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Sample records for mice demonstrate abnormal

  1. Abnormal osmotic regulation in trpv4-/- mice

    PubMed Central

    Liedtke, Wolfgang; Friedman, Jeffrey M.

    2003-01-01

    Osmotic homeostasis is one of the most aggressively defended physiological parameters in vertebrates. However, the molecular mechanisms underlying osmotic regulation are poorly understood. The transient receptor potential channel, vanilloid subfamily (TRPV4), is an osmotically activated ion channel that is expressed in circumventricular organs in the mammalian CNS, which is an important site of osmotic sensing. We have generated trpv4-null mice and observed abnormalities of their osmotic regulation. trpv4-/- mice drank less water and became more hyperosmolar than did wild-type littermates, a finding that was seen with and without administration of hypertonic saline. In addition, plasma levels of antidiuretic hormone were significantly lower in trpv4-/- mice than in wild-type littermates after a hyperosmotic challenge. Continuous s.c. infusion of the antidiuretic hormone analogue, dDAVP, resulted in systemic hypotonicity in trpv4-/- mice, despite the fact that their renal water reabsorption capacity was normal. Thus, the response to both hyper- and hypoosmolar stimuli is impaired in trpv4-/- mice. After a hyperosmolar challenge, there was markedly reduced expression of c-FOS in the circumventricular organ, the organum vasculosum of the lamina terminalis, of trpv4-/- mice compared with wild-type mice. This finding suggests that there is an impairment of osmotic sensing in the CNS of trpv4-/- mice. These data indicate that TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS. PMID:14581612

  2. Absence of cytoglobin promotes multiple organ abnormalities in aged mice

    PubMed Central

    Thuy, Le Thi Thanh; Van Thuy, Tuong Thi; Matsumoto, Yoshinari; Hai, Hoang; Ikura, Yoshihiro; Yoshizato, Katsutoshi; Kawada, Norifumi

    2016-01-01

    Cytoglobin (Cygb) was identified in hepatic stellate cells (HSCs) and pericytes of all organs; however, the effects of Cygb on cellular functions remain unclear. Here, we report spontaneous and age-dependent malformations in multiple organs of Cygb−/− mice. Twenty-six percent of young Cygb−/− mice (<1 year old) showed heart hypertrophy, cystic disease in the kidney or ovary, loss of balance, liver fibrosis and lymphoma. Furthermore, 71.3% (82/115) of aged Cygb−/− mice (1–2 years old) exhibited abnormalities, such as heart hypertrophy and cancer development in multiple organs; by contrast, 5.8% (4/68) of aged wild-type (WT) mice had abnormalities (p < 0.0001). Interestingly, serum and urine analysis demonstrated that the concentration of nitric oxide metabolites increased significantly in Cygb−/− mice, resulting in an imbalance in the oxidative stress and antioxidant defence system that was reversed by NG-monomethyl-L-arginine treatment. A senescent phenotype and evidence of DNA damage were found in primary HSCs and the liver of aged Cygb−/− mice. Moreover, compared with HSC+/+, HSC−/− showed high expression of Il-6 and chemokine mRNA when cocultured with mouse Hepa 1–6 cells. Thus, the absence of Cygb in pericytes provokes organ abnormalities, possibly via derangement of the nitric oxide and antioxidant defence system and through accelerated cellular senescence. PMID:27146058

  3. Chemical induction of sperm abnormalities in mice.

    PubMed Central

    Wyrobek, A J; Bruce, W R

    1975-01-01

    The sperm of (C57BL X C3H)F1 mice were examined 1, 4, and 10 weeks after a subacute treatment with one of 25 chemicals at two or more dose levels. The fraction of sperm that were abnormal in shape was elevated above control values of 1.2-3.4% for methyl methanesulfonate, ethyl methanesulfonate, griseofulvin, benzo[a]pyrene, METEPA [tris(2-methyl-l-aziridinyl)phosphine oxide], THIO-TEPA [tris(l-aziridinyl)phosphine sulfide], mitomycin C, myleran, vinblastine sulphate, hydroxyurea, 3-methylcholanthrene, colchicine, actinomycin D, imuran, cyclophosphamide, 5-iododeoxyuridine, dichlorvos, aminopterin, and trimethylphosphate. Dimethylnitrosamine, urethane, DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane], 1,1-dimethylhydrazine, caffeine, and calcium cyclamate did not induce elevated levels of sperm abnormalities. The results suggest that sperm abnormalities might provide a rapid inexpensive mammalian screen for agents that lead to errors in the differentiation of spermatogenic stem cells in vivo and thus indicate agents which might prove to be mutagenic, teratogenic, or carcinogenic. Images PMID:1060122

  4. Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia

    SciTech Connect

    Zhao Tieqiang; Guo Jun; Li Hui; Huang Wei; Xian Xunde; Ross, Colin J.D.; Hayden, Michael R.; Wen Zongyao . E-mail: rheol@bjmu.edu.cn; Liu George . E-mail: vangeorgeliu@gmail.com

    2006-03-24

    Severe hypertriglyceridemia (HTG) is a metabolic disturbance often seen in clinical practice. It is known to induce life-threatening acute pancreatitis, but its role in atherogenesis remains elusive. Hemorheological abnormality was thought to play an important role in pathogenesis of both pancreatitis and atherosclerosis. However, hemorheology in severe HTG was not well investigated. Recently, we established a severe HTG mouse model deficient in lipoprotein lipase (LPL) in which severe HTG was observed to cause a significant increase in plasma viscosity. Disturbances of erythrocytes were also documented, including decreased deformability, electrophoresis rate, and membrane fluidity, and increased osmotic fragility. Scanning electron microscopy demonstrated that most erythrocytes of LPL deficient mice deformed with protrusions, irregular appearances or indistinct concaves. Analysis of erythrocyte membrane lipids showed decreased cholesterol (Ch) and phospholipid (PL) contents but unaltered Ch/PL ratio. The changes of membrane lipids may be partially responsible for the hemorheological and morphologic abnormalities of erythrocytes. This study indicated that severe HTG could lead to significant impairment of hemorheology and this model may be useful in delineating the role of severe HTG in the pathogenesis of hyperlipidemic pancreatitis and atherosclerosis.

  5. Mutant laboratory mice with abnormalities in pigmentation: annotated tables.

    PubMed

    Nakamura, Motonobu; Tobin, Desmond J; Richards-Smith, Beverly; Sundberg, John P; Paus, Ralf

    2002-01-01

    Mammalian pigment cell research has recently entered a phase of significantly increased activity due largely to the exploitation of the many mutant mouse stocks that are coming on stream. Numerous transgenic, targeted mutagenesis (so-called 'knockouts'), conditional (so-called 'gene switch') and spontaneous mutant mice develop abnormal coat color phenotypes. The number of mice that exhibit such abnormalities is increasing exponentially as genetic engineering methods become routine. Since defined abnormalities in such mutant mice provide important clues to the as yet often poorly understood functional roles of many gene products, this overview includes a corresponding, annotated table of mutant mice with pigmentation alterations. These range from early developmental defects via a large array of coat color abnormalities to a melanoma metastasis model. This overview should provide helpful pointers to investigators who are looking for mouse models to explore or to compare functional activities of genes of interest and for comparing coat color phenotypes of spontaneous or genetically engineered mouse mutants with novel ones. Secondly, this review includes a table of mouse models of specific human diseases with genetically defined pigmentation abnormalities. In summary, this annotated table should serve as a useful reference for anyone interested in the molecular controls of pigmentation.

  6. The MICE Demonstration of Ionization Cooling

    SciTech Connect

    Pasternak, J.; Blackmore, V.; Hunt, C.; Lagrange, J-B.; Long, K.; Collomb, N.; Snopok, P.

    2015-05-01

    Muon beams of low emittance provide the basis for the intense, well-characterised neutrino beams necessary to elucidate the physics of flavour at the Neutrino Factory and to provide lepton-antilepton collisions at energies of up to several TeV at the Muon Collider. The International Muon Ionization Cooling Experiment (MICE) will demonstrate ionization cooling, the technique by which it is proposed to reduce the phase-space volume occupied by the muon beam at such facilities. In an ionization cooling channel, the muon beam passes through a material (the absorber) in which it loses energy. The energy lost is then replaced using RF cavities. The combined effect of energy loss and re-acceleration is to reduce the transverse emittance of the beam (transverse cooling). A major revision of the scope of the project was carried out over the summer of 2014. The revised project plan, which has received the formal endorsement of the international MICE Project Board and the international MICE Funding Agency Committee, will deliver a demonstration of ionization cooling by September 2017. In the revised configuration a central lithium-hydride absorber provides the cooling effect. The magnetic lattice is provided by the two superconducting focus coils and acceleration is provided by two 201 MHz single-cavity modules. The phase space of the muons entering and leaving the cooling cell will be measured by two solenoidal spectrometers. All the superconducting magnets for the ionization cooling demonstration are available at the Rutherford Appleton Laboratory and the first single-cavity prototype is under test in the MuCool Test Area at Fermilab. The design of the cooling demonstration experiment will be described together with a summary of the performance of each of its components. The cooling performance of the revised configuration will also be presented.

  7. Prenatal imaging of distal limb abnormalities using OCT in mice

    NASA Astrophysics Data System (ADS)

    Larina, Irina V.; Syed, Saba H.; Dickinson, Mary E.; Overbeek, Paul; Larin, Kirill V.

    2012-01-01

    Congenital abnormalities of the limbs are common birth defects. These include missing or extra fingers or toes, abnormal limb length, and abnormalities in patterning of bones, cartilage or muscles. Optical Coherence Tomography (OCT) is a 3-D imaging modality, which can produce high-resolution (~8 μm) images of developing embryos with an imaging depth of a few millimeters. Here we demonstrate the capability of OCT to perform 3D imaging of limb development in normal embryos and a mouse model with congenital abnormalities. Our results suggest that OCT is a promising tool to analyze embryonic limb development in mammalian models of congenital defects.

  8. The MICE Demonstration of Muon Ionization Cooling

    SciTech Connect

    Lagrange, Jean-Baptiste; Hunt, Christopher; Palladino, Vittorio; Pasternak, Jaroslaw

    2016-06-01

    Muon beams of low emittance provide the basis for the intense, well-characterised neutrino beams necessary to elucidate the physics of flavour at the Neutrino Factory and to provide lepton-antilepton collisions up to several TeV at the Muon Collider. The international Muon Ionization Cooling Experiment (MICE) will demonstrate muon ionization cooling, the technique proposed to reduce the phase-space volume occupied by the muon beam at such facilities. In an ionization-cooling channel, the muon beam traverses a material (the absorber) loosing energy, which is replaced using RF cavities. The combined effect is to reduce the transverse emittance of the beam (transverse cooling). The configuration of MICE required to deliver the demonstration of ionization cooling is being prepared in parallel to the execution of a programme designed to measure the cooling properties of liquid-hydrogen and lithium hydride. The design of the cooling-demonstration experiment will be presented together with a summary of the performance of each of its components and the cooling performance of the experiment.

  9. Impairment of peripheral circadian clocks precedes metabolic abnormalities in ob/ob mice.

    PubMed

    Ando, Hitoshi; Kumazaki, Masafumi; Motosugi, Yuya; Ushijima, Kentarou; Maekawa, Tomohiro; Ishikawa, Eiko; Fujimura, Akio

    2011-04-01

    Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of metabolic abnormalities, but the chicken-and-egg question remains unresolved. To address this issue, we investigated the cause-effect relationship in obese, diabetic ob/ob mice. Compared with control C57BL/6J mice, the daily mRNA expression profiles of the clock and clock-controlled genes Clock, Bmal1, Cry1, Per1, Per2, and Dbp were substantially dampened in the liver and adipose tissue, but not the hypothalamic suprachiasmatic nucleus, of 10-wk-old ob/ob mice. Four-week feeding of a low-calorie diet and administration of leptin over a 7-d period attenuated, to a significant and comparable extent, the observed metabolic abnormalities (obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia) in the ob/ob mice. However, only leptin treatment improved the impaired peripheral clocks. In addition, clock function, assessed by measuring levels of Per1, Per2, and Dbp mRNA at around peak times, was also reduced in the peripheral tissues of 3-wk-old ob/ob mice without any overt metabolic abnormalities. Collectively these results indicate that the impairment of peripheral clocks in ob/ob mice does not result from metabolic abnormalities but may instead be at least partially caused by leptin deficiency itself. Further studies are needed to clarify how leptin deficiency affects peripheral clocks.

  10. Abnormalities in the cerebellum and brainstem in homozygous lurcher mice.

    PubMed

    Resibois, A; Cuvelier, L; Goffinet, A M

    1997-09-01

    The lurcher mutation induces Purkinje cell degeneration in heterozygous mice, and neonatal death in homozygous animals. Using the D6Mit16 Simple Sequence Length Polymorphic marker in F2 hybrids between AKR +/+ mice and B6+/Lc mice, homozygous lurcher fetuses and newborns as well as heterozygous and normal littermates were identified, and their brain morphology was analysed. In homozygous lurcher embryos at embryonic day 18 and neonates the cerebellum was hypotrophic, particularly in the posterior half. Purkinje cells were smaller in the whole cerebellum and showed a maturational delay. Calretinin-positive cells were less frequently observed in the depth of the vermis than in normal mice. Both Purkinje cells and the vermal calretinin-positive cells were more abnormal in fetuses at day 19 and newborn mutants than one day earlier. An abnormal number of pycnotic cells were observed in the cerebellum, especially in newborn mutants. Brainstem abnormalities were characterized by abnormal curvature, caudal displacement of the pontine gray nuclei which were located caudally along the ventral border of the superior olivary complex, a drastic decrease in Purkinje cell axons in all the vestibular nuclei and the presence of dystrophic processes in at least two calbindin-positive cell groups of the dorsal pontine region. These results show that the mutation, which is semidominant in Purkinje cells, is recessive in other cell groups of the cerebellum and brainstem. They reveal that the sequence leading to Purkinje cell death appears to be similar in homozygous and heterozygous mice, although occurring earlier and worsening more quickly in the former. Lastly, they confirm the absence of effect of the mutation on the neurons of the inferior olivary complex.

  11. Developmental abnormalities in mice transgenic for bovine oncostatin M.

    PubMed Central

    Malik, N; Haugen, H S; Modrell, B; Shoyab, M; Clegg, C H

    1995-01-01

    Oncostatin M belongs to the subfamily of hematopoietin cytokines that binds a receptor complex containing gp130. To date, only the human form of oncostatin M has been identified, and its evolutionary conservation is unresolved. We have isolated a bovine gene whose open reading frame encodes a precursor protein that is 58% identical to human oncostatin M. A comparison of the bovine and human amino acid sequences predicts significant similarity, including the four-alpha-helical-bundle structure and the placement of disulfide bridges. As with the human protein, bovine oncostatin M binds specific receptors on human H2981 cells and inhibits the proliferation of human A375 tumor cells and mouse M1 leukemia cells. To identify activities regulated in vivo, we injected bovine oncostatin M fusion genes containing various tissue-specific promoters into mouse embryos. The frequencies of transgenic mice were reduced significantly, suggesting that overexpression of the bovine cytokine is detrimental to normal mouse development. In addition to deaths associated with expression in neurons and keratinized epithelia, bovine oncostatin M caused abnormalities in bone growth and spermatogenesis, stimulated fibrosis surrounding islets in the pancreas, and disrupted normal lymphoid tissue development. This work establishes the existence of a nonprimate oncostatin M gene and provides the first demonstration that this cytokine can function in a pleiotropic manner in vivo. Information regarding bovine oncostatin M may help characterize the structure and function of this cytokine in other vertebrate species. PMID:7739518

  12. Abnormal megakaryocyte development and platelet function in Nbeal2(-/-) mice.

    PubMed

    Kahr, Walter H A; Lo, Richard W; Li, Ling; Pluthero, Fred G; Christensen, Hilary; Ni, Ran; Vaezzadeh, Nima; Hawkins, Cynthia E; Weyrich, Andrew S; Di Paola, Jorge; Landolt-Marticorena, Carolina; Gross, Peter L

    2013-11-07

    Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with macrothrombocytopenia and α-granule-deficient platelets. GPS has been linked to loss of function mutations in NEABL2 (neurobeachin-like 2), and we describe here a murine GPS model, the Nbeal2(-/-) mouse. As in GPS, Nbeal2(-/-) mice exhibit splenomegaly, macrothrombocytopenia, and a deficiency of platelet α-granules and their cargo, including von Willebrand factor (VWF), thrombospondin-1, and platelet factor 4. The platelet α-granule membrane protein P-selectin is expressed at 48% of wild-type levels and externalized upon platelet activation. The presence of P-selectin and normal levels of VPS33B and VPS16B in Nbeal2(-/-) platelets suggests that NBEAL2 acts independently of VPS33B/VPS16B at a later stage of α-granule biogenesis. Impaired Nbeal2(-/-) platelet function was shown by flow cytometry, platelet aggregometry, bleeding assays, and intravital imaging of laser-induced arterial thrombus formation. Microscopic analysis detected marked abnormalities in Nbeal2(-/-) bone marrow megakaryocytes, which when cultured showed delayed maturation, decreased survival, decreased ploidy, and developmental abnormalities, including abnormal extracellular distribution of VWF. Our results confirm that α-granule secretion plays a significant role in platelet function, and they also indicate that abnormal α-granule formation in Nbeal2(-/-) mice has deleterious effects on megakaryocyte survival, development, and platelet production.

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

    PubMed

    Sengle, Gerhard; Carlberg, Valerie; Tufa, Sara F; Charbonneau, Noe L; Smaldone, Silvia; Carlson, Eric J; Ramirez, Francesco; Keene, Douglas R; Sakai, Lynn Y

    2015-06-01

    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 fibrillin-2 can

  14. M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition

    PubMed Central

    2012-01-01

    Background In the central nervous system (CNS), the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M4 muscarinic receptor knockout (M4R KO) mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI)-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M4R remain unclear. Results In this study, to further investigate precise functional roles of M4R in the CNS, M4R KO mice were subjected to a battery of behavioral tests. M4R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M4R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M4R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M4R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M4R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M4R KO mice demonstrated normal startle response. M4R KO mice also displayed normal performance in the Morris water maze test. Conclusions These findings indicate that M4R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia. PMID:22463818

  15. Morphological and functional platelet abnormalities in Berkeley sickle cell mice.

    PubMed

    Shet, Arun S; Hoffmann, Thomas J; Jirouskova, Marketa; Janczak, Christin A; Stevens, Jacqueline R M; Adamson, Adewole; Mohandas, Narla; Manci, Elizabeth A; Cynober, Therese; Coller, Barry S

    2008-01-01

    Berkeley sickle cell mice are used as animal models of human sickle cell disease but there are no reports of platelet studies in this model. Since humans with sickle cell disease have platelet abnormalities, we studied platelet morphology and function in Berkeley mice (SS). We observed elevated mean platelet forward angle light scatter (FSC) values (an indirect measure of platelet volume) in SS compared to wild type (WT) (37+/-3.2 vs. 27+/-1.4, mean+/-SD; p<0.001), in association with moderate thrombocytopenia (505+/-49 x 10(3)/microl vs. 1151+/-162 x 10(3)/microl; p<0.001). Despite having marked splenomegaly, SS mice had elevated levels of Howell-Jolly bodies and "pocked" erythrocytes (p<0.001 for both) suggesting splenic dysfunction. SS mice also had elevated numbers of thiazole orange positive platelets (5+/-1% vs. 1+/-1%; p<0.001), normal to low plasma thrombopoietin levels, normal plasma glycocalicin levels, normal levels of platelet recovery, and near normal platelet life spans. Platelets from SS mice bound more fibrinogen and antibody to P-selectin following activation with a threshold concentration of a protease activated receptor (PAR)-4 peptide compared to WT mice. Enlarged platelets are associated with a predisposition to arterial thrombosis in humans and some humans with SCD have been reported to have large platelets. Thus, additional studies are needed to assess whether large platelets contribute either to pulmonary hypertension or the large vessel arterial occlusion that produces stroke in some children with sickle cell disease.

  16. Loss of polyubiquitin gene Ubb leads to metabolic and sleep abnormalities in mice

    PubMed Central

    Ryu, K.-Y.; Fujiki, N.; Kazantzis, M.; Garza, J. C.; Bouley, D. M.; Stahl, A.; Lu, X.-Y.; Nishino, S.; Kopito, R. R.

    2010-01-01

    Aims Ubiquitin performs essential roles in a myriad of signalling pathways required for cellular function and survival. Recently, we reported that disruption of the stress-inducible ubiquitin-encoding gene Ubb reduces ubiquitin content in the hypothalamus and leads to adult-onset obesity coupled with a loss of arcuate nucleus neurones and disrupted energy homeostasis in mice. Neuropeptides expressed in the hypothalamus control both metabolic and sleep behaviours. In order to demonstrate that the loss of Ubb results in broad hypothalamic abnormalities, we attempted to determine whether metabolic and sleep behaviours were altered in Ubb knockout mice. Methods Metabolic rate and energy expenditure were measured in a metabolic chamber, and sleep stage was monitored via electroencephalographic/electromyographic recording. The presence of neurodegeneration and increased reactive gliosis in the hypothalamus were also evaluated. Results We found that Ubb disruption leads to early-onset reduced activity and metabolic rate. Additionally, we have demonstrated that sleep behaviour is altered and sleep homeostasis is disrupted in Ubb knockout mice. These early metabolic and sleep abnormalities are accompanied by persistent reactive gliosis and the loss of arcuate nucleus neurones, but are independent of neurodegeneration in the lateral hypothalamus. Conclusions Ubb knockout mice exhibit phenotypes consistent with hypothalamic dysfunction. Our data also indicate that Ubb is essential for the maintenance of the ubiquitin levels required for proper regulation of metabolic and sleep behaviours in mice. PMID:20002312

  17. Airway acidification initiates host defense abnormalities in cystic fibrosis mice

    PubMed Central

    Shah, Viral S.; Meyerholz, David K.; Tang, Xiao Xiao; Reznikov, Leah; Alaiwa, Mahmoud Abou; Ernst, Sarah E.; Karp, Philip H.; Wohlford-Lenane, Christine L.; Heilmann, Kristopher P.; Leidinger, Mariah R.; Allen, Patrick D.; Zabner, Joseph; McCray, Paul B.; Ostedgaard, Lynda S.; Stoltz, David A.; Randak, Christoph O.; Welsh, Michael J.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. PMID:26823428

  18. Central respiratory rhythmogenesis is abnormal in lbx1- deficient mice.

    PubMed

    Pagliardini, Silvia; Ren, Jun; Gray, Paul A; Vandunk, Cassandra; Gross, Michael; Goulding, Martyn; Greer, John J

    2008-10-22

    Lbx1 is a transcription factor that determines neuronal cell fate and identity in the developing medulla and spinal cord. Newborn Lbx1 mutant mice die of respiratory distress during the early postnatal period. Using in vitro brainstem-spinal cord preparations we tested the hypothesis that Lbx1 is necessary for the inception, development and modulation of central respiratory rhythmogenesis. The inception of respiratory rhythmogenesis at embryonic day 15 (E15) was not perturbed in Lbx1 mutant mice. However, the typical age-dependent increase in respiratory frequency observed in wild-type from E15 to P0 was not observed in Lbx1 mutant mice. The slow respiratory rhythms in E18.5 Lbx1 mutant preparations were increased to wild-type frequencies by application of substance P, thyrotropin releasing hormone, serotonin, noradrenaline, or the ampakine drug 1-(1,4-benzodioxan-6-yl-carbonyl) piperidine. Those data suggest that respiratory rhythm generation within the pre-Bötzinger complex (preBötC) is presumably functional in Lbx1 mutant mice with additional neurochemical drive. This was supported by anatomical data showing that the gross structure of the preBötC was normal, although there were major defects in neuronal populations that provide important modulatory drive to the preBötC including the retrotrapezoid nucleus, catecholaminergic brainstem nuclei, nucleus of the solitary tract, and populations of inhibitory neurons in the ventrolateral and dorsomedial medullary nuclei. Finally, we determined that those defects were caused by abnormalities of neuronal specification early in development or subsequent neuronal migration.

  19. Slc4a11 gene disruption in mice: cellular targets of sensorineuronal abnormalities.

    PubMed

    Lopez, Ivan A; Rosenblatt, Mark I; Kim, Charles; Galbraith, Gary C; Jones, Sherri M; Kao, Liyo; Newman, Debra; Liu, Weixin; Yeh, Stacey; Pushkin, Alexander; Abuladze, Natalia; Kurtz, Ira

    2009-09-25

    NaBC1 (the SLC4A11 gene) belongs to the SLC4 family of sodium-coupled bicarbonate (carbonate) transporter proteins and functions as an electrogenic sodium borate cotransporter. Mutations in SLC4A11 cause either corneal abnormalities (corneal hereditary dystrophy type 2) or a combined auditory and visual impairment (Harboyan syndrome). The role of NaBC1 in sensory systems is poorly understood, given the difficulty of studying patients with NaBC1 mutations. We report our findings in Slc4a11(-/-) mice generated to investigate the role of NaBC1 in sensorineural systems. In wild-type mice, specific NaBC1 immunoreactivity was detected in fibrocytes of the spiral ligament, from the basal to the apical portion of the cochlea. NaBC1 immunoreactivity was present in the vestibular labyrinth, in stromal cells underneath the non-immunoreactive sensory epithelia of the macula utricle, sacule, and crista ampullaris, and the membranous vestibular labyrinth was collapsed. Both auditory brain response and vestibular evoked potential waveforms were significantly abnormal in Slc4a11(-/-) mice. In the cornea, NaBC1 was highly expressed in the endothelial cell layer with less staining in epithelial cells. However, unlike humans, the corneal phenotype was mild with a normal slit lamp evaluation. Corneal endothelial cells were morphologically normal; however, both the absolute height of the corneal basal epithelial cells and the relative basal epithelial cell/total corneal thickness were significantly increased in Slc4a11(-/-) mice. Our results demonstrate for the first time the importance of NaBC1 in the audio-vestibular system and provide support for the hypothesis that SLC4A11 should be considered a potential candidate gene in patients with isolated sensorineural vestibular hearing abnormalities.

  20. A Forward Genetic Screen in Mice Identifies Mutants with Abnormal Cortical Patterning

    PubMed Central

    Ha, Seungshin; Stottmann, Rolf W.; Furley, Andrew J.; Beier, David R.

    2015-01-01

    Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain. PMID:23968836

  1. A forward genetic screen in mice identifies mutants with abnormal cortical patterning.

    PubMed

    Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J; Beier, David R

    2015-01-01

    Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain.

  2. Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans

    PubMed Central

    Keays, David A.; Tian, Guoling; Poirier, Karine; Huang, Guo-Jen; Siebold, Christian; Cleak, James; Oliver, Peter L.; Fray, Martin; Harvey, Robert J.; Molnár, Zoltán; Piñon, Maria C.; Dear, Neil; Valdar, William; Brown, Steve D.M.; Davies, Kay E.; Rawlins, J. Nicholas P.; Cowan, Nicholas J.; Nolan, Patrick; Chelly, Jamel; Flint, Jonathan

    2007-01-01

    Summary The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of α-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders. PMID:17218254

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

    PubMed

    Chen, Jane Q; Mori, Hidetoshi; Cardiff, Robert D; Trott, Josephine F; Hovey, Russell C; Hubbard, Neil E; Engelberg, Jesse A; Tepper, Clifford G; Willis, Brandon J; Khan, Imran H; Ravindran, Resmi K; Chan, Szeman R; Schreiber, Robert D; Borowsky, Alexander D

    2015-01-01

    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.

  4. Targeting the NLRP3 Inflammasome to Reduce Diet-Induced Metabolic Abnormalities in Mice

    PubMed Central

    Chiazza, Fausto; Couturier-Maillard, Aurélie; Benetti, Elisa; Mastrocola, Raffaella; Nigro, Debora; Cutrin, Juan C; Serpe, Loredana; Aragno, Manuela; Fantozzi, Roberto; Ryffel, Bernard; Collino, Massimo

    2015-01-01

    Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3−/− littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3−/− mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing. PMID:26623925

  5. Age- and sex-dependent thymic abnormalities in NZB × SJL F1 hybrid mice

    PubMed Central

    Dumont, F.; Robert, F.

    1980-01-01

    The cellular organization of the thymus was investigated in 3- and 12-month-old NZB × SJL F1 hybrid (NS) mice. Age-dependent alterations were demonstrated which differed strikingly according to the sex of the animals. In female mice, marked abnormalities of the thymus developed during ageing. They consisted of a more or less pronounced hypertrophy accompanied by histological changes and modifications in the nature of the lymphocyte populations. Three types of qualitative changes were found at 12 months of age: (1) depletion of cortical thymocytes as evidenced by histology, by the evaluation of peanut-agglutinin (PNA) binding and by cell electrophoresis; (2) hyperplasia of the medullary lymphoid tissue, probably reflecting the expansion of a population of mature T lymphocytes. This was further suggested by a rise (up to 60%) in the frequency of lymphocytes lacking both PNA receptor and B cell markers, by an increased proportion (57%) of high electrophoretic mobility (EPM) lymphocytes and by an augmentation of in vitro reactivities to phytohaemagglutinin (PHA) and, although to a lesser extent, to concanavalin A (Con A). (3) The appearance of significant numbers of B lymphocytes (up to 20%) as assessed by surface immunoglobulin (sIg) and complement receptor (CR) detection which was accompanied by a vigorous responsiveness of thymus cells to lipopolysaccharide (LPS). None of these abnormalities was seen in the male mice. Instead, the thymus of NS males displayed a nearly normal age-related involution without major change in the proportions of its lymphocyte subpopulations. NS mice thus provide an interesting model of thymic disease influenced by sex-linked factors. ImagesFig. 3 PMID:7438550

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

    PubMed Central

    Cardiff, Robert D.; Trott, Josephine F.; Hovey, Russell C.; Hubbard, Neil E.; Engelberg, Jesse A.; Tepper, Clifford G.; Willis, Brandon J.; Khan, Imran H.; Ravindran, Resmi K.; Chan, Szeman R.; Schreiber, Robert D.; Borowsky, Alexander D.

    2015-01-01

    Female 129:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds 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. PMID:26075897

  7. Behavioral and Neurotransmitter Abnormalities in Mice Deficient for Parkin, DJ-1 and Superoxide Dismutase

    PubMed Central

    Hennis, Meghan R.; Seamans, Katherine W.; Marvin, Marian A.; Casey, Bradford H.; Goldberg, Matthew S.

    2013-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by loss of neurons in the substantia nigra that project to the striatum and release dopamine. The cause of PD remains uncertain, however, evidence implicates mitochondrial dysfunction and oxidative stress. Although most cases of PD are sporadic, 5-10% of cases are caused by inherited mutations. Loss-of-function mutations in Parkin and DJ-1 were the first to be linked to recessively inherited Parkinsonism. Surprisingly, mice bearing similar loss-of-function mutations in Parkin and DJ-1 do not show age-dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum. Although the normal cellular functions of Parkin and DJ-1 are not fully understood, we hypothesized that loss-of-function mutations in Parkin and DJ-1 render cells more sensitive to mitochondrial dysfunction and oxidative stress. To test this hypothesis, we crossed mice deficient for Parkin and DJ-1 with mice deficient for the mitochondrial antioxidant protein Mn-superoxide dismutase (SOD2) or the cytosolic antioxidant protein Cu-Zn-superoxide dismutase (SOD1). Aged Parkin-/-DJ-1-/- and Mn-superoxide dismutase triple deficient mice have enhanced performance on the rotorod behavior test. Cu/Zn-superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum in the absence of nigral cell loss. Our studies demonstrate that on a Parkin/DJ-1 null background, mice that are also deficient for major antioxidant proteins do not have progressive loss of dopaminergic neurons but have behavioral and striatal dopamine abnormalities. PMID:24386432

  8. Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

    PubMed Central

    Zhu, Zhu; Hua, Bingxuan; Shang, Zhanxian; Yuan, Gongsheng; Xu, Lirong; Li, Ermin; Li, Xiaobo; Yan, Zuoqin; Qian, Ruizhe

    2016-01-01

    Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation. PMID:27631008

  9. Suprabasal desmoglein 3 expression in the epidermis of transgenic mice results in hyperproliferation and abnormal differentiation.

    PubMed

    Merritt, Anita J; Berika, Mohamed Y; Zhai, Wenwu; Kirk, Sarah E; Ji, Baijing; Hardman, Matthew J; Garrod, David R

    2002-08-01

    The desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) isoforms of the desmosomal cadherins are expressed in the suprabasal layers of epidermis, whereas Dsg3 and Dsc3 are more strongly expressed basally. This differential expression may have a function in epidermal morphogenesis and/or may regulate the proliferation and differentiation of keratinocytes. To test this hypothesis, we changed the expression pattern by overexpressing human Dsg3 under the control of the keratin 1 (K1) promoter in the suprabasal epidermis of transgenic mice. From around 12 weeks of age, the mice exhibited flaking of the skin accompanied by epidermal pustules and thinning of the hair. Histological analysis of affected areas revealed acanthosis, hypergranulosis, hyperkeratosis, localized parakeratosis, and abnormal hair follicles. This phenotype has some features in common with human ichthyosiform diseases. Electron microscopy revealed a mild epidermal spongiosis. Suprabasally, desmosomes showed incorporation of the exogenous protein by immunogold labeling but were normal in structure. The epidermis was hyperproliferative, and differentiation was abnormal, demonstrated by expression of K14 in the suprabasal layer, restriction of K1, and strong induction of K6 and K16. The changes resembled those found in previous studies in which growth factors, cytokines, and integrins had been overexpressed in epidermis. Thus our data strongly support the view that Dsg3 contributes to the regulation of epidermal differentiation. Our results contrast markedly with those recently obtained by expressing Dsg3 in epidermis under the involucrin promoter. Possible reasons for this difference are considered in this paper.

  10. MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase.

    PubMed

    Stohn, J Patrizia; Martinez, M Elena; Matoin, Kassey; Morte, Beatriz; Bernal, Juan; Galton, Valerie Anne; St Germain, Donald; Hernandez, Arturo

    2016-08-01

    Mice deficient in the type 3 deiodinase (D3KO mice) manifest impaired clearance of thyroid hormone (TH), leading to elevated levels of TH action during development. This alteration causes reduced neonatal viability, growth retardation, and central hypothyroidism. Here we examined how these phenotypes are affected by a deficiency in the monocarboxylate transporter 8 (MCT8), which is a major contributor to the transport of the active thyroid hormone, T3, into the cell. MCT8 deficiency eliminated the neonatal lethality of type 3 deiodinase (D3)-deficient mice and significantly ameliorated their growth retardation. Double-mutant newborn mice exhibited similar peripheral thyrotoxicosis and increased brain expression of T3-dependent genes as mice with D3 deficiency only. Later in neonatal life and adulthood, double-mutant mice manifested central and peripheral TH status similar to mice with single MCT8 deficiency, with low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in the hypothalamus. In double-mutant adult mice, both thyroid gland size and the hypothyroidism-induced rise in TSH were greater than those in mice with single D3 deficiency but less than those in mice with MCT8 deficiency alone. Our results demonstrate that the marked phenotypic abnormalities observed in the D3-deficient mouse, including perinatal mortality, growth retardation, and central hypothyroidism in adult animals, require expression of MCT8, confirming the interdependent relationship between the TH transport into cells and the deiodination processes.

  11. NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline.

    PubMed

    Aonurm-Helm, Anu; Anier, Kaili; Zharkovsky, Tamara; Castrén, Eero; Rantamäki, Tomi; Stepanov, Vladimir; Järv, Jaak; Zharkovsky, Alexander

    2015-12-01

    Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.

  12. Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality.

    PubMed

    Horie, Masao; Mekada, Kazuyuki; Sano, Hiromi; Kikkawa, Yoshiaki; Chiken, Satomi; Someya, Takuro; Saito, Keisuke; Hossain, M Ibrahim; Nameta, Masaaki; Abe, Kuniya; Sakimura, Kenji; Ono, Katsuhiko; Nambu, Atsushi; Yoshiki, Atsushi; Takebayashi, Hirohide

    2016-12-01

    We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (Dst(Gt)) mice. Compound heterozygotes showed a typical dt phenotype with sensory degeneration and progressive motor symptoms. DNA sequencing analysis identified a nonsense mutation within the spectrin repeats of the plakin domain. The novel mutant allele was named dt(23Rbrc). Motor abnormalities in homozygous dt(23Rbrc)/dt(23Rbrc) mice are not as severe as homozygous Dst(Gt)/Dst(Gt) mice. Histological analyses showed abnormal neurofilament (NF) accumulation in the nervous system of homozygous dt(23Rbrc)/dt(23Rbrc) mice, which is characteristic of the dt phenotype. We mapped the distribution of abnormal NF-accumulated neurons in the brain and found that they were located specifically in the brainstem, spinal cord, and in regions such as the vestibular nucleus, reticular nucleus, and red nucleus, which are implicated in posture and motor coordination pathways. The quantification of abnormal NF accumulation in the cytoplasm and spheroids (axons) of neurons showed that abnormal NF immunoreactivity was lower in homozygous dt(23Rbrc)/dt(23Rbrc) mice than in homozygous Dst(Gt)/Dst(Gt) mice. Therefore, we have identified a novel hypomorphic allele of dt, which causes histological abnormalities in the central nervous system that may account for the abnormal motor phenotype. This novel spontaneously occurring mutant may become a good model of hereditary sensory and autonomic neuropathy type 6, which is caused by mutations in the human DST

  13. Postnatal lethality and abnormal development of foregut and spleen in Ndrg4 mutant mice

    PubMed Central

    Qu, Xianghu; Li, Jing; Baldwin, H. Scott

    2016-01-01

    NDRG4 is a member of the NDRG family (N-myc downstream-regulated gene), which is highly expressed in brain and heart. Previous studies showed that Ndrg1-deficient mice exhibited a progressive demyelinating disorder of peripheral nerves and Ndrg4-deficient mice had spatial learning deficits and vulnerabilities to cerebral ischemia. Here, we report generation of Ndrg4 mutant alleles that exhibit several development defects different from those previously reported. Our homozygous mice showed growth retardation and postnatal lethality. Spleen and thymuses of Ndrg4−/− mice are considerably reduced in size from 3 weeks of age. Histological analysis revealed abnormal hyperkeratosis in the squamous foregut and abnormal loss of erythrocytes in the spleen of Ndrg4−/− mice. In addition, we observed an abnormal hind limb clasping phenotype upon tail suspension suggesting neurological abnormalities. Consistent to these abnormalities, Ndrg4 is expressed in smooth muscle cells of the stomach, macrophages of the spleen and neurons. Availability of the conditional allele for Ndrg4 should facilitate further detailed analyses of the potential roles of Ndrg4 in gut development, nervous system and immune system. PMID:26801554

  14. Abnormal grooming activity in Dab1(scm) (scrambler) mutant mice.

    PubMed

    Strazielle, C; Lefevre, A; Jacquelin, C; Lalonde, R

    2012-07-15

    Dab1(scm) mutant mice, characterized by cell ectopias and degeneration in cerebellum, hippocampus, and neocortex, were compared to non-ataxic controls for different facets of grooming caused by brief water immersions, as well as some non-grooming behaviors. Dab1(scm) mutants were strongly affected in their quantitative functional parameters, exhibiting higher starting latencies before grooming relative to non-ataxic littermates of the A/A strain, fewer grooming bouts, and grooming components of shorter duration, with an unequal regional distribution targeting almost totally the rostral part (head washing and forelimb licking) of the animal. Only bouts of a single grooming element were preserved. The cephalocaudal order of grooming elements appeared less disorganized, mutant and control mice initiating the grooming with head washing and forelimb licking prior to licking posterior parts. However, mutants differed from controls in that all their bouts were incomplete but uninterrupted, although intergroup difference for percentage of the incorrect transitions was not significant. In contrast to grooming, Dab1(scm) mice ambulated for a longer time. During walking episodes, they exhibited more body scratching than controls, possibly to compensate for the lack of licking different body parts. In conjunction with studies with other ataxic mice, these results indicate that the cerebellar cortex affects grooming activity and is consequently involved in executing various components, but not in its sequential organization, which requires other brain regions such as cerebral cortices or basal ganglia.

  15. Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia.

    PubMed

    Kim, Youngsoo; Kim, Seong Hun; Kim, Kook Hwan; Chae, Sujin; Kim, Chanki; Kim, Jeongjin; Shin, Hee-Sup; Lee, Myung-Shik; Kim, Daesoo

    2015-12-20

    Really interesting new gene (RING) finger protein 170 (RNF170) is an E3 ubiquitin ligase known to mediate ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate receptors (ITPR1). It has recently been demonstrated that a point mutation of RNF170 gene is linked with autosomal-dominant sensory ataxia (ADSA), which is characterized by an age-dependent increase of walking abnormalities, a rare genetic disorder reported in only two families. Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established. Here, we generated mice lacking Rnf170 (Rnf170(-/-)) to evaluate the effect of its loss of function in vivo. Remarkably, Rnf170(-/-) mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires. As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception. Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice. These results suggest that the loss of Rnf170 gene function mediates ADSA-associated phenotypes and this gives insights on the cure of patients with ADSA and other age-dependent walking abnormalities.

  16. Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice

    NASA Technical Reports Server (NTRS)

    Levasseur, Regis; Barrios, Roberto; Elefteriou, Florent; Glass, Donald A 2nd; Lieberman, Michael W.; Karsenty, Gerard

    2003-01-01

    Gamma-glutamyl transpeptidase (GGT) is a widely distributed ectopeptidase responsible for the degradation of glutathione in the gamma-glutamyl cycle. This cycle is implicated in the metabolism of cysteine, and absence of GGT causes a severe intracellular decrease in this amino acid. GGT-deficient (GGT-/-) mice have multiple metabolic abnormalities and are dwarf. We show here that this latter phenotype is due to a decreased of the growth plate cartilage total height resulting from a proliferative defect of chondrocytes. In addition, analysis of vertebrae and tibiae of GGT-/- mice revealed a severe osteopenia. Histomorphometric studies showed that this low bone mass phenotype results from an increased osteoclast number and activity as well as from a marked decrease in osteoblast activity. Interestingly, neither osteoblasts, osteoclasts, nor chondrocytes express GGT, suggesting that the observed defects are secondary to other abnormalities. N-acetylcysteine supplementation has been shown to reverse the metabolic abnormalities of the GGT-/- mice and in particular to restore the level of IGF-1 and sex steroids in these mice. Consistent with these previous observations, N-acetylcysteine treatment of GGT-/- mice ameliorates their skeletal abnormalities by normalizing chondrocytes proliferation and osteoblastic function. In contrast, resorbtion parameters are only partially normalized in GGT-/- N-acetylcysteine-treated mice, suggesting that GGT regulates osteoclast biology at least partly independently of these hormones. These results establish the importance of cysteine metabolism for the regulation of bone remodeling and longitudinal growth.

  17. Abnormal Mammary Adipose Tissue Environment of Brca1 Mutant Mice Show a Persistent Deposition of Highly Vascularized Multilocular Adipocytes.

    PubMed

    Jones, Laundette P; Buelto, Destiney; Tago, Elaine; Owusu-Boaitey, Kwadwo E

    2011-12-08

    A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.

  18. Polyunsaturated fatty acid supplementation reverses cystic fibrosis-related fatty acid abnormalities in CFTR-/- mice by suppressing fatty acid desaturases.

    PubMed

    Njoroge, Sarah W; Laposata, Michael; Boyd, Kelli L; Seegmiller, Adam C

    2015-01-01

    Cystic fibrosis patients and model systems exhibit consistent abnormalities in metabolism of polyunsaturated fatty acids that appear to play a role in disease pathophysiology. Recent in vitro studies have suggested that these changes are due to overexpression of fatty acid desaturases that can be reversed by supplementation with the long-chain polyunsaturated fatty acids docosahexaenoate and eicosapentaenoate. However, these findings have not been tested in vivo. The current study aimed to test these results in an in vivo model system, the CFTR(-/-) knockout mouse. When compared with wild-type mice, the knockout mice exhibited fatty acid abnormalities similar to those seen in cystic fibrosis patients and other model systems. The abnormalities were confined to lung, ileum and pancreas, tissues that are affected by the disease. Similar to in vitro models, these fatty acid changes correlated with increased expression of Δ5- and Δ6-desaturases and elongase 5. Dietary supplementation with high-dose free docosahexaenoate or a combination of lower-dose docosahexaenoate and eicosapentaenoate in triglyceride form corrected the fatty acid abnormalities and reduced expression of the desaturase and elongase genes in the ileum and liver of knockout mice. Only the high-dose docosahexaenoate reduced histologic evidence of disease, reducing mucus accumulation in ileal sections. These results provide in vivo support for the hypothesis that fatty acid abnormalities in cystic fibrosis result from abnormal expression and activity of metabolic enzymes in affected cell types. They further demonstrate that these changes can be reversed by dietary n-3 fatty acid supplementation, highlighting the potential therapeutic benefit for cystic fibrosis patients.

  19. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice

    PubMed Central

    Borghesani, Paul R.; Alt, Frederick W.; Bottaro, Andrea; Davidson, Laurie; Aksoy, Saime; Rathbun, Gary A.; Roberts, Thomas M.; Swat, Wojciech; Segal, Rosalind A.; Gu, Yansong

    2000-01-01

    Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia–telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atmy/y mice. In contrast to other Atm mutant mice, Atmy/y mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atmy/y mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atmy/y animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4+8+ thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T. PMID:10716718

  20. Morphometric and functional abnormalities of kidneys in the progeny of mice fed chocolate during pregnancy and lactation.

    PubMed

    Patera, Janusz; Chorostowska-Wynimko, Joanna; Słodkowska, Janina; Borowska, Adamina; Skopiński, Piotr; Sommer, Ewa; Wasiutyński, Aleksander; Skopińska-Rózewska, Ewa

    2006-01-01

    Even most commonly consumed beverages like tea, coffee, chocolate and cocoa contain methylxanthines, biogenic amines and polyphenols, among them catechins, that exhibit significant biological activity and might profoundly affect the organism homeostasis. We have previously shown that 400 mg of bitter chocolate or 6 mg of theobromine added to the daily diet of pregnant and afterwards lactating mice affected embryonic angiogenesis and caused bone mineralization disturbances as well as limb shortening in 4-weeks old offspring. The aim of the present study was the morphometric and functional evaluation of kidneys in the 4-weeks old progeny mice fed according to the protocol mentioned above. Progeny from the mice fed chocolate presented considerable morphometric abnormalities in the kidney structure, with the lower number of glomeruli per mm2 and their increased diameter. Moreover, higher serum creatinine concentration was observed in that group of offspring. No morphometric or functional irregularities were found in the progeny of mice fed theobromine. Abnormalities demonstrated in the offspring of mice fed chocolate are not related to its theobromine content. Consequently, identification of active compound(s) responsible for the observed effects is of vital importance.

  1. Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

    PubMed Central

    Nielsen, Corinne M.; Cuervo, Henar; Ding, Vivianne W.; Kong, Yupeng; Huang, Eric J.; Wang, Rong A.

    2014-01-01

    Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification by promoting arterial, as opposed to venous, endothelial cell (EC) fate. To understand the essential role of endothelial Notch signaling in postnatal AV organization, we used inducible Cre-loxP recombination to delete Rbpj, a mediator of canonical Notch signaling, from postnatal ECs in mice. Deletion of endothelial Rbpj from birth resulted in features of AVMs by P14, including abnormal AV shunting and tortuous vessels in the brain, intestine and heart. We further analyzed brain AVMs, as they pose particular health risks. Consistent with AVM pathology, we found cerebral hemorrhage, hypoxia and necrosis, and neurological deficits. AV shunts originated from capillaries (and possibly venules), with the earliest detectable morphological abnormalities in AV connections by P8. Prior to AV shunt formation, alterations in EC gene expression were detected, including decreased Efnb2 and increased Pai1, which encodes a downstream effector of TGFβ signaling. After AV shunts had formed, whole-mount immunostaining showed decreased Efnb2 and increased Ephb4 expression within AV shunts, suggesting that ECs were reprogrammed from arterial to venous identity. Deletion of Rbpj from adult ECs led to tortuosities in gastrointestinal, uterine and skin vascular beds, but had mild effects in the brain. Our results demonstrate a temporal requirement for Rbpj in postnatal ECs to maintain proper artery, capillary and vein organization and to prevent abnormal AV shunting and AVM pathogenesis. PMID:25209249

  2. Attenuation effect of Abnormal Savda Munziq on liver and heart toxicity caused by chemotherapy in mice

    PubMed Central

    AIKEMU, AINIWAER; AMAT, NURMUHAMAT; YUSUP, ABDIRYIM; SHAN, LIANLIAN; QI, XINWEI; UPUR, HALMURAT

    2016-01-01

    Abnormal Savda Munziq (ASMq), an Uighur medicine formula commonly used in the treatment of cancer, has been speculated to possess antioxidative and antiproliferative effects, and to regulate immune activity. The present study was designed to systematically elucidate the toxicity-reducing activity of ASMq in mice undergoing combination chemotherapy with doxorubicin and 5-fluorouracil (5-FU). The mice were divided into normal (saline, 10 ml/kg) and doxorubicin + 5-FU groups (doxorubicin, 2.5 mg/kg; 5-FU, 10 mg/kg on alternate days). In addition, three groups received different doses of ASMq (2, 4 and 8 g/kg), in addition to doxorubicin (2.5 mg/kg) and 5-FU (10 mg/kg) treatment on alternate days. The histology of the heart and liver, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activity, malondialdehyde (MDA) concentrations in heart homogenate, and various biochemical parameters of the liver were evaluated. Compared with the normal control group, ASMq dose-dependently improved a number of variables, including body weight, liver index, transaminase and total protein, and partially normalized liver and cardiac pathology. ASMq restored activities of defense antioxidant enzymes SOD and GSH-Px towards normal levels, and decreased MDA concentration in dose-dependent manner. These results demonstrated that ASMq provides significant protection against doxorubicin + 5-FU combination induced hepatotoxicity and cardiotoxicity. Further studies are required to determine the effects of ASMq against doxorubicin + 5-FU-induced toxicity during chemotherapy in vivo. PMID:27347066

  3. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia.

    PubMed

    Miyakawa, Tsuyoshi; Leiter, Lorene M; Gerber, David J; Gainetdinov, Raul R; Sotnikova, Tatyana D; Zeng, Hongkui; Caron, Marc G; Tonegawa, Susumu

    2003-07-22

    Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.

  4. Sodium sulfide prevents water diffusion abnormality in the brain and improves long term outcome after cardiac arrest in mice

    PubMed Central

    Kida, Kotaro; Minamishima, Shizuka; Wang, Huifang; Ren, JiaQian; Yigitkanli, Kazim; Nozari, Ala; Mandeville, Joseph B.; Liu, Philip K.; Liu, Christina H.; Ichinose, Fumito

    2012-01-01

    Aim of the study Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. Previously we demonstrated that administration of sodium sulfide (Na2S), a hydrogen sulfide (H2S) donor, markedly improved the neurological outcome and survival rate at 24h after CA and cardiopulmonary resuscitation (CPR) in mice. In this study, we sought to elucidate the mechanism responsible for the neuroprotective effects of Na2S and its impact on the long-term survival after CA/CPR in mice. Methods Adult male mice were subjected to potassium-induced CA for 7.5 min at 37°C whereupon CPR was performed with chest compression and mechanical ventilation. Mice received Na2S (0.55 mg/kg i.v.) or vehicle 1 min before CPR. Results Mice that were subjected to CA/CPR and received vehicle exhibited a poor 10-day survival rate (4/12) and depressed neurological function. Cardiac arrest and CPR induced abnormal water diffusion in the vulnerable regions of the brain, as demonstrated by hyperintense diffusion-weighted imaging (DWI) 24h after CA/CPR. Extent of hyperintense DWI was associated with matrix metalloproteinase 9 (MMP-9) activation, worse neurological outcomes, and poor survival rate at 10 days after CA/CPR. Administration of Na2S prevented the development of abnormal water diffusion and MMP-9 activation and markedly improved neurological function and long-term survival (9/12, P<0.05 vs. vehicle) after CA/CPR. Conclusion These results suggest that administration of Na2S 1 min before CPR improves neurological function and survival rate at 10 days after CA/CPR by preventing water diffusion abnormality in the brain potentially via inhibiting MMP-9 activation early after resuscitation. PMID:22370005

  5. Behavioral and neuroanatomical abnormalities in pleiotrophin knockout mice.

    PubMed

    Krellman, Jason W; Ruiz, Henry H; Marciano, Veronica A; Mondrow, Bracha; Croll, Susan D

    2014-01-01

    Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.

  6. Striatal magnetic resonance spectroscopy abnormalities in young adult SAPAP3 knockout mice

    PubMed Central

    Mintzopoulos, Dionyssios; Gillis, Timothy E.; Robertson, Holly R.; Dalia, Triana; Feng, Guoping; Rauch, Scott L.; Kaufman, Marc J.

    2015-01-01

    Background Obsessive compulsive disorder (OCD) is a debilitating condition with lifetime prevalence of 1–3%. OCD typically arises in youth but delays in diagnosis impede optimal treatment and developmental studies of the disorder. Research using genetically modified rodents may provide models of etiology that enable earlier detection and intervention. The SAPAP3 knockout (KO) transgenic mouse was developed as an animal model of OCD and related disorders (OCRD). KO mice exhibit compulsive self-grooming behavior analogous to behaviors found in people with OCRD. Striatal hyperactivity has been reported in these mice and in humans with OCD. Methods Striatal and medial frontal cortex 9.4 Tesla proton spectra were acquired from young adult SAPAP3 KO and wild-type control mice to determine whether KO mice have metabolic and neurochemical abnormalities. Results Young adult KO mice had lower striatal lactate (P=0.006) and glutathione (P=0.039) levels. Among all mice, striatal lactate and glutathione levels were associated (R=0.73, P=0.007). We found no group differences in medial frontal cortex metabolites. At the age range studied, only 1 of 8 KO mice had skin lesions indicative of severe compulsive grooming. Conclusion Young adult SAPAP3 KO mice have striatal but not medial frontal cortex MRS abnormalities that may reflect striatal hypermetabolism accompanied by oxidative stress. These abnormalities typically preceded the onset of severe compulsive grooming. Our findings are consistent with striatal hypermetabolism in OCD. Together, these results suggest that striatal MRS measures of lactate or glutathione might be useful biomarkers for early detection of risk for developing compulsive behavior disorders. PMID:26858992

  7. Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2

    PubMed Central

    Lin, Brian M.; Stafa, Klodjan; Kim, Jaekwang; Banerjee, Rebecca; Westerlund, Marie; Pletnikova, Olga; Glauser, Liliane; Yang, Lichuan; Liu, Ying; Swing, Deborah A.; Beal, M. Flint; Troncoso, Juan C.; McCaffery, J. Michael; Jenkins, Nancy A.; Copeland, Neal G.; Galter, Dagmar; Thomas, Bobby; Lee, Michael K.; Dawson, Ted M.; Dawson, Valina L.; Moore, Darren J.

    2011-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD. PMID:21494637

  8. Cnga2 Knockout Mice Display Alzheimer's-Like Behavior Abnormities and Pathological Changes.

    PubMed

    Xie, Ao-Ji; Liu, En-Jie; Huang, He-Zhou; Hu, Yu; Li, Ke; Lu, Youming; Wang, Jian-Zhi; Zhu, Ling-Qiang

    2016-09-01

    Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes.

  9. Abnormal Population Responses in the Somatosensory Cortex of Alzheimer’s Disease Model Mice

    PubMed Central

    Maatuf, Yossi; Stern, Edward A.; Slovin, Hamutal

    2016-01-01

    Alzheimer’s disease (AD) is the most common form of dementia. One of the neuropathological hallmarks of AD is the accumulation of amyloid-β plaques. Overexpression of human amyloid precursor protein in transgenic mice induces hippocampal and neocortical amyloid-β accumulation and plaque deposition that increases with age. The impact of these effects on neuronal population responses and network activity in sensory cortex is not well understood. We used Voltage Sensitive Dye Imaging, to investigate at high spatial and temporal resolution, the sensory evoked population responses in the barrel cortex of aged transgenic (Tg) mice and of age-matched non-transgenic littermate controls (Ctrl) mice. We found that a whisker deflection evoked abnormal sensory responses in the barrel cortex of Tg mice. The response amplitude and the spatial spread of the cortical responses were significantly larger in Tg than in Ctrl mice. At the network level, spontaneous activity was less synchronized over cortical space than in Ctrl mice, however synchronization during evoked responses induced by whisker deflection did not differ between the two groups. Thus, the presence of elevated Aβ and plaques may alter population responses and disrupts neural synchronization in large-scale networks, leading to abnormalities in sensory processing. PMID:27079783

  10. Cerebral abnormalities in cocaine abusers: Demonstration by SPECT perfusion brain scintigraphy. Work in progress

    SciTech Connect

    Tumeh, S.S.; Nagel, J.S.; English, R.J.; Moore, M.; Holman, B.L. )

    1990-09-01

    Single photon emission computed tomography (SPECT) perfusion brain scans with iodine-123 isopropyl iodoamphetamine (IMP) were obtained in 12 subjects who acknowledged using cocaine on a sporadic to a daily basis. The route of cocaine administration varied from nasal to intravenous. Concurrent abuse of other drugs was also reported. None of the patients were positive for human immunodeficiency virus. Brain scans demonstrated focal defects in 11 subjects, including seven who were asymptomatic, and no abnormality in one. Among the findings were scattered focal cortical deficits, which were seen in several patients and which ranged in severity from small and few to multiple and large, with a special predilection for the frontal and temporal lobes. No perfusion deficits were seen on I-123 SPECT images in five healthy volunteers. Focal alterations in cerebral perfusion are seen commonly in asymptomatic drug users, and these focal deficits are readily depicted by I-123 IMP SPECT.

  11. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

    NASA Astrophysics Data System (ADS)

    Meneton, Pierre; Bloch-Faure, May; Hagege, Albert A.; Ruetten, Hartmut; Huang, Wei; Bergaya, Sonia; Ceiler, Debbie; Gehring, Doris; Martins, Isabelle; Salmon, Georges; Boulanger, Chantal M.; Nussberger, Jürg; Crozatier, Bertrand; Gasc, Jean-Marie; Heudes, Didier; Bruneval, Patrick; Doetschman, Tom; Ménard, Joël; Alhenc-Gelas, François

    2001-02-01

    Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to βadrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.

  12. Knockout of G protein β5 impairs brain development and causes multiple neurologic abnormalities in mice

    PubMed Central

    Zhang, Jian-Hua; Pandey, Mritunjay; Seigneur, Erica M.; Panicker, Leelamma M.; Koo, Lily; Schwartz, Owen M.; Chen, Weiping; Chen, Ching-Kang; Simonds, William F.

