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Sample records for a33 antigen-deficient mice

  1. Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response.

    PubMed

    Paran, Nir; Lustig, Shlomo; Zvi, Anat; Erez, Noam; Israely, Tomer; Melamed, Sharon; Politi, Boaz; Ben-Nathan, David; Schneider, Paula; Lachmi, Batel; Israeli, Ofir; Stein, Dana; Levin, Reuven; Olshevsky, Udy

    2013-07-10

    Vaccinia virus protein A33 (A33VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33VACV and A33CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104-120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope's critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox.

  2. Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response

    PubMed Central

    2013-01-01

    Vaccinia virus protein A33 (A33VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33VACV and A33CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104–120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope’s critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox. PMID:23842430

  3. A midgut lysate of the Riptortus pedestris has antibacterial activity against LPS O-antigen-deficient Burkholderia mutants.

    PubMed

    Jang, Ho Am; Seo, Eun Sil; Seong, Min Young; Lee, Bok Luel

    2017-02-01

    Riptortus pedestris, a common pest in soybean fields, harbors a symbiont Burkholderia in a specialized posterior midgut region of insects. Every generation of second nymphs acquires new Burkholderia cells from the environment. We compared in vitro cultured Burkholderia with newly in vivo colonized Burkholderia in the host midgut using biochemical approaches. The bacterial cell envelope of in vitro cultured and in vivo Burkholderia differed in structure, as in vivo bacteria lacked lipopolysaccharide (LPS) O-antigen. The LPS O-antigen deficient bacteria had a reduced colonization rate in the host midgut compared with that of the wild-type Burkholderia. To determine why LPS O-antigen-deficient bacteria are less able to colonize the host midgut, we examined in vitro survival rates of three LPS O-antigen-deficient Burkholderia mutants and lysates of five different midgut regions. The LPS O-antigen-deficient mutants were highly susceptible when cultured with the lysate of a specific first midgut region (M1), indicating that the M1 lysate contains unidentified substance(s) capable of killing LPS O-antigen-deficient mutants. We identified a 17 kDa protein from the M1 lysate, which was enriched in the active fractions. The N-terminal sequence of the protein was determined to be a soybean Kunitz-type trypsin inhibitor. These data suggest that the 17 kDa protein, which was originated from a main soybean source of the R. pedestris host, has antibacterial activity against the LPS O-antigen deficient (rough-type) Burkholderia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. 8 CFR 245a.33 - Filing.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Filing. 245a.33 Section 245a.33 Aliens and... NATIONALITY ACT LIFE Act Amendments Family Unity Provisions § 245a.33 Filing. (a) General. An application for Family Unity benefits under section 1504 of the LIFE Act Amendments must be filed on a Form I-817...

  5. 8 CFR 245a.33 - Filing.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Filing. 245a.33 Section 245a.33 Aliens and... ACT LIFE Act Amendments Family Unity Provisions § 245a.33 Filing. (a) General. An application for Family Unity benefits under section 1504 of the LIFE Act Amendments must be filed on a Form I-817...

  6. 8 CFR 245a.33 - Filing.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Filing. 245a.33 Section 245a.33 Aliens and... ACT LIFE Act Amendments Family Unity Provisions § 245a.33 Filing. (a) General. An application for Family Unity benefits under section 1504 of the LIFE Act Amendments must be filed on a Form I-817...

  7. 8 CFR 245a.33 - Filing.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Filing. 245a.33 Section 245a.33 Aliens and... ACT LIFE Act Amendments Family Unity Provisions § 245a.33 Filing. (a) General. An application for Family Unity benefits under section 1504 of the LIFE Act Amendments must be filed on a Form I-817...

  8. A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal Cancer.

    PubMed

    Li, Yan; Gao, Yuan; Gong, Chunai; Wang, Zhuo; Xia, Qingming; Gu, Fenfen; Hu, Chuling; Zhang, Lijuan; Guo, Huiling; Gao, Shen

    2018-06-20

    Exosomes have emerged as a promising drug carrier with low immunogenicity, high biocompatibility and delivery efficiency. Here in, we isolated exosomes from A33-positive LIM1215 cells (A33-Exo) and loaded them with doxorubicin (Dox). Furthermore, we coated surface-carboxyl superparamagnetic iron oxide nanoparticles (US) with A33 antibodies (A33Ab-US), expecting that these A33 antibodies on the surface of the nanoparticles could bind to A33-positive exosomes and form a complex (A33Ab-US-Exo/Dox) to target A33-positive colon cancer cells. The results showed that A33Ab-US-Exo/Dox had good binding affinity and antiproliferative effect in LIM1215 cells, as shown by increased uptake of the complex. In vivo study showed that A33Ab-US-Exo/Dox had an excellent tumor targeting ability, and was able to inhibit tumor growth and prolong the survival of the mice with reduced cardiotoxicity. In summary, exosomes functionalized by targeting ligands through coating with high-density antibodies may prove to be a novel delivery system for targeted drugs against human cancers. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. 7 CFR 15a.33 - Comparable facilities.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Comparable facilities. 15a.33 Section 15a.33 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Discrimination on the Basis of Sex in Education Programs and...

  10. Heterogeneity in the A33 protein impacts the cross-protective efficacy of a candidate smallpox DNA vaccine.

    PubMed

    Golden, Joseph W; Hooper, Jay W

    2008-07-20

    We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus proteins (A33, L1, B5, and A27). Because any subunit orthopoxvirus vaccine must protect against multiple species of orthopoxviruses, we are interested in understanding the cross-protective potential of our 4pox vaccine target immunogens. In our current studies, we focused on the A33 immunogen. We found one monoclonal antibody against A33, MAb-1G10, which could not bind the monkeypox virus A33 ortholog, A35. MAb-1G10 binding could be rescued if A35 amino acids 118 and 120 were substituted with those from A33. MAb-1G10 has been shown to protect mice from VACV challenge, thus our findings indicated a protective epitope differs among orthopoxviruses. Accordingly, we tested the cross-protective efficacy of a DNA vaccine consisting of A35R against VACV challenge and compared it to vaccination with A33R DNA. Mice vaccinated with A35R had greater mortality and more weight loss compared to those vaccinated with A33R. These findings demonstrate that despite high homology between A33R orthologs, amino acid differences can impact cross-protection. Furthermore, our results caution that adequate cross-protection by any pan-orthopoxvirus subunit vaccine will require not only careful evaluation of cross-protective immunity, but also of targeting of multiple orthopoxvirus immunogens.

  11. Characterization of chimpanzee/human monoclonal antibodies to vaccinia virus A33 glycoprotein and its variola virus homolog in vitro and in a vaccinia virus mouse protection model.

    PubMed

    Chen, Zhaochun; Earl, Patricia; Americo, Jeffrey; Damon, Inger; Smith, Scott K; Yu, Fujuan; Sebrell, Andrew; Emerson, Suzanne; Cohen, Gary; Eisenberg, Roselyn J; Gorshkova, Inna; Schuck, Peter; Satterfield, William; Moss, Bernard; Purcell, Robert

    2007-09-01

    Three distinct chimpanzee Fabs against the A33 envelope glycoprotein of vaccinia virus were isolated and converted into complete monoclonal antibodies (MAbs) with human gamma 1 heavy-chain constant regions. The three MAbs (6C, 12C, and 12F) displayed high binding affinities to A33 (K(d) of 0.14 nM to 20 nM) and may recognize the same epitope, which was determined to be conformational and located within amino acid residues 99 to 185 at the C terminus of A33. One or more of the MAbs were shown to reduce the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro and to more effectively protect mice when administered before or 2 days after intranasal challenge with virulent vaccinia virus than a previously isolated mouse anti-A33 MAb (1G10) or vaccinia virus immunoglobulin. The protective efficacy afforded by anti-A33 MAb was comparable to that of a previously isolated chimpanzee/human anti-B5 MAb. The combination of anti-A33 MAb and anti-B5 MAb did not synergize the protective efficacy. These chimpanzee/human anti-A33 MAbs may be useful in the prevention and treatment of vaccinia virus-induced complications of vaccination against smallpox and may also be effective in the immunoprophylaxis and immunotherapy of smallpox and other orthopoxvirus diseases.

  12. Acute suppurative parotitis in a 33-day-old patient.

    PubMed

    Avcu, Gulhadiye; Belet, Nursen; Karli, Arzu; Sensoy, Gulnar

    2015-06-01

    Acute suppurative parotitis is a rare disease in childhood. Its incidence is higher in premature newborns. Parotid swelling and pus drainage from Stenson's duct is pathognomonic, and Staphylococcus aureus is the causative agent in most cases. Here, a 33-day-old patient with acute suppurative parotitis is presented. © The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Cloning Mice.

