related to the extension of Q away from the spine/fan can be used in tandem to understand observational signatures of reconnection at coronal null points.

  2. Integrated optics for nulling interferometry in the thermal infrared

    Science.gov (United States)

    Barillot, Marc; Barthelemy, Eleonore; Broquin, Jean-Emmanuel; Frayret, Jérôme; Grelin, Jérôme; Hawkins, Gary; Kirschner, Volker; Parent, Gilles; Pradel, Annie; Rossi, Emmanuel; Vigreux, Caroline; Zhang, Shaoqian; Zhang, Xianghua

    2008-07-01

    Modal filtering is based on the capability of single-mode waveguides to transmit only one complex amplitude function to eliminate virtually any perturbation of the interfering wavefronts, thus making very high rejection ratios possible in a nulling interferometer. In the present paper we focus on the progress of Integrated Optics in the thermal infrared [6-20μm] range, one of the two candidate technologies for the fabrication of Modal Filters, together with fiber optics. In conclusion of the European Space Agency's (ESA) "Integrated Optics for Darwin" activity, etched layers of chalcogenide material deposited on chalcogenide glass substrates was selected among four candidates as the technology with the best potential to simultaneously meet the filtering efficiency, absolute and spectral transmission, and beam coupling requirements. ESA's new "Integrated Optics" activity started at mid-2007 with the purpose of improving the technology until compliant prototypes can be manufactured and validated, expectedly by the end of 2009. The present paper aims at introducing the project and the components requirements and functions. The selected materials and preliminary designs, as well as the experimental validation logic and test benches are presented. More details are provided on the progress of the main technology: vacuum deposition in the co-evaporation mode and subsequent etching of chalcogenide layers. In addition, preliminary investigations of an alternative technology based on burying a chalcogenide optical fiber core into a chalcogenide substrate are presented. Specific developments of anti-reflective solutions designed for the mitigation of Fresnel losses at the input and output surface of the components are also introduced.

  3. Serological analysis of cell surface antigens of null cell acute lymphocytic leukemia by mouse monoclonal antibodies.

    OpenAIRE

    Ueda, R; Tanimoto, M; Takahashi, T.; Ogata, S; Nishida, K; Namikawa, R.; Nishizuka, Y; Ota, K.

    1982-01-01

    Nine antigens systems were defined. Two were related to HLA-A,B,C and to Ia-like antigens; the others could be grouped into three categories. (i) NL-22, NL-1: NL-22 antibody reacted with leukemia cells from 12 to 16 cases of null cell acute lymphocytic leukemia (null-ALL) but not with any other type of leukemia tested or with lymphoid cells of various origins. Among cultured cell lines tested, one (NALM-6) of three null-ALL cell lines was positive, the others were negative. Absorption analysi...

  4. The Protective Effects of CD39 Overexpression in Multiple Low-Dose Streptozotocin–Induced Diabetes in Mice

    OpenAIRE

    Chia, Joanne S. J.; McRae, Jennifer L.; Thomas, Helen E.; Fynch, Stacey; Elkerbout, Lorraine; Hill, Prue; Murray-Segal, Lisa; Robson, Simon C.; Chen, Jiang-Fan; d’Apice, Anthony J. F.; Cowan, Peter J.; Dwyer, Karen M.

    2013-01-01

    Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell–mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG)...

  5. Genetic Dissection of the Role of Catechol-O-Methyltransferase in Cognition and Stress Reactivity in Mice

    OpenAIRE

    Papaleo, Francesco; Crawley, Jacqueline N.; Song, Jian; Lipska, Barbara K.; Pickel, Jim; Weinberger, Daniel R.; Chen, Jingshan

    2008-01-01

    The COMT (catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation. Increased COMT enzyme activity in Val-tg mice resulted in disrupte...

  6. Surface electrocardiogram and action potential in mice lacking urea transporter UT-B

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    UT-B is a urea transporter protein expressed in the kidney and in many non-renal tissues including erythrocytes, brain, heart, bladder and the testis. The objective of this study was to determine the phenotype of UT-B deletion in the heart. UT-B expression in the heart was studied in wild-type mice vs UT-B null mice by utilizing RT-PCR and Western blot. A surface electrocardiogram (ECG) recording (lead II) was measured in wild-type mice and UT-B null mice at the ages of 6, 16 and 52 weeks. For the action potential recording, the ventricular myocytes of 16 w mice were isolated and recorded by floating microelectrode method. The sodium current was recorded by the patch clamp technique. RT-PCR and Western blot showed the UT-B expression in the heart of wild-type mice. No UT-B transcript and protein was found in UT-B null mice. The ECG recording showed that the P-R interval was significantly prolonged in UT-B null mice ((43.5 ± 4.2), (45.5 ± 6.9) and (43.8 ± 7.6) ms at ages of 6, 16 and 52 weeks) vs wild-type mice ((38.6 ± 2.9), (38.7 ± 5.6) and (38.2 ± 7.3) ms, P<0.05). The atrial ventricular heart block type II and III only appeared in the aging UT-B null mice (52 w old). The amplitude of action potential and Vmax decreased significantly in UT-B null mice ((92.17 ± 10.56) and (101.89 ± 9.54) mV/s) vs those in wild-type mice (vs (110.51 ± 10.38) and (109.53 ± 10.64) mV/s, P<0.05). The action potential duration at 50% and 90% (APD50 and APD90) was significantly prolonged in UT-B null mice ((123.83 ± 11.17) and (195.43 ± 16.41) ms) vs that in wild-type mice ((108.27 ± 10.85) and (171.00 ± 15.53) ms, P<0.05). The maximal sodium current decreased significantly in UT-B null mice (-8.80 ± 0.92) nA vs that in wild-type mice ((-5.98 ± 1.07) nA, P<0.05). These results provide the first evidence that UT-B deletion causes progressive heart block in mice.

  7. Surface electrocardiogram and action potential in mice lacking urea transporter UT-B

    Institute of Scientific and Technical Information of China (English)

    MENG Yan; ZHAO ChunYan; ZHANG XueXin; ZHAO HuaShan; GUO LiRong; Lü Bin; ZHAO XueJian; YANG BaoXue

    2009-01-01

    UT-B is a urea transporter protein expressed in the kidney and in many non-renal tissues including erythrocytes, brain, heart, bladder and the testis. The objective of this study was to determine the phenotype of UT-B deletion in the heart. UT-B expression in the heart was studied in wild-type mice vs UT-B null mice by utilizing RT-PCR and Western blot. A surface electrocardiogram (ECG) recording (lead Ⅱ) was measured in wild-type mice and UT-B null mice at the ages of 6, 16 and 52 weeks. For the action potential recording, the ventricular myocytes of 16 w mice were isolated and recorded by float-ing microelectrode method. The sodium current was recorded by the patch clamp technique. RT-PCR and Western blot showed the UT-B expression in the heart of wild-type mice. No UT-B transcript and protein was found in UT-B null mice. The ECG recording showed that the P-R interval was significantly prolonged in UT-B null mice ((43.5±4.2), (45.5±6.9) and (43.8±7.6) ms at ages of 6, 16 and 52 weeks) vs wild-type mice ((38.6±2.9), (38.7±5.6) and (38.2±7.3) ms, P<0.05). The atrial ventricular heart block type Ⅱ and Ⅲ only appeared in the aging UT-B null mice (52 w old). The amplitude of action potential and Vmax decreased significantly in UT-B null mice ((92.17±10.56) and (101.89±9.54) mV/s) vs those in wild-type mice (vs (110.51±10.38) and (109.53±10.64) mV/s, P<0.05). The action potential duration at 50% and 90% (APD50 and APD90) was significantly prolonged in UT-B null mice ((123.83±11.17) and (195.43±16.41) ms) vs that in wild-type mice ((108.27±10.85) and (171.00±15.53) ms, P<0.05). The maximal sodium current decreased significantly in UT-B null mice (-8.80±0.92) nA vs that in wild-type mice ((-5.98±1.07) nA, P<0.05). These results provide the first evidence that UT-B deletion causes progressive heart block in mice.

  8. The Determining Method about the Conflict between the Null Constraints and the Set of Functional Dependencies

    Institute of Scientific and Technical Information of China (English)

    刘惟一

    1989-01-01

    In this paper the conflict between the null constraints and the set of functional dependencies is defined.Some rules for determining the conflicts and a method for processing the conflicts are obtained.

  9. Current Singularities at Quasi-Separatrix Layers and Three-Dimensional Magnetic Nulls

    CERN Document Server

    Craig, I J D

    2014-01-01

    The open problem of how singular current structures form in line-tied, three-dimensional magnetic fields is addressed. A Lagrangian magneto-frictional relaxation method is employed to model the field evolution towards the final near-singular state. Our starting point is an exact force-free solution of the governing magnetohydrodynamic (MHD) equations which is sufficiently general to allow for topological features like magnetic nulls to be inside or outside the computational domain, depending on a simple set of parameters. Quasi-separatrix layers (QSLs) are present in these structures and together with the magnetic nulls, they significantly influence the accumulation of current. It is shown that perturbations affecting the lateral boundaries of the configuration lead not only to collapse around the magnetic null, but also to significant QSL currents. Our results show that once a magnetic null is present, the developing currents are always attracted to that specific location and show a much stronger scaling wit...

  10. Dynamics-independent null experiment for testing time-reversal invariance

    Science.gov (United States)

    Arash, Firooz; Moravcsik, Michael J.; Goldstein, Gary R.

    1985-06-01

    It is shown that it is impossible to construct, in any reaction in atomic, nuclear, or particle physics, a null experiment that would unambiguously test the validity of time-reversal invariance independently of dynamical assumptions.

  11. Dynamics-independent null experiment for testing time-reversal invariance

    International Nuclear Information System (INIS)

    It is shown that it is impossible to construct, in any reaction in atomic, nuclear, or particle physics, a null experiment that would unambiguously test the validity of time-reversal invariance independently of dynamical assumptions

  12. Adaptive nulling: a new tool for the interfoeromic exo-planet detection

    Science.gov (United States)

    Lay, O.; Jeganathan, M.; Peters, R.

    2003-01-01

    This paper describes the need for a compensator that can adaptively correct for mismatches between the optical beamtrains of a Mid-IR nulling interferometer, across the science bandwidth with a range of spectral dependences.

  13. Entropy of a generic null surface from its associated Virasoro algebra

    CERN Document Server

    Chakraborty, Sumanta; Padmanabhan, T

    2016-01-01

    Null surfaces act as one-way membranes, blocking information from those observers who do not cross them (e.g., in the black hole and the Rindler spacetimes) and these observers associate an entropy (and temperature) with the null surface. The black hole entropy can be computed from the central charge of an appropriately defined, local, Virasoro algebra on the horizon. We show that one can extend these ideas to a general class of null surfaces, all of which possess a Virasoro algebra and a central charge, leading to an entropy density (i.e., per unit area) which is just $(1/4)$. All the previously known results of associating entropy with horizons arise as special cases of this very general property of null surfaces demonstrated here. The implications are discussed.