    2011-01-01

    Gβ5 is a divergent member of the signal-transducing G protein β subunit family encoded by GNB5 and expressed principally in brain and neuronal tissue. Among heterotrimeric Gβ isoforms, Gβ5 is unique in its ability to heterodimerize with members of the R7 subfamily of the regulator of G protein signaling (RGS) proteins that contain G protein-γ like domains. Previous studies employing Gnb5 knockout (KO) mice have shown that Gβ5 is an essential stabilizer of such RGS proteins and regulates the deactivation of retinal phototransduction and the proper functioning of retinal bipolar cells. However, little is known of the function of Gβ5 in the brain outside the visual system. We show here that mice lacking Gβ5 have a markedly abnormal neurologic phenotype that includes impaired development, tiptoe-walking, motor learning and coordination deficiencies, and hyperactivity. We further show that Gβ5-deficient mice have abnormalities of neuronal development in cerebellum and hippocampus. We find that the expression of both mRNA and protein from multiple neuronal genes is dysregulated in Gnb5 KO mice. Taken together with previous observations from Gnb5 KO mice, our findings suggest a model in which Gβ5 regulates dendritic arborization and/or synapse formation during development, in part by effects on gene expression. PMID:21883221

  13. Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice.

    PubMed

    Rothman, Sarah M; Griffioen, Kathleen J; Fishbein, Kenneth W; Spencer, Richard G; Makrogiannis, Sokratis; Cong, Wei-Na; Martin, Bronwen; Mattson, Mark P

    2014-05-01

    Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such

  14. Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice

    PubMed Central

    Rothman, Sarah M.; Griffioen, Kathleen J.; Fishbein, Kenneth W.; Spencer, Richard G.; Makrogiannis, Sokratis; Cong, Wei-na; Martin, Bronwen; Mattson, Mark P.

    2013-01-01

    Parkinson’s disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared to both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, MRI analysis revealed that WT mice had significantly greater total and visceral body fat compared to SNCA mice (p<0.007). At 24 weeks of age SNCA mice displayed significantly increased hunger compared to WT (p<0.03). At 36 weeks of age, SNCA mice displayed significant hypoleptinemia compared to WT, both on a normal diet and a HCD (p<0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared to WT, as measured in a Comprehensive Lab Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal

  15. Abnormalities in the WFU strain of Taenia crassiceps (Cyclophyllidea: Taeniidae) following years of propagation in mice.

    PubMed

    Aguilar-Vega, L; García-Prieto, L; Zurabian, R

    2016-09-01

    Asexually proliferating Taenia crassiceps (Zeder, 1800) metacestodes isolated within past decades have been successfully sub-cultured under experimental conditions using Mus musculus Linnaeus, 1758 mice. However, during their development, morphological irregularities of scolex structures have been reported in two of the three strains of this cestode species maintained in mice - ORF and KBS. The main goal of this work is to describe the abnormalities observed in a sample of 118 cysticerci of the third T. crassiceps strain used at present - WFU. Morphological abnormalities were detected in 39.8% of the evaginated scoleces; they consisted of supernumerary suckers (n= 2), duplicated (n= 2) or absent rostellum (n= 1), as well as absent or aberrant (n= 29) hooks, which were significantly shorter when compared to the large and short hook lengths referred to in the literature.

  16. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors

    PubMed Central

    Sarnyai, Zoltán; Sibille, Etienne L.; Pavlides, Constantine; Fenster, Robert J.; McEwen, Bruce S.; Tóth, Miklós

    2000-01-01

    The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin1A receptors (5-HT1A receptors). Because chronic stress selectively down-regulates the 5-HT1A receptors in the hippocampus, we hypothesized that mice lacking these receptors may exhibit abnormalities reminiscent of symptoms of stress-related psychiatric disorders. In particular, a hippocampal deficit in the 5-HT1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT1A receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT1A-knockout (KO) mice. 5-HT1A-KO animals showed a deficit in hippocampal-dependent learning and memory tests, such as the hidden platform (spatial) version of the Morris water maze and the delayed version of the Y maze. The performance of KO mice was not impaired in nonhippocampal memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory. Furthermore, paired-pulse facilitation in the dentate gyrus of the hippocampus was impaired in 5-HT1A-KO mice. Finally, 5-HT1A-KO mice, as compared with wild-type animals, displayed higher limbic excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration. These results demonstrate that 5-HT1A receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders. PMID:11121072

  17. Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice.

    PubMed

    Singh, Chanpreet; Bortolato, Marco; Bali, Namrata; Godar, Sean C; Scott, Anna L; Chen, Kevin; Thompson, Richard F; Shih, Jean C

    2013-07-30

    The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.

  18. Persistent expression of Twist1 in chondrocytes causes growth plate abnormalities and dwarfism in mice.

    PubMed

    Guzzo, Rosa M; Andreeva, Viktoria; Spicer, Douglas B; Drissi, M Hicham

    2011-01-01

    Evidence from various in vitro gain and loss of function studies indicate that the bHLH transcription factor Twist1 negatively regulates chondrocyte differentiation; however limited information regarding Twist1 function in postnatal cartilage development and maintenance is available. Twist1 expression within the postnatal growth plate is restricted to immature, proliferating chondrocytes, and is significantly decreased or absent in hypertrophic chondrocytes. In order to examine the effect of maintaining the expression of Twist1 at later stages of chondocyte differentiation, we used type II collagen Cre (Col2-Cre) mice to activate a Cre-inducible Twist1 transgene specifically in chondrocytes (Col2-Twist1). At two weeks, postnatal growth was inhibited in Col2-Twist1 mice, as evidenced by limb shortening. Histological examination revealed abnormal growth plate structure, characterized by poor columnar organization of proliferating cartilaginous cells, decreased cellularity, and expansion of the hypertrophic zone. Moreover, structural defects within the growth plates of Col2-Twist1 transgenic mice included abnormal vascular invasion and focal regions of bony formation. Quantitative analysis of endochondral bone formation via micro-computed topography revealed impaired trabecular bone formation in the hindlimbs of Col2-Twist1 transgenic mice at various timepoints of postnatal development. Taken together, these findings indicate that regulated Twist1 expression contributes to growth plate organization and endochondral ossification to modulate postnatal longitudinal bone growth.

  19. Abnormalities in itch sensation and skin barrier function in atopic NC/Tnd mice.

    PubMed

    Amagai, Yosuke; Matsuda, Hiroshi; Tanaka, Akane

    2013-01-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dryness and itchy skin. Genetic factors as well as other factors, including abnormality in skin barrier function, hypersensitivity of itch sensory nerves, and dysfunction of the immune system, strongly affect the onset and exacerbation of AD. Recently, it has become clear that itch sensation is closely related to pain sensation. By using NC/Tnd mice, a unique spontaneous animal model for human AD, we found abnormalities in sensitivity against external stimuli as compared to two standard strains, BALB/c and B6 mice. Particularly, in conventional NC/Tnd mice with AD, stimulation against transient receptor potential (TRP) V1 reduced the scratching behavior, suggesting the possibility of a TRPV1 modulator in the treatment of atopic itch. The review outlines observations regarding itch sensation and skin barrier function in NC/Tnd mice by using a novel itch quantification system for the laboratory animals, which may bring great progress in the future study of itch.

  20. Biochemical and phenotypic abnormalities in kynurenine aminotransferase II-deficient mice.

    PubMed

    Yu, Ping; Di Prospero, Nicholas A; Sapko, Michael T; Cai, Tao; Chen, Amy; Melendez-Ferro, Miguel; Du, Fu; Whetsell, William O; Guidetti, Paolo; Schwarcz, Robert; Tagle, Danilo A

    2004-08-01

    Kynurenic acid (KYNA) can act as an endogenous modulator of excitatory neurotransmission and has been implicated in the pathogenesis of several neurological and psychiatric diseases. To evaluate its role in the brain, we disrupted the murine gene for kynurenine aminotransferase II (KAT II), the principal enzyme responsible for the synthesis of KYNA in the rat brain. mKat-2(-/-) mice showed no detectable KAT II mRNA or protein. Total brain KAT activity and KYNA levels were reduced during the first month but returned to normal levels thereafter. In contrast, liver KAT activity and KYNA levels in mKat-2(-/-) mice were decreased by >90% throughout life, though no hepatic abnormalities were observed histologically. KYNA-associated metabolites kynurenine, 3-hydroxykynurenine, and quinolinic acid were unchanged in the brain and liver of knockout mice. mKat-2(-/-) mice began to manifest hyperactivity and abnormal motor coordination at 2 weeks of age but were indistinguishable from wild type after 1 month of age. Golgi staining of cortical and striatal neurons revealed enlarged dendritic spines and a significant increase in spine density in 3-week-old mKat-2(-/-) mice but not in 2-month-old animals. Our results show that gene targeting of mKat-2 in mice leads to early and transitory decreases in brain KAT activity and KYNA levels with commensurate behavioral and neuropathological changes and suggest that compensatory changes or ontogenic expression of another isoform may account for the normalization of KYNA levels in the adult mKat-2(-/-) brain.

  1. Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.

    PubMed

    Uchiumi, Osamu; Kasahara, Yoshiyuki; Fukui, Asami; Hall, F Scott; Uhl, George R; Sora, Ichiro

    2013-01-01

    Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α₇ nACh receptor antagonist methyllycaconitine or WAY100635, while the α₄β₂ nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

  2. Trichloroethylene exposure aggravates behavioral abnormalities in mice that are deficient in superoxide dismutase.

    PubMed

    Otsuki, Noriyuki; Homma, Takujiro; Fujiwara, Hiroki; Kaneko, Kenya; Hozumi, Yasukazu; Shichiri, Mototada; Takashima, Mizuki; Ito, Junitsu; Konno, Tasuku; Kurahashi, Toshihiro; Yoshida, Yasukazu; Goto, Kaoru; Fujii, Satoshi; Fujii, Junichi

    2016-08-01

    Trichloroethylene (TCE) has been implicated as a causative agent for Parkinson's disease (PD). The administration of TCE to rodents induces neurotoxicity associated with dopaminergic neuron death, and evidence suggests that oxidative stress as a major player in the progression of PD. Here we report on TCE-induced behavioral abnormality in mice that are deficient in superoxide dismutase 1 (SOD1). Wild-type (WT) and SOD1-deficient (Sod1(-/-)) mice were intraperitoneally administered TCE (500 mg/kg) over a period of 4 weeks. Although the TCE-administrated Sod1(-/-) mice showed marked abnormal motor behavior, no significant differences were observed among the experimental groups by biochemical and histopathological analyses. However, treating mouse neuroblastoma-derived NB2a cells with TCE resulted in the down regulation of the SOD1 protein and elevated oxidative stress under conditions where SOD1 production was suppressed. Taken together, these data indicate that SOD1 plays a pivotal role in protecting motor neuron function against TCE toxicity.

  3. Inactivation of Ceramide Synthase 6 in Mice Results in an Altered Sphingolipid Metabolism and Behavioral Abnormalities*

    PubMed Central

    Ebel, Philipp; vom Dorp, Katharina; Petrasch-Parwez, Elisabeth; Zlomuzica, Armin; Kinugawa, Kiyoka; Mariani, Jean; Minich, David; Ginkel, Christina; Welcker, Jochen; Degen, Joachim; Eckhardt, Matthias; Dere, Ekrem; Dörmann, Peter; Willecke, Klaus

    2013-01-01

    The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for β-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain. PMID:23760501

  4. Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities.

    PubMed

    Ebel, Philipp; Vom Dorp, Katharina; Petrasch-Parwez, Elisabeth; Zlomuzica, Armin; Kinugawa, Kiyoka; Mariani, Jean; Minich, David; Ginkel, Christina; Welcker, Jochen; Degen, Joachim; Eckhardt, Matthias; Dere, Ekrem; Dörmann, Peter; Willecke, Klaus

    2013-07-19

    The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for β-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.

  5. Chromosomal abnormalities in neutron-induced acute myeloid leukemias in CBA/H mice

    SciTech Connect

    Bouffler, S.D.; Meijne, E.I.M.; Huiskamp, R.

    1996-09-01

    Acute myeloid leukemias (AMLs) induced in CBA/H mice by 1 MeV fission neutrons have been examined for chromosomal abnormalities by G-band analysis. In common with X-ray- and {alpha}-particle-induced AMLs in CBA/H mice, more than 90% (16/17) of the myeloid leukemias had chromosome 2 abnormalities, in this case, all interstitial deletions. Chromosome 2 breakpoints were not wholly consistent, but clustering in three specific G-band regions was observed. Very distal (H-region) breakpoints were more common in the neutron AMLs than in X-ray- or {alpha}-particle-induced leukemias. These data indicate that neutron-induced AMLs in CBA/H mice are not characterized by a specific chromosome deletion but that a variety of chromosome 2 deletion types are associated with the disease. Trisomy of chromosome 1 (12.5% AMLs) and aneusomy of chromosomes 6 (31% AMLs) and Y (37.5% AMLs) were noted. While chromatid breakage was observed occasionally in neutron-induced AML, no clear indications of persistent chromosomal instability or high levels of stable chromosomal change were apparent. 19 refs., 1 fig., 1 tab.

  6. Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors.

    PubMed

    Erbel-Sieler, Claudia; Dudley, Carol; Zhou, Yudong; Wu, Xinle; Estill, Sandi Jo; Han, Tina; Diaz-Arrastia, Ramon; Brunskill, Eric W; Potter, S Steven; McKnight, Steven L

    2004-09-14

    Laboratory mice bearing inactivating mutations in the genes encoding the NPAS1 and NPAS3 transcription factors have been shown to exhibit a spectrum of behavioral and neurochemical abnormalities. Behavioral abnormalities included diminished startle response, as measured by prepulse inhibition, and impaired social recognition. NPAS1/NPAS3-deficient mice also exhibited stereotypic darting behavior at weaning and increased locomotor activity. Immunohistochemical staining assays showed that the NPAS1 and NPAS3 proteins are expressed in inhibitory interneurons and that the viability and anatomical distribution of these neurons are unaffected by the absence of either transcription factor. Adult brain tissues from NPAS3- and NPAS1/NPAS3-deficient mice exhibited a distinct reduction in reelin, a large, secreted protein whose expression has been reported to be attenuated in the postmortem brain tissue of patients with schizophrenia. These observations raise the possibility that a regulatory program controlled in inhibitory interneurons by the NPAS1 and NPAS3 transcription factors may be either substantively or tangentially relevant to psychosis.

  7. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: an update.

    PubMed

    Nakamura, Motonobu; Schneider, Marlon R; Schmidt-Ullrich, Ruth; Paus, Ralf

    2013-01-01

    Human hair disorders comprise a number of different types of alopecia, atrichia, hypotrichosis, distinct hair shaft disorders as well as hirsutism and hypertrichosis. Their causes vary from genodermatoses (e.g. hypotrichoses) via immunological disorders (e.g. alopecia areata, autoimmune cicatrical alopecias) to hormone-dependent abnormalities (e.g. androgenetic alopecia). A large number of spontaneous mouse mutants and genetically engineered mice develop abnormalities in hair follicle morphogenesis, cycling, and/or hair shaft formation, whose analysis has proven invaluable to define the molecular regulation of hair growth, ranging from hair follicle development, and cycling to hair shaft formation and stem cell biology. Also, the accumulating reports on hair phenotypes of mouse strains provide important pointers to better understand the molecular mechanisms underlying human hair growth disorders. Since numerous new mouse mutants with a hair phenotype have been reported since the publication of our earlier review on this matter a decade ago, we present here an updated, tabulated mini-review. The updated annotated tables list a wide selection of mouse mutants with hair growth abnormalities, classified into four categories: Mutations that affect hair follicle (1) morphogenesis, (2) cycling, (3) structure, and (4) mutations that induce extrafollicular events (for example immune system defects) resulting in secondary hair growth abnormalities. This synthesis is intended to provide a useful source of reference when studying the molecular controls of hair follicle growth and differentiation, and whenever the hair phenotypes of a newly generated mouse mutant need to be compared with existing ones.

  8. Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria.

    PubMed

    Szarek, Eva; Ball, Evan R; Imperiale, Alessio; Tsokos, Maria; Faucz, Fabio R; Giubellino, Alessio; Moussallieh, François-Marie; Namer, Izzie-Jacques; Abu-Asab, Mones S; Pacak, Karel; Taïeb, David; Carney, J Aidan; Stratakis, Constantine A

    2015-06-01

    Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function

  9. Cardiac and skeletal muscle abnormality in taurine transporter-knockout mice.

    PubMed

    Ito, Takashi; Oishi, Shohei; Takai, Mika; Kimura, Yasushi; Uozumi, Yoriko; Fujio, Yasushi; Schaffer, Stephen W; Azuma, Junichi

    2010-08-24

    Taurine, a sulfur-containing beta-amino acid, is highly contained in heart and skeletal muscle. Taurine has a variety of biological actions, such as ion movement, calcium handling and cytoprotection in the cardiac and skeletal muscles. Meanwhile, taurine deficiency leads various pathologies, including dilated cardiomyopathy, in cat and fox. However, the essential role of taurine depletion on pathogenesis has not been fully clarified. To address the physiological role of taurine in mammalian tissues, taurine transporter-(TauT-) knockout models were recently generated. TauTKO mice exhibited loss of body weight, abnormal cardiac function and the reduced exercise capacity with tissue taurine depletion. In this chapter, we summarize pathological profile and histological feature of heart and skeletal muscle in TauTKO mice.

  10. Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome.

    PubMed

    Wang, Yuexia; Ostlund, Cecilia; Worman, Howard J

    2010-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by mutations in LMNA leading to expression of a truncated prelamin A variant termed progerin. Whereas a farnesylated polypeptide is normally removed from the carboxyl-terminus of prelamin A during endoproteolytic processing to lamin A, progerin lacks the cleavage site and remains farnesylated. Cultured cells from human subjects with HGPS and genetically modified mice expressing progerin have nuclear morphological abnormalities, which are reversed by inhibitors of protein farnesylation. In addition, treatment with protein farnesyltransferase inhibitors improves whole animal phenotypes in mouse models of HGPS. However, improvement in nuclear morphology in tissues after treatment of animals has not been demonstrated. We therefore treated transgenic mice that express progerin in epidermis with the protein farnesyltransferase inhibitor FTI-276 or a combination of pravastatin and zoledronate to determine if they reversed nuclear morphological abnormalities in tissue. Immunofluorescence microscopy and "blinded" electron microscopic analysis demonstrated that systemic administration of FTI-276 or pravastatin plus zoledronate significantly improved nuclear morphological abnormalities in keratinocytes of transgenic mice. These results show that pharmacological blockade of protein prenylation reverses nuclear morphological abnormalities that occur in HGPS in vivo. They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials.

  11. Abnormal epithelial homeostasis in the cornea of mice with a destrin deletion

    PubMed Central

    Zhao, J.; Chen, L.; Urbanowicz, M. M.

    2008-01-01

    Purpose Dstncorn1 mice lack normal destrin expression and develop corneal abnormality shortly after birth such as epithelial hyperplasia and total vascularization. Thus, the mice serve as a model for ocular surface disorders. To determine the nature of epithelial defects, we examined whether epithelial homeostasis is altered in these corneas. Methods Dstncorn1 mice were crossed with ubiquitous GFP mice to generate a double homozygous line, GFP-Dstncorn1, and cell movements were determined by whole-mount histology and in vivo time-lapse microscopy, tracking the change of epithelial GFP patterns. Rates of cell division and the presence of label-retaining cells (LRCs) were determined by systemic bromodeoxyuridine (BrdU). Epithelial expression of keratins 8, 12, and 15, and MUC5AC were determined by whole-mount immunofluorescence. Results Epithelial cells in an adult GFP-Dstncorn1 cornea were generally immobile with no sign of directed movement for the entire life of the animal. These cells were not senescent because more than 70% of basal epithelial cells incorporated BrdU over a 24 h period. LRCs were widely distributed throughout a GFP-Dstncorn1 cornea. The epithelium of a GFP-Dstncorn1 cornea contained a mixed population of cells with a corneal and a conjunctival phenotype as judged by the expression of keratins and MUC5AC. Conclusions Epithelial cells of an adult GFP-Dstncorn1 cornea are generally stationary, mitotically active, and contain LRCs, indicating that the epithelium is self-sustained, which in turn suggests that epithelial stem cells are present within the cornea. Epithelial homeostasis of adult GFP-Dstncorn1 corneas is abnormal, mimicking that of a normal conjunctiva or a pathological, conjunctivalized cornea. PMID:18958303

  12. Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation.

    PubMed

    Chidgey, M; Brakebusch, C; Gustafsson, E; Cruchley, A; Hail, C; Kirk, S; Merritt, A; North, A; Tselepis, C; Hewitt, J; Byrne, C; Fassler, R; Garrod, D

    2001-11-26

    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 epidermal barrier defect. The epidermis is fragile, and acantholysis in the granular layer generates localized lesions, compromising skin barrier function. Neutrophils accumulate in the lesions and further degrade the tissue, causing sloughing (flaking) of lesional epidermis, but rapid wound healing prevents the formation of overt lesions. Null epidermis is hyperproliferative and overexpresses keratins 6 and 16, indicating abnormal differentiation. From 6 wk, null mice develop ulcerating lesions resembling chronic dermatitis. We speculate that ulceration occurs after acantholysis in the fragile 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 blistering diseases is discussed. These results show that Dsc1 is required for strong adhesion and barrier maintenance in epidermis and contributes to epidermal differentiation.

  13. Abnormal Sperm Development in pcd3J-/- Mice: the Importance of Agtpbp1 in Spermatogenesis

    PubMed Central

    Kim, Nameun; Xiao, Rui; Choi, Hojun; Kim, Jin-Hoi; Sang-Jun, Uhm; Chankyu, Park

    2011-01-01

    Homozygous Purkinje cell degeneration (pcd) mutant males exhibit abnormal sperm development. Microscopic examination of the testes from pcd3J-/- mice at postnatal days 12, 15, 18 and 60 revealed histological differences, in comparison to wild-type mice, which were evident by day 18. Greatly reduced numbers of spermatocytes and spermatids were found in the adult testes, and apoptotic cells were identified among the differentiating germ cells after day 15. Our immunohistological analysis using an antihuman AGTPBP1 antibody showed that AGTPBP1 was expressed in spermatogenic cells between late stage primary spermatocytes and round spermatids. A global gene expression analysis from the testes of pcd3J-/- mice showed that expression of cyclin B3 and de-ubiquitinating enzymes USP2 and USP9y was altered by >1.5-fold compared to the expression levels in the wild-type. Our results suggest that the pcd mutant mice have defects in spermatogenesis that begin with the pachytene spermatocyte stage and continue through subsequent stages. Thus, Agtpbp1, the gene responsible for the pcd phenotype, plays an important role in spermatogenesis and is important for survival of germ cells at spermatocytes stage onward. PMID:21110128

  14. Abnormal B-cell function in HTLV-I-tax transgenic mice.

    PubMed

    Peebles, R S; Maliszewski, C R; Sato, T A; Hanley-Hyde, J; Maroulakou, I G; Hunziker, R; Schneck, J P; Green, J E

    1995-03-16

    Transgenic mice that carry the HTLV-I Tax gene develop an exocrinopathy with some similarities to Sjoegren's syndrome. Our experiments reveal that these mice have lymphadenopathy and splenomegaly composed primarily of B lymphocytes, as well as abnormal levels of secreted immunoglobulins. To gain insight into whether the lymphadenopathy manifested by these transgenic mice was the result of induction of cytokines by Tax, we utilized cell lines from these mice to study in vitro B-cell responses. Conditioned media (CM) derived from the cell lines caused B-cells to proliferate when a second signal, surface Ig cross-linking, was provided. The CM also caused a marked enhancement of IgM secretion by spleen cells or by purified B-cells treated with supplemental cytokines. The B-cell proliferative response and enhanced IgM secretion have not been attributed to a known cytokine. These results suggest that the CM from the cell lines contain a factor(s) involved in novel pathways of B-cell growth and differentiation that may participate in the pathologic development of autoimmune disease.

  15. Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice

    PubMed Central

    Yue, M.; Hinkle, K.; Davies, P.; Trushina, E.; Fiesel, F.; Christenson, T.; Schroeder, A.; Zhang, L.; Bowles, E.; Behrouz, B.; Lincoln, S.; Beevers, J.; Milnerwood, A.; Kurti, A.; McLean, P. J.; Fryer, J. D.; Springer, W.; Dickson, D.; Farrer, M.; Melrose, H.

    2015-01-01

    Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression. PMID:25836420

  16. TallyHO obese female mice experience poor reproductive outcomes and abnormal blastocyst metabolism which is reversed by metformin

    PubMed Central

    Louden, Erica D.; Luzzo, Kerri M.; Jimenez, Patricia T.; Chi, Tiffany; Chi, Maggie; Moley, Kelle H.

    2015-01-01

    Objective Obese women experience worse reproductive outcomes compared to normal weight women, specifically infertility, pregnancy loss, fetal malformations and developmental delay. The objective of this study was to use a genetic mouse model of obesity in order to recapitulate the human reproductive phenotype and further examine potential mechanisms and therapies. Methods New inbred, polygenic Type 2 diabetic TallyHO mice and age matched control C57BL/6 mice were superovulated to obtain morulae or blastocysts stage embryos which were cultured in human tubal fluid media. Deoxyglucose uptake was performed on insulin-stimulated individual blastocysts. Apoptosis was detected by confocal microscopy using TUNEL assay and Topro-3 nuclear dye. Embryos were scored for %TUNEL positive/total nuclei. AMPK activation, TNFα expression, and adiponectin expression were analyzed by western immunoblot and confocal immunofluorescent microscopy. Lipid accumulation was assayed by Bodipy. Finally all measured parameters were compared between TallyHO mice in morulaes cultured to blastocyst embryos in either human tubal fluid (HTF) media or HTF with 25ug/ml metformin added. Results TallyHo mice developed whole body abnormal insulin tolerance, decreased litter number and increased NEFA. Blastocysts demonstrated increased apoptosis, decreased insulin sensitivity, and decreased activation of AMP activated protein-kinase (AMPK). As a possible cause of the insulin resistance/abnormal P-AMPK, we found that Tumor necrosis Factor (TNFα) expression and lipid accumulation as detected by BODIPY were increased in TallyHO blastocysts and adiponectin was decreased. Culturing TallyHO morulae with the AMPK activator, metformin lead to a reversal of all abnormal findings, including increased p-AMPK, improved insulin-stimulated glucose uptake and normalization of lipid accumulation. Conclusions Women with obesity and insulin resistance experience poor pregnancy outcomes. Previously we have shown in mouse

  17. No Obvious Abnormality in Mice Deficient in Receptor Protein Tyrosine Phosphatase β

    PubMed Central

    Harroch, S.; Palmeri, M.; Rosenbluth, J.; Custer, A.; Okigaki, M.; Shrager, P.; Blum, M.; Buxbaum, J. D.; Schlessinger, J.

    2000-01-01

    The development of neurons and glia is governed by a multitude of extracellular signals that control protein tyrosine phosphorylation, a process regulated by the action of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Receptor PTPβ (RPTPβ; also known as PTPζ) is expressed predominantly in the nervous system and exhibits structural features common to cell adhesion proteins, suggesting that this phosphatase participates in cell-cell communication. It has been proposed that the three isoforms of RPTPβ play a role in regulation of neuronal migration, neurite outgrowth, and gliogenesis. To investigate the biological functions of this PTP, we have generated mice deficient in RPTPβ. RPTPβ-deficient mice are viable, are fertile, and showed no gross anatomical alterations in the nervous system or other organs. In contrast to results of in vitro experiments, our study demonstrates that RPTPβ is not essential for neurite outgrowth and node formation in mice. The ultrastructure of nerves of the central nervous system in RPTPβ-deficient mice suggests a fragility of myelin. However, conduction velocity was not altered in RPTPβ-deficient mice. The normal development of neurons and glia in RPTPβ-deficient mice demonstrates that RPTPβ function is not necessary for these processes in vivo or that loss of RPTPβ can be compensated for by other PTPs expressed in the nervous system. PMID:11003666

  18. Lack of Tryptophan Hydroxylase-1 in Mice Results in Gait Abnormalities

    PubMed Central

    Suidan, Georgette L.; Vanderhorst, Veronique; Hampton, Thomas G.; Wong, Siu Ling; Voorhees, Jaymie R.; Wagner, Denisa D.

    2013-01-01

    The role of peripheral serotonin in nervous system development is poorly understood. Tryptophan hydroxylase-1 (TPH1) is expressed by non-neuronal cells including enterochromaffin cells of the gut, mast cells and the pineal gland and is the rate-limiting enzyme involved in the biosynthesis of peripheral serotonin. Serotonin released into circulation is taken up by platelets via the serotonin transporter and stored in dense granules. It has been previously reported that mouse embryos removed from Tph1-deficient mothers present abnormal nervous system morphology. The goal of this study was to assess whether Tph1-deficiency results in behavioral abnormalities. We did not find any differences between Tph1-deficient and wild-type mice in general motor behavior as tested by rotarod, grip-strength test, open field and beam walk. However, here we report that Tph1 (−/−) mice display altered gait dynamics and deficits in rearing behavior compared to wild-type (WT) suggesting that tryptophan hydroxylase-1 expression has an impact on the nervous system. PMID:23516593

  19. Abnormal gene expression in cerebellum of Npc1-/- mice during postnatal development

    PubMed Central

    Liao, Guanghong; Wen, Zhining; Irizarry, Kristopher; Huang, Ying; Mitsouras, Katherine; Darmani, Mariam; Leon, Terry; Shi, Leming; Bi, Xiaoning

    2010-01-01

    Niemann-Pick Type C disease is an autosomal recessive neurodegenerative disorder with abnormal lipid storage as the major cellular pathologic hallmark. Genetic analyses have identified mutations in NPC1 gene in the great majority of cases, while mutations in NPC2 account for the remainders. Yet, little is known regarding the cellular mechanisms responsible for NPC pathogenesis, especially for neurodegeneration, which is the usual cause of death. To identify critical steps that could account for the pathological manifestations of the disease in one of the most affected brain structures, we performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Differentially-expressed genes identified by both microarray platforms were then subjected to KEGG pathway analysis. Expression of genes in six pathways was significantly altered in Npc1-/- mice; functionally, these signaling pathways belong to the following three categories: 1) steroid and terpenoid biosynthesis, 2) immune response, and 3) cell adhesion/motility. In addition, the expression of several proteins involved in lipid transport was significantly altered in Npc1-/- mice. Our results provide novel molecular insight regarding the mechanisms of pathogenesis in NPC disease and reveal potential new therapeutic targets. PMID:20153740

  20. Autism-relevant social abnormalities in mice exposed perinatally to extremely low frequency electromagnetic fields.

    PubMed

    Alsaeed, Ibrahim; Al-Somali, Faisal; Sakhnini, Lama; Aljarallah, Omar S; Hamdan, Rayan M M; Bubishate, Saleh A; Sarfaraz, Ziyab Khan; Kamal, Amer

    2014-10-01

    The incidence of autism spectrum disorders (ASD) has been rising, but the causes of ASD remain largely unidentified. Collective data have implicated the increased human exposure to electromagnetic fields (EMF) in the increasing incidence of ASD. There are established biological effects of extremely low-frequency (ELF) EMF, but the relation to ASD is not investigated enough. In this study we examined the effects of perinatal exposure to ELF EMF on some ASD-relevant behavioral parameters in mice. The EMF was delivered via a Helmholtz coil pair. Male BALB/C mice were used and divided into exposed and control groups (n=8 and n=9, respectively). Tests were used to assess sociability, preference for social novelty, locomotion, anxiety, exploratory behavior, motor coordination, and olfaction. The examined mice were all males and exposed to EMF during the last week of gestation and for 7 days after delivery. The exposed mice demonstrated a lack of normal sociability and preference for social novelty while maintaining normal anxiety-like behavior, locomotion, motor coordination, and olfaction. Exposed mice also demonstrated decreased exploratory activity. We concluded that these results are supportive of the hypothesis of a causal link between exposure to ELF-EMF and ASD; however, replications of the study with further tests are recommended.

  1. Dietary Wolfberry Ameliorates Retinal Structure Abnormalities in db/db Mice at the Early Stage of Diabetes

    PubMed Central

    Tang, Ling; Zhang, Yunong; Jiang, Yu; Willard, Lloyd; Ortiz, Edlin; Wark, Logan; Medeiros, Denis; Lin, Dingbo

    2011-01-01

    Hyperglycemia-linked oxidative stress and/or consequent endoplasmic reticulum stress are the causative factors of pathogenesis of diabetic retinopathy. Dietary bioactive components which mitigate oxidative stress may serve as potential chemopreventative agents to prevent or slow down the disease progression. Wolfberry is a traditional Asian fruit consumed for years to prevent aging eye diseases in Asian countries. Here we report that dietary wolfberry ameliorated mouse retinal abnormality at the early stage of type 2 diabetes in db/db mice. Male mice at 6 weeks of age were fed the control diet with or without 1 % (kCal) wolfberry for 8 weeks. Dietary wolfberry restored the thickness of the whole retina, in particular the inner nuclear layer and photoreceptor layer, and the integrity of retinal pigment epithelia (RPE), and the ganglion cell number in db/db mice. Western blotting of whole retinal cell lysates revealed that addition of wolfberry lowered expression of endoplasmic reticulum (ER) stress biomarkers BiP, PERK, ATF6, and caspase-12; and restored AMPK, thioredoxin, Mn SOD, and FOXO3α activities. To determine if our observations were due to the high contents of zeaxanthin and lutein in wolfberry additional studies using these carotenoids were conducted. Using the human adult diploid RPE cell line ARPE-19 we demonstrated that both zeaxanthin and lutein could mimic wolfberry preventive effect on activation of AMPK, thioredoxin, Mn SOD, FOXO3α activities, normalize cellular reactive oxygen species, and attenuate ER stress in ARPE-19 cells exposed to a high glucose challenge. The zeaxanthin preventive effect was abolished by siRNA knockdown of AMPKα. These results suggested that AMPK activation appeared to play a key role in upregulated expression of thioredoxin and Mn SOD, and mitigation of cellular oxidative stress and/or ER stress by wolfberry and zeaxanthin and/or lutein. Taken together, dietary wolfberry on retinal protection in diabetic mice is, at least

  2. Normal human oral keratinocytes demonstrate abnormal DNA end joining activity during replicative senescence.

    PubMed

    Kang, Mo K; Shin, Ki-Hyuk; Yip, Felix K; Park, No-Hee

    2005-04-01

    Repair of DNA double-strand breaks (DSBs) is critical for the maintenance of cellular genetic integrity. DSBs are repaired by cellular end joining activity, which could proceed with varying degrees of accuracy. Abnormal end joining may lead to an accumulation of mutations and contribute to genetic instability and cellular aging. In the present study, we compared the efficiency and accuracy of end joining activities in exponentially replicating and senescing normal human oral keratinocytes (NHOK). We developed an in vitro end joining assay utilizing a plasmid linearized with a unique EcoR I or EcoR V restriction site. The efficiency of end joining was determined by PCR with primers that could amplify the fragment containing the end joining site. The accuracy of end joining was assessed by determining whether the original EcoR I site was restored after end joining. Both replicating and senescing cultures of NHOK yielded a similar level of end joining efficiency, which was noted by the similar intensity of PCR amplification. However, the frequency of end joining errors was significantly elevated in NHOK during replicative senescence. Senescing NHOK could thus accumulate abnormal end joining products, which might contribute to cellular aging and cancer.

  3. Congenital abnormality effect of methamphetamine on histological, cellular and chromosomal defects in fetal mice

    PubMed Central

    Mirjalili, Tahereh; Kalantar, Seyed Mehdi; Shams Lahijani, Maryam; Sheikhha, Mohamad Hasan; Talebi, Alireza

    2013-01-01

    Background: Methamphetamine (MA) is a potent psychomotor stimulant with high abuse and addictive potential. MA is a neurotoxic drug which is widely abused by females of childbearing age, raising serious public health concerns in terms of exposure of the fetus to the drug. Neurotoxic effects of MA on adult are well known, such as dopaminergic nerve terminal degeneration and cell death in regions of brain in some doses. Objective: In the present study, we examined effect of prenatal MA exposure on mouse fetuses. Materials and Methods: In this study, forty 8-12 week-old NMRI female mice were used which were mated with male mice in serial days. When sperm plug was observed it was designated as gestational day (GD) 0. Pregnant mice were individually housed in plastic cages. Pregnant mice were divided into four groups: in first group 10 mg/kg /day MA, in second group 5 mg/kg /day MA and in third group saline were injected subcutaneously from GD 6 to GD 14, corresponding to organogenesis period, while fourth or control group were without injection. On GD 14 fetuses were removed and accomplished chromosome preparation from fetal liver. Then fetal were fixed in formalin for brain hematoxilin and eosine staining and TUNEL assay. Results: We observed morphological abnormality including exencephal fetus in 5mg/kg MA group and premature fetuses in 10 mg/kg MA group. Also brain histological study showed subarachnoid hemorrhage in fetal brain in both experimental groups. Fetal liver karyotyping analysis was normal in fetuses of all groups and TUNEL assay in fetal striatum did not show significant difference in number of apoptotic cells between groups. Conclusion: From our results, it could be concluded that chronic abuse of MA by pregnant females during organogenesis period can cause teratogenic effect and brain hemorrage in fetus. PMID:24639691

  4. Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

    PubMed

    Endo, Toyoshi; Kobayashi, Tetsuro

    2013-09-01

    Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were severely hypothyroid and had similar serum Ca(2+) and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in the growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate compared with that of wild-type mice. Expressions of chondrocyte differentiation marker genes Sox-9 and type IIa collagen in growth plate from THYx mice were 52 and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

  5. In Utero Bisphenol A Exposure Induces Abnormal Neuronal Migration in the Cerebral Cortex of Mice.

    PubMed

    Ling, Wenting; Endo, Toshihiro; Kubo, Ken-Ichiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

    2016-01-01

    Bisphenol A (BPA) has been known to have endocrine-disrupting activity to induce reproductive and behavioral abnormalities in offspring of laboratory animal species. However, morphological basis of this abnormality during brain development is largely unknown. Cerebral cortex plays a crucial role in higher brain function, and its precisely laminated structure is formed by neuronal migration. In the present study, transfecting a plasmid (pCAG-mCherry) by in utero electroporation (IUE), we visualized developing neurons and investigated the possible effects of in utero BPA exposure on neuronal migration. Pregnant mice were exposed to BPA by osmotic pump at estimated daily doses of 0, 40 (BPA-40), or 400 (BPA-400) μg/kg from embryonic day 14.5 (E14.5) to E18.5. IUE was performed at E14.5 and neuronal migration was analyzed at E18.5. Compared with the control group, neuronal migration in the cortical plate was significantly decreased in the BPA-40 group; however, there was no significant difference in the BPA-400 group. Among several neuronal migration-related genes and cortical layer-specific genes, TrkB in the BPA-400 group was found significantly upregulated. In conclusion, in utero exposure to low BPA dose was found to disrupt neuronal migration in the cerebral cortex in a dose-specific manner.

  6. In Utero Bisphenol A Exposure Induces Abnormal Neuronal Migration in the Cerebral Cortex of Mice

    PubMed Central

    Ling, Wenting; Endo, Toshihiro; Kubo, Ken-ichiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

    2016-01-01

    Bisphenol A (BPA) has been known to have endocrine-disrupting activity to induce reproductive and behavioral abnormalities in offspring of laboratory animal species. However, morphological basis of this abnormality during brain development is largely unknown. Cerebral cortex plays a crucial role in higher brain function, and its precisely laminated structure is formed by neuronal migration. In the present study, transfecting a plasmid (pCAG-mCherry) by in utero electroporation (IUE), we visualized developing neurons and investigated the possible effects of in utero BPA exposure on neuronal migration. Pregnant mice were exposed to BPA by osmotic pump at estimated daily doses of 0, 40 (BPA-40), or 400 (BPA-400) μg/kg from embryonic day 14.5 (E14.5) to E18.5. IUE was performed at E14.5 and neuronal migration was analyzed at E18.5. Compared with the control group, neuronal migration in the cortical plate was significantly decreased in the BPA-40 group; however, there was no significant difference in the BPA-400 group. Among several neuronal migration-related genes and cortical layer-specific genes, TrkB in the BPA-400 group was found significantly upregulated. In conclusion, in utero exposure to low BPA dose was found to disrupt neuronal migration in the cerebral cortex in a dose-specific manner. PMID:26869994

  7. The targeted overexpression of a Claudin mutant in the epidermis of transgenic mice elicits striking epidermal and hair follicle abnormalities.

    PubMed

    Troy, Tammy-Claire; Turksen, Kursad

    2007-06-01

    Skin is one of the largest organs of the body, and is formed during development through a highly orchestrated process involving mesenchymal-epithelial interactions, cell commitment, and terminal differentiation. It protects against microorganism invasion and UV irradiation, inhibits water loss, regulates body temperature, and is an important part of the immune system. Using transgenic mouse technology, we have demonstrated that Claudin (Cldn)-containing tight junctions (TJs) are intricately involved in cell signaling during epidermal differentiation and that an epidermal suprabasal overexpression of Cldn6 results in a perturbed epidermal terminal differentiation program with distinct phenotypic abnormalities. To delineate the role of the Cldn cytoplasmic tail domain in epidermal differentiation, we engineered transgenic mice targeting the overexpression of a Cldn6 cytoplasmic tail-truncation mutant in the epidermis. Transgenic mice were characterized by a lethal barrier dysfunction in addition to the existence of hyperproliferative squamous invaginations/cysts replacing hair follicles. Immunohistochemical analysis revealed an epidermal cytoplasmic accumulation of Cldn6, Cldn11, Cldn12, and Cldn18, downregulation of Cldn1 and aberrant expression of various classical markers of epidermal differentiation; namely the basal keratins as well as K1, involucrin, loricrin, and filaggrin. Collectively these studies suggest an important role for Cldns in epidermal/hair follicle differentiation programs likely involving cross talk to signaling pathways (e.g., Notch) directing cell fate selection and differentiation.

  8. Studies on Brahma rasayana in male swiss albino mice: Chromosomal aberrations and sperm abnormalities

    PubMed Central

    Guruprasad, K. P.; Mascarenhas, Roshan; Gopinath, P. M.; Satyamoorthy, K.

    2010-01-01

    Ayurveda, the Indian holistic healthcare system encompasses traditional medicines with a principle of creating harmony and maintaining balance within the natural rhythms of the body. Rasayana is one of the branches of Ayurveda frequently used as rejuvenant therapy to overcome many discomforts and prevent diseases. It has been reported that rasayanas have immunomodulatory, antioxidant and antitumor functions. However, the genotoxic potential of many rasayanas remains to be evaluated. The present study was undertaken to assess the role of Brahma rasayana(BR) on genotoxicity in vivo in a mouse test system. The older mice (9 months) were orally fed with rasayana for 8 weeks. The treated groups showed no signs of dose-dependent toxicity at the dosage levels tested. The body weight loss/gain and feed consumption were unaffected at tested doses. Furthermore, sperm abnormalities and chromosomal aberrations were insignificant in the treatment group when compared to controls. However, there was a marginal increase in sperm count in the BR treated animals. These findings clearly indicate that there are no observed adverse genotoxic effects elicited by BR in experimental animals such as mice. PMID:21829300

  9. Effects of dietary vitamin D on calcium and magnesium levels in mice with abnormal calcium metabolism

    SciTech Connect

    Spurlock, B.G.; West, W.L.; Knight, E.M. )

    1991-03-11

    In previous studies vitamin D has been used to induce cardiac calcium overload in laboratory animals. Interrelationships between calcium and magnesium metabolism are also documented. The authors have investigated the effect of varying vitamin D in the diet on calcium and magnesium levels in plasma, kidney and heart of DBA mice which exhibit genetic abnormalities in cardiac calcium metabolism. Weanling DBA mice were maintained for 28 days on an AIN-76 diet containing either 1,000 I.U. of vitamin D{sub 3} per kg of diet (control); 4,000 I.U. of vitamin D{sub 3} per kg of diet; or no vitamin D. When compared to controls, supplemented animals showed significantly higher plasma magnesium, kidney calcium and kidney magnesium levels; animals receiving the vitamin D-deficient diet exhibited increases in cardiac calcium levels. The authors results support previous findings that vitamin D deficiency increases cardiac calcium uptake and suggest a possible role of vitamin D in magnesium metabolism.

  10. Evolution of gait abnormalities in SOD1(G93A) transgenic mice.

    PubMed

    Mancuso, Renzo; Oliván, Sara; Osta, Rosario; Navarro, Xavier

    2011-08-11

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of upper and lower motoneurons. Clinically, it is manifested by weakness, muscle atrophy and progressive paralysis and ends up with patients' death 2-5 years after diagnosis. Although these symptoms lead in many cases to gait deficits in patients, an exhaustive locomotor profile of animal models mimicking the disease has not been assessed yet. In this work we evaluated the locomotor performance of the SOD1(G93A) mouse model of ALS using computerized treadmill gait analysis. SOD1(G93A) mice presented early (8 weeks of age) gait abnormalities, evidenced by an increase in the time of the propulsion phase of hindlimb stance. The alterations progressed during the disease until a complete disturbance of normal gait. This finding is meaningful to the field because the identification of a significant difference in a functional endpoint as early as 8 weeks might be a step forward resolving the debate about treatment of mice prior to the symptomatic phase in efficacy studies. These results also point out that digitizing analysis of treadmill locomotion may be useful to evaluate whether new therapeutic approaches are improving functional outcome of the animals.

  11. Behavioral, Neurochemical and Neuroendocrine Effects of Abnormal Savda Munziq in the Chronic Stress Mice

    PubMed Central

    Amat, Nurmuhammat; Hoxur, Parida; Ming, Dang; Matsidik, Aynur; Kijjoa, Anake; Upur, Halmurat

    2012-01-01

    Oral administration of Abnormal Savda Munsiq (ASMq), a herbal preparation used in Traditional Uighur Medicine, was found to exert a memory-enhancing effect in the chronic stressed mice, induced by electric foot-shock. The memory improvement of the stressed mice was shown by an increase of the latency time in the step-through test and the decrease of the latency time in the Y-maze test. Treatment with ASMq was found to significantly decrease the serum levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT) and β-endorphin (β-EP) as well as the brain and serum level of norepinephrine (NE). Furthermore, ASMq was able to significantly reverse the chronic stress by decreasing the brain and serum levels of the monoamine neurotransmitters dopamine (DA), 5-hydroxytryptamine (5-HT) and 3,4-dihydroxyphenylalanine (DOPAC). The results obtained from this study suggested that the memory-enhancing effect of ASMq was mediated through regulations of neurochemical and neuroendocrine systems. PMID:22919413

  12. Studies on Brahma rasayana in male swiss albino mice: Chromosomal aberrations and sperm abnormalities.

    PubMed

    Guruprasad, K P; Mascarenhas, Roshan; Gopinath, P M; Satyamoorthy, K

    2010-01-01

    Ayurveda, the Indian holistic healthcare system encompasses traditional medicines with a principle of creating harmony and maintaining balance within the natural rhythms of the body. Rasayana is one of the branches of Ayurveda frequently used as rejuvenant therapy to overcome many discomforts and prevent diseases. It has been reported that rasayanas have immunomodulatory, antioxidant and antitumor functions. However, the genotoxic potential of many rasayanas remains to be evaluated. The present study was undertaken to assess the role of Brahma rasayana(BR) on genotoxicity in vivo in a mouse test system. The older mice (9 months) were orally fed with rasayana for 8 weeks. The treated groups showed no signs of dose-dependent toxicity at the dosage levels tested. The body weight loss/gain and feed consumption were unaffected at tested doses. Furthermore, sperm abnormalities and chromosomal aberrations were insignificant in the treatment group when compared to controls. However, there was a marginal increase in sperm count in the BR treated animals. These findings clearly indicate that there are no observed adverse genotoxic effects elicited by BR in experimental animals such as mice.

  13. Positional cloning of Kreisler, a mutation that causes deafness and segmentation abnormalities in mice

    SciTech Connect

    Cordes, S.P.; Barsh, G.S.

    1994-09-01

    The identification and analysis of mouse deafness mutations is of great interest to human geneticists, not only because deafness is a common problem in clinical genetics, but also because the molecular mechanisms leading to deafness can underly fundamental aspects of mammalian development. Approximately 10 to 20 genes when mutated can lead to deafness in mice or in humans, but none have yet been identified at the molecular level. In mice homozygous for the kreisler (kr) mutation, abnormal development of the hindbrain and otic vesicle leads to neurosensory deafness and loss of vestibular function. Using the techniques of positional cloning combined with ENU mutagenesis, we have now cloned the kr gene and find that it predicts a transcription factor whose absence leads to defects in Hox gene expression and hindbrain segmentation. We used a backcross between different strains of laboratory mice to sublocalize kr on the meiotic map close to the Src gene on mouse chromosome 2. A probe from the Src gene detected high molecular weight restriction fragments of altered size in kr/kr DNA, suggesting that kr was due to a chromosomal rearrangement. Based on the meiotic map location of kr{sup ENU}, a new kr allele that we generated by ENU mutagenesis, cDNAs were selected from 8.5 day mouse embryos using genomic clones that spanned the distal inversion breakpoint. One cDNA that predicted a basic domain leucine zipper (bZIP) transcription factor was found to be expressed in the caudal hindbrain, and was confirmed to encode the kr gene by analysis of the kr{sup ENU} allele, in which a Ser was substituted for an Asn residue conserved in the DNA binding domain of all known bZip family members. kr is not expressed in the otic vesicle, suggesting that abnormal otic development is a consequence of defects in hindbrain segmentation. kr is the first mammalian deafness gene to be isolated, and should provide insights into embryologic mechanisms that underly hindbrain and otic development.

  14. Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome.

    PubMed

    Kellow, J E; Gill, R C; Wingate, D L

    1990-05-01

    Continuous 72-h recordings of duodenojejunal contractile activity were obtained from 20 freely ambulant subjects; pressure was detected by two strain-gauge sensors incorporated in a transnasal catheter attached to an encoder and a miniature tape recorder. The subjects were 12 patients with irritable bowel syndrome, 6 of whom were constipation predominant and 6 of whom were diarrhea predominant, and 8 healthy controls. The procedure was well tolerated by all subjects and did not interfere with sleep or normal activity. In all subjects, the diurnal migrating motor complex cycle was characterized by a brief phase 1 and a prolonged phase 2; this was reversed during sleep when phase 2 was virtually absent. All subjects showed a circadian variation in migrating motor complex propagation velocity, and there was no difference in the patterns of motor activity during sleep between any of the groups. During the day, the duration of postprandial motor activity was shorter in irritable bowel syndrome patients than in controls, and diurnal migrating motor complex intervals were shorter in diarrhea-predominant than in constipation-predominant irritable bowel syndrome. In 11 of 12 inflammatory bowel syndrome patients, episodes of clustered contractions recurring at 0.9-min intervals were noted; these episodes had a mean duration of 46 min and were often associated with transient abdominal pain and discomfort. In both groups of irritable bowel syndrome patients, defecation was significantly (p less than 0.01) prolonged with a greater number of voluntary abdominal contractions (p less than 0.01) than in controls. Prolonged ambulant monitoring of proximal bowel motor activity in subjects who are free to move, eat, and sleep as they choose has, for the first time, clearly defined the striking difference in motility between the sleeping and waking state and shown that abnormalities associated with irritable bowel syndrome are confined to the latter.

  15. Creating the Multiple Personality: An Experiential Demonstration for an Undergraduate Abnormal Psychology Class.

    ERIC Educational Resources Information Center

    Rabinowitz, Fredric E.

    1989-01-01

    Discusses a classroom role-playing exercise in which students and teacher re-enact interviewing techniques that cause subjects to assume characteristics of the multiple personality. Demonstrates the social psychological aspects of multiple personality disorder. Considers the pedagogical and ethical implications of creating the multiple personality…

  16. Abnormal thymic maturation and lymphoproliferation in MRL-Faslpr/lpr mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome.

    PubMed

    Ashman, R F; Singh, N; Lenert, P S

    2016-11-10

    MRL-Fas (lpr/lpr) mice represent an excellent animal model for studying non-malignant lymphoproliferation, regeneration and systemic autoimmunity. Retro-transposon insertion into the second intron of the pro-apoptotic Fas gene appears to be responsible for both lymphoproliferation and autoimmunity, while other genes are more likely to contribute to the regenerative healing characteristic of this mouse strain. Previous studies have shown that neonatal thymectomy can halt the development of abnormal lymphoproliferation. Whereas at four weeks of age primary and secondary lymphoid organs appear to be grossly intact, vigorous lymphoproliferation and autoantibody production subsequently ensues. This is first noticeable at six weeks of age, at which time lymph nodes, spleens and thymuses, but not the bone marrow, become infiltrated with abnormal B220(+)CD3(+)CD4(-)CD8(-) T cells. Around the same time, thymuses show a significant drop in CD4(+)CD8(+)double-positive T cells generating an abnormal ratio between double-positive and single-positive thymocytes. The objective of current study was to evaluate the effect of synthetic oligonucleotides-toll-like receptor antagonists on early lymphoid development in this strain of mice. Herein, we demonstrate the ability of synthetic oligonucleotides made with the nuclease-resistant phosphorothioate backbone to partially reverse abnormal lymphoproliferation and thymic involution in pre-diseased MRL-Fas (lpr/lpr) mice when administered intraperitoneally starting from week four of age. This curative effect of oligonucleotides was primary sequence/secondary oligonucleotide structure-independent, suggesting an effect through the toll-like receptor 7. A similar approach may potentially benefit patients with autoimmune lymphoproliferative syndrome who, like MRL-Fas (lpr/lpr) mice, carry a mutation in the Fas gene.

  17. Transgenic sickle cell trait mice do not exhibit abnormal thermoregulatory and stress responses to heat shock exposure.

    PubMed

    Chen, Yifan; Islam, Aminul

    2016-07-01

    There remains controversy over whether individuals with sickle cell trait (SCT) are vulnerable to health risks during physical activity in high temperatures. We examined thermoregulatory and stress-related responses to heat exposure in SCT and wild-type (WT) mice. No significant differences in core temperature (Tc) were observed between SCT and WT mice during heat exposure. There was no correlation between peak Tc during heat exposure and levels of hemoglobin S in SCT mice. Basal levels of circulating inflammatory and stress-related markers were not significantly different between SCT and WT mice. Although heat exposure caused significant increases in plasma interleukins 1β and 6, and 8-isoprostane in SCT and WT mice, no differences were found between SCT and WT mice with similar thermal response profiles during heat exposure. SCT mice had significantly higher expression of heat shock protein 72 in heart, liver and gastrocnemius muscle than WT mice under control and post-heat conditions. In conclusion, there is neither thermoregulatory dysfunction nor abnormal stress-related response in SCT mice exposed to moderate heat. The hemoglobin variant in mice is associated with altered tissue stress protein homeostasis.

  18. Oxytocin knockout mice demonstrate enhanced intake of sweet and nonsweet carbohydrate solutions.

    PubMed

    Sclafani, Anthony; Rinaman, Linda; Vollmer, Regis R; Amico, Janet A

    2007-05-01

    Oxytocin knockout (OT KO) mice display enhanced intake of nutritive and nonnutritive sweet solutions (i.e., sucrose and saccharin) compared with wild-type (WT) mice of the same C57BL/6 background strain. The present study further investigated the differential behavioral response of OT KO and WT mice to sucrose solutions and also examined intake preferences of OT KO and WT mice for palatable but nonsweet isocaloric solutions of carbohydrate and fat. A progressive ratio operant licking procedure demonstrated that OT KO and WT mice display a similar motivational drive to consume 10% sucrose. A series of two-bottle intake tests revealed that OT KO mice consume significantly larger amounts of both sweet and nonsweet carbohydrate solutions (i.e., sucrose, Polycose, and cornstarch) compared with WT cohorts. Intake pattern analyses revealed that OT KO mice overconsume carbohydrate solutions by initiating more drinking bouts compared with WT mice; bout sizes did not differ between the genotypes. In contrast, OT KO and WT mice did not differ in their intake of Intralipid, a palatable soybean oil emulsion. These findings indicate that the absence of OT in mice does not affect their appetitive drive to consume palatable sucrose solutions. Instead, the absence of OT may increase daily intake of palatable sweet and nonsweet solutions of carbohydrate (but not fat) by selectively blunting or masking processes that contribute to postingestive satiety.

  19. Molecular detection of chromosomal abnormalities in germ and somatic cells of aged male mice

    SciTech Connect

    Lowe, X.; Baulch, J.; Quintana, L.; Ramsey, M.; Breneman, J.; Tucker, J.; Wyrobek, A.; Collins, B.; Allen, J.; Holland, N.

    1994-12-31

    Three cytogenetic methods were applied to eight B6C3F1 male mice aged 22.5 - 30.5mo to determine if advanced age was associated with an elevated risk of producing chromosomally defective germinal and somatic cells; sperm aneuploidy analysis by multi-color fluorescence in situ hybridization for three chromosomes, spermatid micronucleus analysis with anti-kinetochore antibodies, and translocation analysis of somatic metaphases by {open_quotes}painting{close_quotes} for two chromosomes. Eight mice aged 2.4mo served as controls. Sperm aneuploidy was measured by multi-color fluorescence in situ co-hybridization with DNA probes specific for chromosomes X, Y and 8, scoring 10,000 cells per animal. The aged group showed significant 1.5 - 2.0 fold increases in the hyperhaploidy phenotypes X-X-8, Y-Y-8, 8-8-Y, and 8-8-X with the greater effects appearing in animals aged >29mo. The aged group also showed significantly increased frequencies of micronucleated spermatids (2.0 vs 0.4 per 1000; all were kinetochore negative). Analysis of metaphase chromosomes from blood by {open_quotes}painting{close_quotes} of chromosomes 2 and 8 yielded 4 translocation per 858 cell-equivalents in the aged group which was a non-significant elevation over 0/202 in controls. Although interpretation must be cautious due to the small number of animals analyzed, these findings suggest that advanced paternal age may be a risk factor for chromosomal abnormalities of reproductive and somatic importance.