    PubMed

    Ogura, Atsuo

    2017-08-01

    Viable and fertile mice can be generated by somatic nuclear transfer into enucleated oocytes, presumably because the transplanted somatic cell genome becomes reprogrammed by factors in the oocyte. The first somatic cloned offspring of mice were obtained by directly injecting donor nuclei into recipient enucleated oocytes. When this method is used (the so-called Honolulu method of somatic cell nuclear transfer [SCNT]), the donor nuclei readily and completely condense within the enucleated metaphase II-arrested oocytes, which contain high levels of M-phase-promoting factor (MPF). It is believed that the condensation of the donor chromosomes promotes complete reprogramming of the donor genome within the mouse oocytes. Another key to the success of mouse cloning is the use of blunt micropipettes attached to a piezo impact-driving micromanipulation device. This system saves a significant amount of time during the micromanipulation of oocytes and thus minimizes the loss of oocyte viability in vitro. For example, a group of 20 oocytes can be enucleated within 10 min by an experienced operator. This protocol is composed of seven parts: (1) preparing micropipettes, (2) setting up the enucleation and injection micropipettes, (3) collecting and enucleating oocytes, (4) preparing nucleus donor cells, (5) injecting donor nuclei, (6) activating embryos and culturing, and (7) transferring cloned embryos. © 2017 Cold Spring Harbor Laboratory Press.

  14. The Structure of the Poxvirus A33 Protein Reveals a Dimer of Unique C-Type Lectin-Like Domains

    SciTech Connect

    Su, Hua-Poo; Singh, Kavita; Gittis, Apostolos G.

    2010-11-03

    The current vaccine against smallpox is an infectious form of vaccinia virus that has significant side effects. Alternative vaccine approaches using recombinant viral proteins are being developed. A target of subunit vaccine strategies is the poxvirus protein A33, a conserved protein in the Chordopoxvirinae subfamily of Poxviridae that is expressed on the outer viral envelope. Here we have determined the structure of the A33 ectodomain of vaccinia virus. The structure revealed C-type lectin-like domains (CTLDs) that occur as dimers in A33 crystals with five different crystal lattices. Comparison of the A33 dimer models shows that the A33 monomers have amore » degree of flexibility in position within the dimer. Structural comparisons show that the A33 monomer is a close match to the Link module class of CTLDs but that the A33 dimer is most similar to the natural killer (NK)-cell receptor class of CTLDs. Structural data on Link modules and NK-cell receptor-ligand complexes suggest a surface of A33 that could interact with viral or host ligands. The dimer interface is well conserved in all known A33 sequences, indicating an important role for the A33 dimer. The structure indicates how previously described A33 mutations disrupt protein folding and locates the positions of N-linked glycosylations and the epitope of a protective antibody.« less

  15. Epidemiology of Achilles tendon ruptures: increasing incidence over a 33-year period.

    PubMed

    Lantto, I; Heikkinen, J; Flinkkilä, T; Ohtonen, P; Leppilahti, J

    2015-02-01

    We investigated the epidemiology of total Achilles tendon ruptures and complication rates after operative and nonoperative treatments over a 33-year period in Oulu, Finland. Patients with Achilles tendon ruptures from 1979 to 2011 in Oulu were identified from hospital patient records. Demographic data, treatment method, and complications were collected retrospectively from medical records. Overall and sex- and age-specific incidence rates were calculated with 95% confidence intervals (CIs). The overall incidence per 100,000 person-years increased from 2.1 (95% CI 0.3-7.7) in 1979 to 21.5 (95% CI 14.6-30.6) in 2011. The incidence increased in all age groups. The mean annual increase in incidence was 2.4% (95% CI 1.3-4.7) higher for non-sports-related ruptures than for sports-related ruptures (P = 0.036). The incidence of sports-related ruptures increased during the second 11-year period whereas the incidence of non-sports-related ruptures increased steadily over the entire study period. Infection was four times more common after operative treatment compared with nonoperative treatment, re-rupture rates were similar. The incidence of Achilles tendon ruptures increased in all age groups over a 33-year period. Increases were mainly due to sports-related injuries in the second 11-year period and non-sports-related injuries in the last 11-year period. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Anterior segment developmental anomalies in a 33-week-old fetus with MIDAS syndrome.

    PubMed

    Herwig, Martina C; Loeffler, Karin U; Gembruch, Ulrich; Kuchelmeister, Klaus; Müller, Annette M

    2014-01-01

    We report anterior segment abnormalities in both eyes of a 33-week-old fetus endorsing the diagnosis of MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome. After abortion, the fetus was examined by a standard pediatric autopsy that included macroscopic and microscopic examination of both eyes. Postmortem findings included craniofacial stigmata (such as hypertelorism, a flat nose and low-set ears) and an agenesis of the corpus callosum. Array comparative genomic hybridization revealed a deletion of the short arm of the X chromosome (region Xp22.2 to p22.32). Ophthalmopathologic examination of the eyes revealed microphthalmia with anterior segment developmental anomalies, in particular sclerocornea and Peters' anomaly, respectively. General pathology findings plus the ocular findings allowed the diagnosis of MIDAS syndrome. A discussion of differential diagnoses is provided. This case report indicates that ophthalmopathologic investigation of fetal eyes can be of great value for the further classification of syndromes.

  17. Mutations in the Vaccinia Virus A33R and B5R Envelope Proteins That Enhance Release of Extracellular Virions and Eliminate Formation of Actin-Containing Microvilli without Preventing Tyrosine Phosphorylation of the A36R Protein

    PubMed Central

    Katz, Ehud; Ward, Brian M.; Weisberg, Andrea S.; Moss, Bernard

    2003-01-01

    The spread of vaccinia virus in cell cultures is mediated by virions that adhere to the tips of specialized actin-containing microvilli and also by virions that are released into the medium. The use of a small plaque-forming A36R gene deletion mutant to select spontaneous second-site mutants exhibiting enhanced virus release was described previously. Two types of mutations were found: C-terminal truncations of the A33R envelope protein and a single amino acid substitution of the B5R envelope protein. In the present study, we transferred each type of mutation into a wild-type virus background in order to study their effects in vitro and in vivo. The two new mutants conserved the enhanced virus release properties of the original isolates; the A33R mutant produced considerably more extracellular virus than the B5R mutant. The extracellular virus particles contained the truncated A33R protein in one case and the mutated B5R protein in the other. Remarkably, both mutants failed to form actin tails and specialized microvilli, despite the presence of an intact A36R gene. The synthesis of the A36R protein as well as its physical association with the mutated or wild-type A33R protein was demonstrated. Moreover, the A36R protein was tyrosine phosphorylated, a step mediated by a membrane-associated Src kinase that regulates the nucleation of actin polymerization. The presence of large numbers of adherent virions on the cell surface argued against rapid dissociation as having a key role in preventing actin tail formation. Thus, the A33R and B5R proteins may be more directly involved in the formation or stabilization of actin tails than had been previously thought. When mice were inoculated intranasally, the A33R mutant was highly attenuated and the B5R mutant was mildly attenuated compared to wild-type virus. Enhanced virus release, therefore, did not compensate for the loss of actin tails and specialized microvilli. PMID:14581563

  18. Bochdalek hernia and repetitive pancreatitis in a 33 year old woman

    PubMed Central

    Angel, Medina Andrade Luis; David, Coot Polanco Reyes; Laura, Medina Andrade; Abraham, Medina Andrade; Stephanie, Serrano Collazos; Grecia, Ortiz Ramirez

    2014-01-01

    INTRODUCTION Bochdalek hernia presentation in adulthood is rare. The presentation in newborns is the most common, manifesting with data from respiratory failure secondary to pulmonary hypoplasia, requiring urgent surgical intervention with high morbidity and mortality. PRESENTATION OF CASE We present the case of a 33 year old woman admitted in the emergency room with severe abdominal pain in the left upper quadrant and disnea. After physical examination and laboratory test we diagnose mild acute pancreatitis. The patient haven’t colelitiasis by ulstrasound or any risk factor for pancreatitis. Initially she received medical treatment and was discharged after one week. After four weeks she presented the same symptoms in two different occasions, with severe and mild pancreatitis respectively. A computed tomography report a left posterolateral diafragmatic hernia. In spite of the rare association of pancreatitis and Bochdalek hernia, we realized it as the etiology until the second event and planned his surgery. We made a posterolateral torachotomy and diafragmatic plasty with a politetrafluoroetileno mesh and after a 6 months follow up she has coursed asymptomatic. DISCUSSION The high rate of complications in this type of hernia requires us to perform surgical treatment as the hernia is detected. In this case it is prudent medical treatment prior to surgical correction despite this being the origin of the pancreatitis, because the systemic inflammatory response added by the surgical act could result in a higher rate of complications if not performed at the appropriate time. There is no precise rule to determine the type of approach of choice in this type of hernia which thoracotomy or laparotomy may be used. CONCLUSION Bochdalek hernia is a rare find in adults who require treatment immediately after diagnosis because of the high risk of complications. When presented with data from pancreatitis is recommended to complete the medical treatment of pancreatitis before