  14. Vlasov Fluid stability of a 2-D plasma with a linear magnetic field null

    International Nuclear Information System (INIS)

    Vlasov Fluid stability of a 2-dimensional plasma near an O type magnetic null is investigated. Specifically, an elongated Z-pinch is considered, and applied to Field Reversed Configurations at Los Alamos National Laboratory by making a cylindrical approximation of the compact torus. The orbits near an elliptical O type null are found to be very complicated; the orbits are large and some are stochastic. The kinetic corrections to magnetohydrodynamics (MHD) are investigated by evaluating the expectation values of the growth rates of a Vlasov Fluid dispersion functional by using a set of trial functions based on ideal MHD. The dispersion functional involves fluid parts and orbit dependent parts. The latter involves phase integral of two time correlations. The phase integral is replaced by the time integral both for the regular and for the stochastic orbits. Two trial functions are used; one has a large displacement near the null and the other away from the null

  15. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity.

    Science.gov (United States)

    Miyanishi, Masanori; Segawa, Katsumori; Nagata, Shigekazu

    2012-09-01

    Phagocytes, including macrophages, recognize phosphatidylserine exposed on apoptotic cells as an "eat me" signal. Milk Fat Globule EGF Factor VIII (MFG-E8) is secreted by one subset of macrophages, whereas Tim4, a type I membrane protein, is expressed by another. These proteins bind tightly to phosphatidylserine on apoptotic cells and enhance their engulfment by macrophages. To study the contribution of these proteins to the engulfment of apoptotic cells, we established a mouse line that was deficient in the genes encoding MFG-E8 and Tim4. The null mutation of Tim4 impaired the ability of resident peritoneal macrophages, but not thioglycollate-elicited macrophages, to engulf apoptotic cells. Mice deficient in either MFG-E8 or Tim4 on the C57BL/6 background developed hardly any autoantibodies, but aged female mice deficient in both MFG-E8 and Tim4 developed autoantibodies in an age-dependent manner. Tumour necrosis factor (TNF) α is known to protect against systemic lupus erythematosus-type autoimmunity, whereas type I IFN accelerates the disease. Indeed, the administration of an anti-TNFα antibody or a reagent that stimulates the IFN-α production [2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane)] enhanced the production of autoantibodies in the MFG-E8- and Tim4-double-deficient mice. These results suggest that the double deficiency of Tim4 and MFG-E8, phosphatidylserine-binding proteins, can trigger autoimmunity and that TNFα and type I IFN regulate reciprocally the development of autoimmune disease. PMID:22723547

  16. Kahel korral järjest null häält / Maarius Suviste

    Index Scriptorium Estoniae

    Suviste, Maarius, 1966-

    2005-01-01

    Kohalike omavalitsuste volikogude valimistel ei saanud ühtegi häält 233 kandidaati. Oma kandideerimise põhjusi selgitavad juba teist korda valimistel null häält saanud Viljandi tisler Kaljo Jürman, Põlvamaa mahetalunik Liisi Kutkina ja Ida-Virumaa pensionär Vaike Zaitseva. Lisatud statistilised andmed null häält saanud kandidaatide kohta maakondade ja erakondade kaupa

  17. Testing the null hypothesis of no regime switching with an application to GDP growth rates

    OpenAIRE

    Marmer, Vadim

    2009-01-01

    This paper presents tests for the null hypothesis of no regime switching in Hamilton's (1989) regime switching model. The test procedures exploit similarities between regime switching models, autoregressions with measurement errors, and finite mixture models. The proposed tests are computationally simple and, contrary to likelihood based tests, have a standard distribution under the null. When the methodology is applied to US GDP growth rates, no strong evidence of regime switching is found.

  18. Dynamic Stability of Lateral and Yawing Motions in the Double Null-Flux EDS System

    Science.gov (United States)

    Murai, Toshiaki; Yoshioka, Hiroshi; Sugino, Motohiko

    The double null-flux electro-dynamic suspension (EDS) in the superconducting maglev has the coupling lateral and yawing stiffness, which does not coincide with each other, so special attention should be paid to the dynamic stability of lateral and yawing motions. This paper describes their intrinsic dynamic stability by analyzing the lateral and yawing motions of bogie levitated by the double null-flux EDS.

  19. First-Order Adaptive Azimuthal Null-Steering for the Suppression of Two Directional Interferers

    OpenAIRE

    Derkx RenéMM

    2010-01-01

    Abstract An azimuth steerable first-order superdirectional microphone response can be constructed by a linear combination of three eigenbeams: a monopole and two orthogonal dipoles. Although the response of a (rotation symmetric) first-order response can only exhibit a single null, we will look at a slice through this beampattern lying in the azimuthal plane. In this way, we can define maximally two nulls in the azimuthal plane which are symmetric with respect to the main-lobe axis. By placin...

  20. [Development of a new type soybean germplasm with null lipoxygenase isozymes].

    Science.gov (United States)

    Han, Fen-Xia; Ding, An-Lin; Sun, Jun-Ming; Li, Gui-Ying

    2005-02-01

    Soybean protein is a kind of high-quality protein composed of balanced amino acids. It contains all kinds of amino acids, especially eight amino acids necessary for human, but also contains some components that are not good for human and affect food quality, such as Lipoxygenase (Lox) and Trypsin inhibitor (Ti). Nutritional value and processing quality of soybean can be improved by means of development of new variety with null Lox and Ti. In this paper, a new type soybean germplasm with null lipoxygenase isozymes was developed by Institute of Crop Sciences, Chinese Academy of Agricultural Sciences through years of biochemical marker assistant selection for null lipoxygenase by means of isoelectric focusing-polyacrylamid gel electrophoresis (IEF-PAGE) in the hybrid progenies of "96P17" (Female parent, a null lipoxygenase 2.3 line) and "93704" (Male parent, a null lipoxygenase 1.3 line). It is the first new soybean germplasm with null Lox1.2.3 genes in our country, which will contribute to soybean breeding for high quality, soybean production and utilization. In this paper, the development process of new type soybean germplasm is described. PMID:15759868

  1. Why are flare ribbons associated with the spines of magnetic null points generically elongated?

    CERN Document Server

    Pontin, D I; Demoulin, P

    2016-01-01

    Coronal magnetic null points exist in abundance as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, that can be analysed using the `squashing factor', $Q$. In this paper we make a detailed analysis of the distribution of $Q$ in the presence of magnetic nulls. While $Q$ is formally infinite on both the spine and fan of the null, the decay of $Q$ away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, $Q$ decays most slowly away from the spine/fan in the direction in which $|{\\bf B}|$ increases most slowly. In particular, this demonstrates that the extend...

  2. Investigation of nulling and subpulse drifting properties of PSR J1727$-$2739

    CERN Document Server

    Wen, Z G; Yuan, J P; Yan, W M; Manchester, R N; Yuen, R; Gajjar, V

    2016-01-01

    Aims. To make a detailed study of the nulling and subpulse drifting in PSR J1727$-$2739 for investigation of its radiation properties. Methods. The observations were carried out on 20 March, 2004 using the Parkes 64-m radio telescope, with a central frequency of 1518 MHz. A total of 5568 single pulses were analysed. Results. This pulsar shows well defined nulls with lengths lasting from 6 to 281 pulses and separated by burst phases ranging from 2 to 133 pulses. We estimate a nulling fraction of around 68\\%. No emission in the average pulse profile integrated over all null pulses is detected with significance above $3\\sigma$. Most transitions from nulls to bursts are within a few pulses, whereas the transitions from bursts to nulls exhibit two patterns of decay: decrease gradually or rapidly. In the burst phase, we find that there are two distinct subpulse drift modes with vertical spacing between the drift bands of $9.7 \\pm 1.6$ and $5.2 \\pm 0.9$ pulse periods, while sometimes there is a third mode with no su...

  3. Proving the achronal averaged null energy condition from the generalized second law

    International Nuclear Information System (INIS)

    A null line is a complete achronal null geodesic. It is proven that for any quantum fields minimally coupled to semiclassical Einstein gravity, the averaged null energy condition (ANEC) on null lines is a consequence of the generalized second law of thermodynamics for causal horizons. This result is shown to leading order in Planck's constant for perturbations to classical backgrounds satisfying the null energy condition. Auxiliary assumptions include CPT and the existence of a suitable renormalization scheme for the generalized entropy. Although the ANEC can be violated on general geodesics in curved spacetimes, as long as the ANEC holds on null lines there exist theorems showing that semiclassical gravity should satisfy positivity of energy, topological censorship, and should not admit closed timelike curves. It is pointed out that these theorems fail once the linearized graviton field is quantized, because then the renormalized shear-squared term in the Raychaudhuri equation can be negative. A 'shear-inclusive' generalization of the ANEC is proposed to remedy this, and is proven under an additional assumption about perturbations to horizons in classical general relativity.

  4. pyNSMC: A Python Module for Null-Space Monte Carlo Uncertainty Analysis

    Science.gov (United States)

    White, J.; Brakefield, L. K.

    2015-12-01

    The null-space monte carlo technique is a non-linear uncertainty analyses technique that is well-suited to high-dimensional inverse problems. While the technique is powerful, the existing workflow for completing null-space monte carlo is cumbersome, requiring the use of multiple commandline utilities, several sets of intermediate files and even a text editor. pyNSMC is an open-source python module that automates the workflow of null-space monte carlo uncertainty analyses. The module is fully compatible with the PEST and PEST++ software suites and leverages existing functionality of pyEMU, a python framework for linear-based uncertainty analyses. pyNSMC greatly simplifies the existing workflow for null-space monte carlo by taking advantage of object oriented design facilities in python. The core of pyNSMC is the ensemble class, which draws and stores realized random vectors and also provides functionality for exporting and visualizing results. By relieving users of the tedium associated with file handling and command line utility execution, pyNSMC instead focuses the user on the important steps and assumptions of null-space monte carlo analysis. Furthermore, pyNSMC facilitates learning through flow charts and results visualization, which are available at many points in the algorithm. The ease-of-use of the pyNSMC workflow is compared to the existing workflow for null-space monte carlo for a synthetic groundwater model with hundreds of estimable parameters.

  5. Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice.