  20. Immunomodulatory and antitumour effects of abnormal Savda Munziq on S180 tumour-bearing mice

    PubMed Central

    2012-01-01

    Background Abnormal Savda Munziq (ASMq), a traditional uyghur medicine, has shown anti-tumour properties in vitro. This study attempts to confirm these effects in vivo and measure effects on the immune system. Methods Kunming mice transplanted with Sarcoma 180 cells were treated with ASMq (2–8 g/kg/day) by intra-gastric administration compared to model and cyclophosphamide (20 mg/kg/day). After the 14th day post tumour implant, thymus, liver, spleen and tumours were removed, weighed, and processed for histopathological analysis. Blood samples were also taken for haematological and biochemical analyses including TNF-α , IL-1 β and IL-2. Splenic lymphocyte function was measured with MTT; lymphocyte subpopulations were measured by flow cytometry. Results ASMq treated animals had reduced tumour volume compared to model and increased concentrations of TNF-α, IL-1β and IL-2 compared to untreated and to cyclophosphamide-treated animals. No histopathological alterations were observed. The absence of viable S180 cells and the presence of necrotic cells and granulation tissue were observed in tumour tissue of treated animals. The effect on T lymphocytes was unclear. Conclusions ASMq confirmed in vivo anti-tumour effects observed in vitro, which may be at least in part mediated by increased immune activity. PMID:22978453

  1. Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

    PubMed Central

    Kang, Min-Kyung; Park, Sin-Hye; Kim, Yun-Ho; Lee, Eun-Jung; Antika, Lucia Dwi; Kim, Dong Yeon; Choi, Yean-Jung; Kang, Young-Hee

    2016-01-01

    Diabetic retinopathy (DR) develops in a significant proportion of patients with chronic diabetes, characterized by retinal macular edema and abnormal retinal vessel outgrowth leading to vision loss. Chrysin, a naturally-occurring flavonoid found in herb and honeycomb, has anti-inflammatory, antioxidant, and anti-cancer properties. This study sought to determine the protective effects of chrysin on retinal neovascularization with abnormal vessels and blood-retinal barrier (BRB) breakdown in 33 mM glucose-exposed human retinal endothelial cells and in db/db mouse eyes. High glucose caused retinal endothelial apoptotic injury, which was inhibited by submicromolar chrysin. This compound diminished the enhanced induction of HIF-1α, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (VEGFR2) in high glucose-exposed retinal endothelial cells. Consistently, oral administration of 10 mg/kg chrysin reduced the induction of these proteins in db/db mouse eye tissues. In addition, chrysin restored the decrement of VE-cadherin and ZO-1 junction proteins and PECAM-1 in hyperglycemia-stimulated retinal endothelial cells and diabetic mouse retina, possibly maintaining tight cell-cell interactions of endothelial cells and pericytes. Anti-apoptotic chrysin reduced the up-regulation of Ang-1, Ang-2, and Tie-2 crucial to retinal capillary occlusion and BRB permeability. Furthermore, orally treating chrysin inhibited acellular capillary formation, neovascularization, and vascular leakage observed in diabetic retinas. These observations demonstrate, for the first time, that chrysin had a capability to encumber diabetes-associated retinal neovascularization with microvascular abnormalities and BRB breakdown. PMID:27918469

  2. Role of social encounter-induced activation of prefrontal serotonergic systems in the abnormal behaviors of isolation-reared mice.

    PubMed

    Ago, Yukio; Araki, Ryota; Tanaka, Tatsunori; Sasaga, Asuka; Nishiyama, Saki; Takuma, Kazuhiro; Matsuda, Toshio

    2013-07-01

    Isolation-reared male rodents show abnormal behaviors such as hyperlocomotion, aggressive behaviors, deficits of prepulse inhibition, and depression- and anxiety-like behaviors, but the neurochemical mechanism for the effects of psychological stress in these animals is not fully understood. This study examined the effects of social interactions between isolation-reared mice and intruder mice on brain monoaminergic systems. A cage was divided into two compartments by a mesh partition to prevent direct physical interactions. The 20-min encounter with an intruder elicited a restless and hyperexcitable state (hyperactivity) in male, but not in female, isolation-reared mice, whereas encounters with a sleeping intruder or a novel object did not. Although the encounter did not affect prefrontal neuronal-activity-marker c-Fos expression, dopamine (DA) levels, or serotonin (5-HT) levels in male group-reared mice or female isolation-reared mice, it increased prefrontal c-Fos expression, DA levels, and 5-HT levels in male isolation-reared mice. Furthermore, encounter-induced increases in c-Fos expression in the dorsal raphe nucleus and ventral tegmental area, but not in the nucleus accumbens shell, were much greater in isolation-reared than group-reared male mice. A 5-HT1A receptor agonist, a metabotropic glutamate 2/3 receptor agonist, and a gamma-aminobutyric acid A receptor agonist attenuated isolation-induced aggressive behaviors and encounter-induced hyperactivity, c-Fos expression in the prefrontal cortex and dorsal raphe nucleus, and increases in prefrontal 5-HT levels. These findings suggest that the prefrontal DA and 5-HT systems are activated by encounter stimulation in male isolation-reared mice, and the encounter-induced activation of 5-HT system triggers the induction of some abnormal behaviors in male isolation-reared mice. Furthermore, this study implies that the encounter stimulation-induced signal has a pharmacological significance.

  3. A lack of functional NK1 receptors explains most, but not all, abnormal behaviours of NK1R-/- mice1

    PubMed Central

    Porter, A J; Pillidge, K; Tsai, Y C; Dudley, J A; Hunt, S P; Peirson, S N; Brown, L A; Stanford, S C

    2015-01-01

    Mice lacking functional neurokinin-1 receptors (NK1R-/-) display abnormal behaviours seen in Attention Deficit Hyperactivity Disorder (hyperactivity, impulsivity and inattentiveness). These abnormalities were evident when comparing the behaviour of separate (inbred: ‘Hom’) wildtype and NK1R-/- mouse strains. Here, we investigated whether the inbreeding protocol could influence their phenotype by comparing the behaviour of these mice with that of wildtype (NK1R+/+) and NK1R-/- progeny of heterozygous parents (‘Het’, derived from the same inbred strains). First, we recorded the spontaneous motor activity of the two colonies/genotypes, over 7 days. This continuous monitoring also enabled us to investigate whether the diurnal rhythm in motor activity differs in the two colonies/genotypes. NK1R-/- mice from both colonies were hyperactive compared with their wildtypes and their diurnal rhythm was also disrupted. Next, we evaluated the performance of the four groups of mice in the 5-Choice Serial Reaction-Time Task (5-CSRTT). During training, NK1R-/- mice from both colonies expressed more impulsive and perseverative behaviour than their wildtypes. During testing, only NK1R-/- mice from the Hom colony were more impulsive than their wildtypes, but NK1R-/- mice from both colonies were more perseverative. There were no colony differences in inattentiveness. Moreover, a genotype difference in this measure depended on time of day. We conclude that the hyperactivity, perseveration and, possibly, inattentiveness of NK1R-/- mice is a direct consequence of a lack of functional NK1R. However, the greater impulsivity of NK1R-/- mice depended on an interaction between a functional deficit of NK1R and other (possibly environmental and/or epigenetic) factors. PMID:25558794

  4. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency.

    PubMed

    Carbonaro, Denise A; Zhang, Lin; Jin, Xiangyang; Montiel-Equihua, Claudia; Geiger, Sabine; Carmo, Marlene; Cooper, Aaron; Fairbanks, Lynette; Kaufman, Michael L; Sebire, Neil J; Hollis, Roger P; Blundell, Michael P; Senadheera, Shantha; Fu, Pei-Yu; Sahaghian, Arineh; Chan, Rebecca Y; Wang, Xiaoyan; Cornetta, Kenneth; Thrasher, Adrian J; Kohn, Donald B; Gaspar, H Bobby

    2014-03-01

    Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV EFS ADA). In ADA(-/-) mice, LV EFS ADA displayed high-efficiency gene transfer and sufficient ADA expression to rescue ADA(-/-) mice from their lethal phenotype with good thymic and peripheral T- and B-cell reconstitution. Human ADA-deficient CD34(+) cells transduced with 1-5 × 10(7) TU/ml had 1-3 vector copies/cell and expressed 1-2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV EFS ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while reducing the potential for vector-mediated insertional mutagenesis.

  5. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis

    NASA Astrophysics Data System (ADS)

    Black, Joel A.; Dib-Hajj, Sulayman; Baker, David; Newcombe, Jia; Cuzner, M. Louise; Waxman, Stephen G.

    2000-10-01

    Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.

  6. Ames hypopituitary dwarf mice demonstrate imbalanced myelopoiesis between bone marrow and spleen

    PubMed Central

    Capitano, Maegan L.; Chitteti, Brahmananda R.; Cooper, Scott; Srour, Edward F.; Bartke, Andrzej; Broxmeyer, Hal E.

    2015-01-01

    Ames hypopituitary dwarf mice are deficient in growth hormone, thyroid-stimulating hormone, and prolactin. The phenotype of these mice demonstrates irregularities in the immune system with skewing of the normal cytokine milieu towards a more anti-inflammatory environment. However, the hematopoietic stem and progenitor cell composition of the bone marrow (BM) and spleen in Ames dwarf mice has not been well characterized. We found that there was a significant decrease in overall cell count when comparing the BM and spleen of 4–5 month old dwarf mice to their littermate controls. Upon adjusting counts to differences in body weight between the dwarf and control mice, the number of granulocyte-macrophage progenitors, confirmed by immunophenotyping and colony-formation assay was increased in the BM. In contrast, the numbers of all myeloid progenitor populations in the spleen were greatly reduced, as confirmed by colony-formation assays. This suggests that there is a shift of myelopoiesis from the spleen to the BM of Ames dwarf mice; however, this shift does not appear to involve erythropoiesis. The reasons for this unusual shift in spleen to marrow hematopoiesis in Ames dwarf mice are yet to be determined but may relate to the decreased hormone levels in these mice. PMID:25976461

  7. X-y interactions underlie sperm head abnormality in hybrid male house mice.

    PubMed

    Campbell, Polly; Nachman, Michael W

    2014-04-01

    The genetic basis of hybrid male sterility in house mice is complex, highly polygenic, and strongly X linked. Previous work suggested that there might be interactions between the Mus musculus musculus X and the M. m. domesticus Y with a large negative effect on sperm head morphology in hybrid males with an F1 autosomal background. To test this, we introgressed the M. m. domesticus Y onto a M. m. musculus background and measured the change in sperm morphology, testis weight, and sperm count across early backcross generations and in 11th generation backcross males in which the opportunity for X-autosome incompatibilities is effectively eliminated. We found that abnormality in sperm morphology persists in M. m. domesticus Y introgression males, and that this phenotype is rescued by M. m. domesticus introgressions on the X chromosome. In contrast, the severe reductions in testis weight and sperm count that characterize F1 males were eliminated after one generation of backcrossing. These results indicate that X-Y incompatibilities contribute specifically to sperm morphology. In contrast, X-autosome incompatibilities contribute to low testis weight, low sperm count, and sperm morphology. Restoration of normal testis weight and sperm count in first generation backcross males suggests that a small number of complex incompatibilities between loci on the M. m. musculus X and the M. m. domesticus autosomes underlie F1 male sterility. Together, these results provide insight into the genetic architecture of F1 male sterility and help to explain genome-wide patterns of introgression across the house mouse hybrid zone.

  8. X–Y Interactions Underlie Sperm Head Abnormality in Hybrid Male House Mice

    PubMed Central

    Campbell, Polly; Nachman, Michael W.

    2014-01-01

    The genetic basis of hybrid male sterility in house mice is complex, highly polygenic, and strongly X linked. Previous work suggested that there might be interactions between the Mus musculus musculus X and the M. m. domesticus Y with a large negative effect on sperm head morphology in hybrid males with an F1 autosomal background. To test this, we introgressed the M. m. domesticus Y onto a M. m. musculus background and measured the change in sperm morphology, testis weight, and sperm count across early backcross generations and in 11th generation backcross males in which the opportunity for X–autosome incompatibilities is effectively eliminated. We found that abnormality in sperm morphology persists in M. m. domesticus Y introgression males, and that this phenotype is rescued by M. m. domesticus introgressions on the X chromosome. In contrast, the severe reductions in testis weight and sperm count that characterize F1 males were eliminated after one generation of backcrossing. These results indicate that X–Y incompatibilities contribute specifically to sperm morphology. In contrast, X–autosome incompatibilities contribute to low testis weight, low sperm count, and sperm morphology. Restoration of normal testis weight and sperm count in first generation backcross males suggests that a small number of complex incompatibilities between loci on the M. m. musculus X and the M. m. domesticus autosomes underlie F1 male sterility. Together, these results provide insight into the genetic architecture of F1 male sterility and help to explain genome-wide patterns of introgression across the house mouse hybrid zone. PMID:24504187

  9. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes

    PubMed Central

    Kuo, Yien-Ming; Li, Zhishan; Jiao, Yun; Gaborit, Nathalie; Pani, Amar K.; Orrison, Bonnie M.; Bruneau, Benoit G.; Giasson, Benoit I.; Smeyne, Richard J.; Gershon, Michael D.; Nussbaum, Robert L.

    2010-01-01

    Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy number mutations in SNCA which encodes α-synuclein, a primary protein constituent of Lewy bodies, the pathognomonic protein aggregates found in neurons in PD. We set out to develop transgenic mice expressing mutant α-synuclein (either A53T or A30P) from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines show robust abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also has abnormal motor behavior but neither demonstrates cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions or neurodegeneration. These animals recapitulate the early gastrointestinal abnormalities seen in human PD. The animals also serve as an in vivo system in which to investigate therapies for reversing the neurological dysfunction that target α-synuclein toxicity at its earliest stages. PMID:20106867

  10. Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice.

    PubMed

    van der Merwe, Elizabeth L; Kidson, Susan H

    2016-05-01

    Mutations in the FOXC1/Foxc1 gene in humans and mice and Bmp4 in mice are associated with congenital anterior segment dysgenesis (ASD) and the development of the aqueous outflow structures throughout the limbus. The aim of this study was to advance our understanding of anterior segment abnormalities in mouse models of ASD using a 3-D imaging approach. Holistic imaging information combined with quantitative measurements were carried out on PECAM-1 stained individual components of the aqueous outflow vessels and corneal vasculature of Foxc1(+/-) on the C57BL/6Jx129 and ICR backgrounds, Bmp4(+/-) ICR mice, and wildtype mice from each background. In both wildtype and heterozygotes, singular, bifurcated and plexus forms of Schlemm's canal were noted. Of note, missing portions of the canal were seen in the heterozygous groups but not in wildtype animals. In general, we found the number of collector channels to be reduced in both heterozygotes. Lastly, we found a significant increase in the complexity of the corneal arcades and their penetration into the cornea in heterozygotes as compared with wild types. In conclusion, our 3-D imaging studies have revealed a more complex arrangement of both the aqueous vessels and corneal arcades in Foxc1(+/-) and Bmp4(+/-) heterozygotes, and further advance our understanding of how such abnormalities could impact on IOP and the aetiology of glaucoma.

  11. Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation

    PubMed Central

    Barnwell, L. Forbes S.; Lugo, Joaquin N.; Lee, Wai Ling; Willis, Sarah E.; Gertz, Shira J.; Hrachovy, Richard A.; Anderson, Anne E.

    2010-01-01

    Purpose Kv4.2 subunits contribute to the pore-forming region of channels that express a transient, A-type K+ current (A-current) in hippocampal CA1 pyramidal cell dendrites. Here, the A-current plays an important role in signal processing and synaptic integration. Kv4.2 knockout mice show a near elimination of the A-current in area CA1 dendrites producing increased excitability in this region. In these studies, we evaluated young adult Kv4.2 knockout mice for spontaneous seizures and the response to convulsant stimulation in the whole animal in vivo and in hippocampal slices in vitro. Methods Electroencephalogram electrode-implanted Kv4.2 knockout and wildtype mice were observed for spontaneous behavioral and electrographic seizures. The latency to seizure and status epilepticus onset in Kv4.2 knockout and wildtype mice was assessed following intraperitoneal injection of kainate. Extracellular field potential recordings were performed in hippocampal slices from Kv4.2 knockout and wildtype mice following the bath application of bicuculline. Results No spontaneous behavioral or electrographic seizures were observed in Kv4.2 knockout mice. Following kainate, Kv4.2 knockout mice demonstrated a decreased seizure and status epilepticus latency as well as increased mortality compared to wildtype littermates. The background strain modified the seizure susceptibility phenotype in Kv4.2 knockout mice. In response to bicuculline, slices from Kv4.2 knockout mice exhibited an increase in epileptiform bursting in area CA1 as compared to wildtype littermates. Discussion These studies show that loss of Kv4.2 channels is associated with enhanced susceptibility to convulsant stimulation, supporting the concept that Kv4.2 deficiency may contribute to aberrant network excitability and regulate seizure threshold. PMID:19453702

  12. Disruption of glycogen synthase kinase-3-beta activity leads to abnormalities in physiological measures in mice.

    PubMed

    Ahnaou, A; Drinkenburg, W H I M

    2011-08-01

    Dysregulation of glycogen synthase kinase-3-beta (GSK-3β) signaling pathways is thought to underlie the pathophysiology of mood disorders. In order to demonstrate that the loss of normal GSK-3β activity results in disturbances of physiological measures, we attempted to determine whether sleep-wake architecture, circadian rhythms of core body temperature and activity were altered in transgenic mice overexpressing GSK-3β activity specifically in the brain. Cortical electroencephalographic activity, body temperature (BT) and body locomotor activity (LMA) were continuously monitored using a biopotential telemetry probe. Normal circadian patterns were maintained for different measurements in both genotypes. No differences were found in total time spent asleep and waking over the 24-h recording session. However, transgenic animals overexpressing GSK-3β showed alteration in sleep continuity characterized by an increases in number of non rapid eye movement (NREM) sleep episodes (GSK-3β, 227.2 ± 1.7 vs. WT, 172.6 ± 1.4, p < 0.05) and decreases in mean episode duration (GSK-3β, 3.0 ± 0.1 vs. WT, 4.4 ± 0.2, p < 0.05). Additionally, transgenic animals exhibited marked enhancement of basal LMA and BT levels during the first part of the dark period, under both light-dark and free running dark-dark circadian cycles. Our findings indicate that transgenic mice overexpressing GSK-3β activity exhibit severe fragmentation of sleep-wake cycle during both the light and dark periods, without showing deviancy in total durations of vigilance states. The results strongly suggest that GSK-3β activity is elemental for the maintenance of circadian motor behavior levels required for proper regulation of BT and sleep-wake organization.

  13. Expression of Human Complement Factor H Prevents Age-Related Macular Degeneration–Like Retina Damage and Kidney Abnormalities in Aged Cfh Knockout Mice

    PubMed Central

    Ding, Jin-Dong; Kelly, Una; Landowski, Michael; Toomey, Christopher B.; Groelle, Marybeth; Miller, Chelsey; Smith, Stephanie G.; Klingeborn, Mikael; Singhapricha, Terry; Jiang, Haixiang; Frank, Michael M.; Bowes Rickman, Catherine

    2016-01-01

    Complement factor H (CFH) is an important regulatory protein in the alternative pathway of the complement system, and CFH polymorphisms increase the genetic risk of age-related macular degeneration dramatically. These same human CFH variants have also been associated with dense deposit disease. To mechanistically study the function of CFH in the pathogenesis of these diseases, we created transgenic mouse lines using human CFH bacterial artificial chromosomes expressing full-length human CFH variants and crossed these to Cfh knockout (Cfh−/−) mice. Human CFH protein inhibited cleavage of mouse complement component 3 and factor B in plasma and in retinal pigment epithelium/choroid/sclera, establishing that human CFH regulates activation of the mouse alternative pathway. One of the mouse lines, which express relatively higher levels of CFH, demonstrated functional and structural protection of the retina owing to the Cfh deletion. Impaired visual function, detected as a deficit in the scotopic electroretinographic response, was improved in this transgenic mouse line compared with Cfh−/− mice, and transgenics had a thicker outer nuclear layer and less sub–retinal pigment epithelium deposit accumulation. In addition, expression of human CFH also completely protected the mice from developing kidney abnormalities associated with loss of CFH. These humanized CFH mice present a valuable model for study of the molecular mechanisms of age-related macular degeneration and dense deposit disease and for testing therapeutic targets. PMID:25447048

  14. Hemostatic and hematological abnormalities in gain-of-function fps/fes transgenic mice are associated with the angiogenic phenotype.

    PubMed

    Sangrar, W; Senis, Y; Samis, J A; Gao, Y; Richardson, M; Lee, D H; Greer, P A

    2004-11-01

    The Fps/Fes tyrosine kinase has been implicated in the regulation of hematopoiesis and inflammation. Mice expressing an activated variant of Fps/Fes (MFps) encoded by a gain-of-function mutant transgenic fps/fes allele (fps(MF)) exhibited hematological phenotypes, which suggested that Fps/Fes can direct hematopoietic lineage output. These mice also displayed marked hypervascularity and multifocal-hemangiomas which implicated this kinase in the regulation of angiogenesis. Here we explored the potential involvement of Fps/Fes in the regulation of hemostasis through effects on blood cells and the vascular endothelium. Hematological parameters of fps(MF) mice were characterized by peripheral blood analysis, histology, and transmission electron microscopy. Hemostasis parameters and platelet functions were assessed by flow cytometry and measurements of activated partial thromboplastin time, prothrombin time, thrombin clot time, platelet aggregation, bleeding times and in vitro fibrinolytic assays. Hematological and morphological analyses showed that fps(MF) mice displayed mild thrombocytopenia, anemia, red cell abnormalities and numerous hemostatic defects, including hypofibrinogenemia, hyper-fibrinolysis, impaired whole blood aggregation and a mild bleeding diathesis. fps(MF) mice displayed a complex array of hemostatic perturbations which are reminiscent of hemostatic disorders such as disseminated intravascular coagulation (DIC) and of hemangioma-associated pathologies such as Kasabach-Merritt phenomenon (KMS). These studies suggest that Fps/Fes influences both angiogenic and hemostatic function through regulatory effects on the endothelium.

  15. Mice Haploinsufficient for Ets1 and Fli1 Display Middle Ear Abnormalities and Model Aspects of Jacobsen Syndrome.

    PubMed

    Carpinelli, Marina R; Kruse, Elizabeth A; Arhatari, Benedicta D; Debrincat, Marlyse A; Ogier, Jacqueline M; Bories, Jean-Christophe; Kile, Benjamin T; Burt, Rachel A

    2015-07-01

    E26 transformation-specific 1 (ETS1) and friend leukemia integration 1 (FLI1) are members of the ETS family of transcription factors, of which there are 28 in humans. Both genes are hemizygous in Jacobsen syndrome, an 11q contiguous gene deletion disorder involving thrombocytopenia, facial dysmorphism, growth and mental retardation, malformation of the heart and other organs, and hearing impairment associated with recurrent ear infections. To determine whether any of these defects are because of hemizygosity for ETS1 and FLI1, we characterized the phenotype of mice heterozygous for mutant alleles of Ets1 and Fli1. Fli1(+/-) mice displayed mild thrombocytopenia, as did Ets1(+/-)Fli1(+/-) animals. Fli1(+/-) and Ets1(+/-)Fli1(+/-) mice also displayed craniofacial abnormalities, including a small middle ear cavity, short nasal bone, and malformed interface between the nasal bone process and cartilaginous nasal septum. They exhibited hearing impairment, otitis media, fusions of ossicles to the middle ear wall, and deformed stapes. Hearing impairment was more penetrant and stapes malformations were more severe in Ets1(+/-)Fli1(+/-) mice than in Fli1(+/-) mice, indicating partial functional redundancy of these transcription factors during auditory development. Our findings indicate that the short nose, otitis media, and hearing impairment in Jacobsen syndrome are likely because of hemizygosity for ETS1 and FLI1.

  16. Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

    PubMed

    Liu, Peng; Xing, Bo; Chu, Zheng; Liu, Fei; Lei, Gang; Zhu, Li; Gao, Ya; Chen, Teng; Dang, Yong-Hui

    2016-09-26

    Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc.

  17. Progressive Changes in a Distributed Neural Circuit Underlie Breathing Abnormalities in Mice Lacking MeCP2

    PubMed Central

    Huang, Teng-Wei; Kochukov, Mikhail Y.; Ward, Christopher S.; Merritt, Jonathan; Thomas, Kaitlin; Nguyen, Tiffani; Arenkiel, Benjamin R.

    2016-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings from in vitro brainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration. SIGNIFICANCE STATEMENT Breathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations

  18. In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

    PubMed

    Thomas, Elizabeth A; Coppola, Giovanni; Tang, Bin; Kuhn, Alexandre; Kim, SoongHo; Geschwind, Daniel H; Brown, Timothy B; Luthi-Carter, Ruth; Ehrlich, Michelle E

    2011-03-15

    Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.

  19. Dyrk1A Haploinsufficiency Affects Viability and Causes Developmental Delay and Abnormal Brain Morphology in Mice

    PubMed Central

    Fotaki, Vassiliki; Dierssen, Mara; Alcántara, Soledad; Martínez, Salvador; Martí, Eulàlia; Casas, Caty; Visa, Joana; Soriano, Eduardo; Estivill, Xavier; Arbonés, Maria L.

    2002-01-01

    DYRK1A is the human orthologue of the Drosophila minibrain (mnb) gene, which is involved in postembryonic neurogenesis in flies. Because of its mapping position on chromosome 21 and the neurobehavioral alterations shown by mice overexpressing this gene, involvement of DYRK1A in some of the neurological defects of Down syndrome patients has been suggested. To gain insight into its physiological role, we have generated mice deficient in Dyrk1A function by gene targeting. Dyrk1A−/− null mutants presented a general growth delay and died during midgestation. Mice heterozygous for the mutation (Dyrk1A+/−) showed decreased neonatal viability and a significant body size reduction from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay of Dyrk1A+/− mice and specific alterations in adults. Brains of Dyrk1A+/− mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. These data provide evidence about the nonredundant, vital role of Dyrk1A and suggest a conserved mode of action that determines normal growth and brain size in both mice and flies. PMID:12192061

  20. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities

    PubMed Central

    Wöhr, M; Orduz, D; Gregory, P; Moreno, H; Khan, U; Vörckel, K J; Wolfer, D P; Welzl, H; Gall, D; Schiffmann, S N; Schwaller, B

    2015-01-01

    Gene mutations and gene copy number variants are associated with autism spectrum disorders (ASDs). Affected gene products are often part of signaling networks implicated in synapse formation and/or function leading to alterations in the excitation/inhibition (E/I) balance. Although the network of parvalbumin (PV)-expressing interneurons has gained particular attention in ASD, little is known on PV's putative role with respect to ASD. Genetic mouse models represent powerful translational tools for studying the role of genetic and neurobiological factors underlying ASD. Here, we report that PV knockout mice (PV−/−) display behavioral phenotypes with relevance to all three core symptoms present in human ASD patients: abnormal reciprocal social interactions, impairments in communication and repetitive and stereotyped patterns of behavior. PV-depleted mice also showed several signs of ASD-associated comorbidities, such as reduced pain sensitivity and startle responses yet increased seizure susceptibility, whereas no evidence for behavioral phenotypes with relevance to anxiety, depression and schizophrenia was obtained. Reduced social interactions and communication were also observed in heterozygous (PV+/−) mice characterized by lower PV expression levels, indicating that merely a decrease in PV levels might be sufficient to elicit core ASD-like deficits. Structural magnetic resonance imaging measurements in PV−/− and PV+/− mice further revealed ASD-associated developmental neuroanatomical changes, including transient cortical hypertrophy and cerebellar hypoplasia. Electrophysiological experiments finally demonstrated that the E/I balance in these mice is altered by modification of both inhibitory and excitatory synaptic transmission. On the basis of the reported changes in PV expression patterns in several, mostly genetic rodent models of ASD, we propose that in these models downregulation of PV might represent one of the points of convergence, thus

  1. Oral supplements of aqueous extract of tomato seeds alleviate motor abnormality, oxidative impairments and neurotoxicity induced by rotenone in mice: relevance to Parkinson's disease.

    PubMed

    Gokul, Krishna; Muralidhara

    2014-07-01

    Although tomato seeds (an industrial by-product) are known to contain several bioactive compounds, studies describing their health effects are limited. Previously, we evidenced that aqueous extract of tomato seeds (TSE) markedly attenuated rotenone (ROT)-induced oxidative stress and neurotoxicity in Drosophila system. This study investigated the neuroprotective effect of TSE in a chronic ROT model of neurotoxicity in mice. Initially, we assessed the potential of oral supplements of TSE to modulate the levels of endogenous markers of oxidative stress in brain regions of mice. Subsequently, employing a co-exposure paradigm, the propensity of TSE (100 mg/kg bw, 3 weeks) to attenuate ROT-induced behavioral phenotype (gait abnormalities, anxiety-like state), oxidative dysfunctions and neurotoxicity was examined. We found that mice provided with TSE supplements exhibited progressive improvement in gait pattern and exploratory behavior. TSE markedly offset ROT-induced oxidative impairments, restored reduced glutathione levels, antioxidant defenses (superoxide dismutase, glutathione peroxidase) and protein carbonyls content in brain regions. Specifically, TSE effectively diminished ROT induced elevation in the activity levels of acetylcholinesterase and restored the dopamine levels in striatum. Interestingly, in mitochondria, TSE was able to restore the activity of mitochondrial complexes and redox state. Collectively, our findings in the chronic ROT model demonstrate the ability of TSE to alleviate behavioral phenotype, oxidative stress, mitochondrial dysfunction and neurotoxicity. Further studies in dopaminergic cell models are necessary to understand the precise molecular mechanism/s by which tomato seed bioactives offer significant neuroprotection.

  2. Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

    PubMed Central

    2016-01-01

    Background: Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve. Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates. PMID:27996060

  3. ABNORMAL MOTOR FUNCTION AND DOPAMINE NEUROTRANSMISSION IN DYT1 ΔGAG TRANSGENIC MICE

    PubMed Central

    Zhao, Yu; DeCuypere, Michael; LeDoux, Mark S.

    2008-01-01

    A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA- and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia. PMID:18299128

  4. Severe abnormalities in the reproductive organs of mice caused by chemical substances contained in heavy oil.

    PubMed

    Nishimoto, Sogo; Yamawaki, Manami; Akiyama, Koichi; Kakinuma, Yoshimi; Kitamura, Shin-Ichi; Sugahara, Takuya

    2009-04-01

    It is well known that heavy oil pollution results in various negative impacts on the marine environment. Although there is a low possibility of direct exposure to heavy oil, the chemical substances contained in heavy oil may be released into the environment and accumulated by marine organisms which in turn can be taken by humans via the food chain. In this study, we examined the biological risk of heavy oil extract using the common mouse, whose genetic backgrounds and immune system are well known and relatively homologous to humans. Water-soluble fraction (WSF) was extracted from heavy oil with water and the extract orally administrated to female or male mice for 7 days. In the WSF administrated group, cystoma-like formation was observed in the ovary in approximately 80% of female mice. On the other hand, we found that the prostate gland size in male mice was markedly reduced in comparison with male control mice. Continuous administration of WSF for 28 days resulted in continued hypertrophy of the cystoma around the ovary and atrophy in the prostate gland. In addition, it was revealed that chemical substances within WSF have estrogenic activity. A major component of heavy oil, polycyclic aromatic hydrocarbons (PAHs), is known to present estrogenic activity. It is likely that the cystoma-like formation in female mice and atrophy of prostate gland in male resulted of estrogenic substances present in the WSF which might be the PAHs.

  5. Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation.

    PubMed Central

    Guerra, C; Koza, R A; Walsh, K; Kurtz, D M; Wood, P A; Kozak, L P

    1998-01-01

    When placed in the cold (4 degreesC), BALB/cByJ mice of both genders rapidly lose body temperature as compared with the control strain, C57BL/6J. This sensitivity to cold resembles that previously described for mice with a defect in nonshivering thermogenesis due to the targeted inactivation of the brown adipocyte-specific mitochondrial uncoupling protein gene, Ucp1. Genetic mapping of the trait placed the gene on chromosome 5 near Acads, a gene encoding the short chain acyl CoA dehydrogenase, which is mutated in BALB/cByJ mice. The analysis of candidate genes in the region indicated a defect only in the expression of Acads. Confirmation of the importance of fatty acid oxidation to thermogenesis came from our finding that mice carrying the targeted inactivation of the long chain acyl CoA dehydrogenase gene (Acadl) are also sensitive to the cold. Both of these mutations attenuate the induction of genes normally responsive to adrenergic signaling in brown adipocytes. These results suggest that the action of fatty acids as regulators of gene expression has been perturbed in the mutant mice. From a clinical perspective, it is important to determine whether defects in thermogenesis may be a phenotype in human neonates with inherited deficiencies in fatty acid beta-oxidation. PMID:9802886

  6. Abnormalities of synapses and neurons in the hippocampus of neuropsin-deficient mice.

    PubMed

    Hirata, A; Yoshida, S; Inoue, N; Matsumoto-Miyai, K; Ninomiya, A; Taniguchi, M; Matsuyama, T; Kato, K; Iizasa, H; Kataoka, Y; Yoshida, N; Shiosaka, S

    2001-03-01

    In the present study, we produced null-mutant mice of neuropsin, an extracellular matrix serine protease, to examine the neural functions of this protein particularly in the hippocampus. Golgi-Cox impregnation and Nissl-staining revealed morphological change of cell soma in the mutant mice compared to wild-type mice. However, Golgi-Cox impregnation revealed no apparent change in the dendritic arborization and spine density. Quantitative electronmicroscopic analysis revealed that number of asymmetrical synapses were significantly decreased in the stratum radiatum, the major terminal field of Schaffer-collaterals, whereas free boutons still holding synaptic vesicles but with no synaptic specialization were increased in number in the same microscopic fields. An increased number of parvalbumin-immunoreactive cells (known as fast spiking cells) in mutant was also observed. These results strongly suggest that neuropsin is involved in connectivity of a group of CA1 synapses and consequently in the hippocampal networking.

  7. Short-Term Treatment with Bisphenol-A Leads to Metabolic Abnormalities in Adult Male Mice

    PubMed Central

    Batista, Thiago M.; Alonso-Magdalena, Paloma; Vieira, Elaine; Amaral, Maria Esmeria C.; Cederroth, Christopher R.; Nef, Serge; Quesada, Ivan; Carneiro, Everardo M.; Nadal, Angel

    2012-01-01

    Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr308 residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit. In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. Thus, our findings support the notion that BPA can be considered a risk factor for the development of type 2 diabetes. PMID:22470480

  8. Aromatase Deficient Female Mice Demonstrate Altered Expression of Molecules Critical for Renal Calcium Reabsorption

    NASA Astrophysics Data System (ADS)

    Öz, Orhan K.; Hajibeigi, Asghar; Cummins, Carolyn; van Abel, Monique; Bindels, René J.; Kuro-o, Makoto; Pak, Charles Y. C.; Zerwekh, Joseph E.

    2007-04-01

    The incidence of kidney stones increases in women after the menopause, suggesting a role for estrogen deficiency. In order to determine if estrogen may be exerting an effect on renal calcium reabsorption, we measured urinary calcium excretion in the aromatase-deficient female mouse (ArKO) before and following estrogen therapy. ArKO mice had hypercalciuria that corrected during estrogen administration. To evaluate the mechanism by which estrogen deficiency leads to hypercalciuria, we examined the expression of several proteins involved in distal tubule renal calcium reabsorption, both at the message and protein levels. Messenger RNA levels of TRPV5, TRPV6, calbindin-D28K, the Na+/Ca++ exchanger (NCX1), and the plasma membrane calcium ATPase (PMCA1b) were significantly decreased in kidneys of ArKO mice. On the other hand, klotho mRNA levels were elevated in kidneys of ArKO mice. ArKO renal protein extracts had lower levels of calbindin-D28K but higher levels of the klotho protein. Immunochemistry demonstrated increased klotho expression in ArKO kidneys. Estradiol therapy normalized the expression of TRPV5, calbindin-D28K, PMCA1b and klotho. Taken together, these results demonstrate that estrogen deficiency produced by aromatase inactivation is sufficient to produce a renal leak of calcium and consequent hypercalciuria. This may represent one mechanism leading to the increased incidence of kidney stones following the menopause in women.

  9. Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice

    PubMed Central

    Murashima, Aki; Xu, Bingfang; Hinton, Barry T

    2015-01-01

    The development of the Wolffian/epididymal duct is crucial for proper function and, therefore, male fertility. The development of the epididymis is complex; the initial stages form as a transient embryonic kidney; then the mesonephros is formed, which in turn undergoes extensive morphogenesis under the influence of androgens and growth factors. Thus, understanding of its full development requires a wide and multidisciplinary view. This review focuses on mouse models that display abnormalities of the Wolffian duct and mesonephric development, the importance of these mouse models toward understanding male reproductive tract development, and how these models contribute to our understanding of clinical abnormalities in humans such as congenital anomalies of the kidney and urinary tract (CAKUT). PMID:26112482

  10. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice.

    PubMed

    Arnold, Steven E; Lucki, Irwin; Brookshire, Bethany R; Carlson, Gregory C; Browne, Caroline A; Kazi, Hala; Bang, Sookhee; Choi, Bo-Ran; Chen, Yong; McMullen, Mary F; Kim, Sangwon F

    2014-07-01

    Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17days or a moderate high fat diet (HFD, 45% kcal by fat) for 8weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS(616)), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.

  11. Behavioral deficits and cholinergic pathway abnormalities in male Sanfilippo B mice.

    PubMed

    Kan, Shih-Hsin; Le, Steven Q; Bui, Quang D; Benedict, Braeden; Cushman, Jesse; Sands, Mark S; Dickson, Patricia I

    2016-10-01

    Sanfilippo B syndrome is a progressive neurological disorder caused by inability to catabolize heparan sulfate glycosaminoglycans. We studied neurobehavior in male Sanfilippo B mice and heterozygous littermate controls from 16 to 20 weeks of age. Affected mice showed reduced anxiety, with a decrease in the number of stretch-attend postures during the elevated plus maze (p=0.001) and an increased tendency to linger in the center of an open field (p=0.032). Water maze testing showed impaired spatial learning, with reduced preference for the target quadrant (p=0.01). In radial arm maze testing, affected mice failed to achieve above-chance performance in a win-shift working memory task (t-test relative to 50% chance: p=0.289), relative to controls (p=0.037). We found a 12.4% reduction in mean acetylcholinesterase activity (p<0.001) and no difference in choline acetyltransferase activity or acetylcholine in whole brain of affected male animals compared to controls. Cholinergic pathways are affected in adult-onset dementias, including Alzheimer disease. Our results suggest that male Sanfilippo B mice display neurobehavioral deficits at a relatively early age, and that as in adult dementias, they may display deficits in cholinergic pathways.

  12. High Fat Diet Produces Brain Insulin Resistance, Synaptodendritic Abnormalities and Altered Behavior in Mice

    PubMed Central

    Arnold, Steven E.; Lucki, Irwin; Brookshire, Bethany R.; Carlson, Gregory C.; Browne, Carolyn A.; Kazi, Hala; Bang, Sookhee; Choi, Bo-Ran; Chen, Yong; McMullen, Mary F.; Kim, Sangwon F.

    2014-01-01

    Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17 days or a moderate high fat diet (HFD, 45% kcal by fat) for 8 weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS616), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors. PMID:24686304

  13. Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8.

    PubMed

    Trajkovic, Marija; Visser, Theo J; Mittag, Jens; Horn, Sigrun; Lukas, Jan; Darras, Veerle M; Raivich, Genadij; Bauer, Karl; Heuer, Heike

    2007-03-01

    In humans, inactivating mutations in the gene of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8; SLC16A2) lead to severe forms of psychomotor retardation combined with imbalanced thyroid hormone serum levels. The MCT8-null mice described here, however, developed without overt deficits but also exhibited distorted 3,5,3'-triiodothyronine (T3) and thyroxine (T4) serum levels, resulting in increased hepatic activity of type 1 deiodinase (D1). In the mutants' brains, entry of T4 was not affected, but uptake of T3 was diminished. Moreover, the T4 and T3 content in the brain of MCT8-null mice was decreased, the activity of D2 was increased, and D3 activity was decreased, indicating the hypothyroid state of this tissue. In the CNS, analysis of T3 target genes revealed that in the mutants, the neuronal T3 uptake was impaired in an area-specific manner, with strongly elevated thyrotropin-releasing hormone transcript levels in the hypothalamic paraventricular nucleus and slightly decreased RC3 mRNA expression in striatal neurons; however, cerebellar Purkinje cells appeared unaffected, since they did not exhibit dendritic outgrowth defects and responded normally to T3 treatment in vitro. In conclusion, the circulating thyroid hormone levels of MCT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected.

  14. Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1

    PubMed Central

    Hebel, Tobias; Eisinger, Kristina; Neumeier, Markus; Rein-Fischboeck, Lisa; Pohl, Rebekka; Meier, Elisabeth M.; Boettcher, Alfred; Froehner, Stanley C.; Adams, Marvin E.; Liebisch, Gerhard; Krautbauer, Sabrina; Buechler, Christa

    2015-01-01

    The syntrophins alpha (SNTA) and beta 2 (SNTB2) are molecular adaptor proteins shown to stabilize ABCA1, an essential regulator of HDL cholesterol. Furthermore, SNTB2 is involved in glucose stimulated insulin release. Hyperglycemia and dyslipidemia are characteristic features of the metabolic syndrome, a serious public health problem with rising prevalence. Therefore, it is important to understand the role of the syntrophins herein. Mice deficient for both syntrophins (SNTA/B2−/−) have normal insulin and glucose tolerance, hepatic ABCA1 protein and cholesterol. When challenged with a HFD, wild type and SNTA/B2−/− mice have similar weight gain, adiposity, serum and liver triglycerides. Hepatic ABCA1, serum insulin and insulin sensitivity are normal while glucose tolerance is impaired. Liver cholesterol is reduced, and expression of SREBP2 and HMG-CoA-R is increased in the knockout mice. Scavenger receptor-BI (SR-BI) protein is strongly diminished in the liver of SNTA/B2−/− mice while SR-BI binding protein NHERF1 is not changed and PDZK1 is even induced. Knock-down of SNTA, SNTB2 or both has no effect on hepatocyte SR-BI and PDZK1 proteins. Further, SR-BI levels are not reduced in brown adipose tissue of SNTA/B2−/− mice excluding that syntrophins directly stabilize SR-BI. SR-BI stability is regulated by MAPK and phosphorylated ERK2 is induced in the liver of the knock-out mice. Blockage of ERK activity upregulates hepatocyte SR-BI showing that increased MAPK activity contributes to low SR-BI. Sphingomyelin which is well described to regulate cholesterol metabolism is reduced in the liver and serum of the knock-out mice while the size of serum lipoproteins is not affected. Current data exclude a major function of these syntrophins in ABCA1 activity and insulin release but suggest a role in regulating glucose uptake, ERK and SR-BI levels, and sphingomyelin metabolism in obesity. PMID:25625330

  15. Proatherogenic Abnormalities Of Lipid Metabolism In SirT1 Transgenic Mice Are Mediated Through Creb Deacetylation

    PubMed Central

    Qiang, Li; Lin, Hua V.; Kim-Muller, Ja Young; Welch, Carrie L.; Gu, Wei; Accili, Domenico

    2011-01-01

    SUMMARY Dyslipidemia and atherosclerosis are associated with reduced insulin sensitivity and diabetes, but the mechanism is unclear. Gain-of-function of the gene encoding deacetylase SirT1 improves insulin sensitivity, and could be expected to protect against lipid abnormalities. Surprisingly, when transgenic mice overexpressing SirT1 (SirBACO) are placed on atherogenic diet, they maintain better glucose homeostasis, but develop worse lipid profiles and larger atherosclerotic lesions than controls. We show that transcription factor cAMP response element binding protein (Creb) is deacetylated in SirBACO mice. We identify Lys136 is a substrate for SirT1-dependent deacetylation that affects Creb activity by preventing its cAMP-dependent phosphorylation, leading to reduced expression of glucogenic genes, and promoting hepatic lipid accumulation and secretion. Expression of constitutively acetylated Creb (K136Q) in SirBACO mice mimics Creb activation and abolishes the dyslipidemic and insulin-sensitizing effects of SirT1 gain-of-function. We propose that SirT1-dependent Creb deacetylation regulates the balance between glucose and lipid metabolism, integrating fasting signals. PMID:22078933

  16. Daily oral intake of theanine prevents the decline of 5-bromo-2'-deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress.

    PubMed

    Takarada, Takeshi; Nakamichi, Noritaka; Kakuda, Takami; Nakazato, Ryota; Kokubo, Hiroshi; Ikeno, Shinsuke; Nakamura, Saki; Hinoi, Eiichi; Yoneda, Yukio

    2015-03-01

    Posttraumatic stress disorder is a long-lasting psychiatric disease with the consequence of hippocampal atrophy in humans exposed to severe fatal stress. We demonstrated a positive correlation between the transient decline of 5-bromo-2'-deoxyuridine (BrdU) incorporation in the hippocampal dentate gyrus (DG) and long-lasting behavioral abnormalities in mice with traumatic stress. Here, we investigated pharmacological properties of theanine on the declined BrdU incorporation and abnormal behaviors in mice with traumatic stress. Prior daily oral administration of theanine at 50-500 mg/kg for 5 days significantly prevented the decline of BrdU incorporation, while theanine significantly prevented the decline in the DG even when administered for 5 days after stress. Consecutive daily administration of theanine significantly inhibited the prolonged immobility in mice with stress in forced swimming test seen 14 days later. Although traumatic stress significantly increased spontaneous locomotor activity over 30 min even when determined 14 days later, the increased total locomotion was significantly ameliorated following the administration of theanine at 50 mg/kg for 14 days after stress. These results suggest that theanine alleviates behavioral abnormalities together with prevention of the transient decline of BrdU incorporation in the hippocampal DG in adult mice with severe traumatic stress.

  17. Multiple Structural and Functional Abnormalities in the P450 Aromatase Expressing Transgenic Male Mice Are Ameliorated by a P450 Aromatase Inhibitor

    PubMed Central

    Li, Xiangdong; Strauss, Leena; Mäkelä, Sari; Streng, Tomi; Huhtaniemi, Ilpo; Santti, Risto; Poutanen, Matti

    2004-01-01

    The present study was undertaken to analyze the effect of a P450 aromatase inhibitor (finrozole) on 4-month-old transgenic mice expressing human P450 aromatase (P450arom) under the human ubiquitin C promoter (AROM+). AROM+ mice present several dysfunctions, such as adrenal and pituitary hyperplasia, cryptorchidism, Leydig cell hypertrophy and hyperplasia, and gynecomastia. The present study demonstrates that these abnormalities were efficiently treated by administration of a P450arom inhibitor, finrozole. The treatment normalized the reduced intratesticular and serum testosterone levels, while those of estradiol were decreased. The body weight and several affected organ weights were normalized with the treatment. Histological analysis revealed that both the pituitary and adrenal hyperplasia were diminished. Furthermore, the cryptorchid testes present in the untreated AROM+ males descended to scrotum, 4 to 15 days after inhibitor treatment. In addition, the disrupted spermatogenesis was recovered and qualitatively complete spermatogenesis appeared with the inhibitor treatment. This was associated with normalized structure of the interstitial tissue, as analyzed by immunohistochemical staining for Leydig cells and macrophages. One of the features was that the Leydig cell hypertrophy was markedly diminished in the treated mice. AROM+ mice also present with severe gynecomastia, while the development and differentiation of the mammary gland in AROM+ males was markedly diminished with the inhibitor treatment. Interestingly, the mammary gland involution was associated with the induction of androgen receptor in the epithelial cells, while estrogen receptors were still detectable in the epithelium. The data show that AROM+ mouse model is a novel tool to further analyze the use of P450arom inhibitors in the treatment of the dysfunctions in males associated with misbalanced estrogen to androgen ratio, such as pituitary adenoma, testicular dysfunction, and gynecomastia. PMID

  18. Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice.

    PubMed

    Makarova, Elena N; Chepeleva, Elena V; Panchenko, Polina E; Bazhan, Nadezhda M

    2013-12-01

    Maternal obesity increases the risk of obesity in offspring, and obesity is accompanied by an increase in blood leptin levels. The "yellow" mutation at the mouse agouti locus (A(y)) increases blood leptin levels in C57BL preobese pregnant mice without affecting other metabolic characteristics. We investigated the influence of the A(y) mutation or leptin injection at the end of pregnancy in C57BL mice on metabolic phenotypes and the susceptibility to diet-induced obesity (DIO) in offspring. In both C57BL-A(y) and leptin-treated mice, the maternal effect was more pronounced in male offspring. Compared with males born to control mothers, males born to A(y) mothers displayed equal food intake (FI) but decreased body weight (BW) gain after weaning, equal glucose tolerance, and enhanced FI-to-BW ratios on the standard diet but the same FI and BW on the high-fat diet. Males born to A(y) mothers were less responsive to the anorectic effect of exogenous leptin and less resistant to fasting (were not hyperphagic and gained less weight during refeeding after food deprivation) compared with males born to control mothers. However, all progeny displayed equal hypothalamic expression of Agouti gene-related protein (AgRP), neuropeptide Y (NPY), and proopiomelanocortin (POMC) and equal plasma leptin and glucose levels after food deprivation. Leptin injections in C57BL mice on day 17 of pregnancy decreased BW in both male and female offspring but inhibited FI and DIO only in male offspring. Our results show that hyperleptinemia during pregnancy has sex-specific long-term effects on energy balance regulation in progeny and does not predispose offspring to developing obesity.

  19. Abnormal in vitro development of ovarian follicles explanted from mice exposed to tetrachlorvinphos.

    PubMed

    Nayudu, P L; Kiesel, P S; Nowshari, M A; Hodges, J K

    1994-01-01

    A system of mouse ovarian follicle culture in which follicles can be grown from a preantral stage of development through antral formation has been developed and modified recently by Nayudu and colleagues. Follicles have been shown to grow in this culture system at a relatively constant rate and show responsiveness to LH at the end of the culture by ovulation of mature oocytes. Reported here are the distinctly different in vitro growth patterns of follicles explanted from 22- to 24-day-old mice during a period when the colony was being treated for skin parasites with tetrachlorvinphos (TCVP) (Rabond). There is to date no information on the effects of this compound on the mammalian female reproductive system. For follicles from the TCVP treated group, the duration of growth as intact follicles was markedly reduced in comparison to mice of the same strain and source not treated with TCVP. In the treated group, premature termination of follicular growth was also associated with the spontaneous expulsion of oocytes with immature nuclei and without cumulus cells. For those follicles from treated mice that did remain in culture until the day luteinizing hormone was given, the ovulatory response was poor and the maturation response of the oocytes was low in comparison with the follicles from untreated mice. The effect of the treatment on the follicles was further characterized by obvious differences in the patterns of growth. Follicles in the untreated group grew in a linear pattern at around 25 microns/day; a single phase, fast pattern for the whole culture period.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. The sequential development of abnormal prion protein accumulation in mice with Creutzfeldt-Jakob disease.

    PubMed Central

    Muramoto, T.; Kitamoto, T.; Tateishi, J.; Goto, I.

    1992-01-01

    The distribution and sequential development of prion protein (PrP) accumulation in the central nervous system (CNS) and non-neuronal organs of mice infected with Creutzfeldt-Jakob disease (CJD) were investigated immunohistochemically using a new pretreatment method that greatly enhanced the immunoreactivity of PrP. Prion protein accumulation in the CNS was first detected at 30 days after inoculation and then developed near the inoculation site or periventricular area, and later spread to the whole cerebrum and then to the pons. Its staining took some characteristic forms. Among non-neuronal organs, PrP accumulated in the follicular dendritic cells (FDCs) in spleen, lymph node, Peyer's patch, and thymus. FDCs staining appeared in spleen, lymph node, and Peyer's patch at 21 or 30 days after inoculation, and in thymus at 90 days. Germinal centers developed in the thymus of some CJD-infected mice. No PrP staining was detected in any examined organs of age-matched control mice. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1376559

  1. Abnormal spermatogenesis and male infertility in testicular zinc finger protein Zfp318-knockout mice.

    PubMed

    Ishizuka, Masamichi; Ohtsuka, Eri; Inoue, Atsuto; Odaka, Mirei; Ohshima, Hirotaka; Tamura, Norihisa; Yoshida, Kaoru; Sako, Norihisa; Baba, Tadashi; Kashiwabara, Shin-Ichi; Okabe, Masaru; Noguchi, Junko; Hagiwara, Hiromi

    2016-09-01

    Zfp318, a mouse gene with a Cys2/His2 zinc finger motif, is mainly expressed in germ cells in the testis. It encodes two alternative transcripts, which regulate androgen receptor-mediated transcriptional activation or repression by overexpression of them. However, the role of Zfp318 is still obscure in vivo, especially in spermatogenesis. To elucidate the role of Zfp318 during gamete production, we established a knockout mouse line. Zfp318-null male mice exhibited infertility, whereas Zfp318-null female mice displayed normal fertility. ZFP318 was expressed during multiple stages of spermatogenesis, from spermatocytes to round spermatids. The nuclei of secondary spermatocytes showed high levels of expression. Histological analysis and quantitative analysis of DNA content showed decreased numbers of both spermatids in the seminiferous tubules and mature spermatozoa in the epididymides of Zfp318-null mice. These results suggest that Zfp318 is expressed as a functional protein in testicular germ cells and plays an important role in meiosis during spermatogenesis.

  2. Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice.

    PubMed

    Han, Kihoon; Chen, Hogmei; Gennarino, Vincenzo A; Richman, Ronald; Lu, Hui-Chen; Zoghbi, Huda Y

    2015-04-01

    Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized Cyfip2-mutant (Cyfip2(+/-)) mice. We found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1(-/y)) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in Cyfip2(+/-) hippocampus. However, dendritic spines were altered in Cyfip2(+/-) cortex, and the dendritic spine phenotype of Fmr1(-/y) cortex was aggravated in Fmr1(-/y); Cyfip2(+/-) double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.

  3. Pituitary and ovarian abnormalities demonstrated by CT and ultrasound in children with features of the McCune-Albright syndrome

    SciTech Connect

    Rieth, K.G.; Comite, F.; Shawker, T.H.; Cutler, G.B. Jr.

    1984-11-01

    In a random series of 97 children referred to the National Institutes of Health with a presumptive diagnosis of precocious puberty, eight girls were found to have features of the McCune-Albright syndrome, including fibrous dysplasia of bone and/or skin lesions resembling cafe au lait spots. Radiographic evaluation of these patients included computed tomography of the head and pelvic ultrasound. The pituitary glands were suspicious for abnormality in five of the eight girls. Seven girls underwent pelvic ultrasound, and in all of them the ovaries were considered to be abnormal for their chronological age; in addition, two had functional ovarian cysts. The role of diagnostic radiological studies in the diagnosis of this syndrome is discussed.

  4. Early Behavioral Abnormalities and Perinatal Alterations of PTEN/AKT Pathway in Valproic Acid Autism Model Mice.

    PubMed

    Yang, Eun-Jeong; Ahn, Sangzin; Lee, Kihwan; Mahmood, Usman; Kim, Hye-Sun

    2016-01-01

    Exposure to valproic acid (VPA) during pregnancy has been linked with increased incidence of autism, and has repeatedly been demonstrated as a useful autism mouse model. We examined the early behavioral and anatomical changes as well as molecular changes in mice prenatally exposed to VPA (VPA mice). In this study, we first showed that VPA mice showed developmental delays as assessed with self-righting, eye opening tests and impaired social recognition. In addition, we provide the first evidence that primary cultured neurons from VPA-treated embryos present an increase in dendritic spines, compared with those from control mice. Mutations in phosphatase and tensin homolog (PTEN) gene are also known to be associated with autism, and mice with PTEN knockout show autistic characteristics. Protein expression of PTEN was decreased and the ratio of p-AKT/AKT was increased in the cerebral cortex and the hippocampus, and a distinctive anatomical change in the CA1 region of the hippocampus was observed. Taken together, our study suggests that prenatal exposure to VPA induces developmental delays and neuroanatomical changes via the reduction of PTEN level and these changes were detectable in the early days of life.

  5. Early Behavioral Abnormalities and Perinatal Alterations of PTEN/AKT Pathway in Valproic Acid Autism Model Mice

    PubMed Central

    Yang, Eun-Jeong; Ahn, Sangzin; Lee, Kihwan; Mahmood, Usman; Kim, Hye-Sun

    2016-01-01

    Exposure to valproic acid (VPA) during pregnancy has been linked with increased incidence of autism, and has repeatedly been demonstrated as a useful autism mouse model. We examined the early behavioral and anatomical changes as well as molecular changes in mice prenatally exposed to VPA (VPA mice). In this study, we first showed that VPA mice showed developmental delays as assessed with self-righting, eye opening tests and impaired social recognition. In addition, we provide the first evidence that primary cultured neurons from VPA-treated embryos present an increase in dendritic spines, compared with those from control mice. Mutations in phosphatase and tensin homolog (PTEN) gene are also known to be associated with autism, and mice with PTEN knockout show autistic characteristics. Protein expression of PTEN was decreased and the ratio of p-AKT/AKT was increased in the cerebral cortex and the hippocampus, and a distinctive anatomical change in the CA1 region of the hippocampus was observed. Taken together, our study suggests that prenatal exposure to VPA induces developmental delays and neuroanatomical changes via the reduction of PTEN level and these changes were detectable in the early days of life. PMID:27071011

  6. Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1.

    PubMed

    Zhu, Hongyan; Mingler, Melissa K; McBride, Melissa L; Murphy, Andrew J; Valenzuela, David M; Yancopoulos, George D; Williams, Michael T; Vorhees, Charles V; Rothenberg, Marc E

    2010-09-01

    NPSR1 is a G protein coupled receptor expressed in multiple brain regions involved in modulation of stress. Central administration of NPS, the putative endogenous ligand of NPSR1, can induce hyperlocomotion, anxiolytic effects and activation of the HPA axis. The role of NPSR1 in the brain remains unsettled. Here we used NPSR1 gene-targeted mice to define the functional role of NPSR1 under basal conditions on locomotion, anxiety- and/or depression-like behavior, corticosterone levels, acoustic startle with prepulse inhibition, learning and memory, and under NPS-induced locomotor activation, anxiolysis, and corticosterone release. Male, but not female, NPSR1-deficient mice exhibited enhanced depression-like behavior in a forced swim test, reduced acoustic startle response, and minor changes in the Morris water maze. Neither male nor female NPSR1-deficient mice showed alterations of baseline locomotion, anxiety-like behavior, or corticosterone release after exposure to a forced swim test or methamphetamine challenge in an open-field. After intracerebroventricular (ICV) administration of NPS, NPSR1-deficient mice failed to show normal NPS-induced increases in locomotion, anxiolysis, or corticosterone release compared with WT NPS-treated mice. These findings demonstrate that NPSR1 is essential in mediating NPS effects on behavior.

  7. Abnormal Skeletal Muscle Regeneration plus Mild Alterations in Mature Fiber Type Specification in Fktn-Deficient Dystroglycanopathy Muscular Dystrophy Mice

    PubMed Central

    Foltz, Steven J.; Modi, Jill N.; Melick, Garrett A.; Abousaud, Marin I.; Luan, Junna; Fortunato, Marisa J.; Beedle, Aaron M.

    2016-01-01

    Glycosylated α-dystroglycan provides an essential link between extracellular matrix proteins, like laminin, and the cellular cytoskeleton via the dystrophin-glycoprotein complex. In secondary dystroglycanopathy muscular dystrophy, glycosylation abnormalities disrupt a complex O-mannose glycan necessary for muscle structural integrity and signaling. Fktn-deficient dystroglycanopathy mice develop moderate to severe muscular dystrophy with skeletal muscle developmental and/or regeneration defects. To gain insight into the role of glycosylated α-dystroglycan in these processes, we performed muscle fiber typing in young (2, 4 and 8 week old) and regenerated muscle. In mice with Fktn disruption during skeletal muscle specification (Myf5/Fktn KO), newly regenerated fibers (embryonic myosin heavy chain positive) peaked at 4 weeks old, while total regenerated fibers (centrally nucleated) were highest at 8 weeks old in tibialis anterior (TA) and iliopsoas, indicating peak degeneration/regeneration activity around 4 weeks of age. In contrast, mature fiber type specification at 2, 4 and 8 weeks old was relatively unchanged. Fourteen days after necrotic toxin-induced injury, there was a divergence in muscle fiber types between Myf5/Fktn KO (skeletal-muscle specific) and whole animal knockout induced with tamoxifen post-development (Tam/Fktn KO) despite equivalent time after gene deletion. Notably, Tam/Fktn KO retained higher levels of embryonic myosin heavy chain expression after injury, suggesting a delay or abnormality in differentiation programs. In mature fiber type specification post-injury, there were significant interactions between genotype and toxin parameters for type 1, 2a, and 2x fibers, and a difference between Myf5/Fktn and Tam/Fktn study groups in type 2b fibers. These data suggest that functionally glycosylated α-dystroglycan has a unique role in muscle regeneration and may influence fiber type specification post-injury. PMID:26751696

  8. Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice.