  19. Bochdalek hernia and repetitive pancreatitis in a 33 year old woman.

    PubMed

    Angel, Medina Andrade Luis; David, Coot Polanco Reyes; Laura, Medina Andrade; Abraham, Medina Andrade; Stephanie, Serrano Collazos; Grecia, Ortiz Ramirez

    2014-01-01

    Bochdalek hernia presentation in adulthood is rare. The presentation in newborns is the most common, manifesting with data from respiratory failure secondary to pulmonary hypoplasia, requiring urgent surgical intervention with high morbidity and mortality. We present the case of a 33 year old woman admitted in the emergency room with severe abdominal pain in the left upper quadrant and disnea. After physical examination and laboratory test we diagnose mild acute pancreatitis. The patient haven't colelitiasis by ulstrasound or any risk factor for pancreatitis. Initially she received medical treatment and was discharged after one week. After four weeks she presented the same symptoms in two different occasions, with severe and mild pancreatitis respectively. A computed tomography report a left posterolateral diafragmatic hernia. In spite of the rare association of pancreatitis and Bochdalek hernia, we realized it as the etiology until the second event and planned his surgery. We made a posterolateral torachotomy and diafragmatic plasty with a politetrafluoroetileno mesh and after a 6 months follow up she has coursed asymptomatic. The high rate of complications in this type of hernia requires us to perform surgical treatment as the hernia is detected. In this case it is prudent medical treatment prior to surgical correction despite this being the origin of the pancreatitis, because the systemic inflammatory response added by the surgical act could result in a higher rate of complications if not performed at the appropriate time. There is no precise rule to determine the type of approach of choice in this type of hernia which thoracotomy or laparotomy may be used. Bochdalek hernia is a rare find in adults who require treatment immediately after diagnosis because of the high risk of complications. When presented with data from pancreatitis is recommended to complete the medical treatment of pancreatitis before surgery to obtain the best results, unless it exist another

  20. Childhood Attention-Deficit/Hyperactivity Disorder and Homelessness: A 33-Year Follow-Up Study.

    PubMed

    García Murillo, Lourdes; Ramos-Olazagasti, Maria A; Mannuzza, Salvatore; Castellanos, Francisco Xavier; Klein, Rachel G

    2016-11-01

    To examine whether childhood attention-deficit/hyperactivity disorder (ADHD) predicts homelessness in adulthood, and whether the persistence of childhood ADHD through adolescence influences the likelihood of homelessness. A 33-year prospective, controlled, follow-up was performed of clinic-referred, 6- to 12-year-old boys of white ethnicity with ADHD (probands; mean = 8), at a mean age of 41 years (follow-up [FU] = 41). Comparisons, children without ADHD from the same medical center, were matched for age and socioeconomic status (SES). Both groups were evaluated at a mean age of 18 years (FU18). Homelessness was assessed at FU41 in 134 of 207 probands (65%) and 136 of 178 (76%) comparisons. We tested the following: the relationship between childhood ADHD and homelessness; whether adolescent dysfunctions (conduct disorder, non-alcohol substance use disorder, arrests, and school dropout) accounted for this relationship, if found; and whether ADHD that persisted through FU18 elevated probands' homelessness rate. Probands had significantly higher rates of homelessness than comparisons (23.7% vs. 4.4%; χ 2 1  = 21.15, df = 1, p < .001). In a multivariate analysis, including childhood ADHD and covariates, the probands' significant elevation of homelessness remained (odds ratio [OR] = 3.60, 95% CI = 1.32-9.76, p = .01). Probands with persistent ADHD through adolescence had significantly more homelessness than remitted probands (χ 2 1  = 12.73, p < .001), but this relationship was no longer significant when conduct disorder at FU18 was controlled (OR = 1.97, 95% CI = 0.89-4.38, p = .09). Among boys of white ethnicity who were followed into adulthood, childhood ADHD was associated with an elevated rate of homelessness. Findings point to the need for clinical monitoring of childhood ADHD through adolescence, even when ADHD does not persist, in hopes of mitigating a cascade of malfunction that includes homelessness. Copyright © 2016 American Academy of

  1. [Case report: electroconvulsive therapy in a 33-year-old man with hysterical quadriplegia].

    PubMed

    Gaillard, A; Gaillard, R; Mouaffak, F; Radtchenko, A; Lôo, H

    2012-02-01

    Conversion disorder refers to the occurrence of neurological-like symptoms or deficits that are neither intentionally produced nor simulated. While it cannot be explained by an organic disease, it is often related to psychological events. We report the case of a 33-year-old patient with a fluctuating hysterical tetraplegia, which had started three years earlier. After the failure or the exhaustion of several biological (psychotropic medication, transcranial magnetic stimulation) and psychotherapeutic strategies, treatment with electroconvulsive therapy (ECT) was conducted. A total of thirty-five ECT sessions were performed. Whereas the patient's clinical state was initially characterized by a complete quadriplegia and an uncontrollable muscular hypertonia, we noted that the ECT sessions were associated with a slow, though remarkable, progress. At first, the sessions were followed by moments of altered consciousness during which the patient would be relaxed and could make simple movements. Secondarily, not only was our patient able to consciously move his four limbs, but he was also able to walk. However, those improvements remained partial and fluctuating, sometimes allowing the symptom to return temporarily secondary to frustrations or annoyances. Finally, our patient relapsed. Nevertheless, his clinical state presently remains better than that in which we first knew him. The treatment of conversion disorders has been the subject of few studies and predominantly remains symptomatic. Its main goals are: to lessen secondary gains impact by adopting a neutral behaviour towards the symptom and by encouraging physical rehabilitation; to lower the symptom by allowing the patient to understand the normal functioning of the diseased organ, and; to help the patient to deal with stressful situations. There is no evidence that hypnosis is superior to medical and other psychotherapeutic approaches. Pharmacological treatments may be helpful in the case of anxiety, impulsivity

  2. von Willebrand's disease antigen II. A new plasma and platelet antigen deficient in severe von Willebrand's disease.

    PubMed Central

    Montgomery, R R; Zimmerman, T S

    1978-01-01

    Factor VIII-related antigen (VIIIag) is deficient in plasma and platelets of patients with severe von Willebrand's disease. This study reports a second von Willebrand's disease antigen (vWagII), distinct from VIIIag, that is also deficient in the platelets and plasma of patients with severe von Willebrand's disease. VIIIag and vWagII are separable by molecular exclusion chromatography, sucrose density gradient ultracentrifugation, and crossed immunoelectrophoresis. They show reactions of immunologic nonidentity with each other, and thus, do not share a precursor-product relationship. vWagII is released from normal platelets during blood clotting, accounting for a fourfold higher concentration of vWagII in serum over plasma. Images PMID:307007

  3. Mice and Men.

    ERIC Educational Resources Information Center

    Willingham, Shively; Thompson, Charles L.

    Observations and experiments with mice, developed and tested at the Pennsylvania Advancement School with underachieving boys in grades seven and eight, are described in this teachers' guide which includes copies of student worksheets for exercises needing them. In addition to lists of materials and procedural suggestions, ideas for guiding…

  4. Docetaxel chronopharmacology in mice.

    PubMed

    Tampellini, M; Filipski, E; Liu, X H; Lemaigre, G; Li, X M; Vrignaud, P; François, E; Bissery, M C; Lévi, F

    1998-09-01

    Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving

  5. Mice Drawer System

    NASA Technical Reports Server (NTRS)

    Cancedda, Ranieri

    2008-01-01

    The Mice Drawer System (MDS) is an Italian Space Agency (ASI) facility which is able to support mice onboard the International Space Station during long-duration exploration missions (from 100 to 150-days) by living space, food, water, ventilation and lighting. Mice can be accommodated either individually (maximum 6) or in groups (4 pairs). MDS is integrated in the Space Shuttle middeck during transportation (uploading and downloading) to the ISS and in an EXPRESS Rack in Destiny, the US Laboratory during experiment execution. Osteoporosis is a debilitating disease that afflicts millions of people worldwide. One of the physiological changes experienced by astronauts during space flight is the accelerated loss of bone mass due to the lack of gravitational loading on the skeleton. This bone loss experienced by astronauts is similar to osteoporosis in the elderly population. MDS will help investigate the effects of unloading on transgenic (foreign gene that has been inserted into its genome to exhibit a particular trait) mice with the Osteoblast Stimulating Factor-1, OSF-1, a growth and differentiation factor, and to study the genetic mechanisms underlying the bone mass pathophysiology. MDS will test the hypothesis that mice with an increased bone density are likely to be more protected from osteoporosis, when the increased bone mass is a direct effect of a gene involved in skeletogenesis (skeleton formation). Osteoporosis is a debilitating disease that afflicts millions worldwide. One of the physiological changes experienced by astronauts during space flight is the accelerated loss of bone mass due to the lack of gravitational loading on the skeleton, a loss that is similar to osteoporosis in the elderly population on Earth. Osteoblast Stimulating Factor-1 (OSF-1), also known as pleiotrophin (PTN) or Heparin-Binding Growth- Associated Molecule (HB-GAM) belongs to a family of secreted heparin binding proteins..OSF-1 is an extracellular matrix-associated growth and

  6. Mice take calculated risks.

    PubMed

    Kheifets, Aaron; Gallistel, C R

    2012-05-29

    Animals successfully navigate the world despite having only incomplete information about behaviorally important contingencies. It is an open question to what degree this behavior is driven by estimates of stochastic parameters (brain-constructed models of the experienced world) and to what degree it is directed by reinforcement-driven processes that optimize behavior in the limit without estimating stochastic parameters (model-free adaptation processes, such as associative learning). We find that mice adjust their behavior in response to a change in probability more quickly and abruptly than can be explained by differential reinforcement. Our results imply that mice represent probabilities and perform calculations over them to optimize their behavior, even when the optimization produces negligible material gain.