    Science.gov (United States)

    Sclafani, Anthony; Touzani, Khalid; Ackroff, Karen

    2015-10-01

    The oral and post-oral actions of sugar and fat stimulate intake and condition flavor preferences in rodents through a process referred to as appetition. Ghrelin is implicated in food reward processing, and this study investigated its involvement in nutrient conditioning in mice. In Exp. 1 ghrelin receptor-null (GHSR-null) and C57BL/6 wildtype (WT) mice learned to prefer a flavor (CS+) mixed into 8% glucose over another flavor (CS-) mixed into a "sweeter" but non-nutritive 0.1% sucralose+saccharin (S+S) solution. In Exp. 2 treating WT mice with a ghrelin receptor antagonist [(D-Lys3)-GHRP-6] during flavor training did not prevent them from learning to prefer the CS+ glucose over the CS-S+S flavor. GHSR-null and WT mice were trained in Exp. 3 to drink a CS+ paired with intragastric (IG) infusion of 16% glucose and a CS- paired with IG water. Both groups drank more CS+ than CS- in training and preferred the CS+ to CS- in a choice test. The same (Exp. 4) and new (Exp. 5) GHSR-null and WT mice learned to prefer a CS+ flavor paired with IG fat (Intralipid) over a CS- flavor paired with IG water. GHSR-null and WT mice also learned to prefer a CS+ flavor added to 8% fructose over a CS- added to water. Together, these results indicate that ghrelin receptor signaling is not required for flavor preferences conditioned by the oral or post-oral actions of sugar and fat. This contrasts with other findings implicating ghrelin signaling in food reward processing and food-conditioned place preferences. PMID:26003495

  6. Nanomechanical phenotype of chondroadherin-null murine articular cartilage.

    Science.gov (United States)

    Batista, Michael A; Nia, Hadi T; Önnerfjord, Patrik; Cox, Karen A; Ortiz, Christine; Grodzinsky, Alan J; Heinegård, Dick; Han, Lin

    2014-09-01

    Chondroadherin (CHAD), a class IV small leucine rich proteoglycan/protein (SLRP), was hypothesized to play important roles in regulating chondrocyte signaling and cartilage homeostasis. However, its roles in cartilage development and function are not well understood, and no major osteoarthritis-like phenotype was found in the murine model with CHAD genetically deleted (CHAD(-/-)). In this study, we used atomic force microscopy (AFM)-based nanoindentation to quantify the effects of CHAD deletion on changes in the biomechanical function of murine cartilage. In comparison to wild-type (WT) mice, CHAD-deletion resulted in a significant ≈70-80% reduction in the indentation modulus, Eind, of the superficial zone knee cartilage of 11 weeks, 4 months and 1 year old animals. This mechanical phenotype correlates well with observed increases in the heterogeneity collagen fibril diameters in the surface zone. The results suggest that CHAD mainly plays a major role in regulating the formation of the collagen fibrillar network during the early skeletal development. In contrast, CHAD-deletion had no appreciable effects on the indentation mechanics of middle/deep zone cartilage, likely due to the dominating role of aggrecan in the middle/deep zone. The presence of significant rate dependence of the indentation stiffness in both WT and CHAD(-/-) knee cartilage suggested the importance of both fluid flow induced poroelasticity and intrinsic viscoelasticity in murine cartilage biomechanical properties. Furthermore, the marked differences in the nanomechanical behavior of WT versus CHAD(-/-) cartilage contrasted sharply with the relative absence of overt differences in histological appearance. These observations highlight the sensitivity of nanomechanical tools in evaluating structural and mechanical phenotypes in transgenic mice. PMID:24892719

  7. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

    OpenAIRE

    Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J.; Willson, Timothy M.; Edwards, Peter A.

    2006-01-01

    Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. W...

  8. Chronic Exposure to Rifaximin Causes Hepatic Steatosis in Pregnane X Receptor-Humanized Mice

    OpenAIRE

    Cheng, Jie; Krausz, Kristopher W.; Tanaka, Naoki; Gonzalez, Frank, J.

    2012-01-01

    Rifaximin, a nonsystemic antibiotic that exhibits low gastrointestinal absorption, is a potent agonist of human pregnane X receptor (PXR), which contributes to its therapeutic efficacy in inflammatory bowel disease. To investigate the effects of long-term administration of rifaximin on the liver, PXR-humanized mice were administered rifaximin for 6 months; wild-type and Pxr-null mice were treated in parallel as controls. Histological analysis revealed time-dependent intense hepatocellular fat...

  9. The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice

    OpenAIRE

    Barron, Martin J.; Brookes, Steven J.; Draper, Clare E.; Garrod, David; Kirkham, Jennifer; Shore, Roger C.; Dixon, Michael J

    2008-01-01

    Nectin-1 is a member of a sub-family of immunoglobulin-like adhesion molecules and a component of adherens junctions. In the current study, we have shown that mice lacking nectin-1 exhibit defective enamel formation in their incisor teeth. Although the incisors of nectin-1-null mice were hypomineralized, the protein composition of the enamel matrix was unaltered. While strong immunostaining for nectin-1 was observed at the interface between the maturation-stage ameloblasts and the underlying ...

  10. Working memory deficits in retinoid X receptor γ-deficient mice

    OpenAIRE

    Wietrzych, Marta; Meziane, Hamid; Sutter, Anne; Ghyselinck, Norbert; Chapman, Paul F.; Chambon, Pierre; Krȩżel, Wojciech

    2005-01-01

    Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RARβ and RXRγ. Double mutants appeared deficient in spatial working memory as tested in spontaneous alternation in the Y-maze and delayed nonmatch to place (DNMTP) test in the T-maze. These mutant mice did acq...

  11. Defective Differentiation of Adipose Precursor Cells from Lipodystrophic Mice Lacking Perilipin 1

    OpenAIRE

    Ying Lyu; Xueying Su; Jingna Deng; Shangxin Liu; Liangqiang Zou; Xiaojing Zhao; Suning Wei; Bin Geng; Guoheng Xu

    2015-01-01

    Perilipin 1 (Plin1) localizes at the surface of lipid droplets to regulate triglyceride storage and hydrolysis in adipocytes. Plin1 defect leads to low adiposity in mice and partial lipodystrophy in human. This study investigated the roles of Plin1 in adipocyte differentiation. Plin1 null (-/-) mice showed plenty of multilocular adipocytes and small unilocular adipocytes in adipose tissue, along with lack of a subpopulation of adipose progenitor cells capable of in vivo adipogenesis and along...

  12. Attenuated Host Resistance against Mycobacterium bovis BCG Infection in Mice Lacking Osteopontin

    OpenAIRE

    Nau, Gerard J.; Liaw, Lucy; Chupp, Geoffrey L.; Berman, Jeffrey S.; Hogan, Brigid L.M.; Young, Richard A.

    1999-01-01

    Expression of the cytokine osteopontin (OPN) is elevated in granulomas caused by Mycobacterium tuberculosis. We tested the hypothesis that OPN contributes to host protection in a mouse model of mycobacterial infection. When infected with Mycobacterium bovis BCG, mice lacking a functional OPN gene had more severe infections characterized by heavier bacterial loads and a delayed clearance of the bacteria. The OPN-null mice had greater granuloma burdens consistent with the elevated bacterial loa...

  13. SIRTI deficiency in mice impairs energy balance by disrupting hypothalamic melanocortin signaling

    Science.gov (United States)

    The NAD+-dependent deacetylase SIRT1 is induced to adjust energy metabolism in response to caloric restriction and probably mediates mammalian longevity. Due to extremely high rates of SIRT1-null neonatal mice, the physiological significance of SIRT1 has not been fully defined in whole-body energy h...

  14. Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice

    OpenAIRE

    Yao, Jun; Li, Cheng-Gang; Gong, Li-kun; FENG, CHEN-CHEN; Li, Chun-zhu; Gao, Man; Luan, Yang; Qi, Xin-ming; Ren, Jin

    2013-01-01

    Aim: Monocrotaline (MCT) in plants of the genus Crotalaria induces significant toxicity in multiple organs including the liver, lung and kidney. Metabolic activation of MCT is required for MCT-induced toxicity. In this study, we attempted to determine whether the toxicity of MCT in kidney was a consequence of the metabolic activation of MCT in the liver. Methods: Liver-specific cytochrome P450 reductase-null (Null) mice, wild-type (WT) mice and CYP3A inhibitor ketoconazole-pretreated WT (KET-...

  15. Averaged null energy condition and difference inequalities in quantum field theory

    International Nuclear Information System (INIS)

    For a large class of quantum states, all local (pointwise) energy conditions widely used in relativity are violated by the renormalized stress-energy tensor of a quantum field. In contrast, certain nonlocal positivity constraints on the quantum stress-energy tensor might hold quite generally, and this possibility has received considerable attention in recent years. In particular, it is now known that the averaged null energy condition, the condition that the null-null component of the stress-energy tensor integrated along a complete null geodesic is non-negative for all states, holds quite generally in a wide class of spacetimes for a minimally coupled scalar field. Apart from the specific class of spacetimes considered (mainly two-dimensional spacetimes and four-dimensional Minkowski space), the most significant restriction on this result is that the null geodesic over which the average is taken must be achronal. Recently, Ford and Roman have explored this restriction in two-dimensional flat spacetime, and discovered that in a flat cylindrical space, although the stress energy tensor itself fails to satisfy the averaged null energy condition (ANEC) along the (nonachronal) null geodesics, when the ''Casimir-vacuum'' contribution is subtracted from the stress-energy the resulting tensor does satisfy the ANEC inequality. Ford and Roman name this class of constraints on the quantum stress-energy tensor ''difference inequalities.'' Here I give a proof of the difference inequality for a minimally coupled massless scalar field in an arbitrary (globally hyperbolic) two-dimensional spacetime, using the same techniques as those we relied on to prove the ANEC in an earlier paper with Wald. I begin with an overview of averaged energy conditions in quantum field theory

  16. Altered Ca2+ kinetics associated with α-actinin-3 deficiency may explain positive selection for ACTN3 null allele in human evolution.

    Science.gov (United States)

    Head, Stewart I; Chan, Stephen; Houweling, Peter J; Quinlan, Kate G R; Murphy, Robyn; Wagner, Sören; Friedrich, Oliver; North, Kathryn N

    2015-01-01

    Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common null polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 null variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more "energy efficient" in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of Actn3 KO mice showed: (i) an increased rate of decay of the twitch transient; (ii) a fourfold increase in the rate of SR Ca2+ leak; (iii) a threefold increase in the rate of SR Ca2+ pumping; and (iv) enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X null allele in populations living in cold environments during recent

  17. Altered Ca2+ kinetics associated with α-actinin-3 deficiency may explain positive selection for ACTN3 null allele in human evolution.