    PubMed

    Ji, Mu-Huo; Qiu, Li-Li; Yang, Jiao-Jiao; Zhang, Hui; Sun, Xiao-Ru; Zhu, Si-Hai; Li, Wei-Yan; Yang, Jian-Jun

    2015-01-01

    Sevoflurane, a commonly used inhaled anesthetic, can induce neuronal apoptosis in the developing rodent brain and correlate with functional neurological impairment later in life. However, the mechanisms underlying these deleterious effects of sevoflurane remain unclear and no effective treatment is currently available. Herein, the authors investigated whether curcumin can prevent the sevoflurane anesthesia-induced cognitive impairment in mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane 2h daily for 3 consecutive days and were treated with curcumin at the dose of 20 mg/kg or vehicle 30 min before the sevoflurane anesthesia from postnatal days 6 (P6) to P8. Cognitive functions were evaluated by open field, Morris water maze, and fear conditioning tests on P61, P63-69, and P77-78, respectively. In another separate experiment, mice were killed on day P8 or P78, and the brain tissues were harvested and then subjected to biochemistry studies. Our results showed that repeated neonatal sevoflurane exposure led to significant cognitive impairment later in life, which was associated with increased neuronal apoptosis, neuroinflammation, oxidative nitrosative stress, and decreased memory related proteins. By contrast, pre-administration of curcumin ameliorated early neuronal apoptosis, neuroinflammation, oxidative nitrosative stress, memory related proteins, and later cognitive dysfunction. In conclusion, our data suggested that curcumin pre-administration can prevent the sevoflurane exposure-induced cognitive impairment later in life, which may be partly attributed to its ability to attenuate the neural apoptosis, inflammation, and oxidative nitrosative stress in mouse brain.

  9. Loss of Rab27 function results in abnormal lung epithelium structure in mice.

    PubMed

    Bolasco, Giulia; Tracey-White, Dhani C; Tolmachova, Tanya; Thorley, Andrew J; Tetley, Teresa D; Seabra, Miguel C; Hume, Alistair N

    2011-03-01

    Rab27 small GTPases regulate secretion and movement of lysosome-related organelles such as T cell cytolytic granules and platelet-dense granules. Previous studies indicated that Rab27a and Rab27b are expressed in the murine lung suggesting that they regulate secretory processes in the lung. Consistent with those studies, we found that Rab27a and Rab27b are expressed in cell types that contain secretory granules: alveolar epithelial type II (AEII) and Clara cells. We then used Rab27a/Rab27b double knockout (DKO) mice to examine the functional consequence of loss of Rab27 proteins in the murine lung. Light and electron microscopy revealed a number of morphological changes in lungs from DKO mice when compared with those in control animals. In aged DKO mice we observed atrophy of the bronchiolar and alveolar epithelium with reduction of cells numbers, thinning of the bronchiolar epithelium and alveolar walls, and enlargement of alveolar airspaces. In these samples we also observed increased numbers of activated foamy alveolar macrophages and granulocyte containing infiltrates together with reduction in the numbers of Clara cells and AEII cells compared with control. At the ultrastructural level we observed accumulation of cytoplasmic membranes and vesicles in Clara cells. Meanwhile, AEII cells in DKO accumulated large mature lamellar bodies and lacked immature/precursor lamellar bodies. We hypothesize that the morphological changes observed at the ultrastructural level in DKO samples result from secretory defects in AEII and Clara cells and that over time these defects lead to atrophy of the epithelium.

  10. Abnormal Astrocytosis in the Basal Ganglia Pathway of Git1(-/-) Mice.

    PubMed

    Lim, Soo-Yeon; Mah, Won

    2015-06-01

    Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting approximately 5% of children. However, the neural mechanisms underlying its development and treatment are yet to be elucidated. In this study, we report that an ADHD mouse model, which harbors a deletion in the Git1 locus, exhibits severe astrocytosis in the globus pallidus (GP) and thalamic reticular nucleus (TRN), which send modulatory GABAergic inputs to the thalamus. A moderate level of astrocytosis was displayed in other regions of the basal ganglia pathway, including the ventrobasal thalamus and cortex, but not in other brain regions, such as the caudate putamen, basolateral amygdala, and hippocampal CA1. This basal ganglia circuit-selective astrocytosis was detected in both in adult (2-3 months old) and juvenile (4 weeks old) Git1(-/-) mice, suggesting a developmental origin. Astrocytes play an active role in the developing synaptic circuit; therefore, we performed an immunohistochemical analysis of synaptic markers. We detected increased and decreased levels of GABA and parvalbumin (PV), respectively, in the GP. This suggests that astrocytosis may alter synaptic transmission in the basal ganglia. Intriguingly, increased GABA expression colocalized with the astrocyte marker, GFAP, indicative of an astrocytic origin. Collectively, these results suggest that defects in basal ganglia circuitry, leading to impaired inhibitory modulation of the thalamus, are neural correlates for the ADHD-associated behavioral manifestations in Git1(-/-) mice.

  11. Increased sex chromosome expression and epigenetic abnormalities in spermatids from male mice with Y chromosome deletions.

    PubMed

    Reynard, Louise N; Turner, James M A

    2009-11-15

    During male meiosis, the X and Y chromosomes are transcriptionally silenced, a process termed meiotic sex chromosome inactivation (MSCI). Recent studies have shown that the sex chromosomes remain substantially transcriptionally repressed after meiosis in round spermatids, but the mechanisms involved in this later repression are poorly understood. Mice with deletions of the Y chromosome long arm (MSYq-) have increased spermatid expression of multicopy X and Y genes, and so represent a model for studying post-meiotic sex chromosome repression. Here, we show that the increase in sex chromosome transcription in spermatids from MSYq- mice affects not only multicopy but also single-copy XY genes, as well as an X-linked reporter gene. This increase in transcription is accompanied by specific changes in the sex chromosome histone code, including almost complete loss of H4K8Ac and reduction of H3K9me3 and CBX1. Together, these data show that an MSYq gene regulates sex chromosome gene expression as well as chromatin remodelling in spermatids.

  12. Improving abnormal hemorheological parameters in ApoE-/- mice by Ilex kudingcha total saponins.

    PubMed

    Zheng, Jiao; Wang, Xianwei; Li, Haixia; Gu, Yueqing; Tu, Pengfei; Wen, Zongyao

    2009-01-01

    The aim of this study was to test the effects of Ilex kudingcha total saponins on hemorheology of ApoE-/- mice suffering from hypercholesterolemia induced by high-cholesterol diet. The mice were randomly divided into six groups: the control group, the high-cholesterol diet group, 50 mg/kg atorvastatin treatment group, 75, 150 and 300 mg/kg Ilex kudingcha saponins treatment groups, and all the drug treatment groups were fed with a high-cholesterol diet. After administration with saponins (150 mg/kg or more) and atorvastatin (50 mg/kg) for six weeks, the plasma total cholesterol (TC), whole blood viscosity (WBV), plasma viscosity (PV), and erythrocyte aggregation index (EAI) had a remarkable decrease compared with that of the high-cholesterol diet group, but the hematocrit (Hct) and erythrocyte deformation index (DI) had no significant changes. In addition, it is found that the improving effects of saponins on reducing plasma fibrinogen (Fg) levels and prolonging the blood coagulation times including activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT). In conclusion, the Ilex kudingcha total saponins may have a significant therapy application of hypercholesterolemia and atherosclerosis by considering its actions on hemorheological characteristics.

  13. Dystrophin and utrophin "double knockout" dystrophic mice exhibit a spectrum of degenerative musculoskeletal abnormalities.

    PubMed

    Isaac, Christian; Wright, Adam; Usas, Arvydas; Li, Hongshuai; Tang, Ying; Mu, Xiaodong; Greco, Nicholas; Dong, Qing; Vo, Nam; Kang, James; Wang, Bing; Huard, Johnny

    2013-03-01

    Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by the lack of dystrophin expression at the sarcolemma of muscle fibers. In addition, DMD patients acquire osteopenia, fragility fractures, and scoliosis indicating that a deficiency in skeletal homeostasis coexists but little is known about the effects of DMD on bone and other connective tissues within the musculoskeletal system. Recent evidence has emerged implicating adult stem cell dysfunction in DMD myopathogenesis. Given the common mesenchymal origin of muscle and bone, we sought to investigate bone and other musculoskeletal tissues in a DMD mouse model. Here, we report that dystrophin-utrophin double knockout (dko) mice exhibit a spectrum of degenerative changes, outside skeletal muscle, in bone, articular cartilage, and intervertebral discs, in addition to reduced lifespan, muscle degeneration, spinal deformity, and cardiomyopathy previously reported. We also report these mice to have a reduced capacity for bone healing and exhibit spontaneous heterotopic ossification in the hind limb muscles. Therefore, we propose the dko mouse as a model for premature musculoskeletal aging and posit that a similar phenomenon may occur in patients with DMD.

  14. Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology

    PubMed Central

    Desai, Maya K.; Sudol, Kelly L.; Janelsins, Michelle C.; Mastrangelo, Michael A.; Frazer, Maria E.; Bowers, William J.

    2008-01-01

    Alzheimer's disease (AD) is a progressively debilitating brain disorder pathologically defined by extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and synaptic disintegrity. AD has not been widely considered a disease of white matter, but more recent evidence suggests the existence of abnormalities in myelination patterns and myelin attrition in AD-afflicted human brains. Herein, we demonstrate that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock-in mutation, and tau P301L mutant transgene, exhibit significant region-specific alterations in myelination patterns and in oligodendrocyte marker expression profiles at time points preceding the appearance of amyloid and tau pathology. These immunohistochemical signatures are coincident with age-related alterations in axonal and myelin sheath ultrastructure as visualized by comparative electron microscopic examination of 3xTg-AD and non-transgenic mouse brain tissue. Overall, these findings indicate 3xTg-AD mice represent a viable model in which to examine mechanisms underlying AD-related myelination and neural transmission defects that occur early during pre-symptomatic stages of the disease process. PMID:18661556

  15. Demonstration of Nondeclarative Sequence Learning in Mice: Development of an Animal Analog of the Human Serial Reaction Time Task

    ERIC Educational Resources Information Center

    Christie, Michael A.; Hersch, Steven M.

    2004-01-01

    In this paper, we demonstrate nondeclarative sequence learning in mice using an animal analog of the human serial reaction time task (SRT) that uses a within-group comparison of behavior in response to a repeating sequence versus a random sequence. Ten female B6CBA mice performed eleven 96-trial sessions containing 24 repetitions of a 4-trial…

  16. Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production.

    PubMed

    Guidetti, P; Charles, V; Chen, E Y; Reddy, P H; Kordower, J H; Whetsell, W O; Schwarcz, R; Tagle, D A

    2001-06-01

    Mitochondrial defects, which occur in the brain of late-stage Huntington's disease (HD) patients, have been proposed to underlie the selective neuronal loss in the disease. To shed light on the possible role of mitochondrial energy impairment in the early phases of HD pathophysiology, we carried out Golgi impregnation and quantitative histochemical/biochemical studies in HD full-length cDNA transgenic mice that were symptomatic but had not developed to a stage in which neuronal loss could be documented. Golgi staining showed morphologic abnormalities that included a significant decrease in the number of dendritic spines and a thickening of proximal dendrites in striatal and cortical neurons. In contrast, measurements of mitochondrial electron transport Complexes I-IV did not reveal changes in the striatum and cerebral cortex in these mice. Examination of the neostriatum and cerebral cortex in human presymptomatic and pathological Grade 1 HD cases also showed no change in the activity of mitochondrial Complexes I-IV. These data suggest that dendritic alterations precede irreversible cell loss in HD, and that mitochondrial energy impairment is a consequence, rather than a cause, of early neuropathological changes.

  17. Blocking Endogenous Leukemia Inhibitory Factor During Placental Development in Mice Leads to Abnormal Placentation and Pregnancy Loss

    PubMed Central

    Winship, Amy; Correia, Jeanne; Krishnan, Tara; Menkhorst, Ellen; Cuman, Carly; Zhang, Jian-Guo; Nicola, Nicos A.; Dimitriadis, Evdokia

    2015-01-01

    The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Specialized trophoblast cells derived from the embryonic trophectoderm play a pivotal role in the establishment of the placenta. Leukemia inhibitory factor (LIF) is one of the predominant cytokines present in the placenta during early pregnancy. LIF has been shown to regulate trophoblast adhesion and invasion in vitro, however its precise role in vivo is unknown. We hypothesized that LIF would be required for normal placental development in mice. LIF and LIFRα were immunolocalized to placental trophoblasts and fetal vessels in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via intraperitoneal administration of our specific LIFRα antagonist, PEGLA, resulted in abnormal placental trophoblast and vascular morphology and reduced activated STAT3 but not ERK. Numerous genes regulating angiogenesis and oxidative stress were altered in the placenta in response to LIF inhibition. Pregnancy viability was also significantly compromised in PEGLA treated mice. Our data suggest that LIF plays an important role in placentation in vivo and the maintenance of healthy pregnancy. PMID:26272398

  18. Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

    PubMed Central

    Ferreirinha, Fatima; Quattrini, Angelo; Pirozzi, Marinella; Valsecchi, Valentina; Dina, Giorgia; Broccoli, Vania; Auricchio, Alberto; Piemonte, Fiorella; Tozzi, Giulia; Gaeta, Laura; Casari, Giorgio; Ballabio, Andrea; Rugarli, Elena I.

    2004-01-01

    In several neurodegenerative diseases, axonal degeneration occurs before neuronal death and contributes significantly to patients’ disability. Hereditary spastic paraplegia (HSP) is a genetically heterogeneous condition characterized by selective degeneration of axons of the corticospinal tracts and fasciculus gracilis. HSP may therefore be considered an exemplary disease to study the local programs mediating axonal degeneration. We have developed a mouse model for autosomal recessive HSP due to mutations in the SPG7 gene encoding the mitochondrial ATPase paraplegin. Paraplegin-deficient mice are affected by a distal axonopathy of spinal and peripheral axons, characterized by axonal swelling and degeneration. We found that mitochondrial morphological abnormalities occurred in synaptic terminals and in distal regions of axons long before the first signs of swelling and degeneration and correlated with onset of motor impairment during a rotarod test. Axonal swellings occur through massive accumulation of organelles and neurofilaments, suggesting impairment of anterograde axonal transport. Retrograde axonal transport is delayed in symptomatic mice. We speculate that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration. Our data suggest that a timely therapeutic intervention may prevent the loss of axons. PMID:14722615

  19. Abnormal Cerebellar Cytoarchitecture and Impaired Inhibitory Signaling in Adult Mice Lacking Testicular Orphan Nuclear Receptor 4

    PubMed Central

    Chen, Yei-Tsung; Collins, Loretta L.; Uno, Hideo; Chou, Samuel M.; Meshul, Charles K.; Chang, Shu-Shi; Chang, Chawnshang

    2007-01-01

    Since Testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4−/−) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4−/− brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4−/− cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4−/− cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4−/− cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4−/− mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4−/− brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development. PMID:17706948

  20. TallyHO obese female mice experience poor reproductive outcomes and abnormal blastocyst metabolism that is reversed by metformin.

    PubMed

    Louden, Erica D; Luzzo, Kerri M; Jimenez, Patricia T; Chi, Tiffany; Chi, Maggie; Moley, Kelle H

    2014-12-01

    Obese women experience worse reproductive outcomes than normal weight women, specifically infertility, pregnancy loss, fetal malformations and developmental delay of offspring. The aim of the present study was to use a genetic mouse model of obesity to recapitulate the human reproductive phenotype and further examine potential mechanisms and therapies. New inbred, polygenic Type 2 diabetic TallyHO mice and age-matched control C57BL/6 mice were superovulated to obtain morula or blastocyst stage embryos that were cultured in human tubal fluid (HTF) medium. Deoxyglucose uptake was determined for individual insulin-stimulated blastocysts. Apoptosis was detected by confocal microscopy using the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assay and Topro-3 nuclear dye. Embryos were scored for TUNEL-positive as a percentage of total nuclei. AMP-activated protein kinase (AMPK) activation, tumour necrosis factor (TNF)-α expression and adiponectin expression were analysed by western immunoblot and confocal immunofluorescent microscopy. Lipid accumulation was assayed by BODIPY. Comparisons were made between TallyHO morulae cultured to blastocyst embryos in either HTF medium or HTF medium with 25 μg mL(-1) metformin. TallyHO mice developed whole body abnormal insulin tolerance, had decreased litter sizes and increased non-esterified fatty acid levels. Blastocysts from TallyHO mice exhibited increased apoptosis, decreased insulin sensitivity and decreased AMPK. A possible cause for the insulin resistance and abnormal AMPK phosphorylation was the increased TNF-α expression and lipid accumulation, as detected by BODIPY, in TallyHO blastocysts and decreased adiponectin. Culturing TallyHO morulae with the AMPK activator metformin led to a reversal of all the abnormal findings, including increased AMPK phosphorylation, improved insulin-stimulated glucose uptake and normalisation of lipid accumulation. Women with obesity and

  1. Ovariectomy and 17β-estradiol Replacement in Rats and Mice: A Visual Demonstration

    PubMed Central

    Ström, Jakob O.; Theodorsson, Annette; Ingberg, Edvin; Isaksson, Ida-Maria; Theodorsson, Elvar

    2012-01-01

    Estrogens are a family of female sexual hormones with an exceptionally wide spectrum of effects. When rats and mice are used in estrogen research they are commonly ovariectomized in order to ablate the rapidly cycling hormone production, replacing the 17β-estradiol exogenously. There is, however, lack of consensus regarding how the hormone should be administered to obtain physiological serum concentrations. This is crucial since the 17β-estradiol level/administration method profoundly influences the experimental results1-3. We have in a series of studies characterized the different modes of 17β-estradiol administration, finding that subcutaneous silastic capsules and per-oral nut-cream Nutella are superior to commercially available slow-release pellets (produced by the company Innovative Research of America) and daily injections in terms of producing physiological serum concentrations of 17β-estradiol4-6. Amongst the advantages of the nut-cream method, that previously has been used for buprenorphine administration7, is that when used for estrogen administration it resembles peroral hormone replacement therapy and is non-invasive. The subcutaneous silastic capsules are convenient and produce the most stable serum concentrations. This video article contains step-by-step demonstrations of ovariectomy and 17β-estradiol hormone replacement by silastic capsules and peroral Nutella in rats and mice, followed by a discussion of important aspects of the administration procedures. PMID:22710371

  2. Ovariectomy and 17β-estradiol replacement in rats and mice: a visual demonstration.

    PubMed

    Ström, Jakob O; Theodorsson, Annette; Ingberg, Edvin; Isaksson, Ida-Maria; Theodorsson, Elvar

    2012-06-07

    Estrogens are a family of female sexual hormones with an exceptionally wide spectrum of effects. When rats and mice are used in estrogen research they are commonly ovariectomized in order to ablate the rapidly cycling hormone production, replacing the 17β-estradiol exogenously. There is, however, lack of consensus regarding how the hormone should be administered to obtain physiological serum concentrations. This is crucial since the 17β-estradiol level/administration method profoundly influences the experimental results. We have in a series of studies characterized the different modes of 17β-estradiol administration, finding that subcutaneous silastic capsules and per-oral nut-cream Nutella are superior to commercially available slow-release pellets (produced by the company Innovative Research of America) and daily injections in terms of producing physiological serum concentrations of 17β-estradiol. Amongst the advantages of the nut-cream method, that previously has been used for buprenorphine administration, is that when used for estrogen administration it resembles peroral hormone replacement therapy and is non-invasive. The subcutaneous silastic capsules are convenient and produce the most stable serum concentrations. This video article contains step-by-step demonstrations of ovariectomy and 17β-estradiol hormone replacement by silastic capsules and peroral Nutella in rats and mice, followed by a discussion of important aspects of the administration procedures.

  3. Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down syndrome.

    PubMed Central

    Peled-Kamar, M; Lotem, J; Okon, E; Sachs, L; Groner, Y

    1995-01-01

    The copper-zinc superoxide dismutase (CuZnSOD) gene resides on chromosome 21 and is overexpressed in Down syndrome (DS) patients. Transgenic CuZnSOD mice with elevated levels of CuZnSOD were used to determine whether, as in DS, overexpression of CuZnSOD was also associated with thymus and bone marrow abnormalities. Three independently derived transgenic CuZnSOD strains had abnormal thymi showing diminution of the cortex and loss of corticomedullary demarcation, resembling thymic defects in children with DS. Transgenic CuZnSOD mice were also more sensitive than control mice to in vivo injection of lipopolysaccharide (LPS), reflected by an earlier onset and enhanced apoptotic cell death in the thymus. This higher susceptibility to LPS-induced apoptosis was associated with an increased production of hydrogen peroxide and a higher degree of lipid peroxidation. When cultured under suboptimal concentrations of interleukin 3 or in the presence of tumour necrosis factor, bone marrow cells from transgenic CuZnSOD mice produced 2- to 3-fold less granulocyte and macrophage colonies than control. The results indicate that transgenic CuZnSOD mice have certain thymus and bone marrow abnormalities which are similar to those found in DS patients, and that the defects are presumably due to an increased oxidative damage resulting in enhanced cell death by apoptosis. Images PMID:7588627

  4. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice.

    PubMed

    Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi

    2013-11-01

    Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss

  5. Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.

    PubMed

    Araki, Ryota; Hiraki, Yosuke; Nishida, Shoji; Kuramoto, Nobuyuki; Matsumoto, Kinzo; Yabe, Takeshi

    2016-02-01

    In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, β2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation

  6. Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice.

    PubMed

    Gildish, Iness; Manor, David; David, Orit; Sharma, Vijendra; Williams, David; Agarwala, Usha; Wang, Xuemin; Kenney, Justin W; Proud, Chris G; Rosenblum, Kobi

    2012-02-24

    Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment.

  7. Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice

    PubMed Central

    Gildish, Iness; Manor, David; David, Orit; Sharma, Vijendra; Williams, David; Agarwala, Usha; Wang, Xuemin; Kenney, Justin W.; Proud, Chris G.; Rosenblum, Kobi

    2012-01-01

    Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment. PMID:22366775

  8. Mandibular coronoid process in parathyroid hormone-related protein-deficient mice shows ectopic cartilage formation accompanied by abnormal bone modeling.

    PubMed

    Shibata, Shunichi; Suda, Naoto; Fukada, Kenji; Ohyama, Kimie; Yamashita, Yasuo; Hammond, Vicki E

    2003-07-01

    Parathyroid hormone-related protein (PTHrP) null mutant mice were analyzed to investigate an additional role for PTHrP in cell differentiation. We found ectopic cartilage formation in the mandibular coronoid process in newborn mice. While many previous studies involving PTHrP gene knockout mouse have shown that the cartilage in various regions becomes smaller, this is the first report showing an "increase" of cartilage volume. Investigations of mandibular growth using normal mice indicated that coronoid secondary cartilage never formed from E 15 to d 4, but small amount of cartilage temporally formed at d 7, and this also applies to PTHrP-wild type mice. Therefore, PTHrP deficiency consequently advanced the secondary cartilage formation, which is a novel role of PTHrP in chondrocyte differentiation. In situ hybridization of matrix proteins showed that this coronoid cartilage had characteristics of the lower hypertrophic cell zone usually present at the site of endochondral bone formation and/or "chondroid bone" occasionally found in distraction osteogenesis. In addition, the coronoid process in the PTHrP-deficient mouse also showed abnormal expansion of bone marrow and an increase in the number of multinucleated osteoclasts, an indication of abnormal bone modeling. These results indicate that PTHrP is involved in bone modeling as well as in chondrocyte differentiation. In situ hybridization of matrix protein mRNAs in the abnormal mandibular condylar cartilage revealed that this cartilage was proportionally smaller, supporting previous immunohistochemical results.

  9. Improving the Identification of Phenotypic Abnormalities and Sexual Dimorphism in Mice When Studying Rare Event Categorical Characteristics.

    PubMed

    Karp, Natasha A; Heller, Ruth; Yaacoby, Shay; White, Jacqueline K; Benjamini, Yoav

    2017-02-01

    Biological research frequently involves the study of phenotyping data. Many of these studies focus on rare event categorical data, and functional genomics studies typically study the presence or absence of an abnormal phenotype. With the growing interest in the role of sex, there is a need to assess the phenotype for sexual dimorphism. The identification of abnormal phenotypes for downstream research is challenged by the small sample size, the rare event nature, and the multiple testing problem, as many variables are monitored simultaneously. Here, we develop a statistical pipeline to assess statistical and biological significance while managing the multiple testing problem. We propose a two-step pipeline to initially assess for a treatment effect, in our case example genotype, and then test for an interaction with sex. We compare multiple statistical methods and use simulations to investigate the control of the type-one error rate and power. To maximize the power while addressing the multiple testing issue, we implement filters to remove data sets where the hypotheses to be tested cannot achieve significance. A motivating case study utilizing a large scale high-throughput mouse phenotyping data set from the Wellcome Trust Sanger Institute Mouse Genetics Project, where the treatment is a gene ablation, demonstrates the benefits of the new pipeline on the downstream biological calls.

  10. Improving the Identification of Phenotypic Abnormalities and Sexual Dimorphism in Mice When Studying Rare Event Categorical Characteristics

    PubMed Central

    Karp, Natasha A.; Heller, Ruth; Yaacoby, Shay; White, Jacqueline K.; Benjamini, Yoav

    2017-01-01

    Biological research frequently involves the study of phenotyping data. Many of these studies focus on rare event categorical data, and functional genomics studies typically study the presence or absence of an abnormal phenotype. With the growing interest in the role of sex, there is a need to assess the phenotype for sexual dimorphism. The identification of abnormal phenotypes for downstream research is challenged by the small sample size, the rare event nature, and the multiple testing problem, as many variables are monitored simultaneously. Here, we develop a statistical pipeline to assess statistical and biological significance while managing the multiple testing problem. We propose a two-step pipeline to initially assess for a treatment effect, in our case example genotype, and then test for an interaction with sex. We compare multiple statistical methods and use simulations to investigate the control of the type-one error rate and power. To maximize the power while addressing the multiple testing issue, we implement filters to remove data sets where the hypotheses to be tested cannot achieve significance. A motivating case study utilizing a large scale high-throughput mouse phenotyping data set from the Wellcome Trust Sanger Institute Mouse Genetics Project, where the treatment is a gene ablation, demonstrates the benefits of the new pipeline on the downstream biological calls. PMID:27932544

  11. Conditional Expression of Parkinson's Disease-Related R1441C LRRK2 in Midbrain Dopaminergic Neurons of Mice Causes Nuclear Abnormalities without Neurodegeneration

    PubMed Central

    Tsika, Elpida; Kannan, Meghna; Foo, Caroline Shi-Yan; Dikeman, Dustin; Glauser, Liliane; Gellhaar, Sandra; Galter, Dagmar; Knott, Graham W.; Dawson, Ted M.; Dawson, Valina L.; Moore, Darren J.

    2015-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). The clinical and neurochemical features of LRRK2-linked PD are similar to idiopathic disease although neuropathology is somewhat heterogeneous. Dominant mutations in LRRK2 precipitate neurodegeneration through a toxic gain-of-function mechanism which can be modeled in transgenic mice overexpressing human LRRK2 variants. A number of LRRK2 transgenic mouse models have been developed that display abnormalities in dopaminergic neurotransmission and alterations in tau metabolism yet without consistently inducing dopaminergic neurodegeneration. To directly explore the impact of mutant LRRK2 on the nigrostriatal dopaminergic pathway, we developed conditional transgenic mice that selectively express human R1441C LRRK2 in dopaminergic neurons from the endogenous murine ROSA26 promoter. The expression of R1441C LRRK2 does not induce the degeneration of substantia nigra dopaminergic neurons or striatal dopamine deficits in mice up to 2 years of age, and fails to precipitate abnormal protein inclusions containing alpha-synuclein, tau, ubiquitin or autophagy markers (LC3 and p62). Furthermore, mice expressing R1441C LRRK2 exhibit normal motor activity and olfactory function with increasing age. Intriguingly, the expression of R1441C LRRK2 induces age-dependent abnormalities of the nuclear envelope in nigral dopaminergic neurons including reduced nuclear circularity and increased invaginations of the nuclear envelope. In addition, R1441C LRRK2 mice display increased neurite complexity of cultured midbrain dopaminergic neurons. Collectively, these novel R1441C LRRK2 conditional transgenic mice reveal altered dopaminergic neuronal morphology with advancing age, and provide a useful tool for exploring the pathogenic mechanisms underlying the R1441C LRRK2 mutation in PD. PMID:25174890

  12. Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development.

    PubMed

    Song, Zhongchen; Liu, Chao; Iwata, Junichi; Gu, Shuping; Suzuki, Akiko; Sun, Cheng; He, Wei; Shu, Rong; Li, Lu; Chai, Yang; Chen, YiPing

    2013-04-12

    Cleft palate represents one of the most common congenital birth defects in humans. TGFβ signaling, which is mediated by Smad-dependent and Smad-independent pathways, plays a crucial role in regulating craniofacial development and patterning, particularly in palate development. However, it remains largely unknown whether the Smad-independent pathway contributes to TGFβ signaling function during palatogenesis. In this study, we investigated the function of TGFβ activated kinase 1 (Tak1), a key regulator of Smad-independent TGFβ signaling in palate development. We show that Tak1 protein is expressed in both the epithelium and mesenchyme of the developing palatal shelves. Whereas deletion of Tak1 in the palatal epithelium or mesenchyme did not give rise to a cleft palate defect, inactivation of Tak1 in the neural crest lineage using the Wnt1-Cre transgenic allele resulted in failed palate elevation and subsequently the cleft palate formation. The failure in palate elevation in Wnt1-Cre;Tak1(F/F) mice results from a malformed tongue and micrognathia, resembling human Pierre Robin sequence cleft of the secondary palate. We found that the abnormal tongue development is associated with Fgf10 overexpression in the neural crest-derived tongue tissue. The failed palate elevation and cleft palate were recapitulated in an Fgf10-overexpressing mouse model. The repressive effect of the Tak1-mediated noncanonical TGFβ signaling on Fgf10 expression was further confirmed by inhibition of p38, a downstream kinase of Tak1, in the primary cell culture of developing tongue. Tak1 thus functions to regulate tongue development by controlling Fgf10 expression and could represent a candidate gene for mutation in human PRS clefting.

  13. Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach.

    PubMed

    Garner, Joseph P; Thogerson, Collette M; Dufour, Brett D; Würbel, Hanno; Murray, James D; Mench, Joy A

    2011-06-01

    The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

  14. Compared with DBA/2J mice, C57BL/6J mice demonstrate greater preference for saccharin and less avoidance of a cocaine-paired saccharin cue

    PubMed Central

    Freet, Christopher S.; Arndt, Amanda; Grigson, Patricia S.

    2014-01-01

    Rats avoid intake of a saccharin cue when paired with a drug of abuse. While this is true for most subjects, the degree of avoidance of the drug-paired cue depends upon many factors including an individual rat’s preference for rewards. That said, the direction of this effect is complex. For example, reward-preferring Lewis rats exhibit greater cocaine-induced avoidance of a saccharin cue relative to Fischer 344 rats; while reward-preferring mice that over express ΔFosB (NSE-tTA x TetOp-ΔFosB) exhibit less avoidance of the drug-paired taste cue compared to controls. The aim here was to use two strains of commonly used mice, C57BL/6J and DBA/2J, to determine whether known differences in sensitivity to rewards will facilitate or attenuate drug-induced suppression of intake of a drug-paired taste cue. The results of Experiment 1 demonstrate that C57BL/6J mice, compared with DBA/2J mice, exhibit attenuated suppression of saccharin intake when it is paired with cocaine. The results of Experiment 2 demonstrate that strain differences in impulsivity are not likely to account for these differences. It is proposed that, while the C57BL/6J mice typically are more responsive to drug, they also are more responsive to natural rewards (in this case saccharin), and the stronger preference for saccharin serves to militate against drug. PMID:23544599

  15. Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a.

    PubMed

    Blazek, Joshua D; Abeysekera, Irushi; Li, Jiliang; Roper, Randall J

    2015-10-15

    Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS), but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origin of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a.

  16. Human COL2A1-directed SV40 T antigen expression in transgenic and chimeric mice results in abnormal skeletal development

    PubMed Central

    1995-01-01

    The ability of SV40 T antigen to cause abnormalities in cartilage development in transgenic mice and chimeras has been tested. The cis- regulatory elements of the COL2A1 gene were used to target expression of SV40 T antigen to differentiating chondrocytes in transgenic mice and chimeras derived from embryonal stem (ES) cells bearing the same transgene. The major phenotypic consequences of transgenic (pAL21) expression are malformed skeleton, disproportionate dwarfism, and perinatal/neonatal death. Expression of T antigen was tissue specific and in the main characteristic of the mouse alpha 1(II) collagen gene. Chondrocyte densities and levels of alpha 1(II) collagen mRNAs were reduced in the transgenic mice. Islands of cells which express cartilage characteristic genes such as type IIB procollagen, long form alpha 1(IX) collagen, alpha 2(XI) collagen, and aggrecan were found in the articular and growth cartilages of pAL21 chimeric fetuses and neonates. But these cells, which were expressing T antigen, were not properly organized into columns of proliferating chondrocytes. Levels of alpha 1(II) collagen mRNA were reduced in these chondrocytes. In addition, these cells did not express type X collagen, a marker for hypertrophic chondrocytes. The skeletal abnormality in pAL21 mice may therefore be due to a retardation of chondrocyte maturation or an impaired ability of chondrocytes to complete terminal differentiation and an associated paucity of some cartilage matrix components. PMID:7822417

  17. An endocrinology laboratory exercise demonstrating the effect of confinement stress on the immune system of mice.

    PubMed

    Brehe, Jacqueline; Way, Amy L

    2008-06-01

    This article describes a simple laboratory exercise for examining the effect of stress on the immune system in mice. Mice are subjected to confinement stress for 1 h, after which a sample of blood is collected via the caudal vein. Blood samples are smeared onto microscope slides, air dried, and stained with Wright's Giemsa stain. When differential white blood cell counts are performed, there are noticeable differences between the neutrophil and lymphocyte counts of stressed versus control mice. The protocol is simple enough for students to perform, and the entire experiment can be completed within 3 h. Examples of ways in which the basic protocol can be modified to accommodate a shorter laboratory class are provided. This hands-on laboratory experiment provides students with experience using the scientific method to investigate the interaction between the endocrine and immune systems in response to stress.

  18. MRL/MpJ-Fas(lpr) mice show abnormalities in ovarian function and morphology with the progression of autoimmune disease.

    PubMed

    Otani, Yuki; Ichii, Osamu; Otsuka-Kanazawa, Saori; Chihara, Masataka; Nakamura, Teppei; Kon, Yasuhiro

    2015-01-01

    The immune system is known to affect reproductive function, and maternal-fetal immune tolerance is essential for a successful pregnancy. To investigate the relationship between autoimmune disease and female reproductive function, we performed a comparative analysis of the ovarian phenotypes for C57BL/6 mice, autoimmune disease-prone MRL/MpJ (MRL/+) mice and congenic MRL/MpJ-Fas(lpr) (MRL/lpr) mice harboring a mutation in the Fas gene that speeds disease onset. Both MRL-background strains showed earlier vaginal opening than C57BL/6 mice. The estrous cycle became irregular by 6 and 12 months of age in MRL/lpr mice and mice of the other two strains, respectively. Histological analysis at 3 months revealed that the number of primordial follicles was smaller in MRL-background mice than in C57BL/6 mice after 3 months. In addition, MRL/lpr and MRL/+ mice displayed lower numbers of ovarian follicles and corpora lutea at 3 and 6 months, and 6 and 12 months, respectively, than that in age-matched C57BL/6 mice. MRL/lpr and MRL/+ mice developed ovarian interstitial glands after 3 and 6 months, respectively. In particular, MRL/lpr mice showed numerous infiltrating lymphocytes within the ovarian interstitia, and partially stratified ovarian surface epithelia with more developed microvilli than that observed in C57BL/6 mice at 6 months. No significant differences in serum hormone levels were observed between the strains. In conclusion, MRL/lpr mice display altered ovarian development, morphology and function consistent with the progression of severe autoimmune disease, as these findings are less severe in MRL/+ counterparts.

  19. Induction of micronuclei and sister chromatid exchange in bone-marrow cells and abnormalities in sperm of Algerian mice (Mus spretus) exposed to cadmium, lead and zinc.

    PubMed

    Tapisso, Joaquim Torres; Marques, Carla Cristina; Mathias, Maria da Luz; Ramalhinho, Maria da Graça

    2009-08-01

    As a consequence of human activities, large amounts of cadmium, lead and zinc are released in the environment, often simultaneously. The aim of this study was to investigate under experimental conditions the DNA damage induced in Algerian mice (Mus spretus) exposed to cadmium (Cd), lead (Pb) and zinc (Zn) separately, or in selected combinations. Three cytogenetic end points were considered: the frequencies of micronucleated cells (MN) and sister chromatid exchange (SCE) in the bone marrow and the frequency of sperm abnormalities. Mice were treated by intraperitoneal (i.p.) injections with 5 or 10 doses of aqueous solutions of cadmium acetate, lead acetate and zinc acetate in concentrations corresponding to 1/10 of the LD50, respectively, 21.5, 0.46 and 1.5 mg/kg bw. The control groups were injected in the same way with distilled water. With only one exception (Cd + Zn group treated with 5 doses), the results show a significant increase of MN in all groups for both treatments (5 and 10 doses). Similarly, the results concerning the SCE revealed a statistically significant increase in all treated animals, with the exception of the Zn group treated with 5 doses. The number of sperm abnormalities was significantly higher in animals treated with 5 doses, except in the group Pb + Zn. In animals treated with 10 doses the number of sperm abnormalities was always statistically higher compared with controls. This study indicates that cadmium, lead and zinc can induce MN, SCEs and sperm abnormalities in Algerian mice and that the clastogenic potential is dependent on the time of exposure and the interaction between the three elements, confirming the environmental damage that may result from the simultaneous action of several metals. Most relevant is the toxic potential for Zn, related with the dose, which may compromise its protective effect against other metal contaminations, such as cadmium.

  20. Mice deficient in Group VIB phospholipase A2 (iPLA2γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet

    PubMed Central

    Song, Haowei; Wohltmann, Mary; Bao, Shunzhong; Ladenson, Jack H.; Semenkovich, Clay F.

    2010-01-01

    Phospholipases A2 (PLA2) play important roles in metabolic processes, and the Group VI PLA2 family is comprised of intracellular enzymes that do not require Ca2+ for catalysis. Mice deficient in Group VIA PLA2 (iPLA2β) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB PLA2 (iPLA2γ) is a related enzyme distributed in membranous organelles, including mitochondria, and iPLA2γ knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of iPLA2γ-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial β-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA2γ-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD. PMID:20179248

  1. Insulin Receptor Signaling in the GnRH Neuron Plays a Role in the Abnormal GnRH Pulsatility of Obese Female Mice

    PubMed Central

    DiVall, Sara A.; Herrera, Danny; Sklar, Bonnie; Wu, Sheng; Wondisford, Fredric; Radovick, Sally; Wolfe, Andrew

    2015-01-01

    Infertility associated with obesity is characterized by abnormal hormone release from reproductive tissues in the hypothalamus, pituitary, and ovary. These tissues maintain insulin sensitivity upon peripheral insulin resistance. Insulin receptor signaling may play a role in the dysregulation of gonadotropin-releasing hormone (GnRH) secretion in obesity, but the interdependence of hormone secretion in the reproductive axis and the multi-hormone and tissue dysfunction in obesity hinders investigations of putative contributing factors to the disrupted GnRH secretion. To determine the role of GnRH insulin receptor signaling in the dysregulation of GnRH secretion in obesity, we created murine models of diet-induced obesity (DIO) with and without intact insulin signaling in the GnRH neuron. Obese control female mice were infertile with higher luteinizing hormone levels and higher GnRH pulse amplitude and total pulsatile secretion compared to lean control mice. In contrast, DIO mice with a GnRH specific knockout of insulin receptor had improved fertility, luteinizing hormone levels approaching lean mice, and GnRH pulse amplitude and total secretion similar to lean mice. Pituitary responsiveness was similar between genotypes. These results suggest that in the obese state, insulin receptor signaling in GnRH neurons increases GnRH pulsatile secretion and consequent LH secretion, contributing to reproductive dysfunction. PMID:25780937

  2. Executive Function Deficits and Social-Behavioral Abnormality in Mice Exposed to a Low Dose of Dioxin In Utero and via Lactation

    PubMed Central

    Endo, Toshihiro; Kakeyama, Masaki; Uemura, Yukari; Haijima, Asahi; Okuno, Hiroyuki; Bito, Haruhiko; Tohyama, Chiharu

    2012-01-01

    An increasing prevalence of mental health problems has been partly ascribed to abnormal brain development that is induced upon exposure to environmental chemicals. However, it has been extremely difficult to detect and assess such causality particularly at low exposure levels. To address this question, we here investigated higher brain function in mice exposed to dioxin in utero and via lactation by using our recently developed automated behavioral flexibility test and immunohistochemistry of neuronal activation markers Arc, at the 14 brain areas. Pregnant C57BL/6 mice were given orally a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a dose of either 0, 0.6 or 3.0 µg/kg on gestation day 12.5. When the pups reached adulthood, they were group-housed in IntelliCage to assess their behavior. As a result, the offspring born to dams exposed to 0.6 µg TCDD/kg were shown to have behavioral inflexibility, compulsive repetitive behavior, and dramatically lowered competitive dominance. In these mice, immunohistochemistry of Arc exhibited the signs of hypoactivation of the medial prefrontal cortex (mPFC) and hyperactivation of the amygdala. Intriguingly, mice exposed to 3.0 µg/kg were hardly affected in both the behavioral and neuronal activation indices, indicating that the robust, non-monotonic dose-response relationship. In conclusion, this study showed for the first time that perinatal exposure to a low dose of TCDD in mice develops executive function deficits and social behavioral abnormality accompanied with the signs of imbalanced mPFC-amygdala activation. PMID:23251380

  3. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis

    PubMed Central

    Wu, Jianfeng; Huang, Zhe; Ren, Junming; Zhang, Zhirong; He, Peng; Li, Yangxin; Ma, Jianhui; Chen, Wanze; Zhang, Yingying; Zhou, Xiaojuan; Yang, Zhentao; Wu, Su-Qin; Chen, Lanfen; Han, Jiahuai

    2013-01-01

    Mixed lineage kinase domain-like protein (Mlkl) was recently found to interact with receptor interacting protein 3 (Rip3) and to be essential for tumor necrosis factor (TNF)-induced programmed necrosis (necroptosis) in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases (TALENs)-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell development. Mlkl-deficient mouse embryonic fibroblasts (MEFs) and macrophages both showed resistance to necrotic but not apoptotic stimuli. Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their ability to activate NF-κB, ERK, JNK, and p38 in response to TNF and lipopolysaccharides (LPS), respectively. Consistently, Mlkl-deficient macrophages and mice exhibited normal interleukin-1β (IL-1β), IL-6, and TNF production after LPS treatment. Mlkl deficiency protects mice from cerulean-induced acute pancreatitis, a necrosis-related disease, but has no effect on polymicrobial septic shock-induced animal death. Our results provide genetic evidence for the role of Mlkl in necroptosis. PMID:23835476

  4. Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE−/− Mice

    PubMed Central

    Zheng, Jiao; Liu, Binglin; Lun, Qixing; Yao, Weijuan; Zhao, Yunfang; Xiao, Wei; Huang, Wenzhe; Wang, Yonghua; Li, Jun; Tu, Pengfei

    2016-01-01

    Chinese dragon's blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon's blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE−/− mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD-induced ApoE−/− mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE−/− mice, which supported the traditional uses of Chinese dragon's blood as an effective agent for improving blood microcirculation in hypercholesterolemia. PMID:26649134

  5. Mice lacking GD3 synthase display morphological abnormalities in the sciatic nerve and neuronal disturbances during peripheral nerve regeneration.

    PubMed

    Ribeiro-Resende, Victor Túlio; Araújo Gomes, Tiago; de Lima, Silmara; Nascimento-Lima, Maiara; Bargas-Rega, Michele; Santiago, Marcelo Felipe; Reis, Ricardo Augusto de Melo; de Mello, Fernando Garcia

    2014-01-01

    The ganglioside 9-O-acetyl GD3 is overexpressed in peripheral nerves after lesioning, and its expression is correlated with axonal degeneration and regeneration in adult rodents. However, the biological roles of this ganglioside during the regenerative process are unclear. We used mice lacking GD3 synthase (Siat3a KO), an enzyme that converts GM3 to GD3, which can be further converted to 9-O-acetyl GD3. Morphological analyses of longitudinal and transverse sections of the sciatic nerve revealed significant differences in the transverse area and nerve thickness. The number of axons and the levels of myelin basic protein were significantly reduced in adult KO mice compared to wild-type (WT) mice. The G-ratio was increased in KO mice compared to WT mice based on quantification of thin transverse sections stained with toluidine blue. We found that neurite outgrowth was significantly reduced in the absence of GD3. However, addition of exogenous GD3 led to neurite growth after 3 days, similar to that in WT mice. To evaluate fiber regeneration after nerve lesioning, we compared the regenerated distance from the lesion site and found that this distance was one-fourth the length in KO mice compared to WT mice. KO mice in which GD3 was administered showed markedly improved regeneration compared to the control KO mice. In summary, we suggest that 9-O-acetyl GD3 plays biological roles in neuron-glia interactions, facilitating axonal growth and myelination induced by Schwann cells. Moreover, exogenous GD3 can be converted to 9-O-acetyl GD3 in mice lacking GD3 synthase, improving regeneration.

  6. Mice Lacking GD3 Synthase Display Morphological Abnormalities in the Sciatic Nerve and Neuronal Disturbances during Peripheral Nerve Regeneration

    PubMed Central

    Ribeiro-Resende, Victor Túlio; Gomes, Tiago Araújo; de Lima, Silmara; Nascimento-Lima, Maiara; Bargas-Rega, Michele; Santiago, Marcelo Felipe; Reis, Ricardo Augusto de Melo; de Mello, Fernando Garcia

    2014-01-01

    The ganglioside 9-O-acetyl GD3 is overexpressed in peripheral nerves after lesioning, and its expression is correlated with axonal degeneration and regeneration in adult rodents. However, the biological roles of this ganglioside during the regenerative process are unclear. We used mice lacking GD3 synthase (Siat3a KO), an enzyme that converts GM3 to GD3, which can be further converted to 9-O-acetyl GD3. Morphological analyses of longitudinal and transverse sections of the sciatic nerve revealed significant differences in the transverse area and nerve thickness. The number of axons and the levels of myelin basic protein were significantly reduced in adult KO mice compared to wild-type (WT) mice. The G-ratio was increased in KO mice compared to WT mice based on quantification of thin transverse sections stained with toluidine blue. We found that neurite outgrowth was significantly reduced in the absence of GD3. However, addition of exogenous GD3 led to neurite growth after 3 days, similar to that in WT mice. To evaluate fiber regeneration after nerve lesioning, we compared the regenerated distance from the lesion site and found that this distance was one-fourth the length in KO mice compared to WT mice. KO mice in which GD3 was administered showed markedly improved regeneration compared to the control KO mice. In summary, we suggest that 9-O-acetyl GD3 plays biological roles in neuron-glia interactions, facilitating axonal growth and myelination induced by Schwann cells. Moreover, exogenous GD3 can be converted to 9-O-acetyl GD3 in mice lacking GD3 synthase, improving regeneration. PMID:25330147

  7. Leukocyte abnormalities.

    PubMed

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  8. Abnormalities in α/β-CaMKII and related mechanisms suggest synaptic dysfunction in hippocampus of LPA1 receptor knockout mice.

    PubMed

    Musazzi, Laura; Di Daniel, Elena; Maycox, Peter; Racagni, Giorgio; Popoli, Maurizio

    2011-08-01

    Lysophosphatidic acid (LPA) is a natural lysophospholipid that regulates neuronal maturation. In mice, the deletion of the LPA1 receptor causes some phenotypic defects partly overlapping with those found in schizophrenia. In this study, we identified molecular abnormalities in hippocampal synaptic mechanisms involved in glutamatergic neurotransmission, which allow further characterization of synaptic aberrations in LPA1 knockout (KO) mice. At the synaptic level, we found dysregulation of Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) activity and phosphorylation, with markedly higher Ca2+-dependent kinase activity, probably related to increased expression levels of the β isoform of CaMKII. Conversely, although the synaptic Ca2+-independent activity of the enzyme was unchanged, autophosphorylation levels of both α and β isoforms were significantly increased in LPA1 KO mice. Moreover, in LPA1 KO mice the α/β isoform ratio of CaMKII, which plays a key role in neuronal maturation during development, was markedly decreased, as found previously in schizophrenia patients. At post-synaptic level, LPA1 KO mice showed changes in expression, phosphorylation and interactions of NMDA and AMPA receptor subunits that are consistent with basal strengthening of glutamatergic synapses. However, we measured a reduction of nuclear cAMP responsive element-binding protein phosphorylation, suggesting that activation of the NMDA receptor does not occur at the intracellular signalling level. At the presynaptic level, in line with previous evidence from schizophrenia patients and animal models of pathology, LPA1 KO mice showed accumulation of SNARE protein complexes. This study shows that CaMKII and related synaptic mechanisms at glutamatergic synapses are strongly dysregulated in LPA1 KO mice.

  9. Development of antihuman IgG antibodies and hematologic deficits but not clinical abnormalities in C57BL/6 mice after repeated administration of human intravenous immunoglobulin.

    PubMed

    Loeffler, David A; Smith, Lynnae M; Klaver, Andrea C; Brzezinski, Heather A; Morrison, Essie I; Coffey, Mary P; Steficek, Barbara A; Cook, Susan S

    2012-02-01

    Intravenous immunoglobulin (IvIg) preparations consist of purified human immunoglobulins collected from large numbers of healthy persons and are used to treat autoimmune, immunodeficiency, and inflammatory disorders. Studying the effects of IvIg effects in experimental animal models might clarify its mechanisms of action in these disorders, but whether 'serum sickness' or other abnormalities occur after repeated IvIg administration to immunocompetent animals is unknown. In the current study, male C57BL/6 mice (8 to 10 wk old; n = 27) received IvIg (1 g/kg IP) weekly for 6 wk. They were observed for clinical abnormalities, and body weight, temperature, renal function, hematologic parameters, and serum antihuman IgG antibodies were measured before and during treatment. Postmortem evaluations were performed on kidney, spleen, liver, and heart. No clinical or histologic abnormalities were noted despite a transient increase in BUN. Mean antibody levels to human IgG on days 21 and 43 after IvIg administration were increased by 23-fold compared with pretreatment levels. 88% and 89% of the mice were antibody responders on those days. Unexpectedly, hemoglobin, hematocrit, and RBC, WBC, lymphocyte, and platelet counts decreased after IvIg administration. These findings suggest that although it does not produce serum sickness, repeated IvIg administration to immunocompetent mice induces a strong humoral immune response and hematologic deficits of unknown etiology. These factors could cause the effects of IvIg preparations in mouse models of human disease to differ from their effects in the human disorders.

  10. Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes.

    PubMed

    Wu, Jian; Kakoola, Dorothy N; Lenchik, Nataliya I; Desiderio, Dominic M; Marshall, Dana R; Gerling, Ivan C

    2012-01-01

    Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse--a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (~90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes.

  11. Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders

    PubMed Central

    Sakai, Kaori; Shoji, Hirotaka; Kohno, Takao; Miyakawa, Tsuyoshi; Hattori, Mitsuharu

    2016-01-01

    The secreted glycoprotein Reelin is believed to play critical roles in the pathogenesis of several neuropsychiatric disorders. The highly basic C-terminal region (CTR) of Reelin is necessary for efficient activation of its downstream signaling, and the brain structure of knock-in mice that lack the CTR (ΔC-KI mice) is impaired. Here, we performed a comprehensive behavioral test battery on ΔC-KI mice, in order to evaluate the effects of partial loss-of-function of Reelin on brain functions. The ΔC-KI mice were hyperactive and exhibited reduced anxiety-like and social behaviors. The working memory in ΔC-KI mice was impaired in a T-maze test. There was little difference in spatial reference memory, depression-like behavior, prepulse inhibition, or fear memory between ΔC-KI and wild-type mice. These results suggest that CTR-dependent Reelin functions are required for some specific normal brain functions and that ΔC-KI mice recapitulate some aspects of neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder. PMID:27346785

  12. Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells

    PubMed Central

    Jia, Yun-Fang; Song, Ning-Ning; Mao, Rong-Rong; Li, Jin-Nan; Zhang, Qiong; Huang, Ying; Zhang, Lei; Han, Hui-Li; Ding, Yu-Qiang; Xu, Lin

    2014-01-01

    Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders. PMID:25294992

  13. Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection

    PubMed Central

    Hermes, Gretchen; Ajioka, James W; Kelly, Krystyna A; Mui, Ernest; Roberts, Fiona; Kasza, Kristen; Mayr, Thomas; Kirisits, Michael J; Wollmann, Robert; Ferguson, David JP; Roberts, Craig W; Hwang, Jong-Hee; Trendler, Toria; Kennan, Richard P; Suzuki, Yasuhiro; Reardon, Catherine; Hickey, William F; Chen, Lieping; McLeod, Rima

    2008-01-01

    Background Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. Methods To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5–12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied. Results Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus

  14. AKAP13 Rho-GEF and PKD-Binding Domain Deficient Mice Develop Normally but Have an Abnormal Response to β-Adrenergic-Induced Cardiac Hypertrophy

    PubMed Central

    Spindler, Matthew J.; Burmeister, Brian T.; Huang, Yu; Hsiao, Edward C.; Salomonis, Nathan; Scott, Mark J.; Srivastava, Deepak; Carnegie, Graeme K.; Conklin, Bruce R.

    2013-01-01

    Background A-kinase anchoring proteins (AKAPs) are scaffolding molecules that coordinate and integrate G-protein signaling events to regulate development, physiology, and disease. One family member, AKAP13, encodes for multiple protein isoforms that contain binding sites for protein kinase A (PKA) and D (PKD) and an active Rho-guanine nucleotide exchange factor (Rho-GEF) domain. In mice, AKAP13 is required for development as null embryos die by embryonic day 10.5 with cardiovascular phenotypes. Additionally, the AKAP13 Rho-GEF and PKD-binding domains mediate cardiomyocyte hypertrophy in cell culture. However, the requirements for the Rho-GEF and PKD-binding domains during development and cardiac hypertrophy are unknown. Methodology/Principal Findings To determine if these AKAP13 protein domains are required for development, we used gene-trap events to create mutant mice that lacked the Rho-GEF and/or the protein kinase D-binding domains. Surprisingly, heterozygous matings produced mutant mice at Mendelian ratios that had normal viability and fertility. The adult mutant mice also had normal cardiac structure and electrocardiograms. To determine the role of these domains during β-adrenergic-induced cardiac hypertrophy, we stressed the mice with isoproterenol. We found that heart size was increased similarly in mice lacking the Rho-GEF and PKD-binding domains and wild-type controls. However, the mutant hearts had abnormal cardiac contractility as measured by fractional shortening and ejection fraction. Conclusions These results indicate that the Rho-GEF and PKD-binding domains of AKAP13 are not required for mouse development, normal cardiac architecture, or β-adrenergic-induced cardiac hypertrophic remodeling. However, these domains regulate aspects of β-adrenergic-induced cardiac hypertrophy. PMID:23658642

  15. Immunologic abnormalities of mice bearing the gld mutation suggest a common pathway for murine nonmalignant lymphoproliferative disorders with autoimmunity.

    PubMed

    Davidson, W F; Holmes, K L; Roths, J B; Morse, H C

    1985-02-01

    Mice bearing the autosomal recessive mutation gld have been shown to develop massive lymphadenopathy, hypergammaglobulinemia, and autoantibodies and to die prematurely with interstitial pneumonitis. In this study, lymphocytes from C3H gld and C3H +/+ mice were examined for a variety of phenotypic and functional characteristics. Spleens and lymph nodes of mutant mice were expanded by an aberrant population of Ly-5(B220)+ surface immunoglobulin negative cells that were Thy-1+Ly-1+ or Thy-1-Ly-1+. Cells from both tissues of mutant mice older than 8 wk were impaired in their ability to proliferate in response to allogeneic stimuli, and supernatants of cells stimulated with concanavalin A contained significantly reduced levels of interleukin 2. Cytotoxic T-lymphocyte responses of spleen and lymph node cells from C3H gld mice were normal at all ages tested. These results are strikingly similar to those obtained with C3H mice homozygous for the nonallelic autosomal recessive mutation lpr. We suggest that the similarities between the syndromes induced by these two mutations may reflect alterations in different enzymes that act in a common metabolic pathway of major importance to the differentiation and function of T cells.

  16. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age.

    PubMed

    Vaidya, Amita; Mao, Zhiyong; Tian, Xiao; Spencer, Brianna; Seluanov, Andrei; Gorbunova, Vera

    2014-07-01

    Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs), we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ) pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ) events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.

  17. Congenital Abnormalities

    MedlinePlus

    ... Listen Español Text Size Email Print Share Congenital Abnormalities Page Content Article Body About 3% to 4% ... of congenital abnormalities earlier. 5 Categories of Congenital Abnormalities Chromosome Abnormalities Chromosomes are structures that carry genetic ...

  18. Abnormal clock gene expression and locomotor activity rhythms in two month-old female APPSwe/PS1dE9 mice.

    PubMed

    Oyegbami, Olaide; Collins, Hilary M; Pardon, Marie C; Ebling, Fran Jp; Heery, David M; Moran, Paula M

    2017-03-17

    In addition to cognitive decline, Alzheimer's disease (AD) is also characterized by agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or at night and have been referred to as 'sundowning'. These symptoms are especially difficult for carers and there are no specific drug treatments. There is increasing evidence that these symptoms reflect an underlying pathology of circadian rhythm generation and transmission. We investigated whether a transgenic mouse model relevant to AD (APPswe/PS1dE9) exhibits circadian alterations in locomotor activity and expression of clock genes involved in the regulation of the circadian cycle. Female mice at 2 months of age were investigated in their home cage. Results show that the APPswe/PS1dE9 transgene alters levels and patterns in circadian rhythm of locomotor activity. Expression of the clock genes Per1, Per2, Cry1 and Cry2 was found to increase at night compared to day in wild-type control mice in the medulla/pons. This effect was blunted for Cry1 and Cry2 gene expression in APPswe/PS1dE9. In summary, this study suggests altered circadian regulation of locomotor activity is abnormal in female APPswe/PS1dE9 mice and that this alteration has biomolecular analogies in a widely available model of AD. Furthermore, the early age at which these effects are manifest suggests that these circadian effects may precede plaque development. The APPswe/PS1dE9 mouse genetic model may have potential to serve as a tool in understanding the neuropathology of circadian abnormalities in AD and as a model system to test novel therapeutic agents for these symptoms.