  7. Mice take calculated risks

    PubMed Central

    Kheifets, Aaron; Gallistel, C. R.

    2012-01-01

    Animals successfully navigate the world despite having only incomplete information about behaviorally important contingencies. It is an open question to what degree this behavior is driven by estimates of stochastic parameters (brain-constructed models of the experienced world) and to what degree it is directed by reinforcement-driven processes that optimize behavior in the limit without estimating stochastic parameters (model-free adaptation processes, such as associative learning). We find that mice adjust their behavior in response to a change in probability more quickly and abruptly than can be explained by differential reinforcement. Our results imply that mice represent probabilities and perform calculations over them to optimize their behavior, even when the optimization produces negligible material gain. PMID:22592792

  8. Experimental Paracoccidioidomycosis in Mice

    PubMed Central

    Linares, Leonor I.; Friedman, Lorraine

    1972-01-01

    Virulence and infectivity of nine strains of Paracoccidioides brasiliensis were investigated in groups of mice which were inoculated intranasally or intravenously, and some of each were treated with corticosteroids. Fatal infections were not often seen among untreated mice, but mortality usually occurred when corticosteroids were given, regardless of the route of fungus inoculation. Prior treatment did not uniformly increase the incidence of infection, however; only in the case of intranasally inoculated mice was this effect seen. Most strains appeared to be more virulent when administered intravenously, with the exception of a single strain which, under the influence of corticosteroids, repeatedly displayed greatest virulence when given intranasally. All animals that died early in the course of the disease, irrespective of route of inoculation, always had acute pulmonary lesions and usually no other organ was involved. Animals which died later or were sacrificed always had chronic lung lesions. Whether or not chronically diseased animals had additional organ involvement correlated with how the organisms were administered; intravenously inoculated animals usually had extrapulmonary as well as pulmonary lesions, but lesions of those inoculated intranasally were almost exclusively pulmonary. Corticosteroids did not alter the histologic characteristics of either the acute or the chronic type of lesion, but the lesions of treated animals were usually more extensive. Most of the survivors appeared healthy even when infection was extensive. Images PMID:4637603

  9. Development of MGD007, a gpA33 x CD3 bispecific DART® protein for T-cell immunotherapy of metastatic colorectal cancer.

    PubMed

    Moore, Paul A; Shah, Kalpana; Yang, Yinhua; Alderson, Ralph; Roberts, Penny; Long, Vatana; Liu, Daorong; Li, Jonathan C; Burke, Steve; Ciccarone, Valentina; Li, Hua; Fieger, Claudia B; Hooley, Jeff; Easton, Ann; Licea, Monica; Gorlatov, Sergey; King, Kathleen L; Young, Peter; Adami, Arash; Loo, Deryk; Chichili, Gurunadh R; Liu, Liqin; Smith, Douglas H; Brown, Jennifer G; Chen, Francine Z; Koenig, Scott; Mather, Jennie; Bonvini, Ezio; Johnson, Syd

    2018-06-04

    We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART® protein designed to redirect T-cells to target gpA33 expressing colon cancer. The gpA33 target was selected based on an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic CRC specimens, including putative cancer stem cell populations. MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T-cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 µg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33 expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD 1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 µg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer. Copyright ©2018, American Association for Cancer Research.

  10. A 33-Year-Old Man with Gynaecomastia and Galactorrhea as the First Symptoms of Graves Hyperthyroidism.

    PubMed

    Khoohaphatthanakul, Somdul; Sriwijitkamol, Apiradee

    2016-01-01

    Graves' hyperthyroidism has a various number of well-recognized manifestations. Galactorrhea is a rare manifestation in this disease. We describe a 33-year-old man who presented with the symptoms of hyperthyroidism, gynaecomastia, and galactorrhea for 2 months. Physical examination revealed goitre, gynaecomastia, and galactorrhea, bilaterally. Laboratory investigations demonstrated high free thyroxine with suppressed thyroid-stimulating hormone level together with elevated anti-TSH receptor; therefore, the diagnosis of Graves' disease was confirmed. Other investigations to elucidate the etiology of galactorrhea were normal, so the galactorrhea was hypothesized to be caused by Graves' disease. The gynaecomastia and galactorrhea resolved with the successful treatment of hyperthyroidism. Although the galactorrhea is extremely rare in thyrotoxicosis male patients, to the best of our knowledge, this is the third case which reported gynaecomastia and galactorrhea in male patient who presented with thyrotoxicosis.

  11. Of Mice and Dogs

    PubMed Central

    Dewald, Oliver; Ren, Guofeng; Duerr, Georg D.; Zoerlein, Martin; Klemm, Christina; Gersch, Christine; Tincey, Sophia; Michael, Lloyd H.; Entman, Mark L.; Frangogiannis, Nikolaos G.

    2004-01-01

    Large animal models have provided much of the descriptive data regarding the cellular and molecular events in myocardial infarction and repair. The availability of genetically altered mice may provide a valuable tool for specific cellular and molecular dissection of these processes. In this report we compare closed chest models of canine and mouse infarction/reperfusion qualitatively and quantitatively for temporal, cellular, and spatial differences. Much like the canine model, reperfused mouse hearts are associated with marked induction of endothelial adhesion molecules, cytokines, and chemokines. Reperfused mouse infarcts show accelerated replacement of cardiomyocytes by granulation tissue leading to a thin mature scar at 14 days, when the canine infarction is still cellular and evolving. Infarcted mouse hearts demonstrate a robust but transient postreperfusion inflammatory reaction, associated with a rapid up-regulation of interleukin-10 and transforming growth factor-β. Unlike canine infarcts, infarcted mouse hearts show only transient macrophage infiltration and no significant mast cell accumulation. In correlation, the growth factor for macrophages, M-CSF, shows modest and transient up-regulation in the early days of reperfusion; and the obligate growth factor for mast cells, stem cell factor, SCF, is not induced. In summary, the postinfarction inflammatory response and resultant repair in the mouse heart shares many common characteristics with large mammalian species, but has distinct temporal and qualitative features. These important species-specific differences should be considered when interpreting findings derived from studies using genetically altered mice. PMID:14742270

  12. The individuality of mice.

    PubMed

    Lathe, R

    2004-12-01

    Mutant mice simulating human CNS disorders are used as models for therapeutic drug development. Drug evaluation requires a coherent correlation between behavioral phenotype and drug status. Variations in behavioral responses could mask such correlations, a problem highlighted by the three-site studies of Crabbe et al. (1999) and Wahlsten et al. (2003a). Factors contributing to variation are considered, focusing on differences between individual animals. Genetic differences due to minisatellite variation suggest that each mouse is genetically distinct. Effects during gestation, including maternal stress, influence later life behavior; while endocrine exchanges between fetus and parent, and between male and female fetuses dependent on intrauterine position, also contribute. Pre and perinatal nutrition and maternal attention also play a role. In adults, endocrine cyclicity in females is a recognized source of behavioral diversity. Notably, there is increasing recognition that groups of wild and laboratory mice have complex social structures, illustrated through consideration of Crowcroft (1966). Dominance status can markedly modify behavior in test paradigms addressing anxiety, locomotion and aggressiveness, to an extent comparable to mutation or drug status. Understanding how such effects amplify the behavioral spectrum displayed by otherwise identical animals will improve testing.

  13. Resilience in Aging Mice

    PubMed Central

    Kirkland, James L.; Stout, Michael B.

    2016-01-01

    Abstract Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an

  14. Novel psychoactive substances: overdose of 3-fluorophenmetrazine (3-FPM) and etizolam in a 33-year-old man.

    PubMed

    Benesch, Matthew G K; Iqbal, Sahar J

    2018-06-08

    Though illegal in the UK, in many countries novel psychoactive substances are quasi-legal synthetic compounds that are widely available online under the guise of research chemicals. These substances are relatively cheap and are often undetectable in standard drug screens. Nearly 200 such compounds are introduced yearly, and little is usually known about their metabolism or physiological effects. Consequently, managing patients in overdose situations on largely unknown substances usually involves supportive care, however anticipating and managing atypical side effects are challenging in the absence of knowledge of these compounds. In this report, we discuss our encounter with a 33-year-old unconscious man presenting with coingestion of a novel stimulant 3-fluorophenmetrazine with a rarely used benzodiazepine etizolam. This patient developed seizure-like activity and delayed widespread T-wave inversions, both of which ultimately resolved without sequelae. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. Resilience in Aging Mice.