    Directory of Open Access Journals (Sweden)

    Stewart I Head

    Full Text Available Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common null polymorphism (R577X in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 null variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more "energy efficient" in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of Actn3 KO mice showed: (i an increased rate of decay of the twitch transient; (ii a fourfold increase in the rate of SR Ca2+ leak; (iii a threefold increase in the rate of SR Ca2+ pumping; and (iv enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X null allele in populations living in cold environments

  18. Üheksa nulli : null null null null null null null... / Anthony de Kowalsky

    Index Scriptorium Estoniae

    Kowalsky, Anthony de

    2008-01-01

    Lühiarvustus 18.- 20. 07. Põlvamaal Intsikurmu laululaval etendunud vabaõhulavastusele "Üheksa nulliga Eesti". Stsenaariumi on kirjutanud Kadri Pettai, Aapo Ilves, Olavi Ruitlane ja Veiko Märka. Lavastanud Reeda Toots

  19. Current singularities at quasi-separatrix layers and three-dimensional magnetic nulls

    Energy Technology Data Exchange (ETDEWEB)

    Craig, I. J. D.; Effenberger, Frederic, E-mail: feffen@waikato.ac.nz [Department of Mathematics, University of Waikato, P.B. 3105, Hamilton (New Zealand)

    2014-11-10

    The open problem of how singular current structures form in line-tied, three-dimensional magnetic fields is addressed. A Lagrangian magneto-frictional relaxation method is employed to model the field evolution toward the final near-singular state. Our starting point is an exact force-free solution of the governing magnetohydrodynamic equations that is sufficiently general to allow for topological features like magnetic nulls to be inside or outside the computational domain, depending on a simple set of parameters. Quasi-separatrix layers (QSLs) are present in these structures and, together with the magnetic nulls, they significantly influence the accumulation of current. It is shown that perturbations affecting the lateral boundaries of the configuration lead not only to collapse around the magnetic null but also to significant QSL currents. Our results show that once a magnetic null is present, the developing currents are always attracted to that specific location and show a much stronger scaling with resolution than the currents that form along the QSL. In particular, the null-point scalings can be consistent with models of 'fast' reconnection. The QSL currents also appear to be unbounded but give rise to weaker singularities, independent of the perturbation amplitude.

  20. Teleparallelism as a universal connection on null hypersurfaces in general relativity

    Science.gov (United States)

    Mazur, P. O.; Sokolowski, L. M.

    1986-01-01

    It is shown that a close relationship between the inner geometry of a null hypersurface N3 and the Newman-Penrose (NP) (1962, 1963) spin coefficient formalism exists. Projecting the null complex NP tetrad onto N3, two triads of basis vectors in N3 are obtained. The inner geometry of N3 is based on the assumption that these vectors are parallelly transported along the surface; this gives rise to the teleparallel connection as a metric nonsymmetric affine connection. The gauge freedom for the choice of the basis triads is given by the isotropy subgroup of the local Lorentz group leaving invariant the direction of the null generators of N3, and teleparallelism is determined by the equivalence class of the basis triads with respect to the global gauge group. Nine of the twelve NP coefficients are identified as the triad components of the torsion and the second fundamental form of N3. The resulting generalized Gauss-Codazzi equations are identical to nine of the NP equations, i.e., to the half of the Ricci identities. This result gives a geometrical meaning to the entire formalism. Finally a general proof of Penrose's theorem that the shear of the null generators of N3 is the only initial null datum for a gravitational field on N3 is presented.

  1. A Null Space Control of Two Wheels Driven Mobile Manipulator Using Passivity Theory

    Science.gov (United States)

    Shibata, Tsuyoshi; Murakami, Toshiyuki

    This paper describes a control strategy of null space motion of a two wheels driven mobile manipulator. Recently, robot is utilized in various industrial fields and it is preferable for the robot manipulator to have multiple degrees of freedom motion. Several studies of kinematics for null space motion have been proposed. However stability analysis of null space motion is not enough. Furthermore, these approaches apply to stable systems, but they do not apply unstable systems. Then, in this research, base of manipulator equips with two wheels driven mobile robot. This robot is called two wheels driven mobile manipulator, which becomes unstable system. In the proposed approach, a control design of null space uses passivity based stabilizing. A proposed controller is decided so that closed-loop system of robot dynamics satisfies passivity. This is passivity based control. Then, control strategy is that stabilizing of the robot system applies to work space observer based approach and null space control while keeping end-effector position. The validity of the proposed approach is verified by simulations and experiments of two wheels driven mobile manipulator.

  2. First-Order Adaptive Azimuthal Null-Steering for the Suppression of Two Directional Interferers

    Directory of Open Access Journals (Sweden)

    Derkx RenéMM

    2010-01-01

    Full Text Available Abstract An azimuth steerable first-order superdirectional microphone response can be constructed by a linear combination of three eigenbeams: a monopole and two orthogonal dipoles. Although the response of a (rotation symmetric first-order response can only exhibit a single null, we will look at a slice through this beampattern lying in the azimuthal plane. In this way, we can define maximally two nulls in the azimuthal plane which are symmetric with respect to the main-lobe axis. By placing these two nulls on maximally two directional sources to be rejected and compensating for the drop in level for the desired direction, we can effectively reject these directional sources without attenuating the desired source. We present an adaptive null-steering scheme for adjusting the beampattern so as to obtain this suppression of the two directional interferers automatically. Closed-form expressions for this optimal null-steering are derived, enabling the computation of the azimuthal angles of the interferers. It is shown that the proposed technique has a good directivity index when the angular difference between the desired source and each directional interferer is at least 90 degrees.

  3. First-Order Adaptive Azimuthal Null-Steering for the Suppression of Two Directional Interferers

    Science.gov (United States)

    Derkx, René M. M.

    2010-12-01

    An azimuth steerable first-order superdirectional microphone response can be constructed by a linear combination of three eigenbeams: a monopole and two orthogonal dipoles. Although the response of a (rotation symmetric) first-order response can only exhibit a single null, we will look at a slice through this beampattern lying in the azimuthal plane. In this way, we can define maximally two nulls in the azimuthal plane which are symmetric with respect to the main-lobe axis. By placing these two nulls on maximally two directional sources to be rejected and compensating for the drop in level for the desired direction, we can effectively reject these directional sources without attenuating the desired source. We present an adaptive null-steering scheme for adjusting the beampattern so as to obtain this suppression of the two directional interferers automatically. Closed-form expressions for this optimal null-steering are derived, enabling the computation of the azimuthal angles of the interferers. It is shown that the proposed technique has a good directivity index when the angular difference between the desired source and each directional interferer is at least 90 degrees.

  4. Cluster Observation of Electrostatic Solitary Waves around Magnetic Null Point in Thin Current Sheet

    International Nuclear Information System (INIS)

    Electrostatic solitary waves (ESWs) are observed in the vicinity of the magnetic null of the widely studied magnetic reconnection taking place at the near-earth tail when current sheet becomes dramatic thinning during substorm time on 1 October 2001. We use the Imada method for the 2-D reconnection model and study the characteristics of ESWs near the X-line region and the magnetic null points. The result shows that the amplitude of the observed ESWs in the vicinity of X-line region ranges from 0.1 mV/m to 5 mV/m, and the amplitude is larger near the magnetic null points. The generation mechanism and the role of ESWs associated with magnetic reconnection are also discussed. (geophysics, astronomy, and astrophysics)

  5. TPF Planet Detection Testbed: demonstrating deep, stable nulling and planet detection

    Science.gov (United States)

    Martin, Stefan

    2005-01-01

    The design of a testbed being built at the Jet Propulsion Laboratory is described. Simulatiung a dual chopped Bracewell interferometer, the testbed comprises a four beam star and planet source and nulling beam combiner. Since achieving a stable null is of great concern the testbed has many control systems designed to achieve stability of alignment and optical path difference over long periods of time. Comparisons between the testbed and the flight system are drawn and key performance parameters are discussed. The interaction between designs for phaseplate systems that achromatically invert the electric field of one of each pair of the incoming beams to achieve the null and the choice of fringe tracking schemes is also discussed.

  6. Nulling interferometry: performance comparison between Antarctica and other ground-based sites

    CERN Document Server

    Absil, O; Barillot, M; Swain, M R

    2007-01-01

    Detecting the presence of circumstellar dust around nearby solar-type main sequence stars is an important pre-requisite for the design of future life-finding space missions such as ESA's Darwin or NASA's Terrestrial Planet Finder (TPF). The high Antarctic plateau may provide appropriate conditions to perform such a survey from the ground. We investigate the performance of a nulling interferometer optimised for the detection of exozodiacal discs at Dome C, on the high Antarctic plateau, and compare it to the expected performance of similar instruments at temperate sites. Based on the currently available measurements of the turbulence characteristics at Dome C, we adapt the GENIEsim software (Absil et al. 2006, A&A 448) to simulate the performance of a nulling interferometer on the high Antarctic plateau. To feed a realistic instrumental configuration into the simulator, we propose a conceptual design for ALADDIN, the Antarctic L-band Astrophysics Discovery Demonstrator for Interferometric Nulling. We assum...

  7. Quasi-local mass at the null infinity of the Vaidya spacetime

    CERN Document Server

    Chen, Po-Ning; Yau, Shing-Tung

    2016-01-01

    There are two important statements regarding the Trautman-Bondi mass [1,8,5] at null infinity: one is the positivity [7,6], and the other is the Bondi mass loss formula [1], which are both global in nature. The positivity of the quasi-local mass can potentially lead to a local description at null infinity. This is confirmed for the Vaidya spacetime in this note. We study the Wang-Yau quasi-local mass on surfaces of fixed size at the null infinity of the Vaidya spacetime. The optimal embedding equation is solved explicitly and the quasi-local mass is evaluated in terms of the mass aspect function of the Vaidya spacetime.

  8. Kerr/Fluid Duality and Caustics of Null Geodesics on a Horizon

    CERN Document Server

    Fujisawa, Ippei

    2015-01-01

    An equation for a viscous incompressible fluid on a spheroidal surface which is dual to the perturbation around the near-near horizon extreme Kerr (n-NHEK) black hole is derived. It is also shown that an expansion scalar $\\theta$ of a congruence of null geodesics on the null horizon of the perturbed n-NHEK spacetime, which is dual to a viscous incompressible fluid, is not positive semi-definite, even if initial conditions on the velocity are smooth. Unless initial conditions are elaborated, caustics of null congruence will occur on the horizon in the future. A similar result is obtained for a perturbed Schwarzschild black hole spacetime which is dual to a viscous incompressible fluid on $S^2$. An initial condition that $\\theta$ be positive semi-definite at any point on $S^2$ is a necessary condition for the existence of smooth solutions to incompressible Navier-Stokes equation on $S^2$.