  19. Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse

    PubMed Central

    Tyas, David A; Simpson, T Ian; Carr, Catherine B; Kleinjan, Dirk A; van Heyningen, Veronica; Mason, John O; Price, David J

    2006-01-01

    Background The Pax6 transcription factor is expressed during development in the eyes and in specific CNS regions, where it is essential for normal cell proliferation and differentiation. Mice lacking one or both copies of the Pax6 gene model closely humans with loss-of-function mutations in the PAX6 locus. The sequence of the Pax6/PAX6 protein is identical in mice and humans and previous studies have shown structural conservation of the gene's regulatory regions. Results We generated a transgenic mouse expressing green fluorescent protein (GFP) and neomycin resistance under the control of the entire complement of human PAX6 regulatory elements using a modified yeast artificial chromosome (YAC). Expression of GFP was studied in embryos from 9.5 days on and was confined to cells known to express Pax6. GFP expression was sufficiently strong that expressing cells could be distinguished from non-expressing cells using flow cytometry. Conclusion This work demonstrates the functional conservation of the regulatory elements controlling Pax6/PAX6 expression in mice and humans. The transgene provides an excellent tool for studying the functions of different Pax6/PAX6 regulatory elements in controlling Pax6 expression in animals that are otherwise normal. It will allow the analysis and isolation of cells in which Pax6 is activated, irrespective of the status of the endogenous locus. PMID:16674807

  20. Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments

    PubMed Central

    Zumbrennen-Bullough, Kimberly B.; Becker, Lore; Garrett, Lillian; Hölter, Sabine M.; Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia; Racz, Ildiko; Rathkolb, Birgit; Klopstock, Thomas; Wurst, Wolfgang; Zimmer, Andreas; Wolf, Eckhard; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabě; Romney, Steven J.; Leibold, Elizabeth A.

    2014-01-01

    Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2−/− mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2−/− mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments. PMID:24896637

  1. Effector and Naturally Occurring Regulatory T Cells Display No Abnormalities in Activation Induced Cell Death in NOD Mice

    PubMed Central

    Kaminitz, Ayelet; Yolcu, Esma S.; Askenasy, Enosh M.; Stein, Jerry; Yaniv, Isaac; Shirwan, Haval; Askenasy, Nadir

    2011-01-01

    Background Disturbed peripheral negative regulation might contribute to evolution of autoimmune insulitis in type 1 diabetes. This study evaluates the sensitivity of naïve/effector (Teff) and regulatory T cells (Treg) to activation-induced cell death mediated by Fas cross-linking in NOD and wild-type mice. Principal Findings Both effector (CD25−, FoxP3−) and suppressor (CD25+, FoxP3+) CD4+ T cells are negatively regulated by Fas cross-linking in mixed splenocyte populations of NOD, wild type mice and FoxP3-GFP tranegenes. Proliferation rates and sensitivity to Fas cross-linking are dissociated in Treg cells: fast cycling induced by IL-2 and CD3/CD28 stimulation improve Treg resistance to Fas-ligand (FasL) in both strains. The effector and suppressor CD4+ subsets display balanced sensitivity to negative regulation under baseline conditions, IL-2 and CD3/CD28 stimulation, indicating that stimulation does not perturb immune homeostasis in NOD mice. Effective autocrine apoptosis of diabetogenic cells was evident from delayed onset and reduced incidence of adoptive disease transfer into NOD.SCID by CD4+CD25− T cells decorated with FasL protein. Treg resistant to Fas-mediated apoptosis retain suppressive activity in vitro. The only detectable differential response was reduced Teff proliferation and upregulation of CD25 following CD3-activation in NOD mice. Conclusion These data document negative regulation of effector and suppressor cells by Fas cross-linking and dissociation between sensitivity to apoptosis and proliferation in stimulated Treg. There is no evidence that perturbed AICD in NOD mice initiates or promotes autoimmune insulitis. PMID:21738739

  2. Abnormal sperm in mice with targeted deletion of the act (activator of cAMP-responsive element modulator in testis) gene

    PubMed Central

    Kotaja, Noora; De Cesare, Dario; Macho, Betina; Monaco, Lucia; Brancorsini, Stefano; Goossens, Ellen; Tournaye, Herman; Gansmuller, Anne; Sassone-Corsi, Paolo

    2004-01-01

    ACT [activator of cAMP-responsive element modulator (CREM) in testis] is a LIM-only protein that interacts with transcription factor CREM in postmeiotic male germ cells and enhances CREM-dependent transcription. CREM regulates many crucial genes required for spermatid maturation, and targeted mutation of the Crem gene in the mouse germ-line blocks spermatogenesis. Here we report the phenotype of mice in which targeted disruption of the act gene was obtained by homologous recombination. Whereas the seminiferous tubules of the act–/– mice contain all of the developmental stages of germ cells and the mice are fertile, the amount of mature sperm in the epididymis is drastically reduced. The residual sperm display severe abnormalities, including fully folded tails and aberrant head shapes. These results indicate that numerous postmeiotic genes under CREM control require the coactivator function of ACT. Thus, the fine-tuning of sperm development is achieved by the coordinated action of two transcriptional regulators. PMID:15247423

  3. Semaphorin 6A knockout mice display abnormalities across ethologically-based topographies of exploration and in motor learning.

    PubMed

    Håkansson, Kerstin; Runker, Annette E; O'Sullivan, Gerard J; Mitchell, Kevin J; Waddington, John L; O'Tuathaigh, Colm M P

    2017-02-22

    Semaphorins are secreted or membrane-bound proteins implicated in neurodevelopmental processes of axon guidance and cell migration. Exploratory behaviour and motor learning was examined ethologically in Semaphorin 6A (Sema6A) mutant mice. The ethogram of initial exploration in Sema6A knockout mice was characterised by increased rearing to wall with decreased sifting; over subsequent habituation, locomotion, sniffing and rearing to wall were increased, with reduced habituation of rearing seated. Rotarod analysis indicated delayed motor learning in Sema6A heterozygous mutants. Disruption to the axonal guidance and cell migration processes regulated by Sema6A is associated with topographically specific disruption to fundamental aspects of behaviour, namely the ethogram of initial exploration and subsequent habituation to the environment, and motor learning.

  4. Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

    PubMed Central

    Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R.; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

    2011-01-01

    Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID:22216345

  5. Insulin-like growth factor binding protein-6 transgenic mice: postnatal growth, brain development, and reproduction abnormalities.

    PubMed

    Bienvenu, Géraldine; Seurin, Danielle; Grellier, Pascale; Froment, Pascal; Baudrimont, Marielle; Monget, Philippe; Le Bouc, Yves; Babajko, Sylvie

    2004-05-01

    In biological fluids, IGFs bind to six distinct binding proteins (IGFBP-1 to -6). IGFBP-6 is of particular interest because it has been shown to inhibit proliferation in many cell types and to be synthesized in the central nervous system (CNS). It also has the strongest affinity for IGF-II among the IGFBPs. To study IGFBP-6 function in vivo, we established IGFBP-6 transgenic mice in which human IGFBP-6 (hIGFBP-6) cDNA is expressed under the control of the glial fibrillary acidic protein (GFAP) promoter. Northern and Western blot analysis revealed strong transgene expression in the CNS. With histological examination of the CNS, cerebellum size and weight proved to be reduced by about 25% and 35%, respectively, and there were smaller numbers of differentiated, GFAP-expressing astrocytes than in wild-type mice. Between birth and 1 month of age, transgenic mice had high levels of circulating hIGFBP-6 and reduced plasma IGF-I, and, as a result, body weight was significantly reduced. Reproductive physiology was also affected. Litter size was reduced by 27% when wild-type males were mated with 3-month-old transgenic females and by 66% when mated with 6-month-old transgenic females. Histological examination of ovaries of transgenic mice revealed a marked decrease in weight and in the number of corpora lutea, suggesting altered ovulation, and circulating LH levels were reduced by 50%. Our results indicate that this new model of transgenic mouse may prove to be a useful tool in elucidating the in vivo role of IGFBP-6 in the brain, especially in regard to hypothalamic control, and in reproductive physiology.

  6. Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice

    PubMed Central

    Isoda, Takuro; Nakatsu, Yoshimichi; Yamauchi, Kazumi; Piao, Jingshu; Yao, Takashi; Honda, Hiroshi; Nakabeppu, Yusaku; Tsuzuki, Teruhisa

    2014-01-01

    MUTYH is a DNA glycosylase that excises adenine paired with 8-oxoguanine to prevent mutagenesis in mammals. Biallelic germline mutations of MUTYH have been found in patients predisposed to a recessive form of familial adenomatous polyposis (MAP: MUTYH-associated polyposis). We previously reported that Mutyh-deficient mice showed a high susceptibility to spontaneous and oxidative stress-induced intestinal adenoma/carcinoma. Here, we performed mutation analysis of the tumor-associated genes including Apc, Ctnnb1, Kras and Trp53 in the intestinal tumors of Mutyh-deficient mice. In the 62 tumors, we identified 25 mutations in Apc of 18 tumors and 36 mutations in Ctnnb1 of 36 tumors. Altogether, 54 out of the 62 tumors (87.1%) had a mutation in either Apc or Ctnnb1; no tumor displayed mutations simultaneously in the both genes. Similar to MAP, 60 out of 61 mutations (98.3%) were identified as G:C to T:A transversions of which 85% occurred at either AGAA or TGAA sequences. Immunohistochemical analyses revealed the accumulation of β-catenin in the nuclei of tumors. No mutation was found in either Kras or Trp53 in the tumors. These results indicate that the uncontrolled activation of Wnt signaling pathway is causatively associated with oxidative stress-induced intestinal tumorigenesis in the Mutyh-deficient mice. PMID:25170306

  7. Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

    PubMed Central

    Gunton, Jenny E.; Sisavanh, Mary; Stokes, Rebecca A.; Satin, Jon; Satin, Leslie S.; Zhang, Min; Liu, Sue M.; Cai, Weikang; Cheng, Kim; Cooney, Gregory J.; Laybutt, D. Ross; So, Trina; Molero, Juan-Carlos; Grey, Shane T.; Andres, Douglas A.

    2012-01-01

    Aims and Hypothesis Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. Methods Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. Results Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. Conclusions These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling. PMID:22761801

  8. Abnormal cell-intrinsic and network excitability in the neocortex of serotonin-deficient Pet-1 knockout mice.

    PubMed

    Puzerey, Pavel A; Kodama, Nathan X; Galán, Roberto F

    2016-02-01

    Neurons originating from the raphe nuclei of the brain stem are the exclusive source of serotonin (5-HT) to the cortex. Their serotonergic phenotype is specified by the transcriptional regulator Pet-1, which is also necessary for maintaining their neurotransmitter identity across development. Transgenic mice in which Pet-1 is genetically ablated (Pet-1(-/-)) show a dramatic reduction (∼80%) in forebrain 5-HT levels, yet no investigations have been carried out to assess the impact of such severe 5-HT depletion on the function of target cortical neurons. Using whole cell patch-clamp methods, two-dimensional (2D) multielectrode arrays (MEAs), 3D morphological neuronal reconstructions, and animal behavior, we investigated the impact of 5-HT depletion on cortical cell-intrinsic and network excitability. We found significant changes in several parameters of cell-intrinsic excitability in cortical pyramidal cells (PCs) as well as an increase in spontaneous synaptic excitation through 5-HT3 receptors. These changes are associated with increased local network excitability and oscillatory activity in a 5-HT2 receptor-dependent manner, consistent with previously reported hypersensitivity of cortical 5-HT2 receptors. PC morphology was also altered, with a significant reduction in dendritic complexity that may possibly act as a compensatory mechanism for increased excitability. Consistent with this interpretation, when we carried out experiments with convulsant-induced seizures to asses cortical excitability in vivo, we observed no significant differences in seizure parameters between wild-type and Pet-1(-/-) mice. Moreover, MEA recordings of propagating field potentials showed diminished propagation of activity across the cortical sheath. Together these findings reveal novel functional changes in neuronal and cortical excitability in mice lacking Pet-1.

  9. Sperm tail abnormalities in mutant mice with neo(r) gene insertion into an intron of the keratin 9 gene.

    PubMed

    Rivkin, Eugene; Eddy, Edward M; Willis, William D; Goulding, Euginia H; Suganuma, Ryota; Yanagimachi, Ryuzo; Kierszenbaum, Abraham L

    2005-10-01

    Keratin 9 (K9) is one of the components of the perinuclear ring of the manchette found in developing spermatids but is predominantly expressed in the epidermis of the footpad (palm and sole in human epidermis). As an initial step to determine the function of K9 protein in sperm development, we have generated a mutant mouse by homologous recombination of the targeting vector containing the disrupted K9 gene in which the neo(r) gene was inserted into the intron 6. This insertion resulted in the expression of two K9 mRNAs: a wild-type K9 mRNA, in which intron 6 with the neo(r) gene was completely spliced out, and a mutated form in which only a portion of the intron 6 between neo(r) gene and exon 7 was spliced out. While both heterozygous (K9(+/neo)) and homozygous (K9(neo/neo)) mutant mice expressed the wild-type form of K9 protein, the expression profile of the wild-type K9 in K9(neo/neo) mutants was modified. In addition, the open reading frame of the aberrant mRNA terminated at the exon 6/intron 6 splice site, resulting in a truncated K9 protein. Both K9(+neo) and K9(neo/neo) male mice displayed spermatids with ectopic manchette. Coiled tails were seen in maturing spermatids and epididymal sperm of mutant mice and sperm with deformed tails displayed forward motility. A predominant sperm anomaly was residual cytoplasm at the end of the mitochondria-containing middle piece tail segment. The residual cytoplasm displayed vesicles with random in situ motion, suggesting a transport impediment toward the distal end of the sperm tail. All mutant mice were fertile. Surprisingly, in oocyte nuclear injection experiments using K9(neo/neo) sperm donor, 76% of the resulting animals displayed a deletion of the neo(r) gene from the intron 6 of the mutated K9 allele. Results of this study support the view that intron 6 influences the transcriptional efficiency of the K9 gene by decreasing production of wild-type K9 and changing the expression of K9 proteins.

  10. A plant based protective antigen [PA(dIV)] vaccine expressed in chloroplasts demonstrates protective immunity in mice against anthrax.

    PubMed

    Gorantala, Jyotsna; Grover, Sonam; Goel, Divya; Rahi, Amit; Jayadev Magani, Sri Krishna; Chandra, Subhash; Bhatnagar, Rakesh

    2011-06-15

    The currently available anthrax vaccines are limited by being incompletely characterized, potentially reactogenic and have an expanded dosage schedule. Plant based vaccines offer safe alternative for vaccine production. In the present study, we expressed domain IV of Bacillus anthracis protective antigen gene [PA(dIV)] in planta (by nuclear agrobacterium and chloroplast transformation) and E. coli [rPA(dIV)]. The presence of transgene and the expression of PA(dIV) in planta was confirmed by molecular analysis. Expression levels up to 5.3% of total soluble protein (TSP) were obtained with AT rich (71.8% AT content) PA(dIV) gene in transplastomic plants while 0.8% of TSP was obtained in nuclear transformants. Further, we investigated the protective response of plant and E. coli derived PA(dIV) in mice by intraperitoneal (i.p.) and oral immunizations with or without adjuvant. Antibody titers of >10(4) were induced upon i.p. and oral immunizations with plant derived PA(dIV) and oral immunization with E. coli derived PA(dIV). Intraperitoneal injections with adjuvanted E. coli derived PA(dIV), generated highest antibody titers of >10(5). All the immunized groups demonstrated predominant IgG1 titers over IgG2a indicating a polarized Th2 type response. We also evaluated the mucosal antibody response in orally immunized groups. When fecal extracts were analyzed, low sIgA titer was demonstrated in adjuvanted plant and E. coli derived PA(dIV) groups. Further, PA(dIV) antisera enhanced B. anthracis spore uptake by macrophages in vitro and also demonstrated an anti-germinating effect suggesting a potent role at mucosal surfaces. The antibodies from various groups were efficient in neutralizing the lethal toxin in vitro. When mice were challenged with B. anthracis, mice immunized with adjuvanted plant PA(dIV) imparted 60% and 40% protection while E. coli derived PA(dIV) conferred 100% and 80% protection upon i.p. and oral immunizations. Thus, our study is the first attempt in

  11. Mutations in the clathrin-assembly gene Picalm are responsible for the hematopoietic and iron metabolism abnormalities in fit1 mice.

    PubMed

    Klebig, Mitchell L; Wall, Melissa D; Potter, Mark D; Rowe, Erica L; Carpenter, Donald A; Rinchik, Eugene M

    2003-07-08

    Recessive N-ethyl-N-nitrosourea (ENU)-induced mutations recovered at the fitness-1 (fit1) locus in mouse chromosome 7 cause hematopoietic abnormalities, growth retardation, and shortened life span, with varying severity of the defects in different alleles. Abnormal iron distribution and metabolism and frequent scoliosis have also been associated with an allele of intermediate severity (fit14R). We report that fit14R, as well as the most severe fit15R allele, are nonsense point mutations in the mouse ortholog of the human phosphatidylinositol-binding clathrin assembly protein (PICALM) gene, whose product is involved in clathrin-mediated endocytosis. A variety of leukemias and lymphomas have been associated with translocations that fuse human PICALM with the putative transcription factor gene AF10. The Picalmfit1-5R and Picalmfit1-4R mutations are splice-donor alterations resulting in transcripts that are less abundant than normal and missing exons 4 and 17, respectively. These exon deletions introduce premature termination codons predicted to truncate the proteins near the N and C termini, respectively. No mutations in the genes encoding Picalm, clathrin, or components of the adaptor protein complex 2 (AP2) have been previously described in which the suite of disorders present in the Picalmfit1 mutant mice is apparent. These mutants thus provide unique models for exploring how the endocytic function of mouse Picalm and the transport processes mediated by clathrin and the AP2 complex contribute to normal hematopoiesis, iron metabolism, and growth.

  12. Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice.

    PubMed

    Stöhr, Andrea; Friedrich, Felix W; Flenner, Frederik; Geertz, Birgit; Eder, Alexandra; Schaaf, Sebastian; Hirt, Marc N; Uebeler, June; Schlossarek, Saskia; Carrier, Lucie; Hansen, Arne; Eschenhagen, Thomas

    2013-10-01

    Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C. EHTs were generated from cardiac cells of neonatal KI, heterozygous (HET) or wild-type controls (WT) and developed without apparent morphological differences. KI had 70% and HET 20% lower total cMyBP-C levels than WT, accompanied by elevated fetal gene expression. Under standard culture conditions and spontaneous beating, KI EHTs showed more frequent burst beating than WT and occasional tetanic contractions (14/96). Under electrical stimulation (6Hz, 37°C) KI EHTs exhibited shorter contraction and relaxation times and a twofold higher sensitivity to external [Ca(2+)]. Accordingly, the sensitivity to verapamil was 4-fold lower and the response to isoprenaline or the Ca(2+) sensitizer EMD 57033 2- to 4-fold smaller. The loss of EMD effect was verified in 6-week-old KI mice in vivo. HET EHTs were apparently normal under basal conditions, but showed similarly altered contractile responses to [Ca(2+)], verapamil, isoprenaline and EMD. In contrast, drug-induced changes in intracellular Ca(2+) transients (Fura-2) were essentially normal. In conclusion, the present findings in auxotonically contracting EHTs support the idea that cMyBP-C's normal role is to suppress force generation at low intracellular Ca(2+) and stabilize the power-stroke step of the cross bridge cycle. Pharmacological testing in EHT unmasked a disease phenotype in HET. The altered drug response may be clinically relevant.

  13. Involvement of Potassium and Cation Channels in Hippocampal Abnormalities of Embryonic Ts65Dn and Tc1 Trisomic Mice.

    PubMed

    Stern, Shani; Segal, Menahem; Moses, Elisha

    2015-09-01

    Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca(2+)]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~ 30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in Δf / f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after-hyperpolarization amplitude. Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~ 90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~ 65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype.

  14. Involvement of Potassium and Cation Channels in Hippocampal Abnormalities of Embryonic Ts65Dn and Tc1 Trisomic Mice

    PubMed Central

    Stern, Shani; Segal, Menahem; Moses, Elisha

    2015-01-01

    Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca2+]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~ 30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in Δf / f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after-hyperpolarization amplitude. Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~ 90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~ 65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype. PMID:26501103

  15. Effects of dietary fat energy restriction and fish oil feeding on hepatic metabolic abnormalities and insulin resistance in KK mice with high-fat diet-induced obesity.

    PubMed

    Arai, Takeshi; Kim, Hyoun-ju; Hirako, Satoshi; Nakasatomi, Maki; Chiba, Hiroshige; Matsumoto, Akiyo

    2013-01-01

    We investigated the effects of dietary fat energy restriction and fish oil intake on glucose and lipid metabolism in female KK mice with high-fat (HF) diet-induced obesity. Mice were fed a lard/safflower oil (LSO50) diet consisting of 50 energy% (en%) lard/safflower oil as the fat source for 12 weeks. Then, the mice were fed various fat energy restriction (25 en% fat) diets - LSO, FO2.5, FO12.5 or FO25 - containing 0, 2.5, 12.5, or 25 en% fish oil, respectively, for 9 weeks. Conversion from a HF diet to each fat energy restriction diet significantly decreased final body weights and visceral and subcutaneous fat mass in all fat energy restriction groups, regardless of fish oil contents. Hepatic triglyceride and cholesterol levels markedly decreased in the FO12.5 and FO25 groups, but not in the LSO group. Although plasma insulin levels did not differ among groups, the blood glucose areas under the curve in the oral glucose tolerance test were significantly lower in the FO12.5 and FO25 groups. Real-time polymerase chain reaction analysis showed fatty acid synthase mRNA levels significantly decreased in the FO25 group, and stearoyl-CoA desaturase 1 mRNA levels markedly decreased in the FO12.5 and FO25 groups. These results demonstrate that body weight gains were suppressed by dietary fat energy restriction even in KK mice with HF diet-induced obesity. We also suggested that the combination of fat energy restriction and fish oil feeding decreased fat droplets and ameliorated hepatic hypertrophy and insulin resistance with suppression of de novo lipogenesis in these mice.

  16. Pleiotropy in microdeletion syndromes: neurologic and spermatogenic abnormalities in mice homozygous for the p6H deletion are likely due to dysfunction of a single gene.

    PubMed

    Rinchik, E M; Carpenter, D A; Handel, M A

    1995-07-03

    Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p6H deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p6H deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p6H deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p6H deletion homozygotes. Because EtNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p6H deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans.

  17. Alveolar abnormalities

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001093.htm Alveolar abnormalities To use the sharing features on this page, please enable JavaScript. Alveolar abnormalities are changes in the tiny air sacs in ...

  18. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... 2012:chap 71. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol . 2013;31: ...

  19. Structural abnormalities of corpus callosum and cortical axonal tracts accompanied by decreased anxiety-like behavior and lowered sociability in spock3- mutant mice.

    PubMed

    Yamamoto, Ayako; Uchiyama, Koji; Nara, Tomoka; Nishimura, Naomichi; Hayasaka, Michiko; Hanaoka, Kazunori; Yamamoto, Tatsuro

    2014-01-01

    Spock3/Testican-3 is a nervous system-expressed heparan sulfate proteoglycan belonging to a subgroup of the BM-40/SPARC/osteonectin family, the role of which in brain development is unclear. Because Spock1, a member of the Spock family, inhibits their attachment to substrates and the neurite outgrowth of cultured neuronal cells, Spock3 is also thought to be similarly involved in the neuronal development. In the present study, we established a Spock3-mutant mouse harboring a deletion extending from the presumptive upstream regulatory region to exon 4 of the Spock3 locus and performed histological and behavioral studies on these mutant mice. In wild-type (WT) mice, all Spock members were clearly expressed during brain development. In adults, intense Spock1 and Spock2 expressions were observed throughout the entire brain; whereas, Spock3 expression was no longer visible except in the thalamic nuclei. Thus, Spock3 expression is mostly confined to the developmental stage of the brain. In adult mutant mice, the cells of all cortical layers were swollen. The corpus callosum was narrowed around the central region along the rostral-caudal axis and many small spaces were observed without myelin sheaths throughout the entire corpus callosum. In addition, the cortical input and output fibers did not form into thick bundled fibers as well as the WT counterparts did. Moreover, a subpopulation of corticospinal axonal fibers penetrated into the dorsal striatum with moderately altered orientations. Consistent with these modifications of brain structures, the mutant mice exhibited decreased anxiety-like behavior and lowered sociability. Together, these results demonstrate that Spock3 plays an important role in the formation or maintenance of major neuronal structures in the brain.

  20. Chronic treatment with exendin(9-39)amide indicates a minor role for endogenous glucagon-like peptide-1 in metabolic abnormalities of obesity-related diabetes in ob/ob mice.

    PubMed

    Green, B D; Irwin, N; Gault, V A; Bailey, C J; O'Harte, F P M; Flatt, P R

    2005-05-01

    Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic hormone proposed to play a role in both the pathophysiology and treatment of type 2 diabetes. This study has employed the GLP-1 receptor antagonist, exendin-4(9-39)amide (Ex(9-39)) to evaluate the role of endogenous GLP-1 in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob and normal mice. Acute in vivo antagonistic potency of Ex(9-39) was confirmed in ob/ob mice by blockade of the insulin-releasing and anti-hyperglycaemic actions of intraperitoneal GLP-1. In longer term studies, ob/ob mice were given once daily injections of Ex(9-39) or vehicle for 11 days. Feeding activity, body weight, and both basal and glucose-stimulated insulin secretion were not significantly affected by chronic Ex(9-39) treatment. However, significantly elevated basal glucose concentrations and impaired glucose tolerance were evident at 11 days. These disturbances in glucose homeostasis were independent of changes of insulin sensitivity and reversed by discontinuation of the Ex(9-39) for 9 days. Similar treatment of normal mice did not affect any of the parameters measured. These findings illustrate the physiological extrapancreatic glucose-lowering actions of GLP-1 in ob/ob mice and suggest that the endogenous hormone plays a minor role in the metabolic abnormalities associated with obesity-related diabetes.

  1. Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain.

    PubMed

    Pacheco-Costa, Rafael; Davis, Hannah M; Sorenson, Chad; Hon, Mary C; Hassan, Iraj; Reginato, Rejane D; Allen, Matthew R; Bellido, Teresita; Plotkin, Lilian I

    2015-12-01

    Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43(ΔCT/fl)) were studied. Cx43(ΔCT/fl) mice exhibit lower cancellous bone volume but higher cortical thickness than Cx43(fl/fl) controls, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43(ΔCT) is able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43(ΔCT) mice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43(ΔCT) were or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions.

  2. Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality.

    PubMed

    Donley, David W; Olson, Andrew R; Raisbeck, Merl F; Fox, Jonathan H; Gigley, Jason P

    2016-01-01

    Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early-advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.

  3. Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality

    PubMed Central

    Donley, David W.; Olson, Andrew R.; Raisbeck, Merl F.; Fox, Jonathan H.; Gigley, Jason P.

    2016-01-01

    Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early–advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD. PMID:27611938

  4. Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye.

    PubMed

    Hopfer, Ulrike; Fukai, Naomi; Hopfer, Helmut; Wolf, Gunter; Joyce, Nancy; Li, En; Olsen, Bjorn R

    2005-08-01

    Collagen VIII is localized in subendothelial and subepithelial extracellular matrices. It is a major component of Descemet's membrane, a thick basement membrane under the corneal endothelium, where it forms a hexagonal lattice structure; a similar structure, albeit less extensive, may be formed in other basement membranes. We have examined the function of collagen VIII in mice by targeted inactivation of the genes encoding the two polypeptide subunits, Col8a1 and Col8a2. Analysis of these mice reveals no major structural defects in most organs, but demonstrates that type VIII collagen is required for normal anterior eye development, particularly the formation of a corneal stroma with the appropriate number of fibroblastic cell layers and Descemet's membrane of appropriate thickness. Complete lack of type VIII collagen leads to dysgenesis of the anterior segment of the eye: a globoid, keratoglobus-like protrusion of the anterior chamber with a thin corneal stroma. Descemet's membrane is markedly thinned. The corneal endothelial cells are enlarged and reduced in number, and show a decreased ability to proliferate in response to different growth factors in vitro. An important function of collagen VIII may therefore be to generate a peri- or subcellular matrix environment that permits or stimulates cell proliferation.

  5. Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

    PubMed Central

    Kueffer, Peter J.; Maitz, Charles A.; Khan, Aslam A.; Schuster, Seth A.; Shlyakhtina, Natalia I.; Jalisatgi, Satish S.; Brockman, John D.; Nigg, David W.; Hawthorne, M. Frederick

    2013-01-01

    The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2′-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 1012 neutrons per cm2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study. PMID:23536304

  6. Lineage targeted MHC-II transgenic mice demonstrate the role of dendritic cells in bacterial driven colitis

    PubMed Central

    Maggio-Price, Lillian; Seamons, Audrey; Bielefeldt-Ohmann, Helle; Zeng, Weiping; Brabb, Thea; Ware, Carol; Lei, Mingzu; Hershberg, Robert M.

    2012-01-01

    Background Inflammatory bowel disease (IBD) pathogenesis involves an inadequately controlled immune reaction to intestinal microbiota and CD4+ T cells, dependent upon MHC class II (MHC-II) processing and presentation by antigen presenting cells (APC), play important roles The role of professional APC (macrophages and dendritic cells (DC)) and nonprofessional APC (intestinal epithelial cells (IEC)) in microbial driven intestinal inflammation remains controversial. Methods We generated transgenic animals on a MHC-II−/− genetic background in which MHC-II is expressed on a) DC via the CD11c promoter (CD11cTg) or b) IEC via the fatty acid binding protein (liver) promoter (EpithTg). These mice were crossed with Rag2−/− mice to eliminate T and B cells (CD11cTg/Rag2−/− and EpithTg/Rag2−/−). Helicobacter bilis (Hb) infection and adoptive transfer (AT) of naïve CD4+ T cells were used to trigger IBD. Results CD11cTg/Rag2−/− mice infected with Hb+AT developed severe colitis within three weeks post AT, similar to disease in positive control Rag2−/− mice infected with Hb+AT. CD11cTg/Rag2−/− mice given AT alone or Hb alone had significantly less severe colitis. In contrast, EpithTg/Rag2−/− mice infected with Hb+AT developed mild colitis by three weeks and even after 16 weeks post adoptive transfer, had only mild lesions. Conclusions MHC-II expression restricted to DCs is sufficient to induce severe colitis in the presence of T cells and a microorganism such as Hb within three weeks of adoptive transfer. Expression of MHC-II solely on IEC in the presence of a microbial trigger and T cells was insufficient for triggering severe colitis. PMID:22619032

  7. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  8. Narp knockout mice show normal reactivity to novelty but attenuated recovery from neophobia.

    PubMed

    Blouin, Ashley M; Lee, Jongah J; Tao, Bo; Smith, Dani R; Johnson, Alexander W; Baraban, Jay M; Reti, Irving M

    2013-11-15

    Narp knockout (KO) mice demonstrate cognitive inflexibility and addictive behavior, which are associated with abnormal reactivity to a novel stimulus. To assess reactivity to novelty, we tested Narp KO and wild-type (WT) mice on a neophobia procedure. Both Narp KO and WT mice showed a similar decrease in consumption upon initial exposure to a novel flavor, but Narp KO mice did not increase consumption with subsequent exposures to the novel flavor like the WT mice. Therefore, Narp KO mice do not have abnormal reactivity to novelty but show deficits in adapting behavior to reflect the updated value of a stimulus.

  9. The Effects of Sesquiterpenes-Rich Extract of Alpinia oxyphylla Miq. on Amyloid-β-Induced Cognitive Impairment and Neuronal Abnormalities in the Cortex and Hippocampus of Mice

    PubMed Central

    Shi, Shao-Huai; Zhao, Xu; Liu, Bing; Li, Huan; Liu, Ai-Jing; Wu, Bo; Bi, Kai-Shun

    2014-01-01

    As a kind of medicine which can also be used as food, Alpinia oxyphylla Miq. has a long clinical history in China. A variety of studies demonstrated the significant neuroprotective activity effects of chloroform (CF) extract from the fruits of Alpinia oxyphylla. In order to further elucidate the possible mechanisms of CF extract which mainly contains sesquiterpenes with neuroprotection on the cognitive ability, mice were injected with Aβ1−42 and later with CF in this study. The results showed that the long-term treatment of CF enhanced the cognitive performances in behavior tests, increased activities of glutathione peroxidase (GSH-px) and decreased the level of malondialdehyde (MDA), acetylcholinesterase (AChE), and amyloid-β (Aβ), and reversed the activation of microglia, degeneration of neuronal acidophilia, and nuclear condensation in the cortex and hippocampus. These results demonstrate that CF ameliorates learning and memory deficits by attenuating oxidative stress and regulating the activation of microglia and degeneration of neuronal acidophilia to reinforce cholinergic functions. PMID:25180067

  10. Neocortical vasculature abnormalities in the Fragile X mental retardation syndrome.

    PubMed

    Galvan, Ashley M; Galvez, Roberto

    2012-08-30

    The Fragile X syndrome (FXS) is the leading form of inherited mental retardation. To date, the most prominent neuronal phenotype associated with the syndrome is an abundance of long thin spines exhibiting an immature morphology. However, in addition to synaptic abnormalities, recent case studies have demonstrated that Fragile X (FX) patients also exhibit abnormal cerebral blood flow (CBF). To examine the role of the Fragile X mental retardation protein (FMRP) in altering CBF, we examined blood vessel density (BVD) in the visual cortex of Adult and Middle-aged FX mice. Analysis of Middle-aged FX mice demonstrated elevated BVD compared to wildtype controls, suggesting that FX mice exhibit a lack of age-induced BVD plasticity. However, Adult FX and wildtype mice did not exhibit consistent differences in BVD. These data demonstrate that FMRP is required for age-induced neocortical vasculature plasticity. Furthermore, these data suggest a new role for FMRP in blood vessel regulation that would have profound implications towards appropriately timed delivery of neuronal nutrients, thus contributing to or exacerbating FX cognitive and neuronal abnormalities.

  11. Dill seed extract improves abnormalities in lipid metabolism through peroxisome proliferator-activated receptor-α (PPAR-α) activation in diabetic obese mice.

    PubMed

    Takahashi, Nobuyuki; Yao, Lan; Kim, Minji; Sasako, Hiroshi; Aoyagi, Morihiro; Shono, Jinji; Tsuge, Nobuaki; Goto, Tsuyoshi; Kawada, Teruo

    2013-07-01

    Dill, a small annual herb, is widely used as a flavoring agent in dishes including salads. It has been demonstrated that dill extract and its essential oil show hypolipidemic effects in rats. However, the mechanism of these effects has not been elucidated yet. We found that dill seed extract (DSE) activated peroxisome proliferator-activated receptor-α (PPAR-α), an indispensable regulator for hepatic lipid metabolism, by luciferase assay. Thus, we performed DSE feeding experiments using diabetic obese model KK-Ay mice to examine the effects of DSE on PPAR-α activation in vivo. A 4-week feeding of DSE contained in a high-fat diet decreased plasma triacylglyceride and glucose levels and increased the mRNA expression levels of fatty acid oxidation-related genes in the liver. In addition, the DSE feeding as well as bezafibrate (a PPAR-α potent agonist) feeding increased oxygen consumption rate and rectal temperature. These results indicate that DSE suppresses high-fat diet-induced hyperlipidemia through hepatic PPAR-α activation.

  12. A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of SPO11.

    PubMed

    Faieta, Monica; Di Cecca, Stefano; de Rooij, Dirk G; Luchetti, Andrea; Murdocca, Michela; Di Giacomo, Monica; Di Siena, Sara; Pellegrini, Manuela; Rossi, Pellegrino; Barchi, Marco

    2016-06-01

    Meiosis is the biological process that, after a cycle of DNA replication, halves the cellular chromosome complement, leading to the formation of haploid gametes. Haploidization is achieved via two successive rounds of chromosome segregation, meiosis I and II. In mammals, during prophase of meiosis I, homologous chromosomes align and synapse through a recombination-mediated mechanism initiated by the introduction of DNA double-strand breaks (DSBs) by the SPO11 protein. In male mice, if SPO11 expression and DSB number are reduced below heterozygosity levels, chromosome synapsis is delayed, chromosome tangles form at pachynema, and defective cells are eliminated by apoptosis at epithelial stage IV at a spermatogenesis-specific endpoint. Whether DSB levels produced in Spo11 (+/-) spermatocytes represent, or approximate, the threshold level required to guarantee successful homologous chromosome pairing is unknown. Using a mouse model that expresses Spo11 from a bacterial artificial chromosome, within a Spo11 (-/-) background, we demonstrate that when SPO11 expression is reduced and DSBs at zygonema are decreased (approximately 40 % below wild-type level), meiotic chromosome pairing is normal. Conversely, DMC1 foci number is increased at pachynema, suggesting that under these experimental conditions, DSBs are likely made with delayed kinetics at zygonema. In addition, we provide evidences that when zygotene-like cells receive enough DSBs before chromosome tangles develop, chromosome synapsis can be completed in most cells, preventing their apoptotic elimination.

  13. Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

    SciTech Connect

    Woolbright, Benjamin L.; Antoine, Daniel J.; Jenkins, Rosalind E.; Bajt, Mary Lynn; Park, B. Kevin; Jaeschke, Hartmut

    2013-12-15

    Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given D-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis. - Highlights: • The mechanism of cell death during cholestasis remains a controversial topic. • Plasma biomarkers offer new insight into cell death after bile duct ligation. • Cytokeratin-18, microRNA-122 and HMGB

  14. Abnormalities induced by the mutant gene, lpr. Patterns of disease and expression of murine leukemia viruses in SJL/J mice homozygous and heterozygous for lpr.

    PubMed

    Morse, H C; Roths, J B; Davidson, W F; Langdon, W Y; Fredrickson, T N; Hartley, J W

    1985-03-01

    SJL/J mice heterozygous or homozygous for the lpr mutation were compared with SJL/J-+/+ mice for longevity, histopathology, antigenic characteristics of lymphocytes and expression of murine leukemia viruses (MuLV). In comparison to +/+ mice, lpr homozygotes had a markedly shortened life span, died with infiltrative pulmonary disease, but little or no renal disease, and expressed high levels of infectious ecotropic MuLV in lymphoid tissues. SJL-lpr/+ mice had a life span intermediate between SJL-+/+ and -lpr/lpr mice, died with lymphomas that histologically resembled the neoplasms of +/+ mice, and sometimes expressed high levels of ecotropic MuLV. The lymphomas of lpr/+ could be transplanted to +/+ recipients in 78% of cases, and continuous in vitro lines were established from some of them. Similar effects on virus expression or lymphoma development were not observed in other strains homozygous or heterozygous for the lpr mutation. These results indicate that the diseases expressed by mice homozygous for the lpr mutation are highly strain-dependent, and that this gene can have an effect in the heterozygous state in SJL mice.

  15. Bone marrow transplantation from mutant lpr/lpr mice. Functional abnormalities rather than alloantigenic differences appear to determine the development of a graft-vs.-host-like syndrome.

    PubMed

    Allen, R D; Marshall, J D; Roths, J B; Sidman, C L

    1990-09-01

    Transfer of bone marrow (BM) from autoimmunity-prone mice homozygous for the lymphoproliferation (lpr) mutation to irradiated congenic +/+ recipients has previously been shown to result in a syndrome similar to chronic graft-vs.-host (GVH) disease. It has been suggested that this syndrome may be due to an antigenic difference caused by the lpr mutation itself or to antigenic differences at loci closely linked to the lpr locus (Theofilopoulos, A. N. et al., J. Exp. Med. 1985. 162:1; Mosbach-Ozmen, L. and Loor, F., Thymus 1987. 9:197). However, the results presented here indicate that alloantigenic differences do not play a role in this syndrome. Instead, the chronic disease observed in lpr/lpr----(+/+) BM chimeras appears to develop as a result of a functional defect associated with the lpr mutation which is expressed shortly after transfer of lpr/lpr BM to irradiated recipients. This defect causes an increase in the levels of serum IgG1 and IgG2, which peak at 4-5 weeks post-transfer and then decline to normal levels by 9-10 weeks post-transfer. Inflammation similar to that observed in classic GVH reactions accompanies excess IgG production in congenic +/+ recipients but not in lpr/lpr recipients of lpr/lpr BM. We demonstrate that the GVH-like response occurring in lpr/lpr----(+/+) chimeras is dependent on mature T cells, but that either lpr/lpr or (+/+) T cells can support this reaction. These results suggest that transfer of lpr/lpr BM to normal mice causes immunoregulatory disturbances which lead to nonspecific activation of T cells. We speculate that lpr/lpr BM causes a GVH-like reaction in +/+ recipients but a systemic lupus erythematosus-like syndrome in lpr/lpr recipients because of intrinsic differences in the +/+ and lpr/lpr host environments. Considering these findings, the lpr/lpr----+/+ GVH model may be useful for analysis of factors capable of inducing undesirable reactions in clinical BM transplantation between nominally histocompatible donors and

  16. Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception

    PubMed Central

    Warnecke, Marei; Oster, Henrik; Revelli, Jean-Pierre; Alvarez-Bolado, Gonzalo; Eichele, Gregor

    2005-01-01

    The orphan nuclear receptor Ear2 (Nr2f6) is transiently expressed in the rostral part of the rhombic lip in which the locus coeruleus (LC) arises. LC development, regulated by a signaling cascade (Mash1 → Phox2b → Phox2a), is disrupted in Ear2-/- embryos as revealed by an approximately threefold reduction in the number of Phox2a- and Phox2b-expressing LC progenitor cells. Mash1 expression in the rhombic lip, however, is unaffected, placing Ear2 in between Mash1 and Phox2a/b. Dopamine-β-hydroxylase and tyrosine hydroxylase staining demonstrate that >70% of LC neurons are absent in the adult with agenesis affecting primarily the dorsal division of the LC. Normally, this division projects noradrenergic efferents to the cortex that appear to be diminished in Ear2-/- since the cortical concentration of noradrenaline is four times lower in these mice. The rostral region of the cortex is known to contain a circadian pacemaker regulating adaptability to light- and restricted food-driven entrainment. In situ hybridization establishes that the circadian expression pattern of the clock gene Period1 is abolished in the Ear2-/- forebrain. Behavioral experiments reveal that Ear2 mutants have a delayed entrainment to shifted light-dark cycles and adapt less efficiently to daytime feeding schedules. We propose that neurons in the dorsal division of LC contribute to the regulation of the forebrain clock, at least in part, through targeted release of noradrenaline into the cortical area. PMID:15741322

  17. Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice.

    PubMed

    Ye, Maoqing; Coldren, Chris; Liang, Xingqun; Mattina, Teresa; Goldmuntz, Elizabeth; Benson, D Woodrow; Ivy, Dunbar; Perryman, M B; Garrett-Sinha, Lee Ann; Grossfeld, Paul

    2010-02-15

    Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, including an unprecedented high frequency of hypoplastic left heart syndrome (HLHS). We identified an approximately 7 Mb 'cardiac critical region' in distal 11q that contains a putative causative gene(s) for congenital heart disease. In this study, we utilized chromosomal microarray mapping to characterize three patients with 11q- and congenital heart defects that carry interstitial deletions overlapping the 7 Mb cardiac critical region. We propose that this 1.2 Mb region of overlap harbors a gene(s) that causes at least a subset of the congenital heart defects that occur in 11q-. We demonstrate that one gene in this region, ETS-1 (a member of the ETS family of transcription factors), is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of ETS-1 in mice in a C57/B6 background causes, with high penetrance, large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle (one of the hallmarks of HLHS). Our results implicate an important role for the ETS-1 transcription factor in mammalian heart development and should provide important insights into some of the most common forms of congenital heart disease.

  18. Continuous exposure to a novel stressor based on water aversion induces abnormal circadian locomotor rhythms and sleep-wake cycles in mice.

    PubMed

    Miyazaki, Koyomi; Itoh, Nanako; Ohyama, Sumika; Kadota, Koji; Oishi, Katsutaka

    2013-01-01

    Psychological stressors prominently affect diurnal rhythms, including locomotor activity, sleep, blood pressure, and body temperature, in humans. Here, we found that a novel continuous stress imposed by the perpetual avoidance of water on a wheel (PAWW) affected several physiological diurnal rhythms in mice. One week of PAWW stress decayed robust circadian locomotor rhythmicity, while locomotor activity was evident even during the light period when the mice are normally asleep. Daytime activity was significantly upregulated, whereas nighttime activity was downregulated, resulting in a low amplitude of activity. Total daily activity gradually decreased with increasing exposure to PAWW stress. The mice could be exposed to PAWW stress for over 3 weeks without adaptation. Furthermore, continuous PAWW stress enhanced food intake, but decreased body weight and plasma leptin levels, indicating that sleep loss and PAWW stress altered the energy balance in these mice. The diurnal rhythm of corticosterone levels was not severely affected. The body temperature rhythm was diurnal in the stressed mice, but significantly dysregulated during the dark period. Plasma catecholamines were elevated in the stressed mice. Continuous PAWW stress reduced the duration of daytime sleep, especially during the first half of the light period, and increased nighttime sleepiness. Continuous PAWW stress also simultaneously obscured sleep/wake and locomotor activity rhythms compared with control mice. These sleep architecture phenotypes under stress are similar to those of patients with insomnia. The stressed mice could be entrained to the light/dark cycle, and when they were transferred to constant darkness, they exhibited a free-running circadian rhythm with a timing of activity onset predicted by the phase of their entrained rhythms. Circadian gene expression in the liver and muscle was unaltered, indicating that the peripheral clocks in these tissues remained intact.

  19. The role of quantitative changes in the epxression of insulin receptor substrate-1 and nuclear ubiquitin in abnormal glycometabolism in the livers of KKay mice and the relative therapeutic mechanisms of Astragalus polysaccharide.

    PubMed

    Ye, Yan; Deng, Tao; Wan, Xin-Yue; Ouyang, Jing-Ping; Liu, Min; Mao, Xian-Qing

    2014-02-01

    Ubiquitin and the ubiquitination pathway are important regulators of insulin signaling. The insulin receptor substrate‑1 (IRS-1), an ubiquitin-interacting adaptor protein, serves as the key docking protein in insulin signaling. The effects of this dynamic interaction and the changes in ubiquitin expression on hepatic insulin signaling, as well as the relative therapeutic effects of Astragalus polysaccharide (APS) have not yet been elucidated. In this study, we aimed to investigate the abnormal changes which occur in the levels of IRS-1 and ubiquitin in the livers of mice (mice with insulin resistance and diabetes), and to elucidate the possible mechanisms responsible for these changes. A control group (CG), an insulin resistance group (IG) and a diabetes group (DG) were respectively composed of 12-week-old C57BL/6J mice fed a normal diet, C57BL/6J mice fed a high‑fat diet and KKay mice fed a high‑fat diet, and treatment groups were composed of corresponding groups treated with APS (CG + A, IG + A, DG + A). All the mice were age-matched and grouped at random. After eight weeks, the mouse models were successfully established and the related physiological or biochemical indexes were detected using corresponding methods. Ubiquitin expression in the liver was detected by immunohistochemisty, and western blot analysis was used to detect the expression of IRS-1 and ubiquitin. The results revealed that the expression of IRS-1 in the DG was significantly lower compared to that in the CG and IG; however, the nuclear expression of ubiquitin and the ubiquitination levels of IRS-1, including body weight and blood glucose and triglyceride levels in the DG were significantly higher compared to those in the CG or IG (P<0.05). There was a significant improvement in the ubiquitination levels in DG + A, including the blood glucose and triglyceride levels compared with the DG (P<0.05). From the stage of insulin resistance to the stage of diabetes, the reduced expression of IRS-1

  20. Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice

    PubMed Central

    Portal-Núñez, Sergio; Murillo-Cuesta, Silvia; Lozano, Daniel; Cediel, Rafael; Esbrit, Pedro

    2014-01-01

    Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1–36) and PTHrP (107–111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a, cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1–36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1–36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone. PMID:24503961

  1. Mice deficient in Endothelin-Converting Enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord

    PubMed Central

    Miller, L.K.; Hou, X.; Rodriguiz, R.M.; Gagnidze, K.; Sweedler, J. V.; Wetsel, W.C.; Devi, L.A.

    2011-01-01

    An increasing body of evidence suggests that Endothelin-converting enzyme-2 (ECE-2) is a non-classical neuropeptide processing enzyme. Similar to other neuropeptide processing enzymes, ECE-2 exhibits restricted neuroendocrine distribution, intracellular localization, and an acidic pH optimum. However, unlike classical neuropeptide processing enzymes, ECE-2 exhibits a non-classical cleavage site preference for aliphatic and aromatic residues. We previously reported that ECE-2 cleaves a number of neuropeptides at non-classical sites in vitro; however its role in peptide processing in vivo is poorly understood. Given the recognized roles of neuropeptides in pain and opiate responses, we hypothesized that ECE-2 knockout (KO) mice might show altered pain and morphine responses compared to wild-type (WT) mice. We find that ECE-2 KO mice show decreased response to a single injection of morphine in hot-plate and tail-flick tests. ECE-2 KO mice also show more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analyses revealed changes in the levels of a number of spinal cord peptides in ECE-2 KO as compared to WT mice. Taken together, our findings suggest a role for ECE-2 in the non-classical processing of spinal cord peptides and morphine responses; however, the precise mechanisms through which ECE-2 influences morphine tolerance and withdrawal remain unclear. PMID:21972895

  2. The Group 2 Metabotropic Glutamate Receptor Agonist LY379268 Rescues Neuronal, Neurochemical and Motor Abnormalities in R6/2 Huntington’s Disease Mice

    PubMed Central

    Reiner, A.; Lafferty, D.C.; Wang, H.B.; Del Mar, N.; Deng, Y.P.

    2012-01-01

    Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington’s Disease (HD) pathogenesis. Since corticostriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120–125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10 weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15–20% cortical and striatal neuron loss, normalization of SP striatal neuron neurochemistry, and to a lesser extent enkephalinergic striatal neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP striatal neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD. PMID:22472187

  3. Duplication of the EFNB1 Gene in Familial Hypertelorism: Imbalance in Ephrin-B1 Expression and Abnormal Phenotypes in Humans and Mice

    PubMed Central

    Babbs, Christian; Stewart, Helen S; Williams, Louise J; Connell, Lyndsey; Goriely, Anne; Twigg, Stephen RF; Smith, Kim; Lester, Tracy; Wilkie, Andrew OM

    2011-01-01

    Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc. PMID:21542058

  4. Abnormalities in brain structure and biochemistry associated with mdx mice measured by in vivo MRI and high resolution localized (1)H MRS.

    PubMed

    Xu, Su; Shi, Da; Pratt, Stephen J P; Zhu, Wenjun; Marshall, Andrew; Lovering, Richard M

    2015-10-01

    Duchenne muscular dystrophy (DMD), an X-linked disorder caused by the lack of dystrophin, is characterized by the progressive wasting of skeletal muscles. To date, what is known about dystrophin function is derived from studies of dystrophin-deficient animals, with the most common model being the mdx mouse. Most studies on patients with DMD and in mdx mice have focused on skeletal muscle and the development of therapies to reverse, or at least slow, the severe muscle wasting and progressive degeneration. However, dystrophin is also expressed in the CNS. Both mdx mice and patients with DMD can have cognitive and behavioral changes, but studies in the dystrophic brain are limited. We examined the brain structure and metabolites of mature wild type (WT) and mdx mice using magnetic resonance imaging and spectroscopy (MRI/MRS). Both structural and metabolic alterations were observed in the mdx brain. Enlarged lateral ventricles were detected in mdx mice when compared to WT. Diffusion tensor imaging (DTI) revealed elevations in diffusion diffusivities in the prefrontal cortex and a reduction of fractional anisotropy in the hippocampus. Metabolic changes included elevations in phosphocholine and glutathione, and a reduction in γ-aminobutyric acid in the hippocampus. In addition, an elevation in taurine was observed in the prefrontal cortex. Such findings indicate a regional structural change, altered cellular antioxidant defenses, a dysfunction of GABAergic neurotransmission, and a perturbed osmoregulation in the brain lacking dystrophin.

  5. PrP0\\0 mice show behavioral abnormalities that suggest PrPC has a role in maintaining the cytoskeleton.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background/Introduction. PrPC is highly conserved among mammals, but its natural function is unclear. Prnp ablated mice (PrP0/0) appear to develop normally and are able to reproduce. These observations seem to indicate that the gene is not essential for viability, in spite of it being highly conse...

  6. Thioacetamide-induced cirrhosis in selenium-adequate mice displays rapid and persistent abnormity of hepatic selenoenzymes which are mute to selenium supplementation

    SciTech Connect

    Zhang Jinsong Wang Huali; Yu Hanqing

    2007-10-01

    Selenium reduction in cirrhosis is frequently reported. The known beneficial effect of selenium supplementation on cirrhosis is probably obtained from nutritionally selenium-deficient subjects. Whether selenium supplementation truly improves cirrhosis in general needs additional experimental investigation. Thioacetamide was used to induce cirrhosis in selenium-adequate and -deficient mice. Selenoenzyme activity and selenium content were measured and the influence of selenium supplementation was evaluated. In Se-adequate mice, thioacetamide-mediated rapid onset of hepatic oxidative stress resulted in an increase in thioredoxin reductase activity and a decrease in both glutathione peroxidase activity and selenium content. The inverse activity of selenoenzymes (i.e. TrxR activity goes up and GPx activity goes down) was persistent and mute to selenium supplementation during the progress of cirrhosis; accordingly, cirrhosis was not improved by selenium supplementation in any period. On the other hand, selenium supplementation to selenium-deficient mice always more efficiently increased hepatic glutathione peroxidase activity and selenium content compared with those treated with thioacetamide, indicating that thioacetamide impairs the liver bioavailability of selenium. Although thioacetamide profoundly affects hepatic selenium status in selenium-adequate mice, selenium supplementation does not modify the changes. Selenium supplementation to cirrhotic subjects with a background of nutritional selenium deficiency can improve selenium status but cannot restore hepatic glutathione peroxidase and selenium to normal levels.

  7. Abnormal response to physical activity in femurs after heterozygous inactivation of one allele of the Col2a1 gene for type II collagen in mice.

    PubMed

    Nieminen, J; Sahlman, J; Hirvonen, T; Jämsä, T; Tuukkanen, J; Kovanen, V; Kröger, H; Jurvelin, J; Arita, M; Li, S W; Prockop, D J; Hyttinen, M M; Helminen, H J; Lapveteläinen, T; Puustjärvi, K

    2005-08-01

    The objective of this study was to evaluate the influence of heterozygous inactivation of one allele of the type II collagen gene (Col2a1) on biomechanical properties and mineral density of bone under physical loading conditions. C57BL/6-TGN mice with heterozygous knockout (HZK) inactivation of Col2a1 gene and their nontransgenic littermate controls were housed in individual cages with running wheels for 9 and 15 months. The running activity of each mouse was monitored continuously throughout the experiment. Bone mineral density (BMD) of mice femora was measured using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT). Biomechanical properties were determined using three-point bending tests. Vertebral bone samples were prepared for quantitative polarized light microscopy and digital densitometry of proteoglycans. The concentration of total collagen and collagen cross-links were analyzed using high-performance liquid chromatograpy (HPLC). The average daily running distance was shorter for the HZK mice between the age of 4 and 15 months as compared with normal runners (P < 0.05). The ultimate breaking force was 14.8% and 23.6% (9 vs. 15 months) lower in HZK-runners than in wild-type runners. BMD of the femur was 6.1% lower in HZK-runners at the age of 9 months (P < 0.05). Physical activity increased cortical BMD in wild-type runners but not in the HZK runners at the age of 9 months. The collagen network of the HZK mice was less organized. There were only minor changes in BMD and mechanical and structural properties between sedentary HZK mice and their wild-type controls. Increased physical activity induced significantly lower bone density, mechanical properties, and organization of collagen fibers in male HZK mice. However, there were no major differences in biomechanical parameters between sedentary HZK and wild-type male mice. This suggests an important guiding role of collagen type II in bone remodelling and

  8. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

    PubMed Central

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  9. Experimental demonstration of the possible role of Acanthamoeba polyphaga in the infection and disease progression in Buruli Ulcer (BU) using ICR mice

    PubMed Central

    Azumah, Bright K.; Addo, Phyllis G.; Dodoo, Alfred; Awandare, Gordon; Mosi, Lydia; Boakye, Daniel A.

    2017-01-01

    The transmission of Buruli ulcer (BU), caused by Mycobacterium ulcerans (MU), remains puzzling although a number of hypothesis including through bites of infected aquatic insects have been proposed. We report the results of experiments using ICR mice that give credence to our hypothesis that Acanthamoeba species may play a role in BU transmission. We cocultured MU N2 and MU 1615 which expresses red fluorescent protein (RFP) and Acanthamoeba polyphaga (AP), and confirmed infected AP by Ziehl-Neelsen (ZN) staining. We tested for viability of MU inside AP and observed strong RFP signals inside both trophozoites and cysts after 3 and 42 days of coculturing respectively. ICR mice were topically treated, either on shaved intact or shaved pinpricked rumps, with one of the following; MU N2 only (2.25 x 106 colony forming units [CFU] / ml), MU N2:AP coculture (2.96 x 104 CFU: 1.6 x 106 cells/ml), AP only (1.6 x 106 cells/ml), PYG medium and sterile distilled water. Both MU N2 only and MU N2:AP elicited reddening on day (D) 31; edema on D 45 and D 44 respectively, and ulcers on D 49 at pinpricked sites only. To ascertain infectivity and pathogenicity of MU N2 only and MU N2:AP, and compare their virulence, the standard mouse footpad inoculation method was used. MU N2:AP elicited reddening in footpads by D 3 compared to D 14 with MU N2 only of the same dose of MU N2 (2.96 x 104 CFU). ZN-stained MU were observed in both thin sectioned and homogenized lesions, and aspirates from infected sites. Viable MU N2 were recovered from cultures of the homogenates and aspirates. This study demonstrates in ICR mice MU transmission via passive infection, and shows that punctures in the skin are prerequisite for infection, and that coculturing of MU with AP enhances pathogenesis. PMID:28329001

  10. Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

    PubMed Central

    Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Max, Ferretti M.; Liu, Baomei; Baskin, Laurence S.; Cunha, Gerald R.

    2014-01-01

    Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5 to 120 days postnatal to evaluate ExG malformations. Of 23 adult (≥60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18 to 100% in prenatally DES-exposed CD-1 males and 31 to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation. PMID

  11. FVB/NJ mice demonstrate a youthful sensitivity to noise-induced hearing loss and provide a useful genetic model for the study of neural hearing loss

    PubMed Central

    Ho, Maria K.; Li, Xin; Wang, Juemei; Ohmen, Jeffrey D.; Friedman, Rick A.