    PubMed

    Kirkland, James L; Stout, Michael B; Sierra, Felipe

    2016-11-01

    Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context

  16. Transgenic mice in developmental toxicology

    SciTech Connect

    Woychik, R.P.

    1992-12-31

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areasmore » of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.« less

  17. Transgenic mice in developmental toxicology

    SciTech Connect

    Woychik, R.P.

    1992-01-01

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areasmore » of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.« less

  18. Climate change: consequences on the pollination of grasses in Perugia (Central Italy). A 33-year-long study.

    PubMed

    Sofia, Ghitarrini; Emma, Tedeschini; Veronica, Timorato; Giuseppe, Frenguelli

    2017-01-01

    Many works carried out in the last decades have shown that the pollen season for taxa flowering in winter and spring, in temperate regions, has tended to be earlier, probably due to the continuous rise in temperature. The mean annual temperature in Perugia, Central Italy, was about 0.5 °C higher in the last three decades compared with that registered from 1952 to 1981. The increase of temperature took place mainly in winter and spring, while no significant variation was recorded during the summer and autumn. This scenario shows variations in the timing and behavior of flowering of many spontaneous plants such as grasses, whose phenology is strongly influenced by air temperature. This work reports fluctuations in the airborne grass pollen presence in Perugia over a 33-year period (1982-2014), in order to study the influence of the warming registered in recent years on the behavior of pollen release of this taxon. The grass pollen season in Perugia typically lasts from the beginning of May to late July. The start dates showed a marked trend to an earlier beginning of the season (-0.4 day/year), as well as a strong correlation with the average temperatures of March and April. The peak is reached around 30th May, but the annual pollen index (API) is following a decreasing trend. The correlation between starting dates and spring temperatures could be interesting for the constitution of a forecasting model capable of predicting the presence of airborne grass pollen, helping to plan therapies for allergic people.

  19. Palatable Meal Anticipation in Mice

    PubMed Central

    Hsu, Cynthia T.; Patton, Danica F.; Mistlberger, Ralph E.; Steele, Andrew D.

    2010-01-01

    The ability to sense time and anticipate events is a critical skill in nature. Most efforts to understand the neural and molecular mechanisms of anticipatory behavior in rodents rely on daily restricted food access, which induces a robust increase of locomotor activity in anticipation of daily meal time. Interestingly, rats also show increased activity in anticipation of a daily palatable meal even when they have an ample food supply, suggesting a role for brain reward systems in anticipatory behavior, and providing an alternate model by which to study the neurobiology of anticipation in species, such as mice, that are less well adapted to “stuff and starve” feeding schedules. To extend this model to mice, and exploit molecular genetic resources available for that species, we tested the ability of wild-type mice to anticipate a daily palatable meal. We observed that mice with free access to regular chow and limited access to highly palatable snacks of chocolate or “Fruit Crunchies” avidly consumed the snack but did not show anticipatory locomotor activity as measured by running wheels or video-based behavioral analysis. However, male mice receiving a snack of high fat chow did show increased food bin entry prior to access time and a modest increase in activity in the two hours preceding the scheduled meal. Interestingly, female mice did not show anticipation of a daily high fat meal but did show increased activity at scheduled mealtime when that meal was withdrawn. These results indicate that anticipation of a scheduled food reward in mice is behavior, diet, and gender specific. PMID:20941366

  20. Practical pathology of aging mice

    PubMed Central

    Pettan-Brewer, Christina; Treuting, Piper M.

    2011-01-01

    Old mice will have a subset of lesions as part of the progressive decline in organ function that defines aging. External and palpable lesions will be noted by the research, husbandry, or veterinary staff during testing, cage changing, or physical exams. While these readily observable lesions may cause alarm, not all cause undue distress or are life-threatening. In aging research, mice are maintained until near end of life that, depending on strain and genetic manipulation, can be upwards of 33 months. Aging research has unique welfare issues related to age-related decline, debilitation, fragility, and associated pain of chronic diseases. An effective aging research program includes the collaboration and education of the research, husbandry, and veterinary staff, and of the members of the institution animal care and use committee. This collaborative effort is critical to humanely maintaining older mice and preventing excessive censorship due to non-lethal diseases. Part of the educational process is becoming familiar with how old mice appear clinically, at necropsy and histopathologically. This baseline knowledge is important in making the determination of humane end points, defining health span, contributing causes of death and effects of interventions. The goal of this paper is to introduce investigators to age-associated diseases and lesion patterns in mice from clinical presentation to pathologic assessment. To do so, we present and illustrate the common clinical appearances, necropsy and histopathological lesions seen in subsets of the aging colonies maintained at the University of Washington. PMID:22953032

  1. The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters*

    PubMed Central

    Di Noia, Maria Antonietta; Todisco, Simona; Cirigliano, Angela; Rinaldi, Teresa; Agrimi, Gennaro; Iacobazzi, Vito; Palmieri, Ferdinando

    2014-01-01

    The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. PMID:25320081

  2. The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters.

    PubMed

    Di Noia, Maria Antonietta; Todisco, Simona; Cirigliano, Angela; Rinaldi, Teresa; Agrimi, Gennaro; Iacobazzi, Vito; Palmieri, Ferdinando

    2014-11-28

    The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Voluntary Wheel Running in Mice.

    PubMed

    Goh, Jorming; Ladiges, Warren

    2015-12-02

    Voluntary wheel running in the mouse is used to assess physical performance and endurance and to model exercise training as a way to enhance health. Wheel running is a voluntary activity in contrast to other experimental exercise models in mice, which rely on aversive stimuli to force active movement. This protocol consists of allowing mice to run freely on the open surface of a slanted, plastic saucer-shaped wheel placed inside a standard mouse cage. Rotations are electronically transmitted to a USB hub so that frequency and rate of running can be captured via a software program for data storage and analysis for variable time periods. Mice are individually housed so that accurate recordings can be made for each animal. Factors such as mouse strain, gender, age, and individual motivation, which affect running activity, must be considered in the design of experiments using voluntary wheel running. Copyright © 2015 John Wiley & Sons, Inc.

  4. Voluntary Wheel Running in Mice

    PubMed Central

    Goh, Jorming; Ladiges, Warren

    2015-01-01

    Voluntary wheel running in the mouse is used to assess physical performance and endurance and to model exercise training as a way to enhance health. Wheel running is a voluntary activity in contrast to other experimental exercise models in mice, which rely on aversive stimuli to force active movement. The basic protocol consists of allowing mice to run freely on the open surface of a slanted plastic saucer-shaped wheel placed inside a standard mouse cage. Rotations are electronically transmitted to a USB hub so that frequency and rate of running can be captured to a software program for data storage and analysis for variable time periods. Mice are individually housed so that accurate recordings can be made for each animal. Factors such as mouse strain, gender, age, and individual motivation, which affect running activity, must be considered in the design of experiments using voluntary wheel running. PMID:26629772

  5. Mitochondrial DNA evolution in mice.

    PubMed

    Ferris, S D; Sage, R D; Prager, E M; Ritte, U; Wilson, A C

    1983-11-01

    This study extends knowledge of mitochondrial DNA (mtDNA) diversity in mice to include 208 animals belonging to eight species in the subgenus Mus. Highly purified mtDNA from each has been subjected to high-resolution restriction mapping with respect to the known sequence of one mouse mtDNA. Variation attributed to base substitutions was encountered at about 200 of the 300 cleavage sites examined, and a length mutation was located in or near the displacement loop. The variability of different functional regions in this genome was as follows, from least to most: ribosomal RNA, transfer RNA, known proteins, displacement loop and unidentified reading frames. --Phylogenetic analysis confirmed the utility of the Sage and Marshall revision of mouse classification, according to which there are at least four species of commensal mice and three species of aboriginal mice in the complex that was formerly considered to be one species. The most thoroughly studied of these species is Mus domesticus, the house mouse of Western Europe and the Mediterranean region, which is the mitochondrial source of all 50 of the laboratory strains examined and of the representatives of wild house mice introduced by Europeans to North and South America during the past few hundred years. --The level of mtDNA variation among wild representatives of M. domesticus is similar to that for the Eastern European house mouse (M. musculus) and several other mammalian species. By contrast, among the many laboratory strains that are known or suspected to stem from the pet mouse trade, there is little interstrain variation, most strains having the "old inbred" type of domesticus mtDNA, whose frequency in the 145 wild mice examined is low, about 0.04. Also notable is the apparent homogeneity of mtDNA in domesticus races that have fixed six or more fused chromosomes and the close relationship of some of these mtDNAs to those of karyotypically normal mice. --In addition, this paper discusses fossil and other

  6. Mitochondrial DNA Evolution in Mice

    PubMed Central

    Ferris, Stephen D.; Sage, Richard D.; Prager, Ellen M.; Ritte, Uzi; Wilson, Allan C.