  9. Shear Nulling after PSF Gaussianisation: moment-based weak lensing measurements with subpercent noise bias

    CERN Document Server

    Herbonnet, Ricardo; Kuijken, Konrad

    2016-01-01

    Current optical imaging surveys for cosmology are covering large areas of sky. To exploit the statistical power of these surveys for weak lensing measurements requires shape measurement methods with subpercent systematic errors. We introduce a new weak lensing shear measurement algorithm, Shear Nulling after PSF Gaussianisation (SNAPG), designed to avoid the noise biases that affect most other methods. SNAPG operates on images that have been convolved with a kernel that renders the Point Spread Function (PSF) a circular Gaussian, and uses weighted second moments of the sources. The response of such second moments to a shear of the pre-seeing galaxy image can be predicted analytically, allowing us to construct a shear nulling scheme that finds the shear parameters for which the observed galaxies are consistent with an unsheared, isotropically oriented population of sources. The inverse of this nulling shear is then an estimate of the gravitational lensing shear. We identify the uncertainty of the estimated cen...

  10. Observation of the lower hybrid waves near the three-dimensional null pair

    Institute of Scientific and Technical Information of China (English)

    A.; VAIVADS; M.; ANDRE

    2009-01-01

    Magnetic reconnection is a fundamental process in plasma,which is thought to play important roles both in laboratory and natural plasmas through affecting magnetic topology,heating and accelerating particles. During an event on Oct. 1st,2001,the Cluster tetrahedron circled around the magnetic reconnection region several times,and Xiao et al. first identified the null pair and found that the spectrum of the null-point oscillation shows the maximum power near the lower-hybrid frequency. In this paper we report the observation of electromagnetic and electrostatic wave enhancements near lower hybrid frequency associated with the reconnection process near the null pair. The lower hybrid waves(LHWs) with quasi-perpendicular propagation were identified and also confirmed by the power law of the spectrum of electric and magnetic fields.

  11. Impact of criticism of null-hypothesis significance testing on statistical reporting practices in conservation biology.

    Science.gov (United States)

    Fidler, Fiona; Burgman, Mark A; Cumming, Geoff; Buttrose, Robert; Thomason, Neil

    2006-10-01

    Over the last decade, criticisms of null-hypothesis significance testing have grown dramatically, and several alternative practices, such as confidence intervals, information theoretic, and Bayesian methods, have been advocated. Have these calls for change had an impact on the statistical reporting practices in conservation biology? In 2000 and 2001, 92% of sampled articles in Conservation Biology and Biological Conservation reported results of null-hypothesis tests. In 2005 this figure dropped to 78%. There were corresponding increases in the use of confidence intervals, information theoretic, and Bayesian techniques. Of those articles reporting null-hypothesis testing--which still easily constitute the majority--very few report statistical power (8%) and many misinterpret statistical nonsignificance as evidence for no effect (63%). Overall, results of our survey show some improvements in statistical practice, but further efforts are clearly required to move the discipline toward improved practices. PMID:17002771

  12. Forge-Hardened TiZr Null-Matrix Alloy for Neutron Scattering under Extreme Conditions

    Directory of Open Access Journals (Sweden)

    Takuo Okuchi

    2015-12-01

    Full Text Available For neutron scattering research that is performed under extreme conditions, such as high static pressures, high-strength metals that are transparent to the neutron beam are required. The diffraction of the neutron beam by the metal, which follows Bragg’s law, can be completely removed by alloying two metallic elements that have coherent scattering lengths with opposite signs. An alloy of Ti and Zr, which is known as a TiZr null-matrix alloy, is an ideal combination for such purposes. In this study, we increased the hardness of a TiZr null-matrix alloy via extensive mechanical deformation at high temperatures. We successfully used the resulting product in a high-pressure cell designed for high-static-pressure neutron scattering. This hardened TiZr null-matrix alloy may play a complementary role to normal TiZr alloy in future neutron scattering research under extreme conditions.

  13. The symplectic 2-form for gravity in terms of free null initial data

    International Nuclear Information System (INIS)

    A hypersurface N formed of two null sheets, or ‘light fronts’, swept out by the future null normal geodesics emerging from a common spacelike 2-disc can serve as a Cauchy surface for a region of spacetime. Already in the 1960s, free (unconstrained) initial data for general relativity were found for such hypersurfaces. Here, an expression is obtained for the symplectic 2-form of vacuum general relativity in terms of such free data. This can be done, even though variations of the geometry do not in general preserve the nullness of the initial hypersurface, because of the diffeomorphism gauge invariance of general relativity. The present expression for the symplectic 2-form has been used previously (Reisenberger 2008 Phys. Rev. Lett. 101 211101) to calculate the Poisson brackets of the free data. (paper)

  14. Phase Retrieval with One or Two Diffraction Patterns by Alternating Projections of the Null Vector

    CERN Document Server

    Chen, Pengwen; Liu, Gi-Ren

    2015-01-01

    Two versions of alternating projection (AP), the parallel alternating projection (PAP) and the serial alternating projection (SAP), are proposed to solve phase retrieval with at most two coded diffraction patterns. The proofs of geometric convergence are given with sharp bounds on the rates of convergence in terms of a spectral gap condition. To compensate for the local nature of convergence, the null vector method is proposed for initialization and proved to produce asymptotically accurate initialization for the Gaussian case. Extensive numerical experiments are performed to show that the null vector method produces more accurate initialization than the spectral vector method and that PAP/SAP converge faster to more accurate solutions than other iterative schemes for non-convex optimization such as the Wirtinger flow. Moreover, SAP converges still faster than PAP. In practice AP and the null vector method together produce globally convergent iterates to the true object.

  15. Energetics of kinetic reconnection in a three-dimensional null points cluster

    CERN Document Server

    Olshevsky, Vyacheslav; Markidis, Stefano

    2015-01-01

    We performed three-dimensional Particle-in-Cell simulations of magnetic reconnection with multiple magnetic null points. Magnetic field energy conversion into kinetic energy was about five times higher than in traditional Harris sheet configuration. More than 85% of initial magnetic field energy was transferred to particle energy during 25 reversed ion cyclofrequencies. Magnetic reconnection in the cluster of null points evolved in three phases. During the first phase, ion beams were excited, that then gave part of their energy back to magnetic field in the second phase. In the third phase, magnetic reconnection occurs in many small patches around the current channels formed along the stripes of low magnetic field. Magnetic reconnection in null points presents essentially three-dimensional features, with no two dimensional symmetries or current sheets.

  16. Analysis of null sets (zero cat ch) made by the Mexican tuna pur se seine fleet (20002013)

    OpenAIRE

    Michel J Dreyfus-León; Adán Mejía-Trejo; Juan Carlos Villaseñor-Derbez

    2015-01-01

    The world tuna fishing fleet is dominated by purse seine boats . Purse seine sets are sometimes unsuccessful in capturing fish ; these unsuccessful attempts are known as null sets. Null sets h ave been widely documented and the numbers indicate that they h appen in large proportions. In Mexico, the tuna fishery represents the second most important fishery by volume and value. The frequency of oc currence of null sets during the period 20002013 wa s analyzed to identify the r egions, perio...

  17. Integration of Frequency Domain Wideband Antenna Nulling and Wavenumber Domain Image Formation for Multi-Channel SAR

    OpenAIRE

    Bucciarelli, M.; D. Pastina; Cristallini, D.; M. Sedehi; Lombardo, P.

    2016-01-01

    A Multichannel Synthetic Aperture Radar (M-SAR) exploiting an antenna nulling based Electronic Counter-Counter Measures (ECCM) technique shall be able to cancel the effects of noise-like interferences over the collected SAR data. Since SAR systems often work with wide bandwidths to provide high resolution images, ECCM technique must account for the presence of wideband interference signal. In this paper we consider a wideband antenna nulling technique based on space-frequency adaptive nulling...

  18. Balance recovery control for biped robot based on reaction null space method

    Institute of Scientific and Technical Information of China (English)

    Baoping WANG; Renxi HU; Jinming ZHANG; Chuangfeng HUAI

    2009-01-01

    A biped walking robot should be able to keep balance even in the presence of disturbing forces.This paper presents a step strategy concept of biped walking robot that is stabilized by using reaction null space method.The called "step strategy" can be modeled by means of the reaction null space method that introduced earlier to tackle dynamic interaction problems of free-floating robots,or moving base robots in general.6-DOF biped robot model simulations are used to confirm the validity.

  19. From GLC to double-null coordinates and illustration with static black holes

    CERN Document Server

    Nugier, Fabien

    2016-01-01

    We present a system of coordinates deriving directly from the so-called Geodesic Light-Cone (GLC) coordinates and made of two null scalars intersecting on a 2-dimensional sphere parameterized by two constant angles along geodesics. These coordinates are shown to be equivalent to the well-known double-null coordinates. As GLC, they present interesting properties for cosmology and astrophysics. We discuss this latter topic for static black holes, showing simple descriptions for the metric or particles and photons trajectories. We also briefly comment on the time of flight of ultra-relativistic particles.

  20. The symplectic 2-form for gravity in terms of free null initial data

    OpenAIRE

    Reisenberger, Michael P.

    2012-01-01

    A hypersurface formed of two null sheets, or "light fronts", swept out by the future null normal geodesics emerging from a common spacelike 2-disk can serve as a Cauchy surface for a region of spacetime. Already in the 1960s free (unconstrained) initial data for general relativity were found for such hypersurfaces. Here an expression is obtained for the symplectic 2-form of vacuum general relativity in terms of such free data. This can be done, even though variations of the geometry do not in...

  1. A Fortran Code for Null Geodesic Solutions in the Lemaitre-Tolman-Bondi Spacetime

    CERN Document Server

    Ribeiro, M B

    2002-01-01

    This paper describes the Fortran 77 code SIMU, version 1.1, designed for numerical simulations of observational relations along the past null geodesic in the Lemaitre-Tolman-Bondi (LTB) spacetime. SIMU aims at finding scale invariant solutions of the average density, but due to its full modularity it can be easily adapted to any application which requires LTB's null geodesic solutions. In version 1.1 the numerical output can be read by the GNUPLOT plotting package to produce a fully graphical output, although other plotting routines can be easily adapted. Details of the code's subroutines are discussed, and an example of its output is shown.