    2014-01-01

    The hybrid mouse diversity panel (HMDP), a panel of 100 strains, has been employed in genome wide association studies (GWAS) to study complex traits in mice. Hearing is a complex trait and the CBA/CaJ mouse strain is a widely used model for age-related hearing loss (ARHI) and noise induced hearing loss (NIHL). The CBA/CaJ strain's youthful sensitivity to noise and limited age-related loss led us to attempt to identify additional strains segregating a similar phenotype for our panel. FVB/NJ is part of the HMDP and has been previously described as having a similar ARHI phenotype to CBA/CaJ. For these reasons, we have studied the FVB/NJ mouse for ARHI and NIHL phenotypes in hopes of incorporating its phenotype into HMDP studies. We demonstrate that FVB/NJ exhibits ARHI at an earlier age than CBA/CaJ and young FVB/NJ mice are vulnerable to NIHL up until 10 to 12 weeks. This suggests that FVB/NJ may be used as an additional genetic model for neural forms of progressive hearing loss and for the study of youthful sensitivity to noise. PMID:24707282

  12. In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice

    PubMed Central

    Sano, Kazuhiro; Isobe, Tomohiko; Yang, Jiaxin; Win-Shwe, Tin-Tin; Yoshikane, Mitsuha; Nakayama, Shoji F.; Kawashima, Takaharu; Suzuki, Go; Hashimoto, Shunji; Nohara, Keiko; Tohyama, Chiharu; Maekawa, Fumihiko

    2016-01-01

    Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically. PMID:27375407

  13. [Abnormal expression of insulin-like growth factor-I receptor and inhibitory effect of its transcription intervention on nude mice xenograft tumor].

    PubMed

    Yao, M; Yan, X D; Cai, Y; Gu, J J; Yang, X L; Pan, L H; Wang, L; Yao, D F

    2016-11-20

    Objective: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) in liver cancer and the inhibitory effect of its transcription intervention on nude mice xenograft tumor. Methods: A total of 40 patients with primary liver cancer were enrolled, and 40 samples of cancer lesions, peri-cancerous tissues (with a distance of 2 cm to the margin of cancer lesion), or distal liver tissues (with a distance of 5 cm to the margin of cancer lesion), with a weight of 200 mg, were collected after surgery. Some of these samples were used for pathological examination, and the rest were stored at -85°C. A total of 18 BALB/c nude mice aged 4-6 weeks with a body weight of 18-20 g (9 male and 9 female mice) were randomly divided into control group, negative control group, and co-intervention group, with 6 mice in each group, and fed under specific pathogen-free conditions. The cell line was cultured in the dimethyl sulfoxide complete medium containing 10% fetal bovine serum in a CO2incubator at 37°C. When the cell confluence reached 90% after cell inoculation, shRNA was divided into co-intervention group, negative control group, and untreated control group and were transfected to hepatoma cells using PolyJetTM transfection reagent. Stable cell clones obtained by G418 screening and used for the in vivo study. Immunohistochemistry, Western blotting, and quantitative real-time PCR were used to analyze the expression of IGF-IR in the human hepatoma tissue and cell line. The IGF-IR shRNA eukaryotic expression plasmids were established and screened for the most effective sequence; they were transfected to PLC/PRF/5 hepatoma cells, and the CCK-8 assay was used to analyze the changes in cell proliferation. The stable cell line screened out by G418 was inoculated to establish the subcutaneous xenograft tumor in nude mice. The tumor growth curve was plotted and histological examination was performed. Graphpad Prism 5.0 and SPSS 18.0 were used for plotting and data

  14. Demonstration of human papillomavirus (HPV) genomic amplification and viral-like particles from CaSki cell line in SCID mice.

    PubMed

    Wu, T C; Hsieh, S T; Purow, B W; Kurman, R J

    1997-05-01

    We demonstrate that from the CaSki cervical cancer cell line, integrated HPV-16 genome was amplified and viral-like particles were generated in an in vivo SCID mouse model. The in vivo tumor growth of several HPV-containing cell lines and 2 HPV-negative cell lines was examined in SCID mice. Tumor growth was noted with the HeLa, CaSki, ME-180, and MS751 cell lines within 2 months after subcutaneous injection. Squamous differentiation was appreciated in focal areas of tumors derived from CaSki and ME-180. In the CaSki tumors, DNA in situ hybridization revealed homogeneous staining of nuclei in some cells in the differentiated areas, suggesting HPV genomic amplification. In contrast, punctate or speckled patterns of hybridization were identified in the less differentiated areas, suggesting continued integration of the HPV genome. Immunocytochemical staining for HPV-16 L1 capsid protein showed it to be concentrated in cells from the differentiated areas, correlating with the results of hybridization. Electron microscopic studies revealed 50 nm uniform particles, consistent with HPV viral-like particles, in the nuclei of some cells in well-differentiated areas. Furthermore, Southern transfer and hybridization of the Hirt's extract from the CaSki tumors was positive for HPV-16 DNA, indicating non-integrated, low molecular weight HPV-16 DNA. Our results show HPV genomic amplification of integrated viral DNA and generation of HPV viral-like particles in CaSki cancer cells in SCID mice and that viral DNA amplification and the formation of viral-like particles are coupled to cellular differentiation. This experimental model provides a potential system for studying the molecular pathogenesis of HPV infections.

  15. Loss of alpha-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function.

    PubMed

    Ikegami, Koji; Heier, Robb L; Taruishi, Midori; Takagi, Hiroshi; Mukai, Masahiro; Shimma, Shuichi; Taira, Shu; Hatanaka, Ken; Morone, Nobuhiro; Yao, Ikuko; Campbell, Patrick K; Yuasa, Shigeki; Janke, Carsten; Macgregor, Grant R; Setou, Mitsutoshi

    2007-02-27

    Microtubules function as molecular tracks along which motor proteins transport a variety of cargo to discrete destinations within the cell. The carboxyl termini of alpha- and beta-tubulin can undergo different posttranslational modifications, including polyglutamylation, which is particularly abundant within the mammalian nervous system. Thus, this modification could serve as a molecular "traffic sign" for motor proteins in neuronal cells. To investigate whether polyglutamylated alpha-tubulin could perform this function, we analyzed ROSA22 mice that lack functional PGs1, a subunit of alpha-tubulin-selective polyglutamylase. In wild-type mice, polyglutamylated alpha-tubulin is abundant in both axonal and dendritic neurites. ROSA22 mutants display a striking loss of polyglutamylated alpha-tubulin within neurons, including their neurites, which is associated with decreased binding affinity of certain structural microtubule-associated proteins and motor proteins, including kinesins, to microtubules purified from ROSA22-mutant brain. Of the kinesins examined, KIF1A, a subfamily of kinesin-3, was less abundant in neurites from ROSA22 mutants in vitro and in vivo, whereas the distribution of KIF3A (kinesin-2) and KIF5 (kinesin-1) appeared unaltered. The density of synaptic vesicles, a cargo of KIF1A, was decreased in synaptic terminals in the CA1 region of hippocampus in ROSA22 mutants. Consistent with this finding, ROSA22 mutants displayed more rapid depletion of synaptic vesicles than wild-type littermates after high-frequency stimulation. These data provide evidence for a role of polyglutamylation of alpha-tubulin in vivo, as a molecular traffic sign for targeting of KIF1 kinesin required for continuous synaptic transmission.

  16. Chronic Treatment with the IDO1 Inhibitor 1-Methyl-D-Tryptophan Minimizes the Behavioural and Biochemical Abnormalities Induced by Unpredictable Chronic Mild Stress in Mice - Comparison with Fluoxetine

    PubMed Central

    Laugeray, Anthony; Launay, Jean-Marie; Callebert, Jacques; Mutlu, Oguz; Guillemin, Gilles J.; Belzung, Catherine; Barone, Pascal R.

    2016-01-01

    We demonstrated that confronting mice to the Unpredictable Chronic Mild Stress (UCMS) procedure—a validated model of stress-induced depression—results in behavioural alterations and biochemical changes in the kynurenine pathway (KP), suspected to modify the glutamatergic neurotransmission through the imbalance between downstream metabolites such as 3-hydroxykynurenine, quinolinic and kynurenic acids. We showed that daily treatment with the IDO1 inhibitor 1-methyl-D-tryptophan partially rescues UCMS-induced KP alterations as does the antidepressant fluoxetine. More importantly we demonstrated that 1-methyl-D-tryptophan was able to alleviate most of the behavioural changes resulting from UCMS exposure. We also showed that both fluoxetine and 1-methyl-D-tryptophan robustly reduced peripheral levels of proinflammatory cytokines in UCMS mice suggesting that their therapeutic effects might occur through anti-inflammatory processes. KP inhibition might be involved in the positive effects of fluoxetine on mice behaviour and could be a relevant strategy to counteract depressive-like symptoms. PMID:27828964

  17. Effects of early or late prenatal immune activation in mice on behavioral and neuroanatomical abnormalities relevant to schizophrenia in the adulthood.

    PubMed

    da Silveira, Vivian T; Medeiros, Daniel de Castro; Ropke, Jivago; Guidine, Patricia A; Rezende, Gustavo H; Moraes, Marcio Flavio D; Mendes, Eduardo Mazoni A M; Macedo, Danielle; Moreira, Fabricio A; de Oliveira, Antonio Carlos P

    2017-05-01

    Maternal immune activation (MIA) during pregnancy in rodents increases the risk of the offspring to develop schizophrenia-related behaviors, suggesting a relationship between the immune system and the brain development. Here we tested the hypothesis that MIA induced by the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in early or late gestation of mice leads to behavioral and neuroanatomical disorders in the adulthood. On gestational days (GDs) 9 or 17 pregnant dams were treated with poly I:C or saline via intravenous route and the offspring behaviors were measured during adulthood. Considering the progressive structural neuroanatomical alterations in the brain of individuals with schizophrenia, we used magnetic resonance imaging (MRI) to perform brain morphometric analysis of the offspring aged one year. MIA on GD9 or GD17 led to increased basal locomotor activity, enhanced motor responses to ketamine, a psychotomimetic drug, and reduced time spent in the center of the arena, suggesting an increased anxiety-like behavior. In addition, MIA on GD17 reduced glucose preference in the offspring. None of the treatments altered the relative volume of the lateral ventricles. However, a decrease in brain volume, especially for posterior structures, was observed for one-year-old animals treated with poly I:C compared with control groups. Thus, activation of the maternal immune system at different GDs lead to neuroanatomical and behavioral alterations possibly related to the positive and negative symptoms of schizophrenia. These results provide insights on neuroimmunonological and neurodevelopmental aspects of certain psychopathologies, such as schizophrenia.

  18. Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models.

    PubMed

    Magrané, Jordi; Cortez, Czrina; Gan, Wen-Biao; Manfredi, Giovanni

    2014-03-15

    Neuronal mitochondrial morphology abnormalities occur in models of familial amyotrophic lateral sclerosis (ALS) associated with SOD1 and TDP43 mutations. These abnormalities have been linked to mitochondrial axonal transport defects, but the temporal and spatial relationship between mitochondrial morphology and transport alterations in these two distinct genetic forms of ALS has not been investigated in vivo. To address this question, we crossed SOD1 (wild-type SOD1(WT) and mutant SOD1(G93A)) or TDP43 (mutant TDP43(A315T)) transgenic mice with mice expressing the fluorescent protein Dendra targeted to mitochondria in neurons (mitoDendra). At different time points during the disease course, we studied mitochondrial transport in the intact sciatic nerve of living mice and analyzed axonal mitochondrial morphology at multiple sites, spanning from the spinal cord to the motor terminals. Defects of retrograde mitochondrial transport were detected at 45 days of age, before the onset of symptoms, in SOD1(G93A) and TDP43(A315T) mice, but not in SOD1(WT). At later disease stages, also anterograde mitochondrial transport was affected in both mutant mouse lines. In SOD1(G93A) mice, mitochondrial morphological abnormalities were apparent at 15 days of age, thus preceding transport abnormalities. Conversely, in TDP43(A315T) mice, morphological abnormalities appeared after the onset of transport defects. Taken together, these findings demonstrate that neuronal mitochondrial transport and morphology abnormalities occur in vivo and that they are common denominators of different genetic forms of the ALS. At the same time, differences in the temporal and spatial manifestation of mitochondrial abnormalities between the two mouse models of familial ALS imply that different molecular mechanisms may be involved.

  19. PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis

    PubMed Central

    Leone, Teresa C; Lehman, John J; Finck, Brian N; Schaeffer, Paul J; Wende, Adam R; Boudina, Sihem; Courtois, Michael; Wozniak, David F; Sambandam, Nandakumar; Bernal-Mizrachi, Carlos; Chen, Zhouji; O. Holloszy, John; Medeiros, Denis M; Schmidt, Robert E; Saffitz, Jeffrey E; Abel, E. Dale; Semenkovich, Clay F

    2005-01-01

    The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α−/− mice. With age, the PGC-1α−/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life. PMID:15760270

  20. Expressing hNF-LE397K results in abnormal gaiting in a transgenic model of CMT2E

    PubMed Central

    Dale, Jeffrey M.; Villalon, Eric; Shannon, Stephen G.; Barry, Devin M.; Markey, Rachel M.; Garcia, Virginia B.; Garcia, Michael L.

    2012-01-01

    Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gaiting, exacerbation of neuropathy, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing a hNF-LE397K transgene, which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we demonstrated that hNF-LE397K mice developed abnormal gait of the hind limbs. The identification of severe gaiting defects in combination with previously observed muscle atrophy, reduced axon caliber, and decreased nerve conduction velocity suggests that hNF-LE397K mice recapitulate many of clinical signs associated with CMT2E. Therefore, hNF-LE397K mice provide a context for potential therapeutic intervention. PMID:22288874

  1. Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. I. Rapid evolution of encephalomyocarditis virus infection

    PubMed Central

    1976-01-01

    The role of interferon in the pathogenesis of encephalomyocarditis (EMC) virus infection was determined by treating mice with potent, partially purified sheep anti-mouse interferon globulin. In control mice, EMC virus was present in low titers in various visceral organs but attained high titers in the brain towards the 4th to 5th day, at which time mice died with signs of central nervous system disease. In mice treated with anti-mouse interferon globulin, virus was present in high titer in visceral organs 24--36 h after viral inoculation and virtually all mice were dead by 45 h. This rapid evolution of EMC virus infection was not observed in mice treated with the globulin fraction prepared from a normal sheep, from a sheep exhibiting a low anti-mouse interferon-neutralizing titer, nor from a sheep having a high titer of antibody to human leukocyte interferon. The experimental results indicated that anti-interferon globulin neutralized the interferon liberated by virus-infected cells, thus permitting extensive virus multiplication in several visceral organs. We conclude that interferon is an important early component of host resistance to this virus infection. PMID:186554

  2. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  3. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.

    PubMed

    Hsiao, Elaine Y; McBride, Sara W; Hsien, Sophia; Sharon, Gil; Hyde, Embriette R; McCue, Tyler; Codelli, Julian A; Chow, Janet; Reisman, Sarah E; Petrosino, Joseph F; Patterson, Paul H; Mazmanian, Sarkis K

    2013-12-19

    Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.

  4. Demonstration of early-phase transmission of Yersinia pestis by the mouse flea, Aetheca wagneri (Siphonaptera: Ceratophylidae), and implications for the role of deer mice as enzootic reservoirs.

    PubMed

    Eisen, Rebecca J; Holmes, Jennifer L; Schotthoefer, Anna M; Vetter, Sara M; Montenieri, John A; Gage, Kenneth L

    2008-11-01

    The role of deer mice and other species of Peromyscus as enzootic reservoirs for plague remains controversial. In this study, we evaluated early-phase vector efficiency of Aetheca wagneri Baker, a common flea species infesting deer mice, to determine the likelihood that Y. pestis could be spread mouse to mouse by this species. We showed that A. wagneri could transmit plague bacteria to laboratory mice as early as 3 d postinfection (p.i.), but transmission efficiency was quite low (1.03%; 95% CI: 0.19-3.34%) 1-4 d p.i. compared with that for the established plague vector Oropsylla montana Baker (10.63%; 95% CI: 4.18-25.91). Using this early-phase transmission efficiency estimate, we determined through parameterization of a simple predictive model that at least 68 A. wagneri per deer mouse would be required to support levels of transmission adequate for enzootic maintenance. Because deer mice typically harbor fewer than three A. wagneri per host, our data do not support the notion of an independent deer mouse--A. wagneri transmission cycle.

  5. Use of mice tolerant to lipopolysaccharide to demonstrate requirement of cooperation between macrophages and lymphocytes to generate lipopolysaccharide-induced colony-stimulating factor in vivo.

    PubMed Central

    Williams, Z; Hertogs, C F; Pluznik, D H

    1983-01-01

    Injection of lipopolysaccharide (LPS) into mice was followed by a rapid elevation of colony-stimulating factor (CSF) in the serum. A second, challenging injection of LPS given 3 to 4 days later failed to induce elevated levels of CSF in the serum. Such mice tolerant to LPS were used as an experimental tool to identify the CSF-producing cells which respond to LPS. We observed that generation of LPS-induced CSF in mice tolerant to LPS could be restored by an intraperitoneal injection of spleen cells 24 h before the challenging injection of LPS. Depletion of the adherent cells from the spleen cells reduced the ability of the splenic lymphocytes to restore the capacity of the mice tolerant to LPS to generate serum CSF. Reconstitution of the splenic lymphocytes with 5% thioglycolate-elicited peritoneal macrophages, however, reestablished the restorative capacity of these cells, whereas almost no restoration was observed after direct injection of elicited peritoneal macrophages. These data suggest that the spleen cells are active in generating CSF, provided that macrophages are present and can interact with the splenic lymphocytes to generate LPS-induced CSF in the serum. PMID:6602767

  6. Urine - abnormal color

    MedlinePlus

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  7. Tooth - abnormal colors

    MedlinePlus

    ... medlineplus.gov/ency/article/003065.htm Tooth - abnormal colors To use the sharing features on this page, please enable JavaScript. Abnormal tooth color is any color other than white to yellowish- ...

  8. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  9. Skeletal limb abnormalities

    MedlinePlus

    ... medlineplus.gov/ency/article/003170.htm Skeletal limb abnormalities To use the sharing features on this page, please enable JavaScript. Skeletal limb abnormalities refers to a variety of bone structure problems ...

  10. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... PROBLEMS Abnormal Uterine Bleeding • What is a normal menstrual cycle? • When is bleeding abnormal? • At what ages is ... treat abnormal bleeding? •Glossary What is a normal menstrual cycle? The normal length of the menstrual cycle is ...

  11. Increased locomotor activity induced by heroin in mice: pharmacokinetic demonstration of heroin acting as a prodrug for the mediator 6-monoacetylmorphine in vivo.

    PubMed

    Andersen, Jannike Mørch; Ripel, Ase; Boix, Fernando; Normann, Per Trygve; Mørland, Jørg

    2009-10-01

    We investigated the relative importance of heroin and its metabolites in eliciting a behavioral response in mice by studying the relationship between concentrations of heroin, 6-monoacetylmorphine (6MAM), and morphine in brain tissue and the effects on locomotor activity. Low doses (subcutaneous) of heroin (< or =5 micromol/kg) or 6MAM (< or =15 micromol/kg) made the mice run significantly more than mice given equimolar doses of morphine. There were no differences in the response between heroin and 6MAM, although we observed a shift to the left of the dose-response curve for the maximal response of heroin. The behavioral responses were abolished by pretreatment with 1 mg/kg naltrexone. Heroin was detected in brain tissue after injection, but the levels were low and its presence too short-lived to be responsible for the behavioral response observed. The concentration of 6MAM in brain tissue increased shortly after administration of both heroin and 6MAM and the concentration changes during the first hour roughly reflected the changes in locomotor activity. Both the maximal and the total concentration of 6MAM were higher after administration of heroin than after administration of 6MAM itself. The morphine concentration increased slowly after injection and could not explain the immediate behavioral response. In summary, the locomotor activity response after injection of heroin was mediated by 6MAM, which increased shortly after administration. Heroin acted as an effective prodrug. The concentration of morphine was too low to stimulate the immediate response observed but might have an effect on the later part of the heroin-induced behavioral response curve.

  12. Transgenic mice demonstrate that epithelial homing of gamma/delta T cells is determined by cell lineages independent of T cell receptor specificity

    PubMed Central

    1990-01-01

    gamma/delta T cells with different TCR repertoires are compartmentalized in different epithelia. This raises the possibility that the TCR-gamma/delta directs homing of T cells to these epithelia. Alternatively, the signals that induce TCR-gamma/delta expression in developing T cells may also induce homing properties in such cells, presumably in the form of cell surface receptors. We have examined this issue by studying the homing of gamma/delta T cells in transgenic mice constructed with specific pairs of rearranged gamma and delta genes. In such mice, most gamma/delta T cells express the transgene-encoded TCR. We find that homing to both skin and gut epithelia is a property of T cells and is not determined by the type of gamma and delta genes used to encode their TCR. We also studied the effect of TCR replacement on the expression of Thy-1 and CD8 proteins on the gamma/delta T cells associated with gut epithelia. Our results show that the expression of the appropriate type of TCR-gamma/delta is not required for the Thy-1 expression by these T cells, suggesting that Thy-1 is not an activation marker. In contrast, CD8 expression by gut gamma/delta T cells seems to depend on the expression of the appropriate type of TCR. PMID:2109035

  13. A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models

    PubMed Central

    Kjalke, Marianne; Karpf, Ditte M.; Balling, Kristoffer W.; Johansen, Peter B.; Elm, Torben; Øvlisen, Kristine; Möller, Flemming; Holmberg, Heidi L.; Gudme, Charlotte N.; Persson, Egon; Hilden, Ida; Pelzer, Hermann; Rahbek-Nielsen, Henrik; Jespersgaard, Christina; Bogsnes, Are; Pedersen, Anette A.; Kristensen, Anne K.; Peschke, Bernd; Kappers, Wendy; Rode, Frederik; Thim, Lars; Tranholm, Mikael; Ezban, Mirella; Olsen, Eva H. N.; Bjørn, Søren E.

    2013-01-01

    Frequent infusions of intravenous factor VIII (FVIII) are required to prevent bleeding associated with hemophilia A. To reduce the treatment burden, recombinant FVIII with a longer half-life was developed without changing the protein structure. FVIII–polyethylene glycol (PEG) conjugates were prepared using an enzymatic process coupling PEG (ranging from 10 to 80 kDa) selectively to a unique O-linked glycan in the FVIII B-domain. Binding to von Willebrand factor (VWF) was maintained for all conjugates. Upon cleavage by thrombin, the B-domain and the associated PEG were released, generating activated FVIII (FVIIIa) with the same primary structure and specific activity as native FVIIIa. In both FVIII- and VWF-deficient mice, the half-life was found to increase with the size of PEG. In vivo potency and efficacy of FVIII conjugated with a 40-kDa PEG (N8-GP) and unmodified FVIII were not different. N8-GP had a longer duration of effect in FVIII-deficient mouse models, approximately a twofold prolonged half-life in mice, rabbits, and cynomolgus monkeys; however, the prolongation was less pronounced in rats. Binding capacity of N8-GP on human monocyte-derived dendritic cells was reduced compared with unmodified FVIII, resulting in several-fold reduced cellular uptake. In conclusion, N8-GP has the potential to offer efficacious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency. PMID:23335368

  14. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1979-01-01

    Presents two demonstrations which are intended for chemistry college students. These demonstrations are: (1) enhancement of concentration quenching by micelles; and (2) the thermite lecture demonstration. (HM)

  15. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1984-01-01

    Procedures for two demonstrations are presented. The first is a demonstration of chemiluminescence. The second is a demonstration using a secondary battery constructed from common household articles. (JN)

  16. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1978-01-01

    Presents the following chemistry lecture demonstrations and experiments: (1) a versatile kinetic demonstration; (2) the Bakelite Demonstration; (3) applying Beer's law; and (4) entropy calculations. (HM)

  17. Analysis by single-gene reassortment demonstrates that the 1918 influenza virus is functionally compatible with a low-pathogenicity avian influenza virus in mice.

    PubMed

    Qi, Li; Davis, A Sally; Jagger, Brett W; Schwartzman, Louis M; Dunham, Eleca J; Kash, John C; Taubenberger, Jeffery K

    2012-09-01

    The 1918-1919 "Spanish" influenza pandemic is estimated to have caused 50 million deaths worldwide. Understanding the origin, virulence, and pathogenic properties of past pandemic influenza viruses, including the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. The proteins encoded by the 1918 virus differ from typical low-pathogenicity avian influenza viruses at only a small number of amino acids in each open reading frame. In this study, a series of chimeric 1918 influenza viruses were created in which each of the eight 1918 pandemic virus gene segments was replaced individually with the corresponding gene segment of a prototypical low-pathogenicity avian influenza (LPAI) H1N1 virus in order to investigate functional compatibility of the 1918 virus genome with gene segments from an LPAI virus and to identify gene segments and mutations important for mammalian adaptation. This set of eight "7:1" chimeric viruses was compared to the parental 1918 and LPAI H1N1 viruses in intranasally infected mice. Seven of the 1918 LPAI 7:1 chimeric viruses replicated and caused disease equivalent to the fully reconstructed 1918 virus. Only the chimeric 1918 virus containing the avian influenza PB2 gene segment was attenuated in mice. This attenuation could be corrected by the single E627K amino acid change, further confirming the importance of this change in mammalian adaptation and mouse pathogenicity. While the mechanisms of influenza virus host switch, and particularly mammalian host adaptation are still only partly understood, these data suggest that the 1918 virus, whatever its origin, is very similar to avian influenza virus.

  18. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1988-01-01

    Details three demonstrations for use in chemistry classrooms. Includes: "A Demonstration of Corrosion by Differential Aeration"; "A Simple Demonstration of the Activation Energy Concept"; and "A Boiling Demonstration at Room Temperature." Each description includes equipment, materials, and methods. (CW)

  19. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1988-01-01

    Describes two chemistry demonstrations including a demonstration of chemical inhibition and "The Rayleigh Fountain" which demonstrates the polarity of the water molecule. Provides instructions and explanations for each demonstration. (CW)

  20. Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

    PubMed Central

    Chen, Yih-Wen; Harris, Robert A.; Hatahet, Zafer; Chou, Kai-ming

    2015-01-01

    Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η−/−) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η−/− mice exhibits increased DNA damage and a greater DNA damage response, indicated by up-regulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H2AX (γH2AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η−/− mice was observed and measured by up-regulation of senescence markers, including p53, p16Ink4a, p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η−/− mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η−/− mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance. PMID:26240351

  1. Breathing abnormalities in a female mouse model of Rett syndrome.

    PubMed

    Johnson, Christopher M; Cui, Ningren; Zhong, Weiwei; Oginsky, Max F; Jiang, Chun

    2015-09-01

    Rett syndrome (RTT) is a female neurodevelopmental disease with breathing abnormalities. To understand whether breathing defects occur in the early lives of a group of female Mecp2(+/-) mice, a mouse model of RTT, and what percentage of mice shows RTT-like breathing abnormality, breathing activity was measured by plethysmography in conscious mice. Breathing frequency variation and central apnea in a group of Mecp2(+/-) females displayed a distribution pattern similar to Mecp2(-/Y) males, while the rest resembled the wild-type mice. Similar results were obtained using the k-mean clustering statistics analysis. With two independent methods, about 20% of female Mecp2(+/-) mice showed RTT-like breathing abnormalities that began as early as 3 weeks of age in the Mecp2(+/-) mice, and were suppressed with 3% CO2. The finding that only a small proportion of Mecp2(+/-) mice develops RTT-like breathing abnormalities suggests incomplete allele inactivation in the RTT-model Mecp2(+/-) mice.

  2. Mitochondrial Abnormalities and Synaptic Loss Underlie Memory Deficits Seen in Mouse Models of Obesity and Alzheimer’s Disease

    PubMed Central

    Martins, Isaura V.A.; Rivers-Auty, Jack; Allan, Stuart M.; Lawrence, Catherine B.

    2016-01-01

    Obesity is associated with impaired memory in humans, and obesity induced by high-fat diets leads to cognitive deficits in rodents and in mouse models of Alzheimer’s disease (AD). However, it remains unclear how high-fat diets contribute to memory impairment. Therefore, we tested the effect of a high-fat diet on memory in male and female control non-transgenic (Non-Tg) and triple-transgenic AD (3xTgAD) mice and determined if a high-fat diet caused similar ultrastructural abnormalities to those observed in AD. Behavior was assessed in mice on control or high-fat diet at 4, 8, or 14 months of age and ultrastructural analysis at 8 months of age. A high-fat diet increased body weight, fat weight, and insulin levels with some differences in these metabolic responses observed between Non-Tg and 3xTgAD mice. In both sexes, high-fat feeding caused memory impairments in Non-Tg mice and accelerated memory deficits in 3xTgAD mice. In 3xTgAD mice, changes in hippocampal mitochondrial morphology were observed in capillaries and brain neuropil that were accompanied by a reduction in synapse number. A high-fat diet also caused mitochondria abnormalities and a reduction in synapse number in Non-Tg mice, but did not exacerbate the changes seen in 3xTgAD mice. Our data demonstrate that a high-fat diet affected memory in Non-Tg mice and produced similar impairments in mitochondrial morphology and synapse number comparable to those seen in AD mice, suggesting that the detrimental effects of a high-fat diet on memory might be due to changes in mitochondrial morphology leading to a reduction in synaptic number. PMID:27802235

  3. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1987-01-01

    Presented are three demonstrations for chemical education. The activities include: (1) demonstration of vapor pressure; (2) a multicolored luminol-based chemiluminescence demonstration; and (3) a Charles's Law/Vapor pressure apparatus. (RH)

  4. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1982-01-01

    Three chemistry demonstrations are described: (1) partition coefficients; (2) Rutherford simulation experiment; and (3) demonstration of the powerful oxidizing property of dimanganeseheptoxide. Background information, materials needed, and procedures are provided for each demonstration. (JN)

  5. Reflectance Demonstration.

    ERIC Educational Resources Information Center

    Kowalski, Frank

    1993-01-01

    Presents a demonstration in which a mirror "disappears" upon rotation. The author has used the demonstration with students from fourth grade up through college. Suggestions are given for making the demonstration into a permanent hallway display. (MVL)

  6. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1981-01-01

    Provides procedures for demonstrations: (1) the ferrioxalate actinometer, which demonstrates a photochemical reaction; and (2) the silver mirror, which demonstrates the reduction of a metal salt to the metal and/or the reducing power of sugars. (CS)

  7. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  8. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1985-01-01

    Background information (including chemical reactions) and procedures used are provided for (1) three buffer demonstrations and (2) a demonstration of phase transfer catalysis and carbanion formation. (JN)

  9. Cell volume control in phospholemman (PLM) knockout mice: do cardiac myocytes demonstrate a regulatory volume decrease and is this influenced by deletion of PLM?

    PubMed

    Bell, James R; Lloyd, David; Curl, Claire L; Delbridge, Lea M D; Shattock, Michael J

    2009-03-01

    In addition to modulatory actions on Na+-K+-ATPase, phospholemman (PLM) has been proposed to play a role in cell volume regulation. Overexpression of PLM induces ionic conductances, with 'PLM channels' exhibiting selectivity for taurine. Osmotic challenge of host cells overexpressing PLM increases taurine efflux and augments the cellular regulatory volume decrease (RVD) response, though a link between PLM and cell volume regulation has not been studied in the heart. We recently reported a depressed cardiac contractile function in PLM knockout mice in vivo, which was exacerbated in crystalloid-perfused isolated hearts, indicating that these hearts were osmotically challenged. To address this, the present study investigated the role of PLM in osmoregulation in the heart. Isolated PLM wild-type and knockout hearts were perfused with a crystalloid buffer supplemented with mannitol in a bid to prevent perfusate-induced cell swelling and maintain function. Accordingly, and in contrast to wild-type control hearts, contractile function was improved in PLM knockout hearts with 30 mM mannitol. To investigate further, isolated PLM wild-type and knockout cardiomyocytes were subjected to increasing hyposmotic challenges. Initial validation studies showed the IonOptix video edge-detection system to be a simple and accurate 'real-time' method for tracking cell width as a marker of cell size. Myocytes swelled equally in both genotypes, indicating that PLM, when expressed at physiological levels in cardiomyocytes, is not essential to limit water accumulation in response to a hyposmotic challenge. Interestingly, freshly isolated adult cardiomyocytes consistently failed to mount RVDs in response to cell swelling, adding to conflicting reports in the literature. A proposed perturbation of the RVD response as a result of the cell isolation process was not restored, however, with short-term culture in either adult or neonatal cardiomyocytes.

  10. Electrophysiological consequences of KATP Gain-of-function in the heart: Conduction abnormalities in Cantu Syndrome

    PubMed Central

    Levin, Mark D.; Zhang, Haixia; Uchida, Keita; Grange, Dorothy K.; Singh, Gautam K.; Nichols, Colin G.

    2015-01-01

    Background Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities. Objective To better understand the electrophysiological consequences of such GOF mutations in the heart. Methods We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and carried out patch-clamp experiments on isolated ventricular myocytes, invasive electrophysiology on anesthetized mice. Results In Kir6.1-GOF ventricular myocytes, KATP channels show decreased ATP sensitivity, but there is no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice reveal AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiological analyses reveal slowing of conduction and conduction failure through the AV node, but no increase in susceptibility to atrial or ventricular ectopic activity. Surface electrocardiograms recorded from CS patients also demonstrate first degree AV block, and fascicular block. Conclusions The primary electrophysiological consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients, who carry KATP GOF mutations. PMID:26142302

  11. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  12. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1988-01-01

    Describes three flame test demonstrations including "Student-Presented Demonstrations on the Colors of Transition Metal Complexes,""A Flame Test Demonstration Device," and "Vivid Flame Tests." Preparation and procedures are discussed. Included in the first demonstration is an evaluation scheme for grading student…

  13. Tested Demonstrations

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1977-01-01

    Three demonstrations are described: paramagnetic properties of Fe(11) and Fe(111), the preparation of polyurethane foam: a lecture demonstration and the electrolysis of water-fuel cell reactions. A small discussion of the concepts demonstrated is included in each demonstration's description. (MR)

  14. FGFR3 mutation causes abnormal membranous ossification in achondroplasia.

    PubMed

    Di Rocco, Federico; Biosse Duplan, Martin; Heuzé, Yann; Kaci, Nabil; Komla-Ebri, Davide; Munnich, Arnold; Mugniery, Emilie; Benoist-Lasselin, Catherine; Legeai-Mallet, Laurence

    2014-06-01

    FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.

  15. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1987-01-01

    Provides instructions on conducting four demonstrations for the chemistry classroom. Outlines procedures for demonstrations dealing with coupled oscillations, the evaporation of liquids, thioxanthone sulfone radical anion, and the control of variables and conservation of matter. (TW)

  16. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1978-01-01

    Presents two demonstrations; one on Boyle's Law, to illustrate the gas law and serve as a challenging problem for the students; the other is a modified Color Blind Traffic Light demonstration in which the oscillating reactions were speeded up. (GA)

  17. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1978-01-01

    Two demonstrations are described which are suitable for introductory chemistry classes. The first involves the precipitation of silver, and the second is a demonstration of the relationship between rate constants and equilibrium constants using water and beakers. (BB)

  18. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1990-01-01

    Presented are two demonstrations; "Heat of Solution and Colligative Properties: An Illustration of Enthalpy and Entropy," and "A Vapor Pressure Demonstration." Included are lists of materials and experimental procedures. Apparatus needed are illustrated. (CW)

  19. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1989-01-01

    Presented are two demonstrations including a variation of the iodine clock reaction, and a simple demonstration of refractive index. The materials, procedures, and a discussion of probable results are given for each. (CW)

  20. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1981-01-01

    Presents: (1) a simple demonstration which illustrates the driving force of entropy using the familiar effects of the negative thermal expansion coefficient of rubber; and (2) a demonstration of tetrahedral bonding using soap films. (CS)

  1. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1981-01-01

    Two demonstrations are described: (1) red cabbage and electrolysis of water to bring together acid/base and electrochemical concepts; and (2) a model to demonstrate acid/base conjugate pairs utilizing magnets. (SK)

  2. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1987-01-01

    Describes two classroom chemistry demonstrations which focus on the descriptive chemistry of bromine and iodine. Outlines the chemicals and equipment needed, experimental procedures, and discussion of one demonstration of the oxidation states of bromine and iodine, and another demonstration of the oxidation states of iodine. (TW)

  3. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Sands, Robert; And Others

    1982-01-01

    Procedures for two demonstrations are provided. The solubility of ammonia gas in water is demonstrated by introducing water into a closed can filled with the gas, collapsing the can. The second demonstration relates scale of standard reduction potentials to observed behavior of metals in reactions with hydrogen to produce hydrogen gas. (Author/JN)

  4. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1985-01-01

    List of materials needed, procedures used, and results obtained are provided for two demonstrations. The first is an inexpensive and quick method for demonstrating column chromatography of plant pigments of spinach extract. The second is a demonstration of cathodic protection by impressed current. (JN)

  5. Demonstrating Diffusion

    ERIC Educational Resources Information Center

    Foy, Barry G.

    1977-01-01

    Two demonstrations are described. Materials and instructions for demonstrating movement of molecules into cytoplasm using agar blocks, phenolphthalein, and sodium hydroxide are given. A simple method for demonstrating that the rate of diffusion of a gas is inversely proportional to its molecular weight is also presented. (AJ)

  6. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  7. Eye abnormalities in Fryns syndrome.

    PubMed

    Pierson, Diane M; Taboada, Eugenio; Butler, Merlin G

    2004-03-15

    Fryns syndrome is a rare, generally lethal, autosomal recessive multiple congenital anomaly (MCA) syndrome first described in 1979. Patients with the syndrome present with the classical findings of cloudy cornea, brain malformations, diaphragmatic defects, and distal limb deformities. Over 70 patients have been reported revealing a wide variety of phenotypic features. Although initially considered a major feature of Fryns syndrome, cloudy cornea has been relegated as a minor diagnostic sign and not commonly reported in patients since the original description. However, eye findings per se are not uncommon. Abnormal eye findings occasionally reported in Fryns syndrome potentially result in amblyopia and blindness, profoundly affecting neurologic outcome of those who survive the neonatal period. We reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of the reported cases. In addition, we contribute three new patients with Fryns syndrome, one of which demonstrated unilateral microphthalmia and cloudy cornea.

  8. Novel NG2-CreERT2 knock-in mice demonstrate heterogeneous differentiation potential of NG2 glia during development.

    PubMed

    Huang, Wenhui; Zhao, Na; Bai, Xianshu; Karram, Khalad; Trotter, Jacqueline; Goebbels, Sandra; Scheller, Anja; Kirchhoff, Frank

    2014-06-01

    NG2 (nerve/glia antigen-2) is a type I transmembrane glycoprotein and also known as chondroitin sulfate proteoglycan 4. In the parenchyma of the central nervous system, NG2-expressing (NG2(+) ) cells have been identified as a novel type of glia with a strong potential to generate oligodendrocytes (OLs) in the developing white matter. However, the differentiation potential of NG2 glia remained controversial, largely attributable to shortcomings of transgenic mouse models used for fate mapping. To minimize these restrictions and to more faithfully mimic the endogenous NG2 expression in vivo, we generated a mouse line in which the open reading frame of the tamoxifen-inducible form of the Cre DNA recombinase (CreERT2) was inserted into the NG2 locus by homologous recombination. Results from this novel mouse line demonstrate that at different developmental stages of the brain, NG2(+) cells either stayed as NG2 glia or differentiated into OLs during the whole life span. Interestingly, when Cre activity was induced at embryonic stages, a significant number of reporter(+) astrocytes could be detected in the gray matter after birth. However, in other brain regions, such as olfactory bulb, brain stem, and cerebellum, all of the NG2 glia was restricted to the OL lineage. In addition, tamoxifen-sensitive and NG2 gene locus-dependent gene recombination could be detected in a small, but persistent population of cortical NeuN(+) neurons starting from the second postnatal week.

  9. Ethanol Exposure Induces Neonatal Neurodegeneration by Enhancing CB1R Exon1 Histone H4K8 Acetylation and Up-regulating CB1R Function causing Neurobehavioral Abnormalities in Adult Mice

    PubMed Central

    Subbanna, Shivakumar; Nagre, Nagaraja N.; Umapathy, Nagavedi S.; Pace, Betty S.

    2015-01-01

    Background: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. Methods: In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. Results: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanol-induced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Conclusions: Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice. PMID:25609594

  10. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1983-01-01

    Describes a lecture demonstration of a solid state phase transition using a thermodynamic material which changes state at room temperature. Also describes a demonstration on kinetics using a "Big Bang" (trade mark) calcium carbide cannon. Indicates that the cannon is safe to use. (JN)

  11. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1989-01-01

    Presented are two chemistry demonstrations: (1) an alternative method for the demonstration of the properties of alkali metals, water is added to small amounts of metal; (2) an exploration of the properties of hydrogen, helium, propane, and carbon dioxide using an open trough and candle. (MVL)

  12. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1986-01-01

    Outlines a simple, inexpensive way of demonstrating electroplating using the reaction between nickel ions and copper metal. Explains how to conduct a demonstration of the electrolysis of water by using a colored Na2SO4 solution as the electrolyte so that students can observe the pH changes. (TW)

  13. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1982-01-01

    Three chemistry demonstrations are described: (1) modification of copper catalysis demonstration apparatus; (2) experiments in gas-liquid chromatography with simple gas chromatography at room temperature; and (3) equilibria in silver arsenate-arsenic acid and silver phosphate-phosphoric acid systems. Procedures and materials needed are provided.…

  14. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1980-01-01

    Two demonstrations are described: (1) a variant of preparing purple benzene by phase transfer catalysis with quaternary ammonium salts and potassium permanganate in which crown ethers are used; (2) a corridor or "hallway" demonstration in which unknown molecular models are displayed and prizes awarded to students correctly identifying the…

  15. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1984-01-01

    Background information and procedures are provided for a second part to the dichromate volcano demonstration. The green ash produced during the demonstration is reduced to metal using aluminothermy (Goldschmide process). Also describes suitable light sources and spectroscopes for student observation of emission spectra in lecture halls. (JN)

  16. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1983-01-01

    Free radical chlorination of methane is used in organic chemistry to introduce free radical/chain reactions. In spite of its common occurrence, demonstrations of the reaction are uncommon. Therefore, such a demonstration is provided, including background information, preparation of reactants/reaction vessel, introduction of reactants, irradiation,…

  17. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1983-01-01

    Discusses a supplement to the "water to rose" demonstration in which a pink color is produced. Also discusses blood buffer demonstrations, including hydrolysis of sodium bicarbonate, simulated blood buffer, metabolic acidosis, natural compensation of metabolic acidosis, metabolic alkalosis, acidosis treatment, and alkalosis treatment. Procedures…

  18. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1990-01-01

    Presented are three demonstrations: "The Construction and Use of Commercial Voltaic Cell Displays in Freshman Chemistry"; Dramatizing Isotopes: Deuterated Ice Cubes Sink"; and "A Simple Apparatus to Demonstrate Differing Gas Diffusion Rates (Graham's Law)." Materials, procedures, and safety considerations are discussed. (CW)

  19. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1987-01-01

    Describes two laboratory demonstrations in chemistry. One uses dry ice, freon, and freezer bags to demonstrate volume changes, vapor-liquid equilibrium, a simulation of a rain forest, and vaporization. The other uses the clock reaction technique to illustrate fast reactions and kinetic problems in releasing carbon dioxide during respiration. (TW)

  20. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1980-01-01

    Described is a demonstration utilized to measure the heat of vaporization using the Clausius-Clapeyron equation. Explained is that when measurement is made as part of a demonstration, it raises student's consciousness that chemistry is experimentally based. (Author/DS)

  1. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1985-01-01

    Two demonstrations are described. The first (useful as an introduction to kinetics) shows how the rate of a reaction is fast at first and then gradually decreases to zero when one reactant has been used up. The second is a gas density demonstration using 1,1,2-trichloro-1,2,2-trifluoro ethane. (JN)

  2. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1986-01-01

    Provides three descriptions of demonstrations used in various chemistry courses. Includes the use of a simple demonstration model to illustrate principles of chromatography, techniques for using balloons to teach about the behavior of gases, and the use of small concentrations of synthetic polyelectrolytes to induce the flocculation hydrophobic…

  3. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1983-01-01

    Provides directions for setup and performance of two demonstrations. The first demonstrates the principles of Raoult's Law; using a simple apparatus designed to measure vapor pressure. The second illustrates the energy available from alcohol combustion (includes safety precautions) using an alcohol-fueled missile. (JM)

  4. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1989-01-01

    Provided are two demonstrations for an introductory course in chemistry. The first one emphasizes the observation and the interpretation of facts to form hypotheses during the heating of a beaker of water. The second demonstration shows the liquid phase of carbon dioxide using dry ice and a pressure gauge. (YP)

  5. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1986-01-01

    Discusses the photochromic behavior of mercury(II) bis(dithizonate) in providing a colorful demonstration of the effect that visible light can have on the conformation and bonding of molecules in solution. Provides a description of the demonstration itself, along with the preparation needed to complete it. (TW)

  6. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1979-01-01

    Presents two demonstrations for classroom use related to precipitation of ferrous hydroxide and to variation of vapor pressure with temperature. The former demonstration is simple and useful when discussing solubility of ionic compounds electrode potential of transition elements, and mixed valence compounds. (Author/SA)

  7. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1986-01-01

    Describes two demonstrations designed to help chemistry students visualize certain chemical properties. One experiment uses balloons to illustrate the behavior of gases under varying temperatures and pressures. The other uses a makeshift pea shooter and a commercial model to demonstrate atomic structure and the behavior of high-speed particles.…

  8. Epididymal hypo-osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse.

    PubMed

    Joseph, Avenel; Shur, Barry D; Ko, CheMyong; Chambon, Pierre; Hess, Rex A

    2010-05-01

    Estrogen receptor-alpha (ESR1) is highly expressed in the efferent ductules of all species studied as well as in the epididymal epithelium in mice and other select species. Male mice lacking ESR1 (Esr1KO) are infertile, but transplantation studies demonstrated that Esr1KO germ cells are capable of fertilization when placed in a wild-type reproductive tract. These results suggest that extratesticular regions, such as the efferent ductules and epididymis, are the major source of pathological changes in Esr1KO males. Previous studies have shown alterations in ion and fluid transporters in the efferent duct and epididymal epithelia of Esr1KO males, leading to misregulation of luminal fluid pH. To determine the effect of an altered epididymal milieu on Esr1KO sperm, we assayed sperm morphology in the different regions of the epididymis. Sperm recovered from the epididymis exhibited abnormal flagellar coiling and increased incidence of spontaneous acrosome reactions, both of which are consistent with exposure to abnormal epididymal fluid. Analysis of the epididymal fluid revealed that the osmolality of the Esr1KO fluid was reduced relative to wild type, consistent with prior reports of inappropriate fluid absorption from the efferent ductules. This, along with the finding that morphological defects increased with transit through the epididymal duct, suggests that the anomalies in sperm are a consequence of the abnormal luminal environment. Consistent with this, incubating Esr1KO sperm in a more wild-type-like osmotic environment significantly rescued the abnormal flagellar coiling. This work demonstrates that Esr1KO mice exhibit an abnormal fluid environment in the lumen of the efferent ducts and epididymis, precluding normal sperm maturation and instead resulting in progressive deterioration of sperm that contributes to infertility.

  9. Knockout of Foxp2 disrupts vocal development in mice

    PubMed Central

    Castellucci, Gregg A.; McGinley, Matthew J.; McCormick, David A.

    2016-01-01

    The FOXP2 gene is important for the development of proper speech motor control in humans. However, the role of the gene in general vocal behavior in other mammals, including mice, is unclear. Here, we track the vocal development of Foxp2 heterozygous knockout (Foxp2+/−) mice and their wildtype (WT) littermates from juvenile to adult ages, and observe severe abnormalities in the courtship song of Foxp2+/− mice. In comparison to their WT littermates, Foxp2+/− mice vocalized less, produced shorter syllable sequences, and possessed an abnormal syllable inventory. In addition, Foxp2+/− song also exhibited irregular rhythmic structure, and its development did not follow the consistent trajectories observed in WT vocalizations. These results demonstrate that the Foxp2 gene is critical for normal vocal behavior in juvenile and adult mice, and that Foxp2 mutant mice may provide a tractable model system for the study of the gene’s role in general vocal motor control. PMID:26980647

  10. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1986-01-01

    Background information, list of materials needed, and procedures used are provided for a demonstration involving the transformation of a hydrophobic liquid to a partially hydrophobic semisolid. Safety considerations are noted. (JN)

  11. Tested Demonstrations

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1977-01-01

    Describes a room-temperature method for demonstrating phosphorescence by including samples in a polymer matrix. Also discusses the Old Nassau Reaction, a clock reaction which turns orange then black. (MLH)

  12. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1980-01-01

    Presented is a Corridor Demonstration which can be set up in readily accessible areas such as hallways or lobbies. Equipment is listed for a display of three cells (solar cells, fuel cells, and storage cells) which develop electrical energy. (CS)

  13. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Roffia, Sergio; And Others

    1988-01-01

    Reports two electrochemical demonstrations. Uses a hydrogen-oxygen fuel cell to power a clock. Includes description of methods and materials. Investigates the "potato clock" used with different fruits. Lists emf and current for various fruit and electrode combinations. (ML)

  14. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Rehfeld, D. W.; And Others

    1988-01-01

    Describes two demonstrations (1) a dust explosion using a coffee can, candle, rubber tubing, and cornstarch and (2) forming a silicate-polyvinyl alcohol polymer which can be pressed into plastic sheets or molded. Gives specific instructions. (MVL)

  15. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1987-01-01

    Presents three demonstrations suitable for undergraduate chemistry classes. Focuses on experiments with calcium carbide, the induction by iron of the oxidation of iodide by dichromate, and the classical iodine clock reaction. (ML)

  16. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L.

    1990-01-01

    Included are three demonstrations that include the phase change of ice when under pressure, viscoelasticity and colloid systems, and flame tests for metal ions. The materials, procedures, probable results, and applications to real life situations are included. (KR)

  17. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1979-01-01

    Presents a recipe for the Nylon Rope Trick, which is considered to be one of the most spectacular demonstrations in chemistry. Materials for growing the polymer and some safety precautions are given. (SA)

  18. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1988-01-01

    Describes two demonstrations for use in college chemistry classes. Includes "Spectroscopy in Large Lecture Halls" and "The Endothermic Dissolution of Ammonium Nitrate." Gives materials lists and procedures as well as a discussion of the results. (CW)

  19. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L.

    1982-01-01

    Two demonstrations are described: (1) a sunset effect using a gooseneck lamp and 20 sheets of paper and (2) the preparation and determination of structural features of dimethyl sulfoxide (DMSO) by infrared spectroscopy. (SK)

  20. Demonstration Explosion

    NASA Astrophysics Data System (ADS)

    Lee, Charles "Skip"

    1998-05-01

    Last week I did a demonstration that produced a serious explosion. After putting methanol in a big glass carboy and rotating the carboy to build up some methanol vapor, I lit the mouth of the carboy. What normally happens is a "jet engine" effect out of the mouth of the carboy. In my case, the carboy exploded. Two polycarbonate blast shields were shattered and glass was blown as far as 15 feet away. I was not seriously cut and bruised, but had I not been using the two blast shields, I would have been severely injured. At this time, I am not sure what caused the explosion. I have done this demonstration around one hundred times with no problem using the exact same amount of methanol and technique. I think it is important to get the word out that this demonstration may be more dangerous than previously thought. I would also welcome any hypotheses concerning what caused the carboy to explode.

  1. [The relativity of abnormity].

    PubMed

    Nilson, Annika

    2006-01-01

    In the late 19th century and in the beginning of the 20th century, mental diseases and abnormal behavior was considered to be a great danger to culture and society. "Degeneration" was the buzzword of the time, used and misused by artists and scientists alike. At the same time, some scientists saw abnormity as the key to unlock the mysteries of the ordinary mind. Naturalistic curiosity left Pandoras box open when religion declined in Darwins wake. Two swedish scientists, the physician Bror Gadelius (1862-1938) and his friend the philosopher Axel Herrlin (1870-1937), inspired by the French psychologist Theodule Ribots (1839-1916) "psychology without a soul", denied all fixed demarcation lines between abnormity and normality. All humans are natures creatures ruled by physiological laws, not ruled by God or convention. Even ordinary morality was considered to be an utterly backward explanation and guideline for complex human behavior. Different forms of therapy, not various kinds of penalties for wicked and disturbing behavior, are the now the solution for lots of people, "normal" as well as "abnormal". Psychiatry is expanding.

  2. Abnormalities of gonadal differentiation.

    PubMed

    Berkovitz, G D; Seeherunvong, T

    1998-04-01

    Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.

  3. Intracellular calcium handling in ventricular myocytes from mdx mice.

    PubMed

    Williams, Iwan A; Allen, David G

    2007-02-01

    Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice.

  4. FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice

    PubMed Central

    Lysaght, Andrew C.; Yuan, Quan; Fan, Yi; Kalwani, Neil; Caruso, Paul; Cunnane, MaryBeth; Lanske, Beate; Stanković, Konstantina M.

    2014-01-01

    Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf mice are profoundly deaf. Fgf mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf mice demonstrate dysplastic bulla and ossicles; Fgf mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf mice do not match the auditory phenotype of Kl−/− mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development, this work suggests a possible role for FGF23 in otitis media. PMID:25243481

  5. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1985-01-01

    Describes two demonstrations that require almost no preparation time, are visually stimulating, and present a variety of material for class discussion (with sample questions provided). The first involves a sodium bicarbonate hydrochloric acid volcano; the second involves a dissolving polystyrene cup. Procedures used and information on…

  6. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1987-01-01

    Describes two demonstrations to illustrate characteristics of substances. Outlines a method to detect the changes in pH levels during the electrolysis of water. Uses water pistols, one filled with methane gas and the other filled with water, to illustrate the differences in these two substances. (TW)

  7. Tested Demonstrations

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1976-01-01

    Describes two demonstrations: one that illustrates the attainment of equilibrium in first-order reactions by changing the volumes of two beakers of water at a specified rate, and another that illustrates the role of indicators in showing pH changes in buffer solutions. (MLH)

  8. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1989-01-01

    Discusses three broad classes of magnetic behavior: diamagnetic, paramagnetic, and ferromagnetic. Presents a simple lecture demonstration using an overhead projector to synthesize triiron tetraoxide and to show its interaction with a magnetic field and comparing it to a paramagnetic material. (MVL)

  9. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1981-01-01

    Provides instructions and a list of materials needed to demonstrate: (1) a model of the quantum mechanical atom; (2) principles involved in metal corrosion and in the prevention of this destructive process by electrochemical means; and (3) a Thermit reaction, modified to make it more dramatic and interesting for students. (SK)

  10. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L.

    1983-01-01

    An apparatus is described in which effects of pressure, volume, and temperature changes on a gas can be observed simultaneously. Includes use of the apparatus in demonstrating Boyle's, Gay-Lussac's, and Charles' Laws, attractive forces, Dalton's Law of Partial pressures, and in illustrating measurable vapor pressures of liquids and some solids.…

  11. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1984-01-01

    Two demonstrations are described. The first shows the effect of polarity on solubility. The second is based on the unexpected formation of a precipitate of barium nitrate when barium carbonate or barium phosphate is treated with dilute nitric acid. List of materials needed and procedures used are included. (JN)

  12. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Gilbert, George L., Ed.

    1985-01-01

    Background information, procedures, and typical results obtained are provided for two demonstrations. The first involves the colorful complexes of copper(II). The second involves reverse-phase separation of Food, Drug, and Cosmetic (FD & C) dyes using a solvent gradient. (JN)

  13. Tested Demonstrations.

    ERIC Educational Resources Information Center

    Cliche, Jean-Marie; And Others

    1988-01-01

    Describes two demonstrations: 1) the effect of polarity on solubility using sodium dichromate, TTE, ligroin, and water to form nonpolar-polar-nonpolar layers with the polar layer being colored; 2) determination of egg whites to be yellow by determining the content of yellow colored riboflavin in the egg white. (MVL)

  14. Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor.

    PubMed

    Bunger, Maureen K; Glover, Edward; Moran, Susan M; Walisser, Jacqueline A; Lahvis, Garet P; Hsu, Erin L; Bradfield, Christopher A

    2008-11-01

    The aryl hydrocarbon receptor (AHR) is known for its role in the adaptive and toxic responses to a large number of environmental contaminants, as well as its role in hepatovascular development. The classical AHR pathway involves ligand binding, nuclear translocation, heterodimerization with the AHR nuclear translocator (ARNT), and binding of the heterodimer to dioxin response elements (DREs), thereby modulating the transcription of an array of genes. The AHR has also been implicated in signaling events independent of nuclear localization and DNA binding, and it has been suggested that such pathways may play important roles in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report the generation of a mouse model that expresses an AHR protein capable of ligand binding, interactions with chaperone proteins, functional heterodimerization with ARNT, and nuclear translocation, but is unable to bind DREs. Using this model, we provide evidence that DNA binding is required AHR-mediated liver development, as Ahr(dbd/dbd) mice exhibit a patent ductus venosus, similar to what is seen in Ahr(-/-) mice. Furthermore, Ahr(dbd/dbd) mice are resistant to TCDD-induced toxicity for all endpoints tested. These data suggest that DNA binding is necessary for AHR-mediated developmental and toxic signaling.

  15. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

    PubMed Central

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Anderson, George M.; Snyder, Isaac; Blakely, Randy D.; Gershon, Michael D.

    2016-01-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4–mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  16. Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP.

    PubMed

    Hu, Bo; Arpag, Sezgi; Zhang, Xuebao; Möbius, Wiebke; Werner, Hauke; Sosinsky, Gina; Ellisman, Mark; Zhang, Yang; Hamilton, Audra; Chernoff, Jonathan; Li, Jun

    2016-09-01

    Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it "functional demyelination", a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP.

  17. Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP

    PubMed Central

    Hu, Bo; Zhang, Xuebao; Möbius, Wiebke; Werner, Hauke; Sosinsky, Gina; Ellisman, Mark; Zhang, Yang; Hamilton, Audra; Chernoff, Jonathan; Li, Jun

    2016-01-01

    Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it “functional demyelination”, a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP. PMID:27583434

  18. tmie Is required for gentamicin uptake by the hair cells of mice.

    PubMed

    Park, Seojin; Lee, Jeong-Han; Cho, Hyun-Ju; Lee, Kyu-yup; Kim, Myoung Ok; Yun, Byung-Wook; Ryoo, ZaeYoung

    2013-04-01

    The circling (cir/cir) mouse is a spontaneous model of deafness due to deletion of a 40-kb genomic region that includes the transmembrane inner ear (tmie) gene. In addition to being deaf, cir/cir mice exhibit abnormal behaviors including circling and hyperactivity. Here we investigated differences between 3-d-old (that is, before hair-cell degeneration) cir/cir and phenotypically normal (+/cir) mice and the reason underlying the degeneration of the inner ear structure of cir/cir mice. To this end, we used gentamicin, gentamicin-Texas red conjugate, and FM1-43 to investigate mechanotransducer channel activity in the hair cells of cir/cir mice; these compounds are presumed to enter hair cells through the mechanotransducer channel. Although the structure of the inner ear of +/cir mice was equivalent to that of cir/cir mice, the hair cells of cir/cir mice (unlike +/cir) did not take up gentamicin, gentamicin-Texas red conjugate, or FM1-43. These findings suggest that hair cells in cir/cir mice demonstrate abnormal maturation and mechanotransduction. In addition, our current results indicate that tmie is required for maturation and maintenance of hair cells.