    1983-01-01

    This study extends knowledge of mitochondrial DNA (mtDNA) diversity in mice to include 208 animals belonging to eight species in the subgenus Mus. Highly purified mtDNA from each has been subjected to high-resolution restriction mapping with respect to the known sequence of one mouse mtDNA. Variation attributed to base substitutions was encountered at about 200 of the 300 cleavage sites examined, and a length mutation was located in or near the displacement loop. The variability of different functional regions in this genome was as follows, from least to most: ribosomal RNA, transfer RNA, known proteins, displacement loop and unidentified reading frames.—Phylogenetic analysis confirmed the utility of the Sage and Marshall revision of mouse classification, according to which there are at least four species of commensal mice and three species of aboriginal mice in the complex that was formerly considered to be one species. The most thoroughly studied of these species is Mus domesticus, the house mouse of Western Europe and the Mediterranean region, which is the mitochondrial source of all 50 of the laboratory strains examined and of the representatives of wild house mice introduced by Europeans to North and South America during the past few hundred years.—The level of mtDNA variation among wild representatives of (M. musculus) and several other mammalian species. By contrast, among the many laboratory strains that are known or suspected to stem from the pet mouse trade, there is little interstrain variation, most strains having the "old inbred" type of domesticus mtDNA, whose frequency in the 145 wild mice examined is low, about 0.04. Also notable is the apparent homogeneity of mtDNA in domesticus races that have fixed six or more fused chromosomes and the close relationship of some of these mtDNAs to those of karyotypically normal mice.—In addition, this paper discusses fossil and other evidence for the view that in mice, as in many other mammals, the average

  7. Ultrasonic Songs of Male Mice

    PubMed Central

    Guo, Zhongsheng

    2005-01-01

    Previously it was shown that male mice, when they encounter female mice or their pheromones, emit ultrasonic vocalizations with frequencies ranging over 30–110 kHz. Here, we show that these vocalizations have the characteristics of song, consisting of several different syllable types, whose temporal sequencing includes the utterance of repeated phrases. Individual males produce songs with characteristic syllabic and temporal structure. This study provides a quantitative initial description of male mouse songs, and opens the possibility of studying song production and perception in an established genetic model organism. PMID:16248680

  8. Modified Protein Improves Vitiligo Symptoms in Mice

    MedlinePlus

    ... Vitiligo Symptoms in Mice Spotlight on Research Modified Protein Improves Vitiligo Symptoms in Mice By Colleen Labbe, ... D., Ph.D., Rush University. Altering a key protein involved in the development of vitiligo may protect ...

  9. Transplacental Arsenic Carcinogenesis in Mice

    PubMed Central

    Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

    2007-01-01

    Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from day 8 to 18 of gestation, and the offspring were observed for up to two years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and

  10. HZE Radiation Leukemogenesis in Mice

    NASA Astrophysics Data System (ADS)

    Peng, Yuanlin

    Radiation exposure is a risk factor for acute myeloid leukemia (AML). The Leukemogenesis NSCOR was developed to compare this risk for low LET vs HZE radiations as a means to better assess the leukemia risk to astronauts posed by space radiation. Individual projects within the NSCOR explore HZE radiation leukemogenesis in murine model systems and extend the findings to AML in humans. AML sensitive CBA/CaJ mice have been irradiated with 1 GeV 56 Fe particles at NSRL and with 137 Cs gamma-rays at Colorado State University and followed to 800 days of age for the development of AML. Molecular and cytogenetic analyses of HZE- and gamma-induced AML, including assays for chromosomal aberrations, PU.1 deletion, gene expression, array CGH and microsatellite instability are ongoing. Preliminary data indicate that 56 Fe particles are no more effective in inducing AML or shortening lifespan than gamma-rays. Studies designed to address the individual molecular steps in leukemogenesis and determine the effects of radiation and genetic background on each step have been initiated using knockout mice. Deletion of the PU.1 gene on mouse chromosome 2 is a critical step in this murine model of radiation leukemogenesis. Two of the three HZE-induced AMLs that could be assayed and thirteen of fourteen γ-induced AMLs had PU.1 loss as determined by Fluorescence in Situ Hybridization (FISH). We have found that AML sensitive CBA/CaJ mice have a higher incidence of Chr. 2 deletion in bone marrow cells following 56 Fe irradiation than AML resistant C57BL/6 mice. This study is being extended to proton irradiated mice. Our preliminary results indicate that microsatellite instability may be common in HZE irradiated progenitor cells. To determine if these cytogenetic changes can be induced in human myeloid progenitor cells by gamma, proton or HZE irradiation we are generating NOD/SCID mice that have been "humanized" by being transplanted with human hematopoietic stem cells. We are currently

  11. PET-based compartmental modeling of (124)I-A33 antibody: quantitative characterization of patient-specific tumor targeting in colorectal cancer.

    PubMed

    Zanzonico, Pat; Carrasquillo, Jorge A; Pandit-Taskar, Neeta; O'Donoghue, Joseph A; Humm, John L; Smith-Jones, Peter; Ruan, Shutian; Divgi, Chaitanya; Scott, Andrew M; Kemeny, Nancy E; Fong, Yuman; Wong, Douglas; Scheinberg, David; Ritter, Gerd; Jungbluth, Achem; Old, Lloyd J; Larson, Steven M

    2015-10-01

    The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the "best-fit" parameters and model-derived quantities for optimizing biodistribution of intravenously injected (124)I-labeled antitumor antibodies. As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as "A33") were performed in 11 colorectal cancer patients. Serial whole-body PET scans of (124)I-labeled A33 and blood samples were acquired and the resulting tissue time-activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code. Excellent agreement was observed between fitted and measured parameters of tumor uptake, "off-target" uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy. This approach should be generally applicable to antibody-antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient's resulting "best-fit" nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived.

  12. Mice learn to avoid regret.

    PubMed

    Sweis, Brian M; Thomas, Mark J; Redish, A David

    2018-06-01

    Regret can be defined as the subjective experience of recognizing that one has made a mistake and that a better alternative could have been selected. The experience of regret is thought to carry negative utility. This typically takes two distinct forms: augmenting immediate postregret valuations to make up for losses, and augmenting long-term changes in decision-making strategies to avoid future instances of regret altogether. While the short-term changes in valuation have been studied in human psychology, economics, neuroscience, and even recently in nonhuman-primate and rodent neurophysiology, the latter long-term process has received far less attention, with no reports of regret avoidance in nonhuman decision-making paradigms. We trained 31 mice in a novel variant of the Restaurant Row economic decision-making task, in which mice make decisions of whether to spend time from a limited budget to achieve food rewards of varying costs (delays). Importantly, we tested mice longitudinally for 70 consecutive days, during which the task provided their only source of food. Thus, decision strategies were interdependent across both trials and days. We separated principal commitment decisions from secondary reevaluation decisions across space and time and found evidence for regret-like behaviors following change-of-mind decisions that corrected prior economically disadvantageous choices. Immediately following change-of-mind events, subsequent decisions appeared to make up for lost effort by altering willingness to wait, decision speed, and pellet consumption speed, consistent with past reports of regret in rodents. As mice were exposed to an increasingly reward-scarce environment, we found they adapted and refined distinct economic decision-making strategies over the course of weeks to maximize reinforcement rate. However, we also found that even without changes in reinforcement rate, mice transitioned from an early strategy rooted in foraging to a strategy rooted in

  13. Progress of MICE RFCC Module

    SciTech Connect

    Li, D.; Bowring, D.; DeMello, A.

    2012-05-20

    Recent progress on the design and fabrication of the RFCC (RF and superconducting Coupling Coil) module for the international MICE (Muon Ionization Cooling Experiment) are reported. The MICE ionization cooling channel has two RFCC modules, each having four 201- MHz normal conducting RF cavities surrounded by one superconducting coupling coil (solenoid) magnet. The magnet is designed to be cooled by three cryocoolers. Fabrication of the RF cavities is complete; preparation for the cavity electro-polishing, low power RF measurements, and tuning are in progress at Lawrence Berkeley National Laboratory (LBNL). Fabrication of the cold mass of the first coupling coil magnetmore » has been completed in China and the cold mass arrived at LBNL in late 2011. Preparations for testing the cold mass are currently under way at Fermilab. Plans for the RFCC module assembly and integration are being developed and are described.« less

  14. Magnetic eye tracking in mice

    PubMed Central

    Payne, Hannah L

    2017-01-01

    Eye movements provide insights about a wide range of brain functions, from sensorimotor integration to cognition; hence, the measurement of eye movements is an important tool in neuroscience research. We describe a method, based on magnetic sensing, for measuring eye movements in head-fixed and freely moving mice. A small magnet was surgically implanted on the eye, and changes in the magnet angle as the eye rotated were detected by a magnetic field sensor. Systematic testing demonstrated high resolution measurements of eye position of <0.1°. Magnetic eye tracking offers several advantages over the well-established eye coil and video-oculography methods. Most notably, it provides the first method for reliable, high-resolution measurement of eye movements in freely moving mice, revealing increased eye movements and altered binocular coordination compared to head-fixed mice. Overall, magnetic eye tracking provides a lightweight, inexpensive, easily implemented, and high-resolution method suitable for a wide range of applications. PMID:28872455