  2. Role of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: Studies with the hepatic NADPH:Cytochrome P450 reductase null mouse

    International Nuclear Information System (INIS)

    Ellipticine is an antineoplastic agent, which forms covalent DNA adducts mediated by cytochromes P450 (CYP) and peroxidases. We evaluated the role of hepatic versus extra-hepatic metabolism of ellipticine, using the HRN (Hepatic Cytochrome P450 Reductase Null) mouse model, in which cytochrome P450 oxidoreductase (POR) is deleted in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated i.p. with 1 and 10 mg/kg body weight of ellipticine. Multiple ellipticine-DNA adducts detected by 32P-postlabelling were observed in organs from both mouse strains. Highest total DNA binding levels were found in liver, followed by lung, kidney, urinary bladder, colon and spleen. Ellipticine-DNA adduct levels in the liver of HRN mice were up to 65% lower relative to WT mice, confirming the importance of CYP enzymes for the activation of ellipticine in livers, recently shown in vitro with human and rat hepatic microsomes. When hepatic microsomes of both mouse strains were incubated with ellipticine, ellipticine-DNA adduct levels with WT microsomes were up to 2.9-fold higher than with those from HRN mice. The ratios of ellipticine-DNA adducts in extra-hepatic organs between HRN and WT mice of up to 4.7 suggest that these organs can activate ellipticine and that more ellipticine is available in the circulation. These results and the DNA adduct patterns found in vitro and in vivo demonstrate that both CYP1A or 3A and peroxidases participate in activation of ellipticine to reactive species forming DNA adducts in the mouse model used in this study

  3. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.

    Science.gov (United States)

    Zhou, Z; Apte, S S; Soininen, R; Cao, R; Baaklini, G Y; Rauser, R W; Wang, J; Cao, Y; Tryggvason, K

    2000-04-11

    Membrane-type matrix metalloproteinase I (MT1-MMP)-deficient mice were found to have severe defects in skeletal development and angiogenesis. The craniofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and death by 3 wk of age. Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates. Defective vascular invasion of cartilage leads to enlargement of hypertrophic zones of growth plates and delayed formation of secondary ossification centers in long bones. In an in vivo corneal angiogenesis assay, null mice did not have angiogenic response to implanted FGF-2, suggesting that the defect in angiogenesis is not restricted to cartilage alone. In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo. PMID:10737763

  4. Exposure to DEHP decreased four fatty acid levels in plasma of prepartum mice

    International Nuclear Information System (INIS)

    Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) decreased the plasma triglyceride in prepartum mice. To identify the fatty acid (FA) species involved and to understand the underlying mechanisms, pregnant Sv/129 wild-type (mPPARα), peroxisome proliferator-activated receptor α-null (Pparα-null) and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% or 0.1% DEHP. Dams were dissected on gestational day 18 together with fetuses, and on postnatal day 2 together with newborns. n-3/n-6 polyunsaturated, saturated, and monounsaturated FAs in maternal plasma and in liver of wild-type offspring, and representative enzymes for FA desaturation and elongation in maternal liver, were measured. The plasma levels of linoleic acid, α-linolenic acid, palmitic acid and oleic acid were higher in the pregnant control mPPARa mice than in Ppara-null and hPPARa mice. DEHP exposure significantly decreased the levels of these four FAs only in pregnant mPPARα mice. Plasma levels of many FAs were higher in pregnant mice than in postpartum ones in a genotype-independent manner, while it was lower in the livers of fetuses than pups. DEHP exposure slightly increased hepatic arachidonic acid, α-linolenic acid, palmitoleic acid and oleic acid in fetuses, but not in pups. However, DEHP exposure did not clearly influence FA desaturase 1 and 2 nor elongase 2 and 5 expressions in the liver of all maternal mice. Taken together, the levels of plasma four FAs with shorter carbon chains were higher in pregnant mPPARα mice than in other genotypes, and DEHP exposure decreased these specific FA concentrations only in mPPARα mice, similarly to triglyceride levels

  5. Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication.

    Directory of Open Access Journals (Sweden)

    Paul D Bozyk

    Full Text Available In bronchopulmonary dysplasia (BPD, alveolar septae are thickened with collagen and α-smooth muscle actin, transforming growth factor (TGF-β-positive myofibroblasts. Periostin, a secreted extracellular matrix protein, is involved in TGF-β-mediated fibrosis and myofibroblast differentiation. We hypothesized that periostin expression is required for hypoalveolarization and interstitial fibrosis in hyperoxia-exposed neonatal mice, an animal model for this disease. We also examined periostin expression in neonatal lung mesenchymal stromal cells and lung tissue of hyperoxia-exposed neonatal mice and human infants with BPD. Two-to-three day-old wild-type and periostin null mice were exposed to air or 75% oxygen for 14 days. Mesenchymal stromal cells were isolated from tracheal aspirates of premature infants. Hyperoxic exposure of neonatal mice increased alveolar wall periostin expression, particularly in areas of interstitial thickening. Periostin co-localized with α-smooth muscle actin, suggesting synthesis by myofibroblasts. A similar pattern was found in lung sections of infants dying of BPD. Unlike wild-type mice, hyperoxia-exposed periostin null mice did not show larger air spaces or α-smooth muscle-positive myofibroblasts. Compared to hyperoxia-exposed wild-type mice, hyperoxia-exposed periostin null mice also showed reduced lung mRNA expression of α-smooth muscle actin, elastin, CXCL1, CXCL2 and CCL4. TGF-β treatment increased mesenchymal stromal cell periostin expression, and periostin treatment increased TGF-β-mediated DNA synthesis and myofibroblast differentiation. We conclude that periostin expression is increased in the lungs of hyperoxia-exposed neonatal mice and infants with BPD, and is required for hyperoxia-induced hypoalveolarization and interstitial fibrosis.

  6. Bone growth and turnover in progesterone receptor knockout mice.

    Energy Technology Data Exchange (ETDEWEB)

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jaime C.; Waters, Katrina M.; Lydon, John P.; O' Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    2008-05-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bones of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.

  7. Acceleration of type 1 diabetes mellitus in proinsulin 2–deficient NOD mice

    OpenAIRE

    Thébault-Baumont, Karine; Dubois-Laforgue, Danielle; Krief, Patricia; Briand, Jean-Paul; Halbout, Philippe; Vallon-Geoffroy, Karine; Morin, Joëlle; Laloux, Véronique; Lehuen, Agnès; Carel, Jean-Claude; Jami, Jacques; Muller, Sylviane; Boitard, Christian

    2003-01-01

    Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2–deficient 129 mice onto the NOD background along with 16 genetic markers (including I-Ag7 MHC molecule) associated with diabetes. Intercross mice from the fourth backcross generatio...

  8. Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation

    DEFF Research Database (Denmark)

    Chidgey, M; Brakebusch, C; Gustafsson, E;

    2001-01-01

    epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human......The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate...

  9. Path Length Control in a Nulling Coronagraph with a MEMS Deformable Mirror and a Calibration Interferometer

    Science.gov (United States)

    Rao, Shanti R.; Wallacea, J. Kent; Samuele, Rocco; Chakrabarti, Supriya; Cook, Timothy; Hicks, Brian; Jung, Paul; Lane, Benjamin; Levine, B. Martin; Mendillo, Chris; Schmidtlin, Edouard; Shao, Mike; Stewart, Jason B.

    2008-01-01

    We report progress on a nulling coronagraph intended for direct imaging of extrasolar planets. White light is suppressed in an interferometer, and phase errors are measured by a second interferometer. A 1020-pixel MEMS deformable mirror in the first interferometer adjusts the path length across the pupil. A feedback control system reduces deflections of the deformable mirror to order of 1 nm rms.

  10. Quasi-local energy-momentum and energy flux at null infinity

    OpenAIRE

    Wu, Xiaoning; Chen, Chiang-Mei; Nester, James M.

    2005-01-01

    The null infinity limit of the gravitational energy-momentum and energy flux determined by the covariant Hamiltonian quasi-local expressions is evaluated using the NP spin coefficients. The reference contribution is considered by three different embedding approaches. All of them give the expected Bondi energy and energy flux.

  11. The frequency of GSTT1 null genotype in Turkish population and lung cancer risk

    Directory of Open Access Journals (Sweden)

    Demir A

    2005-01-01

    Full Text Available BACKGROUND : Previous studies have suggested that Glutathione S -transferase (GST genotypes may play a role in determining susceptibility to lung cancer, though the data are often conflicting. In different ethnic groups variations in null allele frequency has been observed. AIMS: We aimed to evaluate whether genetic polymorphisms of Glutathione S -transferase theta (GSTT1 influence individual susceptibility to lung cancer in Turkish population. We tried to clarify the frequencies of GSTM1 gene polymorphisms in a Turkish population. METHODS: DNA samples, extracted from the whole blood were amplified using polymerase chain reaction (PCR method in all of the 68 cases, composed of 31 previously diagnosed lung cancer and 37 healthy controls. RESULTS: The prevalence of GSTT1 null genotype in the lung cancer patients was 29%, compared to 11% in control group. GSTT1 null genotype was found to be higher in cancer group compared to the control group, although it was not statistically significant (OR = 3.37, 95% CI = 0.92-12.32, P = 0.06. There was also no significant relation in GSTT1 genotypes among histopathology types of lung cancers. The frequency of GSTT1 was found to be 25.4% ( n = 952 when the studies of Turkish population were reviewed. CONCLUSION: It can be concluded that carrying the GSTT1 null genotype may be accepted as a weak risk factor for the susceptibility to lung cancer.

  12. Determination of the true null electrode spacing of an extrapolation chamber for X-ray dosimetry

    International Nuclear Information System (INIS)

    An accurate determination of the actual null distance is critical for the establishment of primary measurement method for absorbed dose in tissue, since the concept of the true null electrode spacing is used to define the sensitive volume of an extrapolation chamber. In this paper, a critical analysis of two methodologies for determining the true null electrode spacing of an extrapolation chamber was done. Firstly, the ionization current as a function of electrode spacing was measured in ISO 4037 low energy X-ray beams. In the second procedure, a LC Bridge was used to measure the capacitance between the electrodes of a 23392 Böhm model PTW ionization chamber and a reliable relationship between capacitance and relative distance was established. Results showed that the true null spacing values varied from 0.0015 to 0.38 mm. Since capacitance meters with high resolution are not always available in calibration laboratories, the second method showed values with large uncertainties. The first method proved to be highly sensitive to the quality of the X-ray beams used. (author)

  13. Stable deep nulling in polychromatic unpolarized light with multiaxial beam combination.

    Science.gov (United States)

    Buisset, Christophe; Rejeaunier, Xavier; Rabbia, Yves; Barillot, Marc

    2007-11-10

    In the context of the space-based nulling mission ESA-Darwin, Thales Alenia Space has developed a nulling breadboard for the European Space Agency (ESA): the multiaperture imaging interferometer (MAII) to demonstrate deep and stable nulling and to investigate various subsystems of the ESA-Darwin interferometer. Recently, we have extended our investigations to the multiaxial beam combination. This combination scheme presents many advantages: simplicity, compactness, and a high coupling efficiency for a three-beam combination. The near-infrared (lambda approximately 1.55 microm) MAII breadboard has been upgraded to the multiaxial beam combination. Polarization and stability issues have been thoroughly investigated. We report on the recent results we have obtained with the multiaxial configuration of MAII in unpolarized light with a relative spectral bandwidth of 5%: nulling ratios of mean value N=1.7 x 10(-5), stable over 1 h with a standard deviation sigma( N )=5.7 x 10(-7). These results indicate that the multiaxial beam combination has the potential to meet Darwin requirements. PMID:17994130

  14. Limit structure of Future Null Infinity tangent -- topology of the event horizon and gravitational wave tail

    CERN Document Server

    Tomizawa, S; Tomizawa, Shinya; Siino, Masaru

    2006-01-01

    We investigated the relation between the behavior of gravitational wave at late time and the limit structure of future null infinity tangent which will determine the topology of the event horizon far in the future. In the present article, we mainly consider a spacetime with two black holes. Although in most of cases, the black holes coalesce and its event horizon is topologically a single sphere far in the future, there are several possibilities that the black holes never coalesce and such exact solutions as examples. In our formulation, the tangent vector of future null infinity is, under conformal embedding, related to the number of black holes far in the future through the Poincar\\'e-Hopf's theorem. Under the conformal embedding, the topology of event horizon far in the future will be affected by the geometrical structure of the future null infinity. In this article, we related the behavior of Weyl curvature to this limit behavior of the generator vector of the future null infinity. We show if Weyl curvatu...