  19. Abnormalities occurring during female gametophyte development result in the diversity of abnormal embryo sacs and leads to abnormal fertilization in indica/japonica hybrids in rice.

    PubMed

    Zeng, Yu-Xiang; Hu, Chao-Yue; Lu, Yong-Gen; Li, Jin-Quan; Liu, Xiang-Dong

    2009-01-01

    Embryo sac abortion is one of the major reasons for sterility in indica/japonica hybrids in rice. To clarify the causal mechanism of embryo sac abortion, we studied the female gametophyte development in two indica/japonica hybrids via an eosin B staining procedure for embryo sac scanning using confocal laser scanning microscope. Different types of abnormalities occurred during megasporogenesis and megagametogenesis were demonstrated. The earliest abnormality was observed in the megasporocyte. A lot of the chalazal-most megaspores were degenerated before the mono-nucleate embryo sac stage. Disordered positioning of nucleus and abnormal nucellus tissue were characteristics of the abnormal female gametes from the mono-nucleate to four-nucleate embryo sac stages. The abnormalities that occurred from the early stage of the eight-nucleate embryo sac development to the mature embryo sac stage were characterized by smaller sizes and wrinkled antipodals. Asynchronous nuclear migration, abnormal positioning of nucleus, and degeneration of egg apparatus were also found at the eight-nucleate embryo sac stage. The abnormalities that occurred during female gametophyte development resulted in five major types of abnormal embryo sacs. These abnormal embryo sacs led to abnormal fertilization. Hand pollination using normal pollens on the spikelets during anthesis showed that normal pollens could not exclude the effect of abnormal embryo sac on seed setting.

  20. Heritable bovine fetal abnormalities.

    PubMed

    Whitlock, B K; Kaiser, L; Maxwell, H S

    2008-08-01

    The etiologies for congenital bovine fetal anomalies can be divided into heritable, toxic, nutritional, and infectious categories. Although uncommon in most herds, inherited congenital anomalies are probably present in all breeds of cattle and propagated as a result of specific trait selection that inadvertently results in propagation of the defect. In some herds, the occurrence of inherited anomalies has become frequent, and economically important. Anomalous traits can affect animals in a range of ways, some being lethal or requiring euthanasia on humane grounds, others altering structure, function, or performance of affected animals. Veterinary practitioners should be aware of the potential for inherited defects, and be prepared to investigate and report animals exhibiting abnormal characteristics. This review will discuss the morphologic characteristics, mode of inheritance, breeding lines affected, and the availability of genetic testing for selected heritable bovine fetal abnormalities.

  1. Liver abnormalities in pregnancy.

    PubMed

    Than, Nwe Ni; Neuberger, James

    2013-08-01

    Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication.

  2. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed.

  3. Anatomical Abnormalities in Autism?

    PubMed

    Haar, Shlomi; Berman, Sigal; Behrmann, Marlene; Dinstein, Ilan

    2016-04-01

    Substantial controversy exists regarding the presence and significance of anatomical abnormalities in autism spectrum disorders (ASD). The release of the Autism Brain Imaging Data Exchange (∼1000 participants, age 6-65 years) offers an unprecedented opportunity to conduct large-scale comparisons of anatomical MRI scans across groups and to resolve many of the outstanding questions. Comprehensive univariate analyses using volumetric, thickness, and surface area measures of over 180 anatomically defined brain areas, revealed significantly larger ventricular volumes, smaller corpus callosum volume (central segment only), and several cortical areas with increased thickness in the ASD group. Previously reported anatomical abnormalities in ASD including larger intracranial volumes, smaller cerebellar volumes, and larger amygdala volumes were not substantiated by the current study. In addition, multivariate classification analyses yielded modest decoding accuracies of individuals' group identity (<60%), suggesting that the examined anatomical measures are of limited diagnostic utility for ASD. While anatomical abnormalities may be present in distinct subgroups of ASD individuals, the current findings show that many previously reported anatomical measures are likely to be of low clinical and scientific significance for understanding ASD neuropathology as a whole in individuals 6-35 years old.

  4. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  5. Mice Expressing Mutant Trpv4 Recapitulate the Human TRPV4 Disorders††

    PubMed Central

    Chen, Yuqing; Lee, Brendan; Cohn, Daniel H.

    2014-01-01

    Activating mutations in TRPV4 are known to cause a spectrum of skeletal dysplasias ranging from autosomal dominant brachyolmia to lethal metatropic dysplasia. To develop an animal model of these disorders, we created transgenic mice expressing either wild-type or mutant TRPV4. Mice transgenic for wild-type Trpv4 showed no morphological changes at embryonic day 16.5, but did have a delay in bone mineralization. Overexpression of a mutant TRPV4 caused a lethal skeletal dysplasia that phenocopied many abnormalities associated with metatropic dysplasia in humans, including dumbbell-shaped long bones, a small ribcage, abnormalities in the autopod, and abnormal ossification in the vertebrae. The difference in phenotype between embryos transgenic for wild-type or mutant Trpv4 demonstrates that an increased amount of wild-type protein can be tolerated and that an activating mutation of this protein is required to produce a skeletal dysplasia phenotype. PMID:24644033

  6. [Molecular abnormalities in lymphomas].

    PubMed

    Delsol, G

    2010-11-01

    Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas. Overall, four types of molecular abnormalities are involved: mutations, translocations, amplifications and deletions of tumor suppressor genes. Several techniques are available to detect these molecular anomalies: conventional cytogenetic analysis, multicolor FISH, CGH array or gene expression profiling using DNA microarrays. In some lymphomas, genetic abnormalities are responsible for the expression of an abnormal protein (e.g. tyrosine-kinase, transcription factor) detectable by immunohistochemistry. In the present review, molecular abnormalities observed in the most frequent B, T or NK cell lymphomas are discussed. In the broad spectrum of diffuse large B-cell lymphomas microarray analysis shows mostly two subgroups of tumors, one with gene expression signature corresponding to germinal center B-cell-like (GCB: CD10+, BCL6 [B-Cell Lymphoma 6]+, centerine+, MUM1-) and a subgroup expressing an activated B-cell-like signature (ABC: CD10-, BCL6-, centerine-, MUM1+). Among other B-cell lymphomas with well characterized molecular abnormalies are follicular lymphoma (BCL2 deregulation), MALT lymphoma (Mucosa Associated Lymphoid Tissue) [API2-MALT1 (mucosa-associated-lymphoid-tissue-lymphoma-translocation-gene1) fusion protein or deregulation BCL10, MALT1, FOXP1. MALT1 transcription factors], mantle cell lymphoma (cycline D1 [CCND1] overexpression) and Burkitt lymphoma (c-Myc expression). Except for ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma, well characterized molecular anomalies are rare in lymphomas developed from T or NK cells. Peripheral T cell lymphomas not otherwise specified are a heterogeneous group of tumors with frequent but not recurrent molecular abnormalities

  7. Impairment of mice spermatogenesis by sodium arsenite.

    PubMed

    Ferreira, Mónica; Matos, Rita Cerejeira; Oliveira, Helena; Nunes, Bruno; Pereira, Maria de Lourdes

    2012-03-01

    In order to assess the effect of arsenic on the male reproductive impairment in mice, 7-week-old animals were exposed to 7.5 mg sodium arsenite (NaAsO(2))/kg body weight, during 35 days (one spermatogenic cycle). One group of animals was sacrificed after exposure, while another group received distilled water for an additional period of 35 days, in order to study the spermatoxic effect and the recovery of spermatogenesis. In mice sacrificed after NaAsO(2) exposure, a decrease in testis/body weight ratio and reduction of tubular diameter were observed. Both groups of NaAsO(2)-exposed animals showed remarkable histopathological changes, such as sloughing of immature germ cells. Animals sacrificed after NaAsO(2) exposure showed decreased sperm motility, increased abnormal sperm morphology and decreased sperm viability. The effects of NaAsO(2) on sperm motility recovered to normal values after one spermatogenic cycle, while increased sperm abnormality was maintained. However, at this period, a decrease in acrosome integrity was detected. Concerning oxidative stress parameters, animals sacrificed after NaAsO(2) exposure showed a decreased selenium-dependent glutathione peroxidase activity, which was not detected after the recovery. Conversely, at this period, total glutathione peroxidase activity increased in exposed animals. These results demonstrate the toxic effects of NaAsO(2) on mice spermatogenesis and show the lack of recovery after one spermatogenic cycle.

  8. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  9. GASIS demonstration

    SciTech Connect

    Vidas, E.H.

    1995-04-01

    A prototype of the GASIS database and retrieval software has been developed and is the subject of this poster session and computer demonstration. The prototype consists of test or preliminary versions of the GASIS Reservoir Data System and Source Directory datasets and the software for query and retrieval. The prototype reservoir database covers the Rocky Mountain region and contains the full GASIS data matrix (all GASIS data elements) that will eventually be included on the CD-ROM. It is populated for development purposes primarily by the information included in the Rocky Mountain Gas Atlas. The software has been developed specifically for GASIS using Foxpro for Windows. The application is an executable file that does not require Foxpro to run. The reservoir database software includes query and retrieval, screen display, report generation, and data export functions. Basic queries by state, basin, or field name will be assisted by scrolling selection lists. A detailed query screen will allow record selection on the basis of any data field, such as depth, cumulative production, or geological age. Logical operators can be applied to any-numeric data element or combination of elements. Screen display includes a {open_quotes}browse{close_quotes} display with one record per row and a detailed single record display. Datasets can be exported in standard formats for manipulation with other software packages. The Source Directory software will allow record retrieval by database type or subject area.

  10. Abnormal Web Usage Control by Proxy Strategies.

    ERIC Educational Resources Information Center

    Yu, Hsiang-Fu; Tseng, Li-Ming

    2002-01-01

    Approaches to designing a proxy server with Web usage control and to making the proxy server effective on local area networks are proposed to prevent abnormal Web access and to prioritize Web usage. A system is implemented to demonstrate the approaches. The implementation reveals that the proposed approaches are effective, such that the abnormal…

  11. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  12. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  13. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.

    PubMed

    Peça, João; Feliciano, Cátia; Ting, Jonathan T; Wang, Wenting; Wells, Michael F; Venkatraman, Talaignair N; Lascola, Christopher D; Fu, Zhanyan; Feng, Guoping

    2011-04-28

    Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.

  14. Reduced Chrna7 expression in mice is associated with decreases in hippocampal markers of inhibitory function: implications for neuropsychiatric diseases

    PubMed Central

    Adams, Catherine E.; Yonchek, Joan C.; Schulz, Kalynn M.; Graw, Sharon L.; Stitzel, Jerry; Teschke, Patricia U.; Stevens, Karen E.

    2012-01-01

    The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the release of both the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the excitatory neurotransmitter glutamate in the hippocampal formation. A heterozygous deletion at 15q13.3 containing CHRNA7 is associated with increased risk for schizophrenia, autism and epilepsy. Each of these diseases is characterized by abnormalities in excitatory and inhibitory hippocampal circuit function. Reduced Chrna7 expression results in decreased hippocampal α7* receptor density, abnormal hippocampal auditory sensory processing and increased hippocampal CA3 pyramidal neuron activity in C3H mice heterozygous for a null mutation in Chrna7. These abnormalities demonstrate that decreased Chrna7 expression alters hippocampal inhibitory circuit function. The current study examined the specific impact of reduced Chrna7 expression on hippocampal inhibitory circuits by measuring the levels of GABA, GABAA receptors, the GABA synthetic enzyme glutamate decarboxylase-65 (GAD-65) and the vesicular GABA transporter GAT-1 in wild type (Chrna7 +/+) and heterozygous (Chrna7 +/−) C3H α7 mice of both genders. GAD-65 levels were significantly decreased in male and female heterozygous C3H α7 mice while GABAA receptors were significantly reduced only in male heterozygous C3H α7 mice. No changes in GABA and GAT-1 levels were detected. These data suggest that reduced CHRNA7 expression may contribute to the abnormalities in hippocampal inhibitory circuits observed in schizophrenia, autism and/or epilepsy. PMID:22314319

  15. p21 is associated with the proliferation and apoptosis of bone marrow-derived mesenchymal stem cells from non-obese diabetic mice.

    PubMed

    Gu, Z; Jiang, J; Xia, Y; Yue, X; Yan, M; Tao, T; Cao, X; Da, Z; Liu, H; Liu, H; Miao, Y; Li, L; Wang, Z

    2013-11-01

    Recent studies have shown that autologous and allogeneic transplantation of the BM-MSCs had therapeutic effects on T1DM, whereas the BM-MSCs from the NOD mice itself did not have this therapeutic effect. We previously demonstrated that Bone Marrow (BM) -MSCs from the non-obese diabetic (NOD) mice had the abnormal migration and adhesion. So we hypothesized that the proliferation and apoptosis of the BM-MSCs from the NOD mice were dysregulated. Our team compared the proliferation and apoptosis between NOD mice and imprinting control region (ICR) mice. Then we assessed whether the NF-κB-p53/p21 pathway was involved in the process. The cell proliferation ability of the BM-MSCs from the NOD mice were significantly decreased, while the percent of apoptotic cells was increased compared to those from the ICR mice. The p21 expression was significantly increased in the NOD-MSCs. The p65 level was enhanced in the BM-MSCs from the NOD mice when compared to the ICR mice, coincided with the expression of p21. Expressions of p65 and p21 were significantly decreased in the -BM-MSCs treated with p65 inhibitor. The knockdown p21 expression reversed the abnormal proliferation, colony formation and apoptosis of the BM-MSCs from the NOD mice. These data provide important preclinical references supporting the basis for further development of autologous MSC-based therapies for type1 diabetes mellitus (T1DM).

  16. Epilepsy and chromosomal abnormalities

    PubMed Central

    2010-01-01

    Background Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities. PMID:20438626

  17. Neuromuscular junction defects in mice with mutation of dynein heavy chain 1.

    PubMed

    Courchesne, Stephanie L; Pazyra-Murphy, Maria F; Lee, Daniel J; Segal, Rosalind A

    2011-02-04

    Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization.

  18. Neuromuscular Junction Defects in Mice with Mutation of dynein heavy chain 1

    PubMed Central

    Lee, Daniel J.; Segal, Rosalind A.

    2011-01-01

    Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization. PMID:21346813

  19. Abnormal glutamate release in aged BTBR mouse model of autism.

    PubMed

    Wei, Hongen; Ding, Caiyun; Jin, Guorong; Yin, Haizhen; Liu, Jianrong; Hu, Fengyun

    2015-01-01

    Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Most of the available research on autism is focused on children and young adults and little is known about the pathological alternation of autism in older adults. In order to investigate the neurobiological alternation of autism in old age stage, we compared the morphology and synaptic function of excitatory synapses between the BTBR mice with low level sociability and B6 mice with high level sociability. The results revealed that the number of excitatory synapse colocalized with pre- and post-synaptic marker was not different between aged BTBR and B6 mice. The aged BTBR mice had a normal structure of dendritic spine and the expression of Shank3 protein in the brain as well as that in B6 mice. The baseline and KCl-evoked glutamate release from the cortical synaptoneurosome in aged BTBR mice was lower than that in aged B6 mice. Overall, the data indicate that there is a link between disturbances of the glutamate transmission and autism. These findings provide new evidences for the hypothesis of excitation/inhibition imbalance in autism. Further work is required to determine the cause of this putative abnormality.

  20. Knockout of Lysosomal Enzyme-Targeting Gene Causes Abnormalities in Mouse Pup Isolation Calls

    PubMed Central

    Barnes, Terra D.; Holy, Timothy E.

    2017-01-01

    Humans lacking a working copy of the GNPTAB gene suffer from the metabolic disease Mucolipidosis type II (MLII). MLII symptoms include mental retardation, skeletal deformities and cartilage defects as well as a speech delay with most subjects unable to utter single words (Otomo et al., 2009; Cathey et al., 2010; Leroy et al., 2012). Here we asked whether mice lacking a copy of Gnptab gene exhibited vocal abnormities. We recorded ultrasonic vocalizations from 5 to 8 day old mice separated from their mother and littermates. Although Gnptab−/− pups emitted a similar number of calls, several features of the calls were different from their wild type littermates. Gnptab−/− mice showed a decrease in the length of calls, an increase in the intra-bout pause duration, significantly fewer pitch jumps with smaller mean size, and an increase in the number of isolated calls. In addition, Gnptab−/− mice vocalizations had less power, particularly in the higher frequencies. Gnptab+/− mouse vocalizations did not appear to be affected. We then attempted to classify these recordings using these features to determine the genotype of the animal. We were able to correctly identify 87% of the recordings as either Gnptab−/− or Gnptab+/+ pup, significantly better than chance, demonstrating that genotype is a strong predictor of vocalization phenotype. These data show that deletion of genes in the lysosomal enzyme targeting pathway affect mouse pup isolation calls. PMID:28101008

  1. Skeletal abnormalities in homocystinuria.

    PubMed Central

    Brenton, D. P.

    1977-01-01

    The skeletal changes of thirty-four patients with the biochemical and clinical features of cystathionine synthase deficiency are described. It is emphasized that there is clinical evidence of excessive bone growth and the formation for bone which is structurally weaker than normal. The similarities and differences between this condition and Marfan's syndrome are stressed and the possible nature of the connective tissue defect leading to the skeletal changes discussed. The most characteristic skeletal changes in homocystinuria are the skeletal disproportion (pubis-heel length greater than crown-pubis length), the abnormal vertebrae, sternal deformities, genu valgum and large metaphyses and epiphyses. Images Fig. 2 Fig. 3 Fig. 4 Fig. 8 Fig. 9 Fig. 10 PMID:917963

  2. Eye movement abnormalities.

    PubMed

    Moncayo, Jorge; Bogousslavsky, Julien

    2012-01-01

    Generation and control of eye movements requires the participation of the cortex, basal ganglia, cerebellum and brainstem. The signals of this complex neural network finally converge on the ocular motoneurons of the brainstem. Infarct or hemorrhage at any level of the oculomotor system (though more frequent in the brain-stem) may give rise to a broad spectrum of eye movement abnormalities (EMAs). Consequently, neurologists and particularly stroke neurologists are routinely confronted with EMAs, some of which may be overlooked in the acute stroke setting and others that, when recognized, may have a high localizing value. The most complex EMAs are due to midbrain stroke. Horizontal gaze disorders, some of them manifesting unusual patterns, may occur in pontine stroke. Distinct varieties of nystagmus occur in cerebellar and medullary stroke. This review summarizes the most representative EMAs from the supratentorial level to the brainstem.

  3. Androgens Attenuate Vitamin D Production Induced by UVB Irradiation of the Skin of Male Mice by an Enzymatic Mechanism.

    PubMed

    Xue, Yingben; Ying, Lee; Horst, Ronald L; Watson, Gordon; Goltzman, David

    2015-12-01

    Cutaneous exposure to UVB irradiation is an important source of vitamin D. Here, we examined sex-specific differences in cutaneous vitamin D production in mice. Both male and female mice on a vitamin D-deficient diet manifested vitamin D deficiency, with mineral abnormalities, secondary hyperparathyroidism, and osteomalacia. UVB irradiation significantly increased vitamin D levels in the skin of female mice and normalized serum 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 levels, as well as mineral and skeletal abnormalities. However, in male mice, the vitamin D response to UVB was attenuated and mineral and skeletal abnormalities were not normalized. The vitamin D precursor, 7-dehydrocholesterol (7DHC), was significantly lower in the skin of male than female mice. This reduction was due to local androgen action in the skin as demonstrated by castration studies and skin-specific androgen receptor deletion in male mice, both of which reversed the male phenotype. Local androgen regulation in the skin of the CYP11A1 gene, which encodes a crucial enzyme that metabolizes cholesterol, 7DHC, and vitamin D, appeared to contribute to the gender differences in UVB-induced vitamin D production and to its reversal of vitamin D deficiency. Sex-specific, enzymatically regulated differences in cutaneous production of vitamin D may therefore be of importance to ensure vitamin D sufficiency.

  4. Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.

    PubMed

    Carson, Robert P; Van Nielen, Dominic L; Winzenburger, Peggy A; Ess, Kevin C

    2012-01-01

    Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the mTORC1 signaling pathway in TSC has been consistently demonstrated. Here we address abnormal brain development in TSC by inactivating the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell lineages. Tsc1(Emx1-Cre) conditional knockout (CKO) animals die by 25 days of life. Their brains have increased size and contain prominent large cells within the cerebral cortex that have greatly increased mTORC1 signaling and decreased mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic astrocytes and decreased myelination were also found. Tsc1(Emx1-Cre) CKO mice were then treated with rapamycin to see if the premature death and brain abnormalities can be rescued. Postnatal rapamycin treatment completely prevented premature death and largely reversed the glia pathology but not abnormal neuronal lamination. These findings support a model that loss of function of the TSC genes in embryonic neural progenitor cells causes cortical malformations in patients with TSC. The dramatic effect of rapamycin suggests that even with extensive multi-lineage abnormalities, a postnatal therapeutic window may exist for patients with TSC.

  5. Meiotic chromosome abnormalities in human spermatogenesis.

    PubMed

    Martin, Renée H

    2006-08-01

    The last few years have witnessed an explosion in the information about chromosome abnormalities in human sperm and the meiotic events that predispose to these abnormalities. We have determined that all chromosomes are susceptible to nondisjunction, but chromosomes 21 and 22 and, especially, the sex chromosomes have an increased frequency of aneuploidy. Studies are just beginning on the effects of potential mutagens on the chromosomal constitution of human sperm. The effects of pesticides and cancer therapeutic agents have been reviewed. In the last decade, there has been a great impetus to study chromosome abnormalities in sperm from infertile men because the advent of intracytoplasmic sperm injection (ICSI) made it possible for these men to father pregnancies. A large number of studies have demonstrated that infertile men have an increased frequency of chromosomally abnormal sperm and children, even when they have a normal somatic karyotype. Meiotic studies on the pachytene stage of spermatogenesis have demonstrated that infertile men have impaired chromosome synapsis, a significantly decreased frequency of recombination, and an increased frequency of chromosomes completely lacking a recombination site. Such errors make these cells susceptible to meiotic arrest and the production of aneuploid gametes.

  6. Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

    PubMed

    Imai, Rika; Asai, Kanae; Hanai, Jun-ichi; Takenaka, Masaru

    2015-07-01

    Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

  7. The role of Fas in the immune system biology of IL-2R alpha knockout mice: interplay among regulatory T cells, inflammation, hemopoiesis, and apoptosis.

    PubMed

    Sharma, Rahul; Bagavant, Harini; Jarjour, Wael N; Sung, Sun-Sang J; Ju, Shyr-Te

    2005-08-01

    Introducing lpr mutation prevents early mortality associated with IL-2Ralpha knockout (KO) mice, prompting us to determine the role of Fas in the immune system biology of IL-2Ralpha KO mice. Consistent with a defect in CD4+CD25+ regulatory T (Treg) cell expression, spontaneous lymphocyte activation in lymphoid organs was observed in 6-wk-old mice. In 16- to 22-wk-old mice, infiltration of leukocytes was observed in bone marrow, colon, lung, pancreas, lacrimal gland, and salivary gland, but not in heart, thyroid, liver, stomach, small intestine, ovary, and kidney. In the lymphocytes-infiltrated bone marrow, B cell lymphopoiesis was blocked at pro-B to pre-B/immature B stage, culminating in an age-dependent B cell loss in the periphery. These phenotypes were also observed in IL-2Ralpha KO mice bearing the lpr mutation (DM mice), indicating Treg cell function and the phenotypes attributed directly to Treg cell abnormality are largely Fas-independent. However, anemia and body weight loss were partially prevented, tissue cell apoptosis was inhibited, and lifespan was improved in the DM mice, demonstrating Fas-dependent elements in these processes. Our age-dependent, lifelong analysis of IL-2Ralpha KO and DM mice supports a CD4+CD25+ Treg cell-based mechanism for the abnormal immune system biology observed in IL-2Ralpha KO mice and provides a global view of the interplays among Treg cells, multiorgan inflammation, hemopoiesis, and apoptosis.

  8. Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway.

    PubMed

    Xie, Xi; Li, Wenyuan; Lan, Tian; Liu, Weihua; Peng, Jing; Huang, Kaipeng; Huang, Juan; Shen, Xiaoyan; Liu, Peiqing; Huang, Heqing

    2011-01-01

    Recently, it is implicated that the abnormality of Akt signaling pathway is involved in the diabetic pathology. Previous studies have demonstrated that berberine could decrease blood glucose by elevating liver glycogen synthesis. However, the underlying mechanism is still unclear. In the present study, we investigated the effects of berberine on fasting blood glucose, liver glycogen, Akt, Glycogen synthase kinase-3, glucokinase and insulin receptor substrate (IRS) in alloxan-induced diabetic mice, exploring its possible hypoglycemic mechanism. We found that in alloxan-induced diabetic mice, the high blood glucose was significantly lowered by berberine treatment. Liver glycogen content, the expression and activity of glucokinase and the phosphorylated Akt and IRS were all significantly reduced in diabetic mice whereas berberine blocked these changes. Berberine also depressed the increasing of phosphorylated GSK-3β in diabetic mice. Collectively, Berberine upregulates the activity of Akt possibly via insulin signaling pathway, eventually lowering high blood glucose in alloxan-induced diabetic mice.

  9. Chromosomal abnormalities in a psychiatric population

    SciTech Connect

    Lewis, K.E.; Lubetsky, M.J.; Wenger, S.L.; Steele, M.W.

    1995-02-27

    Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance. 5 refs., 1 fig., 2 tabs.

  10. Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

    PubMed

    Sabharwal, Rasna; Chapleau, Mark W

    2014-04-01

    New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

  11. Three-dimensional analysis of abnormal ultrastructural alteration in mitochondria of hippocampus of APP/PSEN1 transgenic mouse.

    PubMed

    Choi, Ki Ju; Kim, Mi Jeong; Je, A Reum; Jun, Sangmi; Lee, Chulhyun; Lee, Eunji; Jo, Mijung; Huh, Yang Hoon; Kweon, Hee-Seok

    2014-03-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The deterioration of subcellular organelles, including the mitochondria, is another major ultrastructural characteristic of AD pathogenesis, in addition to amyloid plaque deposition. However, the three-dimensional (3-D) study of mitochondrial structural alteration in AD remains poorly understood. Therefore, ultrastructural analysis, 3-D electron tomography, and immunogold electron microscopy were performed in the present study to clarify the abnormal structural alterations in mitochondria caused by the progression of AD in APP/PSEN1 transgenic mice, expressing human amyloid precursor protein, as a model for AD. Amyloid beta (A beta) plaques accumulated and dystrophic neurites (DN) developed in the hippocampus of transgenic AD mouse brains. We also identified the loss of peroxiredoxin 3, an endogenous cytoprotective antioxidant enzyme and the accumulation of A beta in the hippocampal mitochondria of transgenic mice, which differs from those in age-matched wild-type mice. The mitochondria in A beta plaque-detected regions were severely disrupted, and the patterns of ultrastructural abnormalities were classified into three groups: disappearance of cristae, swelling of cristae, and bulging of the outer membrane. These results demonstrated that morpho-functional alterations of mitochondria and AD progression are closely associated and may be beneficial in investigating the function of mitochondria in AD pathogenesis.

  12. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  13. Systemic abnormalities in liver disease

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases. PMID:19554648

  14. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

    PubMed

    Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

    2016-03-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼ 0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism.

  15. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4–9 Deletion Mouse Model of Autism

    PubMed Central

    Jaramillo, Thomas C.; Speed, Haley E.; Xuan, Zhong; Reimers, Jeremy M.; Liu, Shunan; Powell, Craig M.

    2016-01-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ~0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4–9, a region implicated in ASD patients. We find that homozygous deletion of exons 4–9 (Shank3e4–9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4–9 heterozygous (HET) and Shank3e4–9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4–9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4–9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4–9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4–9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4–9 mutant mouse model of autism. PMID:26559786

  16. Characterization of physiological phenotypes of dentate gyrus synapses of PDZ1/2 domain-deficient PSD-95-knockin mice.

    PubMed

    Nagura, Hitoshi; Doi, Tomoko; Fujiyoshi, Yoshinori

    2016-03-01

    The hippocampal formation is involved in several important brain functions of animals, such as memory formation and pattern separation, and the synapses in the dentate gyrus (DG) play critical roles as the first step in the hippocampal circuit. Previous studies have reported that mice with genetic modifications of the PDZ1/2 domains of postsynaptic density (PSD)-95 exhibit altered synaptic properties in the DG and impaired hippocampus-dependent behaviors. Based on the involvement of the DG in the regulation of behaviors, these data suggest that the abnormal behavior of these knockin (KI) mice is due partly to altered DG function. Precise understanding of the phenotypes of these mutant mice requires characterization of the synaptic properties of the DG, and here we provide detailed studies of DG synapses. We have demonstrated global changes in the PSD membrane-associated guanylate kinase expression pattern in the DG of mutant mice, and DG synapses in these mice exhibited increased long-term potentiation under a wide range of stimulus intensities, although the N-methyl-d-aspartic acid receptor dependence of the long-term potentiation was unchanged. Furthermore, our data also indicate increased silent synapses in the DG of the KI mice. These findings suggest that abnormal protein expression and physiological properties disrupt the function of DG neurons in these KI mice.

  17. Transgenic Mice Expressing MCP-1 by the Urothelium Demonstrate Bladder Hypersensitivity, Pelvic Pain and Voiding Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study

    PubMed Central

    Wang, Yaoqin; Lutgendorf, Susan; Bradley, Catherine; Schrepf, Andrew; Kreder, Karl; O'Donnell, Michael; Luo, Yi

    2016-01-01

    Monocyte chemoattractant protein-1 (MCP-1) is one of the key chemokines that play important roles in diverse inflammatory and chronic pain conditions. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and voiding dysfunction. To facilitate IC/BPS research, we used transgenic technology to develop a novel urothelial MCP-1 secretion mouse model (URO-MCP-1). A transgene consisting of the uroplakin II gene promoter and the mouse MCP-1 coding sequence with a secretory element was constructed and microinjected. URO-MCP-1 mice were found to express MCP-1 mRNA in the bladder epithelium and MCP-1 protein in the urine, and developed bladder inflammation 24 hours after intravesical administration of a single sub-noxious dose of lipopolysaccharide (LPS). The inflamed bladders of URO-MCP-1 mice exhibited elevated mRNAs for interleukin (IL)-1ß, IL-6, substance P precursor, and nerve growth factor as well as increased macrophage infiltration. In parallel with these phenotypic changes, URO-MCP-1 mice manifested significant functional changes at days 1 and 3 after cystitis induction. These functional changes included pelvic pain as measured by von Frey filament stimulation and voiding dysfunction (increased urinary frequency, reduced average volume voided per micturition, and reduced maximum volume voided per micturition) as measured by micturition cages. Micturition changes remained evident at day 7 after cystitis induction, although these changes were not statistically significant. Control wild-type C57BL/6 mice manifested no clear changes in histological, biochemical and behavioral features after similar cystitis induction with LPS. Taken together, our results indicate that URO-MCP-1 mice are hypersensitive to bladder irritants such as LPS and develop pelvic pain and voiding dysfunction upon cystitis induction, providing a novel model for IC

  18. ETOPOSIDE INDUCES CHROMOSOMAL ABNORMALITIES IN SPERMATOCYTES AND SPERMATOGONIAL STEM CELLS

    SciTech Connect

    Marchetti, F; Pearson, F S; Bishop, J B; Wyrobek, A J

    2005-07-15

    Etoposide (ET) is a chemotherapeutic agent widely used in the treatment of leukemia, lymphomas and many solid tumors, such as testicular and ovarian cancers, that affect patients in their reproductive years. The purpose of the study was to use sperm FISH analyses to characterize the long-term effects of ET on male germ cells. We used a mouse model to characterize the induction of chromosomal aberrations (partial duplications and deletions) and whole chromosomal aneuploidies in sperm of mice treated with a clinical dose of ET. Semen samples were collected at 25 and 49 days after dosing to investigate the effects of ET on meiotic pachytene cells and spermatogonial stem-cells, respectively. ET treatment resulted in major increases in the frequencies of sperm carrying chromosomal aberrations in both meiotic pachytene (27- to 578-fold) and spermatogonial stem-cells (8- to 16-fold), but aneuploid sperm were induced only after treatment of meiotic cells (27-fold) with no persistent effects in stem cells. These results demonstrate that male meiotic germ cells are considerably more sensitive to ET than spermatogonial stem-cell and that increased frequencies of sperm with structural aberrations persist after spermatogonial stem-cell treatment. These findings predict that patients who undergo chemotherapy with ET may have transient elevations in the frequencies of aneuploid sperm, but more importantly, may have persistent elevations in the frequencies of sperm with chromosomal aberrations, placing them at higher risk for abnormal reproductive outcomes long after the end of their chemotherapy.

  19. Chromosomal abnormalities and mental illness.

    PubMed

    MacIntyre, D J; Blackwood, D H R; Porteous, D J; Pickard, B S; Muir, W J

    2003-03-01

    Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.

  20. Mice with cardiac overexpression of PPARγ have impaired repolarization and spontaneous fatal ventricular arrhythmias (Morrow, PPARγ overexpression induces fatal arrhythmias)

    PubMed Central

    Morrow, John P.; Katchman, Alexander; Son, Ni-Huiping; Trent, Chad M.; Khan, Raffay; Shiomi, Takayuki; Huang, Haiyan; Amin, Vaibhav; Lader, Joshua M.; Vasquez, Carolina; Morley, Gregory E.; D'Armiento, Jeanine; Homma, Shunichi; Goldberg, Ira J.; Marx, Steven O.

    2011-01-01

    Background Diabetes and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electrical properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation versus the contribution of global metabolic defects to the increased incidence of sudden death and electrical abnormalities. Methods and Results In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes and obesity, we studied cardiac-specific transgenic mice expressing PPARγ1 via the cardiac α-myosin heavy-chain promoter. The PPARγ-transgenic mice develop abnormal accumulation of intracellular lipids and die as young adults, prior to a significant reduction in systolic function. Using implantable ECG telemeters, we found that these mice have prolongation of the QRS and QT intervals, and spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillation. Isolated cardiomyocytes demonstrated prolonged action potential duration caused by reduced expression and function of the potassium channels responsible for repolarization. Short-term exposure to pioglitazone, a PPARγ agonist, had no effect on mortality or rhythm in WT mice, but further exacerbated the arrhythmic phenotype and increased the mortality in the PPARγ TG mice. Conclusions Our findings support an important link between PPARγ activation, cardiomyocyte lipid accumulation, ion channel remodeling and increased cardiac mortality. PMID:22124376

  1. Haematological abnormalities in mitochondrial disorders

    PubMed Central

    Finsterer, Josef; Frank, Marlies

    2015-01-01

    INTRODUCTION This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as ‘definite’, ‘probable’ or ‘possible’ according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS A total of 46 patients (‘definite’ = 5; ‘probable’ = 9; ‘possible’ = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION MID should be considered if a patient’s abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID:26243978

  2. ABNORMALITY OF SEROTONERGIC NEUROTRANSMISSION IN ANIMAL MODELS OF SUDEP

    PubMed Central

    Feng, Hua-Jun; Faingold, Carl L.

    2015-01-01

    Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGS). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a non-selective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. 5-HT transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared to fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGS. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed. PMID:26272185

  3. Abnormalities of serotonergic neurotransmission in animal models of SUDEP.

    PubMed

    Feng, Hua-Jun; Faingold, Carl L

    2015-08-10

    Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGSs). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a nonselective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. Serotonergic (5-HT) transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram, and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared with the effects of fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGSs. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed. This

  4. Neuropathological changes in transgenic mice carrying copies of a transcriptionally activated Mos protooncogene.

    PubMed

    Propst, F; Rosenberg, M P; Cork, L C; Kovatch, R M; Rauch, S; Westphal, H; Khillan, J; Schulz, N T; Vande Woude, G F; Neumann, P E; Newmann, P E

    1990-12-01

    Independent transgenic mouse lines carrying the mouse Mos protooncogene linked to a retroviral transcriptional control sequence display behavioral abnormalities including circling, head tilting, and head bobbing. This dominant phenotype shows various degrees of penetrance in different transgenic founder animals and lines. Neuronal and axonal degeneration, gliosis, and inflammatory infiltrates are found in all transgenic mouse lines in which behavioral traits are present. Recordings of auditory-evoked potentials in mice of one of these lines demonstrate that transgenic mice are deaf; in these mice spiral ganglia degenerate and most of the cochlear hair cells are absent. By using an S1 nuclease protection assay, we have detected RNA expression of the transgene in all tissues examined and, in particular, at high levels in brain. In situ hybridization experiments show that Mos expression can be detected in specific areas of the central nervous system. Lesions are present in areas with demonstrable overexpression of Mos.

  5. Slc4a11 Gene Disruption in Mice

    PubMed Central

    Lopez, Ivan A.; Rosenblatt, Mark I.; Kim, Charles; Galbraith, Gary C.; Jones, Sherri M.; Kao, Liyo; Newman, Debra; Liu, Weixin; Yeh, Stacey; Pushkin, Alexander; Abuladze, Natalia; Kurtz, Ira

    2009-01-01

    NaBC1 (the SLC4A11 gene) belongs to the SLC4 family of sodium-coupled bicarbonate (carbonate) transporter proteins and functions as an electrogenic sodium borate cotransporter. Mutations in SLC4A11 cause either corneal abnormalities (corneal hereditary dystrophy type 2) or a combined auditory and visual impairment (Harboyan syndrome). The role of NaBC1 in sensory systems is poorly understood, given the difficulty of studying patients with NaBC1 mutations. We report our findings in Slc4a11−/− mice generated to investigate the role of NaBC1 in sensorineural systems. In wild-type mice, specific NaBC1 immunoreactivity was detected in fibrocytes of the spiral ligament, from the basal to the apical portion of the cochlea. NaBC1 immunoreactivity was present in the vestibular labyrinth, in stromal cells underneath the non-immunoreactive sensory epithelia of the macula utricle, sacule, and crista ampullaris, and the membranous vestibular labyrinth was collapsed. Both auditory brain response and vestibular evoked potential waveforms were significantly abnormal in Slc4a11−/− mice. In the cornea, NaBC1 was highly expressed in the endothelial cell layer with less staining in epithelial cells. However, unlike humans, the corneal phenotype was mild with a normal slit lamp evaluation. Corneal endothelial cells were morphologically normal; however, both the absolute height of the corneal basal epithelial cells and the relative basal epithelial cell/total corneal thickness were significantly increased in Slc4a11−/− mice. Our results demonstrate for the first time the importance of NaBC1 in the audio-vestibular system and provide support for the hypothesis that SLC4A11 should be considered a potential candidate gene in patients with isolated sensorineural vestibular hearing abnormalities. PMID:19586905

  6. Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function.

    PubMed

    Allen, Justin M; Zamurs, Laura; Brachvogel, Bent; Schlötzer-Schrehardt, Ursula; Hansen, Uwe; Lamandé, Shireen R; Rowley, Lynn; Fitzgerald, Jamie; Bateman, John F

    2009-05-01

    WARP is a recently identified extracellular matrix molecule with restricted expression in permanent cartilages and a distinct subset of basement membranes in peripheral nerves, muscle, and the central nervous system vasculature. WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures. To understand the in vivo function of WARP, we generated a WARP-deficient mouse strain. WARP-null mice were healthy, viable, and fertile with no overt abnormalities. Motor function and behavioral testing demonstrated that WARP-null mice exhibited a significantly delayed response to acute painful stimulus and impaired fine motor coordination, although general motor function was not affected, suggesting compromised peripheral nerve function. Immunostaining of WARP-interacting ligands demonstrated that the collagen VI microfibrillar matrix was severely reduced and mislocalized in peripheral nerves of WARP-null mice. Further ultrastructural analysis revealed reduced fibrillar collagen deposition within the peripheral nerve extracellular matrix and abnormal partial fusing of adjacent Schwann cell basement membranes, suggesting an important function for WARP in stabilizing the association of the collagenous interstitial matrix with the Schwann cell basement membrane. In contrast, other WARP-deficient tissues such as articular cartilage, intervertebral discs, and skeletal muscle showed no detectable abnormalities, and basement membranes formed normally. Our data demonstrate that although WARP is not essential for basement membrane formation or musculoskeletal development, it has critical roles in the structure and function of peripheral nerves.

  7. Congenital abnormalities and selective abortion.

    PubMed

    Seller, M J

    1976-09-01

    The technique of amniocentesis, by which an abnormal fetus can be detected in utero, has brought a technological advance in medical science but attendant medical and moral problems. Dr Seller describes those congenital disabilities which can be detected in the fetus before birth, for which the "remedy" is selective abortion. She then discusses the arguments for and against selective abortion, for the issue is not simple, even in the strictly genetic sense of attempting to ensure a population free of congenital abnormality.

  8. High-Resolution Magnetic Resonance Microscopy and Diffusion Tensor Imaging to Assess Brain Structural Abnormalities in the Murine Mucopolysaccharidosis VII Model

    PubMed Central

    Poptani, Harish; Kumar, Manoj; Nasrallah, Ilya M; Kim, Sungheon; Ittyerah, Ranjit; Pickup, Stephen; Li, Joel; Parente, Michael K; Wolfe, John H.

    2014-01-01

    High-resolution microscopic magnetic resonance imaging (μMRI) and diffusion tensor imaging (DTI) were performed to characterize brain structural abnormalities in a mouse model of mucopolysaccharidosis type VII (MPS VII). μMRI demonstrated a decrease in the volume of anterior commissure and corpus callosum and a slight increase in the volume of the hippocampus in MPS VII vs. wild-type mice. DTI indices were analyzed in gray and white matter. In vivo and ex vivo DTI demonstrated significantly reduced fractional anisotropy in the anterior commissure, corpus callosum, external capsule and hippocampus in MPS VII vs. control brains. Significantly increased mean diffusivity was also found in the anterior commissure and corpus callosum from ex-vivo DTI. Significantly reduced linear anisotropy was observed from the hippocampus from in-vivo DTI, whereas significantly decreased planar anisotropy and spherical anisotropy were observed in the external capsule from only ex-vivo DTI. There were corresponding morphological differences in the brains of MPS VII mice by hematoxylin and eosin staining. Luxol fast blue staining demonstrated less intense staining of the corpus callosum and external capsule; myelin abnormalities in the corpus callosum were also demonstrated quantitatively in toluidine blue-stained sections and confirmed by electron microscopy. These results demonstrate the potential for μMRI and DTI for quantitative assessment of brain pathology in murine models of brain diseases. PMID:24335527

  9. Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

    PubMed

    Mito, Takayuki; Kikkawa, Yoshiaki; Shimizu, Akinori; Hashizume, Osamu; Katada, Shun; Imanishi, Hirotake; Ota, Azusa; Kato, Yukina; Nakada, Kazuto; Hayashi, Jun-Ichi

    2013-01-01

    Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J) nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0)) mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

  10. Mitochondrial DNA Mutations in Mutator Mice Confer Respiration Defects and B-Cell Lymphoma Development

    PubMed Central

    Mito, Takayuki; Kikkawa, Yoshiaki; Shimizu, Akinori; Hashizume, Osamu; Katada, Shun; Imanishi, Hirotake; Ota, Azusa; Kato, Yukina; Nakada, Kazuto; Hayashi, Jun-Ichi

    2013-01-01

    Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J) nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ0) mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan. PMID:23418460

  11. Abnormal plasticity in dystonia: Disruption of synaptic homeostasis.

    PubMed

    Quartarone, Angelo; Pisani, Antonio

    2011-05-01

    Work over the past two decades lead to substantial changes in our understanding of dystonia, which was, until recently, considered an exclusively sporadic movement disorder. The discovery of several gene mutations responsible for many inherited forms of dystonia has prompted much effort in the generation of transgenic mouse models bearing mutations found in patients. The large majority of these rodent models do not exhibit overt phenotypic abnormalities, or neuronal loss in specific brain areas. Nevertheless, both subtle motor abnormalities and significant alterations of synaptic plasticity have been recorded in mice, suggestive of an altered basal ganglia circuitry. In addition, robust evidence from experimental and clinical work supports the assumption that dystonia may indeed be considered a disorder linked to the disruption of synaptic "scaling", with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. Notably, neurophysiological studies from patients carrying gene mutations as well as from non-manifesting carriers have shown the presence of synaptic plasticity abnormalities, indicating the presence of specific endophenotypic traits in carriers of the gene mutation. In this survey, we review findings from a broad range of data, obtained both from animal models and human research, and propose that the abnormalities of synaptic plasticity described in mice and humans may be considered an endophenotype to dystonia, and a valid and powerful tool to investigate the pathogenic mechanisms underlying this movement disorder. This article is part of a Special Issue entitled "Advances in dystonia".

  12. Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men

    PubMed Central

    Yang, Jasmine J.; Caligioni, Claudia S.; Chan, Yee-Ming

    2012-01-01

    Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3−/− mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, and fertility. Tacr3−/− mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3−/− males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3−/− females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3−/− females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3−/− females achieved fertility when mated. However, Tacr3−/− females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release. PMID:22253416

  13. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).

    PubMed

    Nykjaer, A; Fyfe, J C; Kozyraki, R; Leheste, J R; Jacobsen, C; Nielsen, M S; Verroust, P J; Aminoff, M; de la Chapelle, A; Moestrup, S K; Ray, R; Gliemann, J; Willnow, T E; Christensen, E I

    2001-11-20

    Steroid hormones are central regulators of a variety of biological processes. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D(3) complexed to its plasma carrier, the vitamin D-binding protein, enters renal proximal tubules by receptor-mediated endocytosis. Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D(3) in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabolism. Similarly, human patients with mutations causing cubilin dysfunction exhibit urinary excretion of 25(OH) vitamin D(3). This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.

  14. Effect of chrysotile asbestos fibers on germ cells of mice

    SciTech Connect

    Rita, P.; Reddy, P.P.

    1986-10-01

    An Indian form of chrysotile asbestos procured from a local asbestos factory (Hyderabad) was tested for its toxic effects on spermatocytes and sperm of mice. Swiss albino male mice were fed orally with chrysotile asbestos suspended in water. The concentration tested was 20 mg/kg/day. Chronic oral administration of chrysotile failed to induce chromosomal aberrations and abnormal sperms in mice.

  15. Exacerbated experimental colitis in TNFAIP8-deficient mice.

    PubMed

    Sun, Honghong; Lou, Yunwei; Porturas, Thomas; Morrissey, Samantha; Luo, George; Qi, Ji; Ruan, Qingguo; Shi, Songlin; Chen, Youhai H

    2015-06-15

    The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiologic and pathologic functions are unclear. In this study, we describe the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation. TIPE-deficient mice were generated by germ line gene targeting and were born without noticeable developmental abnormalities. Their major organs, including lymphoid organs and intestines, were macroscopically and microscopically normal. However, after drinking dextran sodium sulfate-containing water, TIPE-deficient mice developed more severe colitis than wild type mice did, as demonstrated by decreased survival rates, increased body weight loss, and enhanced leukocyte infiltration, bacterial invasion, and inflammatory cytokine production in the colon. Bone marrow chimeric experiments revealed that TIPE deficiency in nonhematopoietic cells was responsible for the exacerbated colitis in TIPE-deficient mice. Consistent with this result, TIPE-deficient intestinal epithelial cells had increased rate of cell death and decreased rate of proliferation as compared with wild type controls. These findings indicate that TIPE plays an important role in maintaining colon homeostasis and in protecting against colitis.

  16. Exacerbated Experimental Colitis In TNFAIP8-deficient Mice

    PubMed Central

    Sun, Honghong; Lou, Yunwei; Porturas, Thomas; Morrissey, Samantha; Luo, George; Qi, Ji; Ruan, Qingguo; Shi, Songlin; Chen, Youhai H.

    2015-01-01

    The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiological and pathological functions are unclear. We describe here the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation. TIPE-deficient mice were generated by germ line gene targeting and were born without noticeable developmental abnormalities. Their major organs including lymphoid organs and intestines were macroscopically and microscopically normal. However, after drinking dextran sodium sulfate-containing water, TIPE-deficient mice developed more severe colitis than wild type mice, as demonstrated by decreased survival rates, increased body weight loss, and enhanced leukocyte infiltration, bacterial invasion, and inflammatory cytokine production in the colon. Bone marrow chimeric experiments revealed that TIPE deficiency in non-hematopoietic cells was responsible for the exacerbated colitis in TIPE-deficient mice. Consistent with this result, TIPE-deficient intestinal epithelial cells had increased rate of cell death and decreased rate of proliferation as compared to wild type controls. Taken together, these findings indicate that TIPE plays an important role in maintaining colon homeostasis and in protecting against colitis. PMID:25948814

  17. [Diagnosticum of abnormalities of plant meiotic division].

    PubMed

    Shamina, N V

    2006-01-01

    Abnormalities of plant meiotic division leading to abnormal meiotic products are summarized schematically in the paper. Causes of formation of monads, abnormal diads, triads, pentads, polyads, etc. have been observed in meiosis with both successive and simultaneous cytokinesis.

  18. Evidence of proteinuria, but no other characteristics of pre-eclampsia, in relaxin-deficient mice.

    PubMed

    O'Sullivan, Kelly P; Marshall, Sarah A; Cullen, Scott; Saunders, Tahnee; Hannan, Natalie J; Senadheera, Sevvandi N; Parry, Laura J

    2016-08-04

    Pre-eclampsia (PE) is a leading cause of maternal and fetal death, characterised by an imbalance of placental growth factors and hypertension at >20 weeks gestation. Impaired maternal systemic vascular adaptations and fetal growth restriction are features of both PE and pregnant relaxin-deficient (Rln-/-) mice. The aim of the present study was to investigate whether these phenotypes in Rln-/- mice are associated with abnormal placental growth factor expression, increased soluble fms-like tyrosine kinase-1 (sFlt-1), proteinuria and/or hypertension during pregnancy. In addition, we examined relaxin and relaxin receptor (relaxin/insulin like family peptide receptor 1 (RXFP1)) mRNA expression in placentas of women with PE. There was no significant difference in placental vascular endothelial growth factor A (VegfA) and placenta growth factor (Plgf) gene expression between Rln-/- and wild-type mice. Circulating plasma sFlt-1 concentrations in pregnant mice of both genotypes and ages were increased compared with non-pregnant mice but were lower in younger pregnant Rln-/- mice compared with aged-matched Rln+/+ mice. Aged pregnant Rln-/- mice had higher urinary albumin:creatinine ratios compared with age-matched Rln+/+ mice, indicative of proteinuria. Systolic and diastolic blood pressures did not differ between genotypes. In addition, PE in women was not associated with altered placental mRNA expression of RLN2 or RXFP1 at term. Overall, the data demonstrate that pregnant Rln-/- mice do not have the typical characteristics of PE. However, these mice show evidence of proteinuria, but we suggest that this results from systemic renal vascular dysfunction before pregnancy.

  19. Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation

    PubMed Central

    Maeshima, Keisuke; Stanford, Stephanie M.; Hammaker, Deepa; Sacchetti, Cristiano; Zeng, Li-fan; Ai, Rizi; Zhang, Vida; Boyle, David L.; Aleman Muench, German R.; Feng, Gen-Sheng; Whitaker, John W.; Zhang, Zhong-Yin; Wang, Wei; Bottini, Nunzio; Firestein, Gary S.

    2016-01-01

    The PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for PTPN11 overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in PTPN11 intron 1, which contained a glucocorticoid receptor–binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS. RA FLS stimulation with the glucocorticoid dexamethasone induced GR binding to the enhancer and PTPN11 expression. Glucocorticoid responsiveness of PTPN11 was significantly higher in RA FLS than OA FLS and required the differentially methylated CpGs for full enhancer function. SHP-2 expression was enriched in the RA synovial lining, and heterozygous Ptpn11 deletion in radioresistant or innate immune cells attenuated K/BxN serum transfer arthritis in mice. Treatment with SHP-2 inhibitor 11a-1 reduced RA FLS migration and responsiveness to TNF and IL-1β stimulation and reduced arthritis severity in mice. Our findings demonstrate how abnormal epigenetic regulation of a pathogenic gene determines FLS behavior and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for RA. PMID:27275015

  20. Discoidin domain receptor 2 (DDR2) regulates body size and fat metabolism in mice.

    PubMed

    Kawai, Ikuma; Matsumura, Hirokazu; Fujii, Wataru; Naito, Kunihiko; Kusakabe, Ken; Kiso, Yasuo; Kano, Kiyoshi

    2014-02-01

    Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens, which act as its endogenous ligand. DDR2 regulates cell proliferation, cell adhesion, migration, extracellular matrix remodeling and reproductive functions. Both DDR2 null allele mice and mice with a recessive, loss-of-function allele for Ddr2 exhibit dwarfing and a reduction in body weight. However, the detailed mechanisms by which DDR2 exerts its positive systemic regulation of whole body size, local skeletal size and fat tissue volume remain to be clarified. To investigate the systemic role of DDR2 in body size regulation, we produced transgenic mice in which the DDR2 protein is overexpressed, then screened the transgenic mice for abnormalities using systematic mouse abnormality screening. The modified-SHIPRA screen revealed that only the parameter of body size was significantly different among the genotypes. We also discovered that the body length was significantly increased, while the body weight was significantly decreased in transgenic mice compared to their littermate controls. We also found that the epididymal fat pads were significantly decreased in transgenic mice compared to normal littermate mice, which may have been the cause of the leptin decrement in the transgenic mice. The new insight that DDR2 might promote metabolism in adipocyte cells is very interesting, but more experiments will be needed to elucidate the direct relation between DDR2 and adipose-derived hormones. Taken together, our data demonstrated that DDR2 might play a systemic role in the regulation of body size thorough skeletal formation and fat metabolism.

  1. Genetic and phenotypic properties of vero cell-adapted Japanese encephalitis virus SA14-14-2 vaccine strain variants and a recombinant clone, which demonstrates attenuation and immunogenicity in mice.

    PubMed

    Gromowski, Gregory D; Firestone, Cai-Yen; Bustos-Arriaga, José; Whitehead, Stephen S

    2015-01-01

    The live-attenuated Japanese encephalitis virus (JEV) SA14-14-2 vaccine, produced in primary hamster kidney cells, is safe and effective. Past attempts to adapt this virus to replicate in cells that are more favorable for vaccine production resulted in mutations that significantly reduced immunogenicity. In this study, 10 genetically distinct Vero cell-adapted JEV SA14-14-2 variants were isolated and a recombinant wild-type JEV clone, modified to contain the JEV SA14-14-2 polyprotein amino acid sequence, was recovered in Vero cells. A single capsid protein mutation (S66L) was important for Vero cell-adaptation. Mutations were also identified that modulated virus sensitivity to type I interferon-stimulation in Vero cells. A subset of JEV SA14-14-2 variants and the recombinant clone were evaluated in vivo and exhibited levels of attenuation that varied significantly in suckling mice, but were avirulent and highly immunogenic in weanling mice and are promising candidates for the development of a second-generation, recombinant vaccine.

  2. Magnetic resonance imaging and histological studies of corpus callosal and hippocampal abnormalities linked to doublecortin deficiency.

    PubMed

    Kappeler, Caroline; Dhenain, Marc; Phan Dinh Tuy, Françoise; Saillour, Yoann; Marty, Serge; Fallet-Bianco, Catherine; Souville, Isabelle; Souil, Evelyne; Pinard, Jean-Marc; Meyer, Gundela; Encha-Razavi, Ferechté; Volk, Andreas; Beldjord, Cherif; Chelly, Jamel; Francis, Fiona

    2007-01-10

    Mutated doublecortin (DCX) gives rise to severe abnormalities in human cortical development. Adult Dcx knockout mice show no major neocortical defects but do have a disorganized hippocampus. We report here the developmental basis of these hippocampal abnormalities. A heterotopic band of neurons was identified starting at E17.5 in the CA3 region and progressing throughout the CA1 region by E18.5. At neonatal stages, the CA1 heterotopic band was reduced, but the CA3 band remained unchanged, continuing into adulthood. Thus, in mouse, migration of CA3 neurons is arrested during development, whereas CA1 cell migration is retarded. On the Sv129Pas background, magnetic resonance imaging (MRI) also suggested abnormal dorsal hippocampal morphology, displaced laterally and sometimes rostrally and associated with medial brain structure abnormalities. MRI and cryosectioning showed agenesis of the corpus callosum in Dcx knockout mice on this background and an intermediate, partial agenesis in heterozygote mice. Wild-type littermates showed no callosal abnormalities. Hippocampal and corpus callosal abnormalities were also characterized in DCX-mutated human patients. Severe hippocampal hypoplasia was identified along with variable corpus callosal defects ranging from total agenesis to an abnormally thick or thin callosum. Our data in the mouse, identifying roles for Dcx in hippocampal and corpus callosal development, might suggest intrinsic roles for human DCX in the development of these structures.

  3. Interleukin-11 alters placentation and causes preeclampsia features in mice

    PubMed Central

    Winship, Amy L.; Koga, Kaori; Menkhorst, Ellen; Van Sinderen, Michelle; Rainczuk, Katarzyna; Nagai, Miwako; Cuman, Carly; Yap, Joanne; Zhang, Jian-Guo; Simmons, David; Young, Morag J.; Dimitriadis, Evdokia

    2015-01-01

    Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and proteinuria after 20 wk gestation. Abnormal extravillous trophoblast (EVT) invasion and remodeling of uterine spiral arterioles is thought to contribute to PE development. Interleukin-11 (IL11) impedes human EVT invasion in vitro and is elevated in PE decidua in women. We demonstrate that IL11 administered to mice causes development of PE features. Immunohistochemistry shows IL11 compromises trophoblast invasion, spiral artery remodeling, and placentation, leading to increased systolic blood pressure (SBP), proteinuria, and intrauterine growth restriction, although nonpregnant mice were unaffected. Real-time PCR array analysis identified pregnancy-associated plasma protein A2 (PAPPA2), associated with PE in women, as an IL11 regulated target. IL11 increased PAPPA2 serum and placental tissue levels in mice. In vitro, IL11 compromised primary human EVT invasion, whereas siRNA knockdown of PAPPA2 alleviated the effect. Genes regulating uterine natural killer (uNK) recruitment and differentiation were down-regulated and uNK cells were reduced after IL11 treatment in mice. IL11 withdrawal in mice at onset of PE features reduced SBP and proteinuria to control levels and alleviated placental labyrinth defects. In women, placental IL11 immunostaining levels increased in PE pregnancies and in serum collected from women before development of early-onset PE, shown by ELISA. These results indicate that elevated IL11 levels result in physiological changes at the maternal–fetal interface, contribute to abnormal placentation, and lead to the development of PE. Targeting placental IL11 may provide a new treatment option for PE. PMID:26655736

  4. Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder.

    PubMed

    Faust, P L; Hatten, M E

    1997-12-01

    Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2-deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2-deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar-lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease.