  15. Idiotypic manipulation in mice: BALB/c mice can express the crossreactive idiotype of A/J mice.

    PubMed Central

    Moser, M; Leo, O; Hiernaux, J; Urbain, J

    1983-01-01

    The response of A/J mice to arsonate-coupled keyhole limpet hemocyanin is characterized by a crossreactive idiotype (CRIA). CRIA+ antibodies are restricted to the Igh-Ic haplotype and are never expressed in BALB/c mice after immunization with antigen. Studies at the DNA level suggest that the gene encoding the CRIA heavy chain in A/J mice is probably absent in the genome of BALB/c mice. Despite this, using the immunization cascade tool, we have been able to induce the expression of CRIA+ antibodies in BALB/c mice. These studies led to an apparent paradox, whose understanding will provide new insights into the regulatory mechanisms of the immune system. We suggest that clones secreting CRIA-like Igs in BALB/c mice are "somatic variants" that could arise from gene conversion events. PMID:6576348

  16. Mice acquire flavor preferences during shipping.

    PubMed

    Tordoff, Michael G; Alarcón, Laura K; Byerly, Erica A; Doman, Samantha A

    2005-11-15

    Vigorous motion can cause rodents to develop flavor aversions and show other signs of malaise. We tested whether a flavor aversion could be induced by shipping mice from an animal breeder to a test site. Boxes of 12 male C57BL/6J mice were shipped approximately 950 km from Bar Harbor, ME to Philadelphia, PA by truck. For some boxes, the gel provided for hydration was flavored with almond and for others it was flavored with banana. After the journey, the mice were individually housed and allowed to recover for 5 days. They then received a choice between the two flavors of gel. Contrary to expectations, mice preferred the flavor they had previously ingested during shipping. Controls given flavored gel under similar conditions but while stationary did not show a preference. These results suggest that mice find shipping or its sequelae pleasurable. If mice are travel sick this must be inconsequential relative to other components of the shipping experience.

  17. Recurrent Cutaneous Herpes Simplex in Hairless Mice

    PubMed Central

    Underwood, Gerald E.; Weed, Sheldon D.

    1974-01-01

    Passively immunized hairless mice were inoculated cutaneously with herpes simplex virus. Thirty-nine days later, when the primary cutaneous lesions had completely healed, the mice were treated subcutaneously with prednisone. Within 12 to 30 days after starting prednisone treatment, herpesvirus was recovered by skin swabs from 12 of 71 (17%) of the treated mice. This new model has potential application for understanding and treating recurrent cutaneous herpes infections. PMID:4372171

  18. Therapeutic cloning in individual parkinsonian mice

    PubMed Central

    Tabar, Viviane; Tomishima, Mark; Panagiotakos, Georgia; Wakayama, Sayaka; Menon, Jayanthi; Chan, Bill; Mizutani, Eiji; Al-Shamy, George; Ohta, Hiroshi; Wakayama, Teruhiko; Studer, Lorenz

    2009-01-01

    Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. ‘Therapeutic cloning’ is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response. PMID:18376409

  19. How Ketamine Affects Livers of Pregnant Mice and Developing Mice?

    PubMed

    Cheung, Hoi Man; Chow, Tony Chin Hung; Yew, David Tai Wai

    2017-05-19

    It is well known that ketamine abuse can induce liver damage in adult addicts, but the effects of ketamine abuse in pregnant mothers on their offspring have received less attention. In this study, we investigated the effects of 5-day ketamine injections (30 mg/kg) to pregnant Institute for Cancer Research (ICR) mice during early gestation or mid-gestation on the aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities of the mothers and the offspring. We also looked into whether administering ketamine treatment to the mothers had any effects on the extent of fibrosis, cell proliferation and cell death in the livers of the newborns. No significant biochemical differences were found between treatment and control groups in the mothers. In the offspring, ketamine treatment mildly suppressed the gradual increase of hepatic AST activity in neonates during liver maturation. Measurements of hepatic ALP activity and lactic acid dehydrogenase (LDH) immunoreactivity revealed that ketamine treatment may lead to increased cell death. Proliferation of liver cells of the newborns was also retarded as shown by reduced proliferative cell nuclear antigen (PCNA) immunoreactivity in the ketamine groups. No obvious fibrosis was evident. Thus, we demonstrated that ketamine administration to pregnant mice suppressed hepatic development and also induced liver cell death of the offspring.

  20. Testosterone and Dihydrotestosterone Differentially Improve Cognition in Aged Female Mice

    ERIC Educational Resources Information Center

    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to…

  1. Mice cloned from skin cells.

    PubMed

    Li, Jinsong; Greco, Valentina; Guasch, Géraldine; Fuchs, Elaine; Mombaerts, Peter

    2007-02-20

    Adult stem cells represent unique populations of undifferentiated cells with self-renewal capacity. In many tissues, stem cells divide less often than their progeny. It has been widely speculated, but largely untested, that their undifferentiated and quiescent state may make stem cells more efficient as donors for cloning by nuclear transfer (NT). Here, we report the use of nuclei from hair follicle stem cells and other skin keratinocytes as NT donors. When keratinocyte stem cells (KSCs) were used as NT donors, 19 liveborn mice were obtained, 9 of which survived to adulthood. Embryonic keratinocytes and cumulus cells also gave rise to cloned mice. Although cloning efficiencies were similar (<6% per transferred blastocyst), success rates were consistently higher for males than for females. Adult keratinocyte stem cells were better NT donors than so-called transit amplifying (TA) keratinocytes in both sexes (1.6% vs. 0% in females and 5.4% vs. 2.8% in males). Our findings reveal skin as a source of readily accessible stem cells, the nuclei of which can be reprogrammed to the pluripotent state by exposure to the cytoplasm of unfertilized oocytes.

  2. Mice embryology: a microscopic overview.

    PubMed

    Salvadori, Maria Letícia Baptista; Lessa, Thais Borges; Russo, Fabiele Baldino; Fernandes, Renata Avancini; Kfoury, José Roberto; Braga, Patricia Cristina Baleeiro Beltrão; Miglino, Maria Angélica

    2012-10-01

    In this work, we studied the embryology of mice of 12, 14, and 18 days of gestation by gross observation, light microscopy, and scanning electron microscopy. Grossly, the embryos of 12 days were observed in C-shaped region of the brain, eye pigmentation of the retina, first, second, and third pharyngeal arches gill pit nasal region on the fourth ventricle brain, cervical curvature, heart, liver, limb bud thoracic, spinal cord, tail, umbilical cord, and place of the mesonephric ridge. Microscopically, the liver, cardiovascular system and spinal cord were observed. In the embryo of 14 days, we observed structures that make up the liver and heart. At 18 days of gestation fetuses, it was noted the presence of eyes, mouth, and nose in the cephalic region, chest and pelvic region with the presence of well-developed limbs, umbilical cord, and placenta. Scanning electron microscopy in 18 days of gestation fetuses evidenced head, eyes closed eyelids, nose, vibrissae, forelimb, heart, lung, kidney, liver, small bowel, diaphragm, and part of the spine. The results obtained in this work describe the internal and external morphology of mice, provided by an integration of techniques and review of the morphological knowledge of the embryonic development of this species, as this animal is of great importance to scientific studies. Copyright © 2012 Wiley Periodicals, Inc.

  3. Reduced alcohol consumption in mice lacking preprodynorphin.

    PubMed Central

    Blednov, Yuri A.; Walker, Danielle; Martinez, Marni; Harris., R. Adron

    2007-01-01

    Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the κ-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower amounts of alcohol in a two-bottle choice test as compared with wild-type littermates. In the same test, knockout mice of both sexes showed a strong reduction of preference for saccharin compared to control mice. In contrast, under conditions of limited (4 hours) access (light phase of the light/dark cycle), null mutant mice did not show any differences in consumption of saccharin but they showed significantly reduced intake of sucrose. To determine the possible cause for reduction of ethanol preference and intake, we studied other ethanol-related behaviors in mice lacking the preprodynorphin gene. There were no differences between null mutant and wild type mice in ethanol-induced loss of righting reflex, acute ethanol withdrawal, ethanol-induced conditioned place preference or conditioned taste aversion to ethanol. These results indicate that deletion of preprodynorphin leads to substantial reduction of alcohol intake in female mice, and suggest thath this is caused by decreased orosensory reward of alcohol (sweet taste and/or palatability). PMID:17307643

  4. Reduced alcohol consumption in mice lacking preprodynorphin.

    PubMed

    Blednov, Yuri A; Walker, Danielle; Martinez, Marni; Harris, R Adron

    2006-10-01

    Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the kappa-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower amounts of alcohol in a two-bottle choice test as compared with wild-type littermates. In the same test, knockout mice of both sexes showed a strong reduction of preference for saccharin compared to control mice. In contrast, under conditions of limited (4 h) access (light phase of the light/dark cycle), null mutant mice did not show any differences in consumption of saccharin, but they showed significantly reduced intake of sucrose. To determine the possible cause for reduction of ethanol preference and intake, we studied other ethanol-related behaviors in mice lacking the preprodynorphin gene. There were no differences between null mutant and wild-type mice in ethanol-induced loss of righting reflex, acute ethanol withdrawal, ethanol-induced conditioned place preference, or conditioned taste aversion to ethanol. These results indicate that deletion of preprodynorphin leads to substantial reduction of alcohol intake in female mice, and suggest that this is caused by decreased orosensory reward of alcohol (sweet taste and/or palatability).