  15. Global Null Controllability of the 1-Dimensional Nonlinear Slow Diffusion Equation

    Institute of Scientific and Technical Information of China (English)

    Jean-Michel CORON; Jesús Ildefonso D(I)AZ; Abdelmalek DRICI; Tommaso MINGAZZINI

    2013-01-01

    The authors prove the global null controllability for the 1-dimensional nonlinear slow diffusion equation by using both a boundary and an internal control.They assume that the internal control is only time dependent.The proof relies on the return method in combination with some local controllability results for nondegenerate equations and rescaling techniques.

  16. A critical discussion of null hypothesis significance testing and statistical power analysis within psychological research

    DEFF Research Database (Denmark)

    Jones, Allan; Sommerlund, Bo

    2007-01-01

    The uses of null hypothesis significance testing (NHST) and statistical power analysis within psychological research are critically discussed. The article looks at the problems of relying solely on NHST when dealing with small and large sample sizes. The use of power-analysis in estimating the...

  17. Propagation of errors from a null balance terahertz reflectometer to a sample's relative water content

    OpenAIRE

    Hadjiloucas, Sillas; Walker, Gillian Claire; Bowen, John Wesley; Zafiropoulos, Apostolos

    2009-01-01

    The THz water content index of a sample is defined and advantages in using such metric in estimating a sample's relative water content are discussed. The errors from reflectance measurements performed at two different THz frequencies using a quasi-optical null-balance reflectometer are propagated to the errors in estimating the sample water content index.

  18. Development of IR single mode optical fibers for DARWIN-nulling interferometry

    NARCIS (Netherlands)

    Chakkalakkal Abdulla, S.M.; Cheng, L.K.; Bosch, B. van den; Dijkhuizen, N.; Nieuwland, R.A.; Gielesen, W.L.M.; Lucas, J.; Boussard-Plédel, C.; Conseil, C.; Bureau, B.; Carmo, J.P. do

    2014-01-01

    The DARWIN mission aims to detect weak infra-red emission lines from distant orbiting earth-like planets using nulling interferometry. This requires filtering of wavefront errors using single mode waveguides operating at a wavelength range of 6.5-20 μm. This article describes the optical design of t

  19. Numerical Study of the Gravitational and Electromagnetic Waves on the Null Cone

    Science.gov (United States)

    Babiuc, Maria

    2015-04-01

    The numerical calculation of the Einstein-Maxwell equations in a characteristic framework has not been done numerically before and is expected to shed new light on nonlinear phenomena like null memory. The main objective of this study is the analytical and numerical modeling of the of gravitational and electromagnetic radiation in a fully general relativistic framework, as it propagates on the null cone to null infinity, with no simplifications due to assumed symmetries. Moreover, the global interaction between the gravitational and electromagnetic radiation will be closely monitored, in order to reveal the electromagnetic radiation memory induced by the gravitational field. The numerical approach used, called the ``Cauchy-characteristic extraction'' method, is the most precise method for the computation of gravitational waveforms at infinite distance from a world-tube that encloses the source. The analytical and numerical models presented here will be implemented in the PittNull code, and the experience gained will be disseminated, in order to facilitate new standalone characteristic codes.This will lead to more insight on the interaction between gravitational and electromagnetic fields, and even point to new effects.

  20. A Panel Test of Purchasing Power Parity Under the Null of Stationarity

    OpenAIRE

    Hunter, J; Simpson, M.

    2001-01-01

    Purchasing Power Parity (PPP) is tested using a sample of real exchange rate data for twelve European countries. Acknowledging that Augmented Dickey Fuller tests have low power, we apply a Panel test that considers the null of stationarity and corrects for serial dependence using a non-parametric kernel based method.

  1. Active optics null test system based on a liquid crystal programmable spatial light modulator

    Energy Technology Data Exchange (ETDEWEB)

    Ares, Miguel; Royo, Santiago; Sergievskaya, Irina; Riu, Jordi

    2010-11-10

    We present an active null test system adapted to test lenses and wavefronts with complex shapes and strong local deformations. This system provides greater flexibility than conventional static null tests that match only a precisely positioned, individual wavefront. The system is based on a cylindrical Shack-Hartmann wavefront sensor, a commercial liquid crystal programmable phase modulator (PPM), which acts as the active null corrector, enabling the compensation of large strokes with high fidelity in a single iteration, and a spatial filter to remove unmodulated light when steep phase changes are compensated. We have evaluated the PPM's phase response at 635 nm and checked its performance by measuring its capability to generate different amounts of defocus aberration, finding root mean squared errors below {lambda}/18 for spherical wavefronts with peak-to-valley heights of up to 78.7{lambda}, which stands as the limit from which diffractive artifacts created by the PPM have been found to be critical under no spatial filtering. Results of a null test for a complex lens (an ophthalmic customized progressive addition lens) are presented and discussed.

  2. Preventive effects of metallothionein against DNA and lipid metabolic damages in dyslipidemic mice under repeated mild stress

    OpenAIRE

    Higashimoto, Minoru; Isoyama, Naohiro; Ishibashi, Satoshi; Ogawa, Naoko; Takiguchi, Masufumi; Suzuki, Shinya; Ohnishi, Yoshinari; Sato, Masao

    2013-01-01

    The effects of repeated mild stress on DNA and lipid metabolic damages in multiple organs of dyslipidemic mice, and the preventive role of metallothionein (MT) were investigated. Female adult wild-type and MT-null mice fed high-fat diet (HFD) or standard diet (STD) were repeatedly subjected to fasting or restraint for three weeks. The liver, pancreas, spleen, bone marrow and serum samples were taken for evaluating DNA damage, MT, glutathione (GSH), corticosterone, carnitine and adiponectin. B...

  3. Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice

    OpenAIRE

    Parry, David A.; Toomes, Carmel; Bida, Lina; Danciger, Michael; Towns, Katherine V.; McKibbin, Martin; Jacobson, Samuel G.; Logan, Clare V.; Ali, Manir; Bond, Jacquelyn; Chance, Rebecca; Swendeman, Steven; Daniele, Lauren L.; Springell, Kelly; Adams, Matthew

    2009-01-01

    Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical proc...

  4. Erythropoietic defect associated with reduced cell proliferation in mice lacking the 26S proteasome shuttling factor Rad23b

    NARCIS (Netherlands)

    S. Bergink (Steven); A.F. Theil (Arjan); W. Toussaint (Wendy); I.M. de Cuyper (Iris); D.I. Kulu (Divine); T. Clapes (Thomas); R. van der Linden (Reinier); J.A.A. Demmers (Jeroen); E.P. Mul (Eric); F.P. van Alphen (Floris); J.A. Marteijn (Jurgen); T. van Gent (Teus); A. Maas (Alex); C. Robin (Catherine); J.N.J. Philipsen (Sjaak); W. Vermeulen (Wim); J.R. Mitchell (James); L. Gutiérrez (Laura)

    2013-01-01

    textabstractRad23a and Rad23b proteins are linked to nucleotide excision DNA repair (NER) via association with the DNA damage recognition protein xeroderma pigmentosum group C (XPC) are and known to be implicated in protein turnover by the 26S proteasome. Rad23b-null mice are NER proficient, likely

  5. Erythropoietic Defect Associated with Reduced Cell Proliferation in Mice Lacking the 26S Proteasome Shuttling Factor Rad23b

    NARCIS (Netherlands)

    Bergink, Steven; Theil, Arjan F.; Toussaint, Wendy; De Cuyper, Iris M.; Kulu, Divine I.; Clapes, Thomas; van der Linden, Reinier; Demmers, Jeroen A.; Mul, Eric P.; van Alphen, Floris P.; Marteijn, Jurgen A.; van Gent, Teus; Maas, Alex; Robin, Catherine; Philipsen, Sjaak; Vermeulen, Wim; Mitchell, James R.; Gutierrez, Laura

    2013-01-01

    Rad23a and Rad23b proteins are linked to nucleotide excision DNA repair (NER) via association with the DNA damage recognition protein xeroderma pigmentosum group C (XPC) are and known to be implicated in protein turnover by the 26S proteasome. Rad23b-null mice are NER proficient, likely due to the r

  6. Isolation of two independent allyl alcohol resistant Adh-1 null mutants following selection of pollen and seeds.

    NARCIS (Netherlands)

    Wisman, E.; Ramanna, M.S.; Zabel, P.

    1993-01-01

    The Adh-1 null mutant (B15-1-8) isolated previously was used to establish conditions that allow the selection of ADH-deficient pollen grains and seeds of tomato. New Adh-1 null mutants were then selected among the progenies derived from crosses between the genetically unstable tomato lines Yvms, Sul

  7. Effects of Lipoxygenase Null Genes of Soybean in Controlling Beany-flavor of Soymilk and Soyflour

    Institute of Scientific and Technical Information of China (English)

    MA Hao; GUAN Chun-yun; HE Xiao-ling; ZHANG Guo-zheng; DIN An-lin

    2002-01-01

    The flavor of the soymilk and soyflour obtained from the lipoxygenase mutant isolines was concentrated by simultaneous distillation and extraction (SDE), and its constituents were identified by gas chromatography (GC) and gas chromatography-mass spectrometry. Results showed that the same 24 flavor constituents were isolated in both soymilk and soyflour, and most of them were aldehydes and alcohols. Lox2 was most responsible for the production of the volatile and beany-flavor components, and Lox1 less responsible.Lox3 was least responsible and can reduce the yield of hexanal. Either Lx1 or Lx2 could significantly reduce the volatile and beany-flavor, and Lx3 could significantly increase the yield of hexanal. Primary and secondary interactions existed among the null mutant genes, and the major effects and interactions could be affected by processing conditions. The isoline with triple lipoxygenase null genes yielded the least volatile and beany-flavor components, and the isoline without the lipoxygenase gene Lx3 produced the greatest amount of the volatile and beany-flavor components. The amounts of volatile and beany-flavor components produced by the other isolines were between that of the isoline with triple lipoxygenase null genes and the isoline without lipoxygenase gene Lx3. According to the correlation analysis, the hexanal amount could be used as an index in evaluating the importance of lipoxygenase isozymes in the yield of beany-flavor compounds, and the effects of the different types of lipoxygenase null mutants in controlling beany-flavor compounds. The cultivars with triple lipoxygenase null genes will be a quality raw material for soyfood processing.