  5. Severe hearing loss in Dlxl mutant mice.

    PubMed

    Polley, Daniel B; Cobos, Inma; Merzenich, Michael M; Rubenstein, John L R

    2006-04-01

    The Dlx homeobox gene family participates in regulating middle and inner ear development. A significant role for Dlxl, in particular,has been demonstrated in the development of the middle ear ossicles, but the functional consequences of Dlx.l gene mutation on hearing thresholds has not been assessed. The present study characterizes auditory brainstem responses to click and tonal stimuli in a non-lethal variant of a Dlxl gene knockout. We found that peripheral hearing thresholds for click and tonal stimuli were significantly elevated in homozygous Dlxl knockout (Dlxl-/ ) compared to both heterozygous (Dlxl+/ ) and wild type (Dlxl+/+) mice. Thus, abnormal mor-phogenesis of the incus and stapes that has been documented previously with histological measures is now known to result in a severe peripheral hearing deficit.

  6. Coffee improves auditory neuropathy in diabetic mice.

    PubMed

    Hong, Bin Na; Yi, Tae Hoo; Park, Raekil; Kim, Sun Yeou; Kang, Tong Ho

    2008-08-29

    Coffee is a widely consumed beverage and has recently received considerable attention for its possible beneficial effects. Auditory neuropathy is a hearing disorder characterized by an abnormal auditory brainstem response. This study examined the auditory neuropathy induced by diabetes and investigated the action of coffee, trigonelline, and caffeine to determine whether they improved diabetic auditory neuropathy in mice. Auditory brainstem responses, auditory middle latency responses, and otoacoustic emissions were evaluated to assess auditory neuropathy. Coffee or trigonelline ameliorated the hearing threshold shift and delayed latency of the auditory evoked potential in diabetic neuropathy. These findings demonstrate that diabetes can produce a mouse model of auditory neuropathy and that coffee consumption potentially facilitates recovery from diabetes-induced auditory neuropathy. Furthermore, the active constituent in coffee may be trigonelline.

  7. Abnormal insulin levels and vertigo.

    PubMed

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  8. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  9. Repetitive Closed-Skull Traumatic Brain Injury in Mice Causes Persistent Multifocal Axonal Injury and Microglial Reactivity

    PubMed Central

    Shitaka, Yoshitsugu; Tran, Hien T.; Bennett, Rachel E.; Sanchez, Laura; Levy, Marilyn A.; Dikranian, Krikor; Brody, David L.

    2011-01-01

    Repetitive mild or “concussive” traumatic brain injury (TBI) can cause substantial neurological impairment, but the pathology of TBI is not well understood. We report an experimental model of TBI in which the closed skulls of anesthetized male C57BL/6J mice are struck with an electromagnetically controlled rubber impactor twice with an interval of 24 hours between impacts. The mice had deficits in Morris water maze performance in the first week after injury that only partially resolved 7 weeks later. By routine histology there was no apparent bleeding, neuronal cell loss, or tissue disruption and amyloid precursor protein immunohistochemistry demonstrated very few immunoreactive axonal varicosities. In contrast, silver staining revealed extensive abnormalities in the corpus callosum and bilateral external capsule, the ipsilateral cortex and thalamus, and the contralateral hippocampal CA1 stratum radiatum and stratum oriens. Electron microscopy of white matter regions demonstrated axonal cytoskeletal disruption, intra-axonal organelle compaction and irregularities in axon caliber. Reactive microglia were observed in the same areas as the injured axons by both electron microscopy and Iba1 immunohistochemistry. Quantitative analyses of silver staining and Iba1 immunohistochemistry at multiple time points demonstrated transient cortical and thalamic abnormalities; white matter axonal cytoskeletal abnormalities and microglial reaction persisted to 7 weeks after injury. Thus, prominent and long-lasting abnormalities in this TBI model were underestimated using conventional approaches. The model may be useful for mechanistic investigations and preclinical assessment of candidate therapeutics. PMID:21666502

  10. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization

    PubMed Central

    Liu, Kun; Zhao, Enpeng; Ilyas, Ghulam; Lalazar, Gadi; Lin, Yu; Haseeb, Muhammad; Tanaka, Kathryn E; Czaja, Mark J

    2015-01-01

    Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury. PMID:25650776

  11. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization.

    PubMed

    Liu, Kun; Zhao, Enpeng; Ilyas, Ghulam; Lalazar, Gadi; Lin, Yu; Haseeb, Muhammad; Tanaka, Kathryn E; Czaja, Mark J

    2015-01-01

    Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.

  12. A critical role of solute carrier 22a14 in sperm motility and male fertility in mice

    PubMed Central

    Maruyama, Shin-ya; Ito, Momoe; Ikami, Yuusuke; Okitsu, Yu; Ito, Chizuru; Toshimori, Kiyotaka; Fujii, Wataru; Yogo, Keiichiro

    2016-01-01

    We previously identified solute carrier 22a14 (Slc22a14) as a spermatogenesis-associated transmembrane protein in mice. Although Slc22a14 is a member of the organic anion/cation transporter family, its expression profile and physiological role have not been elucidated. Here, we show that Slc22a14 is crucial for sperm motility and male fertility in mice. Slc22a14 is expressed specifically in male germ cells, and mice lacking the Slc22a14 gene show severe male infertility. Although the overall differentiation of sperm was normal, Slc22a14−/− cauda epididymal spermatozoa showed reduced motility with abnormal flagellar bending. Further, the ability to migrate into the female reproductive tract and fertilise the oocyte were also impaired in Slc22a14−/− spermatozoa. The abnormal flagellar bending was thought to be partly caused by osmotic cell swelling since osmotic challenge or membrane permeabilisation treatment alleviated the tail abnormality. In addition, we found structural abnormalities in Slc22a14−/− sperm cells: the annulus, a ring-like structure at the mid-piece–principal piece junction, was disorganised, and expression and localisation of septin 4, an annulus component protein that is essential for the annulus formation, was also impaired. Taken together, our results demonstrated that Slc22a14 plays a pivotal role in normal flagellar structure, motility and fertility in mouse spermatozoa. PMID:27811987

  13. Ectodermal dysplasia and abnormal thumbs.

    PubMed

    Lucky, A W; Esterly, N B; Tunnessen, W W

    1980-05-01

    Two unrelated children, a girl and a boy, with alopecia, anomalous cutaneous pigmentation, abnormal thumbs, and endocrine disorders, including short stature and delayed bone age in one patient and juvenile onset diabetes mellitus in the other, are described. In one instance, the mother and the maternal grandmother had similar abnormalities, although of a less severe nature. Both children had normal nails and no unusual susceptibility to infections. We believe these two patients represent a previously undescribed syndrome of ectodermal dysplasia that may be inherited as an autosomal-dominant trait.

  14. Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA damage and abnormal chromatin packaging.

    PubMed

    Riel, Jonathan M; Yamauchi, Yasuhiro; Sugawara, Atsushi; Li, Ho Yan J; Ruthig, Victor; Stoytcheva, Zoia; Ellis, Peter J I; Cocquet, Julie; Ward, Monika A

    2013-02-01

    In mouse and man Y chromosome deletions are frequently associated with spermatogenic defects. Mice with extensive deletions of non-pairing Y chromosome long arm (NPYq) are infertile and produce sperm with grossly misshapen heads, abnormal chromatin packaging and DNA damage. The NPYq-encoded multi-copy gene Sly controls the expression of sex chromosome genes after meiosis and Sly deficiency results in a remarkable upregulation of sex chromosome genes. Sly deficiency has been shown to be the underlying cause of the sperm head anomalies and infertility associated with NPYq gene loss, but it was not known whether it recapitulates sperm DNA damage phenotype. We produced and examined mice with transgenically (RNAi) silenced Sly and demonstrated that these mice have increased incidence of sperm with DNA damage and poorly condensed and insufficiently protaminated chromatin. We also investigated the contribution of each of the two Sly-encoded transcript variants and noted that the phenotype was only observed when both variants were knocked down, and that the phenotype was intermediate in severity compared with mice with severe NPYq deficiency. Our data demonstrate that Sly deficiency is responsible for the sperm DNA damage/chromatin packaging defects observed in mice with NPYq deletions and point to SLY proteins involvement in chromatin reprogramming during spermiogenesis, probably through their effect on the post-meiotic expression of spermiogenic genes. Considering the importance of the sperm epigenome for embryonic and fetal development and the possibility of its inter-generational transmission, our results are important for future investigations of the molecular mechanisms of this biologically and clinically important process.

  15. Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

    PubMed

    Milekic, M H; Xin, Y; O'Donnell, A; Kumar, K K; Bradley-Moore, M; Malaspina, D; Moore, H; Brunner, D; Ge, Y; Edwards, J; Paul, S; Haghighi, F G; Gingrich, J A

    2015-08-01

    Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.

  16. Vestibular abnormalities in congenital disorders.

    PubMed

    Sando, I; Orita, Y; Miura, M; Balaban, C D

    2001-10-01

    This paper reviews the histopathologic features of vestibular abnormalities in congenital disorders affecting the inner ear, based upon a comprehensive literature survey and a review of cases in our temporal bone collection. The review proceeds in three systematic steps. First, we surveyed associated diseases with the major phenotypic features of congenital abnormalities of the inner ear (including the internal auditory canal and otic capsule). Second, the vestibular anomalies are examined specifically. Finally, the anomalies are discussed from a developmental perspective. Among vestibular anomalies, a hypoplastic endolymphatic duct and sac are observed most frequently. Anomalies of the semicircular canals are also often observed. From embryological and clinical viewpoints, many of these resemble the structural features from fetal stages and appear to be associated with vestibular dysfunction. It is expected that progress in genetic analysis and accumulation of temporal bone specimens with vestibular abnormalities in congenital diseases will provide crucial information not only for pathology of those diseases, but also for genetic factors that are responsible for the specific vestibular abnormalities.

  17. Origin and course of the coronary arteries in normal mice and in iv/iv mice

    PubMed Central

    ICARDO, JOSÉ M.; COLVEE, ELVIRA

    2001-01-01

    This paper reports on the origin and distribution of the coronary arteries in normal mice and in mice of the iv/iv strain, which show situs inversus and heterotaxia. The coronary arteries were studied by direct observation of the aortic sinuses with the scanning electron microscope, and by examination of vascular corrosion casts. In the normal mouse, the left and right coronaries (LC, RC) arise from the respective Valsalva sinus and course along the ventricular borders to reach the heart apex. Along this course the coronary arteries give off small branches at perpendicular or acute angles to supply the ventricles. The ventricular septum is supplied by the septal artery, which arises as a main branch from the right coronary. Conus arteries arise from the main coronary trunks, from the septal artery and/or directly from the Valsalva sinus. The vascular casts demonstrate the presence of intercoronary anastomoses. The origin of the coronary arteries was found to be abnormal in 84% of the iv/iv mice. These anomalies included double origin, high take-off, slit-like openings and the presence of a single coronary orifice. These anomalies occurred singly or in any combination, and were independent of heart situs. The septal artery originated from RC in most cases of situs solitus but originated predominantly from LC in situs inversus hearts. Except for this anomalous origin no statistical correlation was found between the coronary anomalies and heart situs or a particular mode of heterotaxia. The coronary anomalies observed in the iv/iv mice are similar to those found in human hearts. Most coronary anomalies appear to be due to defective connections between the aortic root and the developing coronaries. iv/iv mice may therefore constitute a good model to study the development of similar anomalies in the human heart. PMID:11693308

  18. Novel brain MRI abnormalities in Gitelman syndrome

    PubMed Central

    Norbash, Alexander; Vattoth, Surjith

    2015-01-01

    Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. The syndrome is caused by a defective thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubules of the kidneys. Gitelman syndrome could be confused with Bartter syndrome; the main differentiating feature is the presence of low urinary calcium excretion in the former. Descriptions of neuroradiological imaging findings associated with Gitelman syndrome are very scarce in the literature and include basal ganglia calcification, idiopathic intracranial hypertension and sclerochoroidal calcification. Cauda equina syndrome-like presentation has been reported, but without any corresponding imaging findings on lumbar spine MRI. We report a 13-year-old male with Gitelman syndrome who presented with altered mental status following a fall and scalp laceration and unremarkable brain CT, followed during hospitalization by somnolence and seizures. Metabolically the patient demonstrated hypokalemia and hypomagnesemia. MRI demonstrated features of encephalopathy including predominantly right-sided cerebral hemispheric signal abnormality and cytotoxic edema, with bilateral symmetric involvement of the thalami, midbrain tegmentum and tectum and cerebellar dentate nuclei. MRI after five months obtained during a later episode of encephalopathy showed resolution of the signal abnormalities with setting in of brain atrophy and also areas of newly developed cytotoxic edema in the left thalamus, bilateral dorsal midbrain and right greater than left dentate nuclei. The described abnormalities, either recurrent or in isolation, have not previously been published in patients with Gitelman syndrome. We believe that the findings are due to alteration of respiratory chain function secondary to the metabolic derangement and hence have a similar imaging appearance as encephalopathy related to mitochondrial cytopathy or

  19. Abnormal movements in sleep as a post-polio sequelae.

    PubMed

    Bruno, R L

    1998-01-01

    Nearly two-thirds of polio survivors report abnormal movements in sleep, with 52% reporting that their sleep is disturbed by these movements. Sleep studies were performed in seven polio survivors to document objectively abnormal movements in sleep. Two patients demonstrated generalized random myoclonus, with brief contractions and even ballistic movements of the arms and legs, slow repeated grasping movements of the hands, slow flexion of the arms, and contraction of the shoulder and pectoral muscles. Two other patients demonstrated periodic movements in sleep with muscle contractions and ballistic movements of the legs, two had periodic movements in sleep plus restless legs syndrome, and one had sleep starts involving only contraction of the arm muscles. Abnormal movements in sleep occurred in Stage II sleep in all patients, in Stage I in some patients, and could significantly disturb sleep architecture even though patients were totally unaware of muscle contractions. Poliovirus-induced damage to the spinal cord and brain is presented as a possible cause of abnormal movements in sleep. The diagnosis of post-polio fatigue, evaluation of abnormal movements in sleep, and management of abnormal movements in sleep using benzodiazepines or dopamimetic agents are described.

  20. Increased recombination frequency showing evidence of loss of interference is associated with abnormal testicular histopathology.

    PubMed

    Varmuza, Susannah; Ling, Ling

    2003-04-01

    Nondisjunction leading to aneuploid gametes has been linked genetically to both increases and decreases in recombination frequency on the aneuploid chromosome. In the present study, we present physical evidence of increased frequency of recombination nodules as measured by Mut-S-like homologue-1 (MLH1) foci on pachytene chromosomes from sterile male mice homozygous for a mutation in the protein phosphatase 1cgamma (PP1cgamma) gene. The pattern of elevated recombination frequency in PP1cgamma mutant spermatocytes is consistent with a loss of interference. Previous studies demonstrated: (1) spermiogenesis is impaired starting at step 8 with a severe reduction in elongating and condensed spermatids; (2) spermatids and sperm exhibit elevated rates of DNA fragmentation; and (3) haploid gametes exhibit elevated levels of aneuploidy. Morphometric analysis of developing testes revealed that the first wave of meiosis proceeds at a normal rate in mutant testes, a surprising result given that the PP1 inhibitor okadaic acid has been shown to accelerate progression of spermatocytes from pachytene to the first meiotic division (MI). Evidence of abnormal testicular histopathology is apparent at 3 weeks, before the appearance of haploid gametes, eliminating the possibility that the mutant phenotype is caused by the presence of abnormal spermatids, but coincident with the appearance of the first set of mid to late pachytene spermatocytes. These observations lead us to conclude that the PP1cgamma mutation causes a complex phenotype, including subtle adverse effects on meiosis, possibly mediated by defective signaling between germ cells and Sertoli cells.

  1. Age-associated cardiomyopathy in heterozygous carrier mice of a pathological mutation of carnitine transporter gene, OCTN2.

    PubMed

    Xiaofei, E; Wada, Yasuhiko; Dakeishi, Miwako; Hirasawa, Fujiko; Murata, Katsuyuki; Masuda, Hirotake; Sugiyama, Toshihiro; Nikaido, Hiroko; Koizumi, Akio

    2002-07-01

    The purpose of this study was to test whether heterozygotes of juvenile visceral steatosis mice, a model for systemic carnitine deficiency, may develop age-associated cardiomyopathy. Tissue morphological observations were carried out by light and electron microscopy to compare the heterozygous and age-matched control mice at periods of 1 and 2 years. Possible effects of the pathological mutation on lipid and glucose levels was also evaluated in humans and mice. Except mild increases in serum cholesterol levels in male heterozygous mice and humans, no changes were found in other factors, indicating that none of the confounding factors seems to be profound. Results demonstrated that heterozygous mice had larger left ventriclular myocyte diameters than the control mice. Morphological changes in cardiac muscles by electron microscopy revealed age-associated changes of lipid deposition and abnormal mitochondria in heterozygous mice. Two out of 60 heterozygous cohort and one out of nine heterozygous trim-kill mice had cardiac hypertrophy at ages older than 2 years. The present study and our previous work suggest that the carrier state of OCTN2 pathological mutations might be a risk factor for age-associated cardiomyopathy.

  2. The effect of abnormal cell proportion on specimen classifier performance

    NASA Technical Reports Server (NTRS)

    Castleman, K. R.; White, B. S.

    1981-01-01

    An analysis is presented of the results obtained from a cell classifier which is confronted with an abnormal/normal cell ratio which is different from the ratio assumed in the calibration of the classifier. False negative and false positive error rates are determined in advance for classifier operation, along with the necessary sample size in order to validate the predicted distributions. Changes are demonstrated to happen only regarding the false negative rate, where reductions in the abnormal cell rate below the expected rates would cause totally unreliable data. Substantial overproduction of abnormal cells would be quickly noticeable, while production rates beyond, but close to, the expected rates would only require more extensive sampling. Classifier systems for 10% proportions of abnormal cells are concluded to be possible, but difficulties are present with much lower rates

  3. Comparative effects of dimethoate and deltamethrin on reproductive system in male mice.

    PubMed

    Abdallah, F Ben; Slima, A Ben; Dammak, I; Keskes-Ammar, L; Mallek, Z

    2010-06-01

    The effects of dimethoate (5, 15 and 28 mg kg(-1) day(-1)), deltamethrin (5 mg kg(-1) day(-1)) and their mixture (5 mg kg(-1) day(-1)) on male reproduction in mice were studied. The insecticides were given orally by gavage to male mice for 21 days. At the end of the treatment period, body, testes and epididymides weights and sperm parameters were determined. Alone mixture treatment has significantly decreased body weights. Dimethoate at 28 mg kg(-1) day(-1), deltamethrin at 5 mg kg(-1) day(-1) and their mixture at 5 mg kg(-1) day(-1) were associated with a significantly decreased sperm count, motility and viability and significantly increased percent morphologically abnormal spermatozoa compared with the controls. This study demonstrated the adverse effects of dimethoate at high dose, deltamethrin and their combining at 5 mg kg(-1) day(-1) on reproductive system and sperm parameters in male mice.

  4. A 7-month cigarette smoke inhalation study in C57BL/6 mice demonstrates reduced lung inflammation and emphysema following smoking cessation or aerosol exposure from a prototypic modified risk tobacco product.

    PubMed

    Phillips, Blaine; Veljkovic, Emilija; Peck, Michael J; Buettner, Ansgar; Elamin, Ashraf; Guedj, Emmanuel; Vuillaume, Gregory; Ivanov, Nikolai V; Martin, Florian; Boué, Stéphanie; Schlage, Walter K; Schneider, Thomas; Titz, Bjoern; Talikka, Marja; Vanscheeuwijck, Patrick; Hoeng, Julia; Peitsch, Manuel C

    2015-06-01

    Modified risk tobacco products (MRTP) are designed to reduce smoking-related health risks. A murine model of chronic obstructive pulmonary disease (COPD) was applied to investigate classical toxicology end points plus systems toxicology (transcriptomics and proteomics). C57BL/6 mice were exposed to conventional cigarette smoke (3R4F), fresh air (sham), or a prototypic MRTP (pMRTP) aerosol for up to 7 months, including a cessation group and a switching-to-pMRTP group (2 months of 3R4F exposure followed by fresh air or pMRTP for up to 5 months respectively). 3R4F smoke induced the typical adaptive changes in the airways, as well as inflammation in the lung, associated with emphysematous changes (impaired pulmonary function and alveolar damage). At nicotine-matched exposure concentrations of pMRTP aerosol, no signs of lung inflammation and emphysema were observed. Both the cessation and switching groups showed a similar reversal of inflammatory responses and no progression of initial emphysematous changes. A significant impact on biological processes, including COPD-related inflammation, apoptosis, and proliferation, was identified in 3R4F-exposed, but not in pMRTP-exposed lungs. Smoking cessation or switching reduced these perturbations to near sham-exposed levels. In conclusion, the mouse model indicated retarded disease progression upon cessation or switching to pMRTP which alone had no adverse effects.

  5. Complement inhibition and statins prevent fetal brain cortical abnormalities in a mouse model of preterm birth.

    PubMed

    Pedroni, Silvia M A; Gonzalez, Juan M; Wade, Jean; Jansen, Maurits A; Serio, Andrea; Marshall, Ian; Lennen, Ross J; Girardi, Guillermina

    2014-01-01

    Premature babies are particularly vulnerable to brain injury. In this study we focus on cortical brain damage associated with long-term cognitive, behavioral, attentional or socialization deficits in children born preterm. Using a mouse model of preterm birth (PTB), we demonstrated that complement component C5a contributes to fetal cortical brain injury. Disruption of cortical dendritic and axonal cytoarchitecture was observed in PTB-mice. Fetuses deficient in C5aR (-/-) did not show cortical brain damage. Treatment with antibody anti-C5, that prevents generation of C5a, also prevented cortical fetal brain injury in PTB-mice. C5a also showed a detrimental effect on fetal cortical neuron development and survival in vitro. Increased glutamate release was observed in cortical neurons in culture exposed to C5a. Blockade of C5aR prevented glutamate increase and restored neurons dendritic and axonal growth and survival. Similarly, increased glutamate levels - measured by (1)HMRS - were observed in vivo in PTB-fetuses compared to age-matched controls. The blockade of glutamate receptors prevented C5a-induced abnormal growth and increased cell death in isolated fetal cortical neurons. Simvastatin and pravastatin prevented cortical fetal brain developmental and metabolic abnormalities -in vivo and in vitro. Neuroprotective effects of statins were mediated by Akt/PKB signaling pathways. This study shows that complement activation plays a crucial role in cortical fetal brain injury in PTL and suggests that complement inhibitors and statins might be good therapeutic options to improve neonatal outcomes in preterm birth.

  6. Metabolomics reveals significant impairments in the immune system of the APP/PS1 transgenic mice of Alzheimer's disease.

    PubMed

    González-Domínguez, Raúl; García-Barrera, Tamara; Vitorica, Javier; Gómez-Ariza, José Luis

    2015-02-01

    Inflammatory processes and other failures related to the immune system are common features associated with Alzheimer's disease (AD), in both brain and the peripheral system. Thus, the study of the main organs of the immune system may have a great potential for the elucidation of pathological mechanisms underlying these abnormalities. This is the first metabolomic investigation performed in spleen and thymus from transgenic mice of AD. Tissues were fingerprinted using a metabolomic platform comprising GC-MS and ultra-HPLC-MS. Multivariate statistics demonstrated significant differences in numerous metabolites between the APP/PS1 mice and wild-type controls, and it was proven that multiple biochemical pathways are disturbed in these organs including abnormal metabolism of phospholipids, energy deficiencies, altered homeostasis of amino acids, oxidative stress, and others. Therefore, these findings highlight the importance of the proper metabolic functioning of peripheral immune system in the development of neurodegenerative disorders such as AD.

  7. Insertional Mutation on Mouse Chromosome 18 with Vestibular and Craniofacial Abnormalities

    PubMed Central

    Ting, C. N.; Kohrman, D.; Burgess, D. L.; Boyle, A.; Altschuler, R. A.; Gholizadeh, G.; Samuelson, L. C.; Jang, W.; Meisler, M. H.

    1994-01-01

    A dominant mutation was generated in transgenic mice as a consequence of insertional mutation. Heterozygous mice from transgenic line 9257 (Tg(9257)) are hyperactive with bidirectional circling behavior and have a distinctive facial appearance due to hypoplasia of the nasal bone. Morphological analysis of the inner ear revealed asymmetric abnormalities of the horizontal canal and flattening or invagination of the crista ampullaris, which can account for the circling behavior. The sensory epithelium appeared to be normal. The transgene insertion site was localized by in situ hybridization to the B1 band of mouse chromosome 18. Genetic mapping in an interspecific backcross demonstrated the gene order centromere--Tg(9257)--8.8 +/- 3.4--Grl-1, Egr-1, Fgf-1, Apc--14.7 +/- 4.3--Pdgfr. The phenotype and the mapping data suggest that the transgene may be inserted at the Twirler locus. Homozygosity for the transgene results in prenatal lethality, but compound heterozygotes carrying the Tw allele and the transgene are viable. The function of the closely linked ataxia locus is not disrupted by the transgene insertion. This insertional mutant will provide molecular access to genes located in the Twirler region of mouse chromosome 18. PMID:7511123

  8. Enzyme replacement prevents enamel defects in hypophosphatasia mice

    PubMed Central

    Yadav, Manisha C.; de Oliveira, Rodrigo Cardoso; Foster, Brian L.; Fong, Hanson; Cory, Esther; Narisawa, Sonoko; Sah, Robert L.; Somerman, Martha; Whyte, Michael P.; Millán, José Luis

    2012-01-01

    Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity leading to rickets or osteomalacia and to dental defects. HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl−/−, a.k.a. Akp2−/−) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl−/− mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the Alpl−/− mice, histological, μCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP (sALP-FcD10, a.k.a. ENB-0040) at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization, and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP. PMID:22461224

  9. Endocrine abnormalities in anorexia nervosa.

    PubMed

    Lawson, Elizabeth A; Klibanski, Anne

    2008-07-01

    Anorexia nervosa (AN) is a psychiatric disease associated with notable medical complications and increased mortality. Endocrine abnormalities, including hypogonadotropic hypogonadism, hypercortisolemia, growth hormone resistance and sick euthyroid syndrome, mediate the clinical manifestations of this disease. Alterations in anorexigenic and orexigenic appetite-regulating pathways have also been described. Decreases in fat mass result in adipokine abnormalities. Although most of the endocrine changes that occur in AN represent physiologic adaptation to starvation, some persist after recovery and might contribute to susceptibility to AN recurrence. In this Review, we summarize key endocrine alterations in AN, with a particular focus on the profound bone loss that can occur in this disease. Although AN is increasingly prevalent among boys and men, the disorder predominantly affects girls and women who are, therefore, the focus of this Review.

  10. [Chromosome abnormalities in human cancer].

    PubMed

    Salamanca-Gómez, F

    1995-01-01

    Recent investigation on the presence of chromosome abnormalities in neoplasias has allowed outstanding advances in the knowledge of malignant transformation mechanisms and important applications in the clinical diagnosis and prognosis of leukaemias, lymphomas and solid tumors. The purpose of the present paper is to discuss the most relevant cytogenetic aberrations, some of them described at the Unidad de Investigación Médica en Genética Humana, Instituto Mexicano del Seguro Social, and to correlate these abnormalities with recent achievements in the knowledge of oncogenes, suppressor genes or antioncogenes, their chromosome localization, and their mutations in human neoplasia; as well as their perspectives in prevention and treatment of cancer that such findings permit to anticipate.

  11. Neuroendocrine abnormalities in Parkinson's disease.

    PubMed

    De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T

    2017-02-01

    Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

  12. Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome

    PubMed Central

    McCauley, Mark D.; Wang, Tiannan; Mike, Elise; Herrera, Jose; Beavers, David L.; Huang, Teng-Wei; Ward, Christopher S.; Skinner, Steven; Percy, Alan K.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

    2013-01-01

    Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in Methyl-CpG-Binding Protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms (ECGs) in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), indicating a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally-mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current in order to prevent lethal cardiac arrhythmias. PMID:22174313

  13. Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome.

    PubMed

    McCauley, Mark D; Wang, Tiannan; Mike, Elise; Herrera, Jose; Beavers, David L; Huang, Teng-Wei; Ward, Christopher S; Skinner, Steven; Percy, Alan K; Glaze, Daniel G; Wehrens, Xander H T; Neul, Jeffrey L

    2011-12-14

    Rett syndrome is a neurodevelopmental disorder typically caused by mutations in methyl-CpG-binding protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), an indication of a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2(Null/Y), also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2(Null/+), show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2(Null/Y) mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2(Null/Y) mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2(Null/Y) mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current to prevent lethal cardiac arrhythmias.

  14. Congenital abnormalities of the goat.

    PubMed

    Basrur, P K

    1993-03-01

    Congenital abnormalities of genetic and environmental causes constitute a striking proportion of the afflictions seen in goats. These include a variety of malformations and metabolic diseases that could occur in all breeds but tend to exhibit predisposition in some breeds of goats. Genetic abnormalities for which the carrier state is detectable with the aid of enzymes and surface protein markers can be eliminated from goat populations, whereas common polygenic disorders including udder problems in does and gynecomastia in bucks are more difficult to eradicate because the mutant genes responsible for these traits generally do not declare themselves until inbreeding brings together a critical concentration of liability genes to create a crisis. A substantial reduction of common abnormalities in this species, such as intersexuality in dairy breeds, abortion in Angora breed, and arthritis in the Pygmy breed, will require a change in breeders' preference and selection practice. In making these changes, however, the beneficial traits will have to be balanced against the undesirable effects of the selected mutant genes (pleiotropy), which hold the key to success or failure of a breed under domestication.

  15. Meiotic abnormalities in infertile males.

    PubMed

    Egozcue, J; Sarrate, Z; Codina-Pascual, M; Egozcue, S; Oliver-Bonet, M; Blanco, J; Navarro, J; Benet, J; Vidal, F

    2005-01-01

    Meiotic anomalies, as reviewed here, are synaptic chromosome abnormalities, limited to germ cells that cannot be detected through the study of the karyotype. Although the importance of synaptic errors has been underestimated for many years, their presence is related to many cases of human male infertility. Synaptic anomalies can be studied by immunostaining of synaptonemal complexes (SCs), but in this case their frequency is probably underestimated due to the phenomenon of synaptic adjustment. They can also be studied in classic meiotic preparations, which, from a clinical point of view, is still the best approach, especially if multiplex fluorescence in situ hybridization is at hand to solve difficult cases. Sperm chromosome FISH studies also provide indirect evidence of their presence. Synaptic anomalies can affect the rate of recombination of all bivalents, produce achiasmate small univalents, partially achiasmate medium-sized or large bivalents, or affect all bivalents in the cell. The frequency is variable, interindividually and intraindividually. The baseline incidence of synaptic anomalies is 6-8%, which may be increased to 17.6% in males with a severe oligozoospermia, and to 27% in normozoospermic males with one or more previous IVF failures. The clinical consequences are the production of abnormal spermatozoa that will produce a higher number of chromosomally abnormal embryos. The indications for a meiotic study in testicular biopsy are provided.

  16. Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans.

    PubMed

    Lee, Una J; Gustilo-Ashby, A Marcus; Daneshgari, Firouz; Kuang, Mei; Vurbic, Drina; Lin, Dan Li; Flask, Chris A; Li, Tiansen; Damaser, Margot S

    2008-08-01

    Female pelvic floor dysfunction (FPFD) is a complex group of conditions that include urinary incontinence and pelvic organ prolapse (POP). In humans, elastin homeostasis has been implicated in the pathophysiology of FPFD. Lysyl oxidase-like 1 knockout (LOXL1-KO) mice demonstrate abnormal elastic fiber homeostasis and develop FPFD after parturition. We compared the lower urogenital tract (LUT) anatomy and function in LOXL1-KO mice with and without POP. LUT anatomy was assessed in LOXL1-KO mice over 28 wk. Pelvic visceral anatomy in LOXL1-KO was evaluated with a 7-Tesla magnetic resonance imaging (MRI) scanner. LUT function was assessed using conscious cystometry and leak point pressure (LPP) testing. Quantitative histological analysis of elastic fibers was performed on external urethral sphincter (EUS) cross sections. By 25 wk of age, 50% of parous LOXL1-KO mice developed POP. LOXL1-KO mice with POP had greater variability in the size and location of the bladder on MRI compared with mice without POP. Parity and POP were associated with lower LPP. Elastin clusters were significantly increased in the EUS of LOXL1-KO mice with POP. Because parity triggers POP in LOXL1-KO mice, LOXL1-KO mice with POP have variable internal pelvic anatomy, and both parity and POP are associated with a decrease in LPP, we conclude that LOXL1 LUT anatomical and functional phenotype resembles FPFD in humans. The increase in elastin clusters in the urethra of LOXL1-KO mice with POP suggests that elastin disorganization may lead to functional abnormalities. We conclude that LOXL1 warrants further investigation in the pathphysiology of FPFD.

  17. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on the prostate and its response to castration in senescent C57BL/6J mice.

    PubMed

    Fritz, Wayne A; Lin, Tien-Min; Moore, Robert W; Cooke, Paul S; Peterson, Richard E

    2005-08-01

    In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure inhibits ventral, dorsolateral, and anterior prostate development in C57BL/6 mice. To determine if prostatic abnormalities persist into senescence, mice born to dams given TCDD (5 mug/kg, po) or vehicle on gestation day 13 were examined at 100 and 510 days of age. Half the mice were castrated ten days prior to necropsy in order to assess androgen dependence, while the remaining mice were sham castrated. Effects of TCDD on the dorsolateral and anterior prostate of senescent sham-castrated mice were relatively subtle, whereas the ventral prostate was rudimentary or absent. Castration of vehicle-exposed mice caused far greater reductions in prostate lobe weights, epithelial cell height, and androgen-dependent gene expression (MP25 and probasin) in young mice than in senescent ones, while cell proliferation was decreased by castration in young mice and increased in senescence. Responses to castration were similar at 100 days of age in vehicle- and TCDD-exposed mice. At 510 days, however, TCDD-exposed mice were substantially more responsive to castration by most indices than vehicle-exposed mice. These results demonstrate that prostatic androgen dependence in mice declines substantially with age in several key ways, and that in utero and lactational TCDD exposure protects against this decline. Surprisingly, TCDD increased the incidence of cribriform structures in dorsolateral prostate ducts, from 2-3% in vehicle-exposed senescent mice to 16% in sham-castrated and to 7% in castrated senescent mice. Collectively, these results demonstrate that effects of in utero and lactational TCDD exposure on the prostate persist into senescence, and suggest that in utero and lactational TCDD exposure retards the aging process in the prostate. However, because cribriform structures are often considered to be associated with prostate carcinogenesis, these results also suggest that TCDD exposure early in

  18. Partial Return Yoke for MICE

    SciTech Connect

    Witte H.; Plate, S

    2013-05-03

    The international Muon Ionization Cooling Experiment (MICE) is a large scale experiment which is presently assembled at the Rutherford Appleton Laboratory in Didcot, UK. The purpose of MICE is to demonstrate the concept of ionization cooling experimentally. Ionization cooling is an important accelerator concept which will be essential for future HEP experiments such as a potential Muon Collider or a Neutrino Factory. The MICE experiment will house up to 18 superconducting solenoids, all of which produce a substantial amount of magnetic flux. Recently it was realized that this magnetic flux leads to a considerable stray magnetic field in the MICE hall. This is a concern as technical equipment in the MICE hall may may be compromised by this. In July 2012 a concept called partial return yoke was presented to the MICE community, which reduces the stray field in the MICE hall to a safe level. This report summarizes the general concept, engineering considerations and the expected shielding performance.

  19. Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6.

    PubMed

    Clark, Daniel D; Gorman, Michael R; Hatori, Megumi; Meadows, Jason D; Panda, Satchidananda; Mellon, Pamela L

    2013-02-01

    The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is the central pacemaker for peripheral and organismal circadian rhythms. The development of this hypothalamic structure depends on genetic programs throughout embryogenesis. We have investigated the role of the homeodomain transcription factor Six6 in the development of the SCN. We first showed that Six6 mRNA has circadian regulation in the mouse SCN. We then characterized the behavioral activity patterns of Six6-null mice under various photoperiod manipulations and stained their hypothalami using SCN-specific markers. Six6-null mice display abnormal patterns of circadian behavior indicative of SCN abnormalities. The ability of light exposure to reset rhythms correlates with the presence or absence of optic nerves, but all Six6-null mice show irregular rhythms. In contrast, wild-type mice with crushed optic nerves maintain regular rhythms regardless of light exposure. Using immunohistochemistry for arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and β-galactosidase, we demonstrated the lack of these SCN markers in all Six6-null mice regardless of the presence of optic nerve or partial circadian rhythms. Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN.

  20. Aberrant Development of the Suprachiasmatic Nucleus and Circadian Rhythms in Mice Lacking the Homeodomain Protein Six6

    PubMed Central

    Clark, Daniel D.; Gorman, Michael R.; Hatori, Megumi; Meadows, Jason D.; Panda, Satchidananda; Mellon, Pamela L.

    2013-01-01

    The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is the central pacemaker for peripheral and organismal circadian rhythms. The development of this hypothalamic structure depends on genetic programs throughout embryogenesis. We have investigated the role of the homeodomain transcription factor Six6 in the development of the SCN. We first showed that Six6 mRNA has circadian regulation in the mouse SCN. We then characterized the behavioral activity patterns of Six6-null mice under various photoperiod manipulations and stained their hypothalami using SCN-specific markers. Six6-null mice display abnormal patterns of circadian behavior indicative of SCN abnormalities. The ability of light exposure to reset rhythms correlates with the presence or absence of optic nerves, but all Six6-null mice show irregular rhythms. In contrast, wild-type mice with crushed optic nerves maintain regular rhythms regardless of light exposure. Using immunohistochemistry for arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and β-galactosidase, we demonstrated the lack of these SCN markers in all Six6- null mice regardless of the presence of optic nerve or partial circadian rhythms. Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN. PMID:23382588

  1. Visual pathway abnormalities in tuberculous meningitis.

    PubMed

    Maurya, Pradeep Kumar; Singh, Ajai Kumar; Sharma, Lalit; Kulshreshtha, Dinkar; Thacker, Anup Kumar

    2016-11-01

    Ophthalmological complications are common and disabling in patients with tuberculous meningitis. We aimed to study the visual pathway abnormalities in patients with tuberculous meningitis. Forty-three patients with tuberculous meningitis were subjected to visual evoked responses (VER) and neuroophthalmologic assessment. Neuroophthalmologic assessment revealed abnormalities in 22 (51.3%) patients. VER were found to be abnormal in 27 (62.8%) patients. The VER abnormalities included prolonged P100 latencies with relatively normal amplitude and significant interocular latency differences. Visual pathways abnormalities are common in patients with tuberculous meningitis and are often subclinical. Pathophysiologic explanations for electrophysiological abnormalities on VER in these patients are incompletely understood and needs further exploration.

  2. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

    PubMed Central

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-01-01

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage. PMID:26371321

  3. Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice.

    PubMed Central

    Bezerra, J A; Carrick, T L; Degen, J L; Witte, D; Degen, S J

    1998-01-01

    Hepatocyte growth factor-like protein (HGFL) is a liver-derived serum glycoprotein involved in cell proliferation and differentiation, and is proposed to have a fundamental role in embryogenesis, fertility, hematopoiesis, macrophage activation, and tissue repair. To assess the in vivo effects of total loss of HGFL, we generated mice with targeted disruption of the gene resulting in loss of the protein. Disruption of the HGFL gene allowed for normal embryogenesis, and followed a Mendelian pattern of genetic transmission. Mice homozygous for the targeted allele (HGFL-/- mice) are fertile, and grow to adulthood without obvious phenotypic abnormalities in unchallenged animals, except for development of lipid-containing cytoplasmic vacuoles in hepatocytes throughout the liver lobules. These histologic changes are not accompanied by discernible changes in synthetic or excretory hepatic functions. Hematopoiesis appears unaltered, and although macrophage activation is delayed in the absence of HGFL, migration to the peritoneal cavity upon challenge with thioglycollate was similar in HGFL-/- and wild-type mice. Challenged with incision to skin, HGFL-/- mice display normal wound healing. These data demonstrate that HGFL is not essential for embryogenesis, fertility, or wound healing. HGFL-deficient mice will provide a valuable means to assess the role of HGFL in hepatic and systemic responses to inflammatory and infectious stimuli in vivo. PMID:9486989

  4. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.

    PubMed

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-09-29

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

  5. Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice

    PubMed Central

    Hargett, Stefan R.; Walker, Natalie N.; Hussain, Syed S.; Hoehn, Kyle L.

    2015-01-01

    Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling. PMID:26015432

  6. Cadmium modulates adipocyte functions in metallothionein-null mice

    SciTech Connect

    Kawakami, Takashige; Nishiyama, Kaori; Kadota, Yoshito; Sato, Masao; Inoue, Masahisa; Suzuki, Shinya

    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.

  7. Chromosomal abnormalities associated with cyclopia and synophthalmia.

    PubMed Central

    Howard, R O

    1977-01-01

    At the present time, essentially all known facts concerning cyclopia are consistent with some chromosomal disease, including clinical features of the pregnancy (fetal wastage, prematurity, intrauterine growth retardation, maternal age factor, complications of pregnancy), the generalized developmental abnormalities, specific ocular dysgenesis, by the high incidence of chromosomal abnormality already demonstrated, and the possibility of error in those cases of cyclopia with normal chromosomes. Even if chromosomal aberrations represent only one group of several different etiologic factors leading to cyclopia, at the present time chromosomal errors would seem to be the most common cause of cyclopia now recognized. Further studies will establish or disprove a chromosomal error in those instances which are now considered to be the result of an environmental factor alone or those with apparent familial patterns of inheritance. This apparent diverse origin of cyclopia can be clarified if future cyclopic specimens are carefully investigated. The evaluation should include a careful gross and microscopic examination of all organs, including the eye, and chromosome banding studies of all organs, including the eye, and chromosome banding studies of at least two cyclopic tissues. Then the presence or absence of multiple causative factors can be better evaluated. Images FIGURE 2 A FIGURE 2 B FIGURE 1 A FIGURE 1 B FIGURE 1 C FIGURE 1 D FIGURE 1 E FIGURE 1 F FIGURE 3 A FIGURE 3 B FIGURE 4 A FIGURE 4 B FIGURE 4 C FIGURE 4 D FIGURE 5 FIGURE 6 FIGURE 7 A FIGURE 7 B PMID:418547

  8. The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice.

    PubMed

    Tiala, Inkeri; Wakkinen, Janica; Suomela, Sari; Puolakkainen, Pauli; Tammi, Raija; Forsberg, Sofi; Rollman, Ola; Kainu, Kati; Rozell, Björn; Kere, Juha; Saarialho-Kere, Ulpu; Elomaa, Outi

    2008-04-01

    The CCHCR1 gene (Coiled-Coil alpha-Helical Rod protein 1) within the major psoriasis susceptibility locus PSORS1 is a plausible candidate gene for the risk effect. We have previously generated transgenic mice overexpressing either the psoriasis-associated risk allele CCHCR1*WWCC or the normal allele of CCHCR1. All transgenic CCHCR1 mice appeared phenotypically normal, but exhibited altered expression of genes relevant to the pathogenesis of psoriasis, including upregulation of hyperproliferation markers keratins 6, 16 and 17. Here, we challenged the skin of CCHCR1 transgenic mice with wounding or 12-O-tetradecanoyl-13-acetate (TPA), treatments able to induce epidermal hyperplasia and proliferation that both are hallmarks of psoriasis. These experiments revealed that CCHCR1 regulates keratinocyte proliferation. Early wound healing on days 1 and 4 was delayed, and TPA-induced epidermal hyperproliferation was less pronounced in mice with the CCHCR1*WWCC risk allele than in mice with the normal allele or in wild-type animals. Finally, we demonstrated that overexpression of CCHCR1 affects basal keratinocyte proliferation in mice; CCHCR1*WWCC mice had less proliferating keratinocytes than the non-risk allele mice. Similarly, keratinocytes isolated from risk allele mice proliferated more slowly in culture than wild-type cells when measured by BrdU labeling and ELISA. Our data show that CCHCR1 may function as a negative regulator of keratinocyte proliferation. Thus, aberrant function of CCHCR1 may lead to abnormal keratinocyte proliferation which is a key feature of psoriatic epidermis.

  9. An Auditory Processing Abnormality Specific to Liability for Schizophrenia

    PubMed Central

    Force, Rachel B.; Venables, Noah C.; Sponheim, Scott R.

    2013-01-01

    Abnormal brain activity during the processing of simple sounds is evident in individuals with increased genetic liability for schizophrenia; however, the diagnostic specificity of these abnormalities has yet to be fully examined. Because recent evidence suggests that schizophrenia and bipolar disorder may share aspects of genetic etiology the present study was conducted to determine whether individuals with heightened genetic liability for each disorder manifested distinct neural abnormalities during auditory processing. Utilizing a dichotic listening paradigm, we assessed target tone discrimination and electrophysiological responses in schizophrenia patients, first-degree biological relatives of schizophrenia patients, bipolar disorder patients, first-degree biological relatives of bipolar patients and nonpsychiatric control participants. Schizophrenia patients and relatives of schizophrenia patients demonstrated reductions in an early neural response (i.e. N1) suggestive of deficient sensory registration of auditory stimuli. Bipolar patients and relatives of bipolar patients demonstrated no such abnormality. Both schizophrenia and bipolar patients failed to significantly augment N1 amplitude with attention. Schizophrenia patients also failed to show sensitivity of longer-latency neural processes (N2) to stimulus frequency suggesting a disorder specific deficit in stimulus classification. Only schizophrenia patients exhibited reduced target tone discrimination accuracy. Reduced N1 responses reflective of early auditory processing abnormalities are suggestive of a marker of genetic liability for schizophrenia and may serve as an endophenotype for the disorder. PMID:18571375

  10. SpaceFibre Demonstrator (Demonstration and Testing)

    NASA Astrophysics Data System (ADS)

    Helfers, T.; Rastetter, P.; Papadas, C.; Parkes, S.

    2014-08-01

    Currently Astrium GmbH and ISD S.A. are planning the development of a demonstrator for SpaceFibre. The SpaceFibre demonstrator will be used to execute functional performance tests and EMC (Electro Magnetic Compatibility) tests. University of Dundee is program prime contractor and provides Astrium with the SpaceFibre IP core. The work si shared between the two partners in the following way: • Astrium: Prime Contractor and Technical Coordination; FPGA Design; EMC Testing• ISD: Development of Demonstrator Board including housing, development of test bed and functional performance testingThe driving requirements for this development are:• SpaceFibre performance, while implementing it into space equivalent components• Design and MAIT of the demonstrator in such a way that representative EMC testing is possible.

  11. Pleiotrophin is a driver of vascular abnormalization in glioblastoma.

    PubMed

    Zhang, Lei; Dimberg, Anna

    2016-01-01

    In a recent report by Zhang et al., pleiotrophin (PTN) was demonstrated to enhance glioma growth by promoting vascular abnormalization. PTN stimulates glioma vessels through anaplastic lymphoma kinase (Alk)-mediated perivascular deposition of vascular endothelial growth factor (VEGF). Targeting of Alk or VEGF signaling normalizes tumor vessels in PTN-expressing tumors.

  12. Low-set ears and pinna abnormalities

    MedlinePlus

    Low-set ears; Microtia; "Lop" ear; Pinna abnormalities; Genetic defect-pinna; Congenital defect-pinna ... most cases, a health care provider finds pinna abnormalities during the first well-baby exam. This exam ...

  13. Abnormalities of the erythrocyte membrane.

    PubMed

    Gallagher, Patrick G

    2013-12-01

    Primary abnormalities of the erythrocyte membrane are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis patients are more likely to experience symptomatic anemia. Treatment of hereditary spherocytosis with splenectomy is curative in most patients. Growing recognition of the long-term risks of splenectomy has led to re-evaluation of the role of splenectomy. Management guidelines acknowledge these considerations and recommend discussion between health care providers, patient, and family. The hereditary elliptocytosis syndromes are the most common primary disorders of erythrocyte membrane proteins. However, most elliptocytosis patients are asymptomatic and do not require therapy.

  14. Foot abnormalities of wild birds

    USGS Publications Warehouse

    Herman, C.M.; Locke, L.N.; Clark, G.M.

    1962-01-01

    The various foot abnormalities that occur in birds, including pox, scaly-leg, bumble-foot, ergotism and freezing are reviewed. In addition, our findings at the Patuxent Wildlife Research Center include pox from dove, mockingbird, cowbird, grackle and several species of sparrows. Scaly-leg has been particularly prevalent on icterids. Bumble foot has been observed in a whistling swan and in a group of captive woodcock. Ergotism is reported from a series of captive Canada geese from North Dakota. Several drug treatments recommended by others are presented.

  15. Deafness in occludin-deficient mice with dislocation of tricellulin and progressive apoptosis of the hair cells.

    PubMed

    Kitajiri, Shin-Ichiro; Katsuno, Tatsuya; Sasaki, Hiroyuki; Ito, Juichi; Furuse, Mikio; Tsukita, Shoichiro

    2014-07-25

    Occludin is the first identified protein in the tight junction (TJ), but its function has remained for the most part obscure. TJs have been demonstrated to play important roles in the inner ear function, and occludin is expressed in all the epithelial TJs in the inner ear. Thus, we examined the inner ears of occludin-deficient (Occ(-/-)) mice. Although inner ears initially developed normally in Occ(-/-) mice, apoptosis occurs in hair cells in the organ of Corti around day 12 after birth, and deafness develops. Since hair cell degeneration was not observed in cochlear explant cultures of Occ(-/-) mice, environmental changes were considered to be the trigger of cell death. As for the vestibular system, both the morphologies and functions are normal in Occ(-/-) mice. These phenotypes of Occ(-/-) mice are very similar with those of claudin-14 or claudin-9 deficient mice, leading us to speculate on the existence of imbalance induced by TJ abnormalities, such as localized ionic components. Moreover, the occludin deficiency led to dislocalization of tricellulin, a gene responsible for human deafness DFNB49. The deafness in Occ(-/-) mice may be due to this dislocalization of tricellulin.

  16. FcRγ-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice

    PubMed Central

    Ogawa, Yasuhiro; Sano, Takafumi; Irisa, Masahiro; Kodama, Takashi; Saito, Takahiro; Furusawa, Eiri; Kaizu, Katsutoshi; Yanagi, Yusuke; Tsukimura, Takahiro; Togawa, Tadayasu; Yamanaka, Shoji; Itoh, Kohji; Sakuraba, Hitoshi; Oishi, Kazuhiko

    2017-01-01

    Sandhoff disease (SD) is caused by the loss of β-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from Hexb mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. Hexb−/− mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. Hexb−/− mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16–18 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (Hexb−/−) were crossed to mice lacking an activating immune receptor (FcRγ−/−) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of Hexb−/− mice during the asymptomatic phase, and were inhibited in Hexb−/− FcRγ−/− mice. Moreover, early astrogliosis and impaired motor coordination in Hexb−/− mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD. PMID:28084424

  17. Central diabetes insipidus associated with impaired renal aquaporin-1 expression in mice lacking liver X receptor β.

    PubMed

    Gabbi, Chiara; Kong, Xiaomu; Suzuki, Hitoshi; Kim, Hyun-Jin; Gao, Min; Jia, Xiao; Ohnishi, Hideo; Ueta, Yoichi; Warner, Margaret; Guan, Youfei; Gustafsson, Jan-Åke

    2012-02-21

    The present study demonstrates a key role for the oxysterol receptor liver X receptor β (LXRβ) in the etiology of diabetes insipidus (DI). Given free access to water, LXRβ(-/-) but not LXRα(-/-) mice exhibited polyuria (abnormal daily excretion of highly diluted urine) and polydipsia (increased water intake), both features of diabetes insipidus. LXRβ(-/-) mice responded to 24-h dehydration with a decreased urine volume and increased urine osmolality. To determine whether the DI was of central or nephrogenic origin, we examined the responsiveness of the kidney to arginine vasopressin (AVP). An i.p. injection of AVP to LXRβ(-/-) mice revealed a partial kidney response: There was no effect on urine volume, but there was a significant increase of urine osmolality, suggesting that DI may be caused by a defect in central production of AVP. In the brain of WT mice LXRβ was expressed in the nuclei of magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. In LXRβ(-/-) mice the expression of AVP was markedly decreased in the magnocellular neurons as well as in urine collected over a 24-h period. The persistent high urine volume after AVP administration was traced to a reduction in aquaporin-1 expression in the kidney of LXRβ(-/-) mice. The LXR agonist (GW3965) in WT mice elicited an increase in urine osmolality, suggesting that LXRβ is a key receptor in controlling water balance with targets in both the brain and kidney, and it could be a therapeutic target in disorders of water balance.

  18. [Ultrasonic diagnosis of congenital uterine abnormalities].

    PubMed

    Funk, A; Fendel, H

    1988-01-01

    1-2% of women has abnormal uterine development due to nonunification of the Müllerian ducts in the embryonal period. At the RWTH Aachen, in the department of gynaecology and obstetrics, between January and June 1987, we had searched systematically for maldevelopment of the uterus in 2299 echosonografies. In 13 cases we found maldevelopment of internal genital; 5 of these cases were diagnosed by an echosonografic routine-examination. The echografic criteria of the different grades of uterine malformations have been determined, systematized and discussed in relation to the symptoms. The most frequent malformations as uterus subseptus, uterus septus, uterus bicornis and uterus duplex are subject of a detailed discussion. This work demonstrates that echosonografic is a very efficient instrument to diagnose uterine malformations and gives us a very exact anatomic interpretation of malformations.

  19. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

    PubMed

    Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

    2015-12-08

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

  20. A Fluorescence Lecture Demonstration.

    ERIC Educational Resources Information Center

    Bozzelli, Joseph W.; Kemp, Marwin

    1982-01-01

    Describes fluorescence demonstrations related to several aspects of molecular theory and quantitized energy levels. Demonstrations use fluorescent chemical solutions having luminescence properties spanning the visible spectrum. Also describes a demonstration of spontaneous combustion of familiar substances in chlorine. (JN)

  1. ORION II bus demonstration. Demonstration report (Final)

    SciTech Connect

    Shanley, J.

    1989-02-01

    The Central New York Regional Transportation Authority conducted an 18-month demonstration to determine how the ORION II bus operates in actual service. The ORION II vehicle is a small low floor, accessible heavy duty, diesel-powered transit bus designed to meet the needs of the elderly and handicapped. It has the capacity to seat 26 passengers with 4 wheelchair lockdowns. Side and rear doors are equipped with electrically powered ramps. Eight Thomas vehicles (22-foot, 11,500 lbs, wheelchair equipped, gasoline fueled) were also tested during the demonstration period. Operations (fuel and oil usage) and maintenance (scheduled and unscheduled) data were collected and charted-out in the report as well as driver, passenger, and maintenance surveys. This report provides descriptions, photographs, and comparison charts of both the diesel-fueled ORION II transit bus and the gasoline-fueled Thomas vehicles along with the demonstration test plan, evaluations, conclusions, and survey results.

  2. Lower extremity abnormalities in children.

    PubMed

    Sass, Pamela; Hassan, Ghinwa

    2003-08-01

    Rotational and angular problems are two types of lower extremity abnormalities common in children. Rotational problems include intoeing and out-toeing. Intoeing is caused by one of three types of deformity: metatarsus adductus, internal tibial torsion, and increased femoral anteversion. Out-toeing is less common than intoeing, and its causes are similar but opposite to those of intoeing. These include femoral retroversion and external tibial torsion. Angular problems include bowlegs and knock-knees. An accurate diagnosis can be made with careful history and physical examination, which includes torsional profile (a four-component composite of measurements of the lower extremities). Charts of normal values and values with two standard deviations for each component of the torsional profile are available. In most cases, the abnormality improves with time. A careful physical examination, explanation of the natural history, and serial measurements are usually reassuring to the parents. Treatment is usually conservative. Special shoes, cast, or braces are rarely beneficial and have no proven efficacy. Surgery is reserved for older children with deformity from three to four standard deviations from the normal.

  3. Normal and abnormal lid function.

    PubMed

    Rucker, Janet C

    2011-01-01

    This chapter on lid function is comprised of two primary sections, the first on normal eyelid anatomy, neurological innervation, and physiology, and the second on abnormal eyelid function in disease states. The eyelids serve several important ocular functions, the primary objectives of which are protection of the anterior globe from injury and maintenance of the ocular tear film. Typical eyelid behaviors to perform these functions include blinking (voluntary, spontaneous, or reflexive), voluntary eye closure (gentle or forced), partial lid lowering during squinting, normal lid retraction during emotional states such as surprise or fear (startle reflex), and coordination of lid movements with vertical eye movements for maximal eye protection. Detailed description of the neurological innervation patterns and neurophysiology of each of these lid behaviors is provided. Abnormal lid function is divided by conditions resulting in excessive lid closure (cerebral ptosis, apraxia of lid opening, blepharospasm, oculomotor palsy, Horner's syndrome, myasthenia gravis, and mechanical) and those resulting in excessive lid opening (midbrain lid retraction, facial nerve palsy, and lid retraction due to orbital disease).

  4. Triple-phase bone image abnormalities in Lyme arthritis

    SciTech Connect

    Brown, S.J.; Dadparvar, S.; Slizofski, W.J.; Glab, L.B.; Burger, M. )

    1989-10-01

    Arthritis is a frequent manifestation of Lyme disease. Limited triple-phase Tc-99m MDP bone imaging of the wrists and hands with delayed whole-body images was performed in a patient with Lyme arthritis. This demonstrated abnormal joint uptake in the wrists and hands in all three phases, with increased activity seen in other affected joints on delayed whole-body images. These findings are nonspecific and have been previously described in a variety of rheumatologic conditions, but not in Lyme disease. Lyme disease should be considered in the differential diagnosis of articular and periarticular bone scan abnormalities.

  5. Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model.

    PubMed

    Zou, JiangHuan; Xiong, XiWen; Lai, BeiBei; Sun, Min; Tu, Xin; Gao, Xiang

    2015-04-01

    Bone was reported as a crucial organ for regulating glucose homeostasis. In this study, we found that Phex mutant mice (PUG), a model of human X-linked hypophosphatemic rickets (XLH), displayed metabolic abnormality in addition to abnormal phosphate homeostasis, skeletal deformity and growth retardation. Glucose tolerance was elevated with enhanced insulin sensitivity in PUG, though circulating insulin level decreased. Interestingly, bone mineral density defects and glucose metabolic abnormality were both rescued by adding phosphorus- and calcium-enriched supplements in daily diet. Serum insulin level, glucose tolerance and insulin sensitivity showed no differences between PUG and wild-type mice with rescued osteocalcin (OCN) following treatment. Our study suggested that OCN is a potential mediator between mineral homeostasis and glucose metabolism. This investigation brings a new perspective on glucose metabolism regulation through skeleton triggered mineral homeostasis and provides new clues in clinical therapeutics of potential metabolic disorders in XLH patients.

  6. Detecting rare, abnormally large grains by x-ray diffraction

    DOE PAGES

    Boyce, Brad L.; Furnish, Timothy Allen; Padilla, H. A.; ...

    2015-07-16

    Bimodal grain structures