  8. Humanized mice

    OpenAIRE

    Macchiarini, Francesca; Manz, Markus G.; Palucka, A Karolina; Shultz, Leonard D.

    2005-01-01

    Animal models have been instrumental in increasing the understanding of human physiology, particularly immunity. However, these animal models have been limited by practical considerations and genetic diversity. The creation of humanized mice that carry partial or complete human physiological systems may help overcome these obstacles. The National Institute of Allergy and Infectious Diseases convened a workshop on humanized mouse models for immunity in Bethesda, MD, on June 13–14, 2005, during...

  9. MICE Overview

    OpenAIRE

    Coney, L

    2009-01-01

    Muon ionization cooling provides the only practical solution for preparing high brightness beams necessary for a neutrino factory or muon collider. The Muon Ionization Cooling Experiment (MICE) is under development at the Rutherford Appleton Laboratory (UK). It comprises a dedicated beam line designed to generate a range of input emittances and momenta with time-of-flight and Cherenkov detectors to select a pure muon beam. A first measurement of emittance is performed in the upstream magnetic...

  10. Distinct luminal type mammary carcinomas arise from orthotopic Trp53 null mammary transplantation of juvenile versus adult mice

    OpenAIRE

    Nguyen, David H.; Ouyang, Haoxu; Mao, Jian-Hua; Hlatky, Lynn; Barcellos-Hoff, Mary Helen

    2014-01-01

    Age and physiological status, like menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently implanted dur...

  11. Effects on thyroid hormone and retinoid metabolism in transthyretin-null mice by polychlorinated biphenyl isomers 118 and 114

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, N.; Yonemoto, J.; Takeuchi, Y.; Yokoi, C.; Tohyama, C. [National Inst. for Environmental Studies, Tsukuba (Japan)

    2004-09-15

    Some congeners/isomers of polychlorinated biphenyls (PCBs) and their metabolites are known to disturb thyroid and retinoid metabolism in laboratory animals and humans. Among 209 isomers of PCBs, 12 PCB isomers termed as the coplanar PCBs are grouped into dioxin-like chemicals based on their resemblance of toxic effects and mechanism(s) to dioxins. Mechanism(s) of toxicity by the dioxin-like chemicals have been established to be mediated through aryl hydrocarbon receptor (AhR). The toxic potency of each congener/isomer of dioxin-like chemicals has been evaluated by relative potency to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the toxic equivalent factor (TEF). Because dioxins in environments are generally distributed as mixtures, the toxic equivalency (TEQ) concept has been adopted to evaluate the health risk of exposure to complex environmental mixtures. TEQ values are calculated by multiplication of the sum of the chemical concentrations by the corresponding TEF values. The present study was undertaken to investigate the effects of two coplanar PCBs, PCB118, highly detected in human tissues and milk (TEF value: 0.0001), and PCB114 (TEF value: 0.0005) on thyroid hormone and retinoid metabolism. Possible involvement of transthyretin (TTR), the principal carrier of thyroid hormone and retinol-binding protein in the rodent, in PCBs-induced disruption of thyroid and retinoid homeostasis was investigated.

  12. Increased Sensitivity of Glutathione S-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity

    OpenAIRE

    Conklin, Daniel J.; Haberzettl, Petra; Lesgards, Jean-Francois; Prough, Russell A.; Srivastava, Sanjay; Bhatnagar, Aruni

    2009-01-01

    Hemorrhagic cystitis and diffuse inflammation of the bladder, common side effects of cyclophosphamide (CY) treatment, have been linked to the generation of acrolein derived from CY metabolism. Metabolic removal of acrolein involves multiple pathways, which include reduction, oxidation, and conjugation with glutathione. Herein, we tested the hypothesis that glutathione S-transferase P (GSTP), the GST isoform that displays high catalytic efficiency with acrolein, protects against CY-induced uro...

  13. Increased lipolysis and altered lipid homeostasis protect y-synuclein null mutant mice from diet-induced obesity

    Science.gov (United States)

    Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. In neurons a-synuclein promotes assembly of SNARE complexes required for fusion of synaptic vesicles with the plasma membrane during neurotransmitter release. Y-synuclein is highly expressed ...

  14. Revitalization of a diastemal tooth primordium in Spry2 null mice results from increased proliferation and decreased apoptosis

    Czech Academy of Sciences Publication Activity Database

    Peterková, Renata; Churavá, Svatava; Lesot, H.; Rothová, Michaela; Procházka, Jan; Peterka, Miroslav; Klein, O. D.

    312B, č. 4 (2009), s. 292-308. ISSN 1552-5007 R&D Projects: GA ČR GA304/05/2665; GA ČR GA304/07/0223; GA MŠk OC B23.002 Grant ostatní: GA MŠk(CZ) MSM0021620843 Institutional research plan: CEZ:AV0Z50390512 Keywords : embryonic signaling center * inner dental epithelium * mouse molar Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.938, year: 2009

  15. Impairment of Bilirubin Clearance and Intestinal Interleukin-6 Expression in Bile Duct-Ligated Vitamin D Receptor Null Mice

    OpenAIRE

    Ishizawa, Michiyasu; Ogura, Michitaka; Kato, Shigeaki; Makishima, Makoto

    2012-01-01

    The vitamin D receptor (VDR) mediates the physiological and pharmacological actions of 1α,25-dihydroxyvitamin D3 in bone and calcium metabolism, cellular growth and differentiation, and immunity. VDR also responds to secondary bile acids and belongs to the NR1I subfamily of the nuclear receptor superfamily, which regulates expression of xenobiotic metabolism genes. When compared to knockout mouse investigations of the other NR1I nuclear receptors, pregnane X receptor and constitutive androsta...

  16. Increased susceptibility of HIF-1 alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes

    Czech Academy of Sciences Publication Activity Database

    Bohuslavová, Romana; Škvorová, Lada; Sedmera, David; Semenza, G.L.; Pavlínková, Gabriela

    2013-01-01

    Roč. 60, Jul (2013), s. 129-141. ISSN 0022-2828 R&D Projects: GA ČR GA301/09/0117; GA ČR(CZ) GAP302/11/1308 Institutional research plan: CEZ:AV0Z50520701 Institutional support: RVO:67985823 Keywords : Diabetic embryopathy * Heart defect * Hypoxia-inducible factor 1 alpha Subject RIV: EB - Genetics ; Molecular Biology; FA - Cardiovascular Diseases incl. Cardiotharic Surgery (FGU-C) Impact factor: 5.218, year: 2013

  17. Defective Dendrite Elongation but Normal Fertility in Mice Lacking the Rho-Like GTPase Activator Dbl

    Science.gov (United States)

    Hirsch, Emilio; Pozzato, Michela; Vercelli, Alessandro; Barberis, Laura; Azzolino, Ornella; Russo, Chiara; Vanni, Cristina; Silengo, Lorenzo; Eva, Alessandra; Altruda, Fiorella

    2002-01-01

    Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho and Cdc42 and to induce a transformed phenotype. Dbl is specifically expressed in brain and gonads, but its in vivo functions are largely unknown. To assess its role in neurogenesis and gametogenesis, targeted deletion of the murine Dbl gene was accomplished in embryonic stem cells. Dbl-null mice are viable and did not show either decreased reproductive performances or obvious neurological defects. Histological analysis of mutant testis showed normal morphology and unaltered proliferation and survival of spermatogonia. Dbl-null brains indicated a correct disposition of the major neural structures. Analysis of cortical stratification indicated that Dbl is not crucial for neuronal migration. However, in distinct populations of Dbl-null cortical pyramidal neurons, the length of dendrites was significantly reduced, suggesting a role for Dbl in dendrite elongation. PMID:11940671

  18. Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization.

    Science.gov (United States)

    Petit, Bérengère; Giraudet, Fabrice; Béchon, Céline; Bardin, Laurent; Avan, Paul; Boespflug-Tanguy, Odile; Bégou, Mélina

    2014-05-01

    Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 - mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis. PMID:24423646

  19. Predictive uncertainty analysis of a saltwater intrusion model using null-space Monte Carlo

    DEFF Research Database (Denmark)

    Herckenrath, Daan; Langevin, Christian D.; Doherty, John

    2011-01-01

    . Random noise was added to the observations to approximate realistic field conditions. The NSMC method was used to calculate 1000 calibration-constrained parameter fields. If the dimensionality of the solution space was set appropriately, the estimated uncertainty range from the NSMC analysis encompassed......Because of the extensive computational burden and perhaps a lack of awareness of existing methods, rigorous uncertainty analyses are rarely conducted for variable-density flow and transport models. For this reason, a recently developed null-space Monte Carlo (NSMC) method for quantifying prediction...... the truth. Several variants of the method were implemented to investigate their effect on the efficiency of the NSMC method. Reducing the dimensionality of the null-space for the processing of the random parameter sets did not result in any significant gains in efficiency and compromised the ability...

  20. Nonminimal curvature-matter coupled wormholes with matter satisfying the null energy condition

    Energy Technology Data Exchange (ETDEWEB)

    Garcia, Nadiezhda Montelongo; Lobo, Francisco S N, E-mail: nadiezhda@cosmo.fis.fc.ul.pt, E-mail: flobo@cii.fc.ul.pt [Centro de Astronomia e Astrofisica da Universidade de Lisboa, Campo Grande, Edificio C8 1749-016 Lisboa (Portugal)

    2011-04-21

    Recently, the exact solutions of wormhole geometries supported by a nonminimal curvature-matter coupling were found, where the nonminimal coupling minimizes the violation of the null energy condition of normal matter at the throat. In this brief report, we present a solution where normal matter satisfies the energy conditions at the throat and it is the higher order curvature derivatives of the nonminimal coupling that are responsible for the null energy condition violation, and consequently for supporting the respective wormhole geometries. For simplicity, we consider a linear R nonmiminal curvature-matter coupling and an explicit monotonically increasing function for the energy density. Thus, the solution found is not asymptotically flat, but may in principle be matched to an exterior vacuum solution.