  5. Euthanasia of neonatal mice with carbon dioxide

    USGS Publications Warehouse

    Pritchett, K.; Corrow, D.; Stockwell, J.; Smith, A.

    2005-01-01

    Exposure to carbon dioxide (CO2) is the most prevalent method used to euthanize rodents in biomedical research. The purpose of this study was to determine the time of CO2 exposure required to euthanize neonatal mice (0 to 10 days old). Multiple groups of mice were exposed to 100% CO 2 for time periods between 5 and 60 min. Mice were placed in room air for 10 or 20 min after CO2 exposure, to allow for the chance of recovery. If mice recovered at one time point, a longer exposure was examined. Inbred and outbred mice were compared. Results of the study indicated that time to death varied with the age of the animals and could be as long as 50 min on the day of birth and differed between inbred and outbred mice. Institutions euthanizing neonatal mice with CO2 may wish to adjust their CO 2 exposure time periods according the age of the mice and their genetic background. Copyright 2005 by the American Association for Laboratory Animal Science.

  6. Development of diabetic nephropathy in nude mice.

    PubMed

    Lin, S; Xu, P C; Huang, Q E; Jia, J Y; Jia, Z H; Wei, L; Zheng, Z F; Shang, W Y

    2013-12-01

    Immune dysfunction is very common in diabetes mellitus (DM). However, there is no evidence whether such immune dysfunction can influence the development of DM, especially the development of diabetic nephropathy (DN). To investigate the influence of absence of T cells on DN. Balb/c nude mice and Balb/c wild-type nude (WT) mice were injected with streptozotocin (STZ). Serum tumor necrosis factor α (TNF-α), blood glucose, body weight, urine albumin/creatinine ratio and rate of kidney weight to body weight (KW/BW) were measured. After modeling, there was no difference of blood glucose level between nude mice and WT mice except at week 2 (28.3 ± 4.9 mmol/l vs 23.1 ± 3.9 mmol/l, p<0.01). At week 4, the serum TNF- α level of nude mice got to 175.08 ± 46.03 pg/ml (p<0.05, compared with baseline level 80.19 ± 8.46 pg/ml), whereas the TNF- α levels of WT mice was stable. At week 4, the body weight of nude mice was lower than that of WT mice (14.7 ± 3.15 g vs 17.97 ± 2.85 g, p<0.05); the urine albumin/creatinine ratio (Alb/Cr) of nude mice was higher than that of WT mice (50.96 ± 5.57 mg/mmol vs 41.09 ± 5.79 mg/mmol, p<0.05); the kidney weight to body weight of nude mice was higher than that of WT mice (0.01352 ± 0.00163 vs 0.01173 ± 0.00131, p<0.05). Correlation analysis showed urine Alb/Cr positively correlated with serum TNF-α level at week 4 (r = 0.588, p<0.01). At week 4, the increase of type IV collagen in the glomeruli was more prominent in diabetic nude mice than in diabetic WT mice (p<0.05). Absence of T cells in DM might influence the development of DN.

  7. Quiet breathing in hindlimb casted mice.

    PubMed

    Receno, Candace N; Roffo, Katelynn E; Mickey, Marisa C; DeRuisseau, Keith C; DeRuisseau, Lara R

    2018-06-07

    The hindlimb casting model was developed to study skeletal muscle reloading following a period of unloading. It is unknown if ventilation parameters of mice are affected by the casting model. We tested the hypothesis that hindlimb casted mice have similar ventilatory patterns compared to mice with the casts removed. Male CD-1 mice underwent 14 days of hindlimb immobilization via plaster casting. Breathing parameters were obtained utilizing unrestrained barometric plethysmography (UBP). Breathing traces were analyzed with Ponemah software for breathing frequency, tidal volume (TV), and minute ventilation (MV). Frequency, TV and MV did not show any differences in quiet breathing patterns during or post-casting in mice. Thus, the hindlimb casting model does not complicate breathing during and after casting and should not interfere with the unloading and reloading of skeletal muscle. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Pion contamination in the MICE muon beam

    NASA Astrophysics Data System (ADS)

    Adams, D.; Alekou, A.; Apollonio, M.; Asfandiyarov, R.; Barber, G.; Barclay, P.; de Bari, A.; Bayes, R.; Bayliss, V.; Bertoni, R.; Blackmore, V. J.; Blondel, A.; Blot, S.; Bogomilov, M.; Bonesini, M.; Booth, C. N.; Bowring, D.; Boyd, S.; Brashaw, T. W.; Bravar, U.; Bross, A. D.; Capponi, M.; Carlisle, T.; Cecchet, G.; Charnley, C.; Chignoli, F.; Cline, D.; Cobb, J. H.; Colling, G.; Collomb, N.; Coney, L.; Cooke, P.; Courthold, M.; Cremaldi, L. M.; DeMello, A.; Dick, A.; Dobbs, A.; Dornan, P.; Drews, M.; Drielsma, F.; Filthaut, F.; Fitzpatrick, T.; Franchini, P.; Francis, V.; Fry, L.; Gallagher, A.; Gamet, R.; Gardener, R.; Gourlay, S.; Grant, A.; Greis, J. R.; Griffiths, S.; Hanlet, P.; Hansen, O. M.; Hanson, G. G.; Hart, T. L.; Hartnett, T.; Hayler, T.; Heidt, C.; Hills, M.; Hodgson, P.; Hunt, C.; Iaciofano, A.; Ishimoto, S.; Kafka, G.; Kaplan, D. M.; Karadzhov, Y.; Kim, Y. K.; Kuno, Y.; Kyberd, P.; Lagrange, J.-B.; Langlands, J.; Lau, W.; Leonova, M.; Li, D.; Lintern, A.; Littlefield, M.; Long, K.; Luo, T.; Macwaters, C.; Martlew, B.; Martyniak, J.; Mazza, R.; Middleton, S.; Moretti, A.; Moss, A.; Muir, A.; Mullacrane, I.; Nebrensky, J. J.; Neuffer, D.; Nichols, A.; Nicholson, R.; Nugent, J. C.; Oates, A.; Onel, Y.; Orestano, D.; Overton, E.; Owens, P.; Palladino, V.; Pasternak, J.; Pastore, F.; Pidcott, C.; Popovic, M.; Preece, R.; Prestemon, S.; Rajaram, D.; Ramberger, S.; Rayner, M. A.; Ricciardi, S.; Roberts, T. J.; Robinson, M.; Rogers, C.; Ronald, K.; Rubinov, P.; Rucinski, P.; Sakamato, H.; Sanders, D. A.; Santos, E.; Savidge, T.; Smith, P. J.; Snopok, P.; Soler, F. J. P.; Speirs, D.; Stanley, T.; Stokes, G.; Summers, D. J.; Tarrant, J.; Taylor, I.; Tortora, L.; Torun, Y.; Tsenov, R.; Tunnell, C. D.; Uchida, M. A.; Vankova-Kirilova, G.; Virostek, S.; Vretenar, M.; Warburton, P.; Watson, S.; White, C.; Whyte, C. G.; Wilson, A.; Winter, M.; Yang, X.; Young, A.; Zisman, M.

    2016-03-01

    The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240 MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less than ~1% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is fπ < 1.4% at 90% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling.

  9. Leptin regulates ACE activity in mice.

    PubMed

    Hilzendeger, Aline Mourao; Morais, Rafael Leite; Todiras, Mihail; Plehm, Ralph; da Costa Goncalves, Andrey; Qadri, Fatimunnisa; Araujo, Ronaldo Carvalho; Gross, Volkmar; Nakaie, Clovis Ryuichi; Casarini, Dulce Elena; Carmona, Adriana Karaoglanovic; Bader, Michael; Pesquero, João Bosco

    2010-09-01

    Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

  10. Mobile optogenetic modules for mice

    NASA Astrophysics Data System (ADS)

    Rusakov, Konstantin; Radzewicz, Czesław; Czajkowski, Rafał; Konopka, Witold; Chilczuk, Joanna

    2017-08-01

    We present a set of novel optogenetic devices for mice freely moving in cages. The purpose of the devices is to stimulate specific brain regions using light. The devices we have constructed consist of an electrical connector, cannula and micro- LED chip operating at 470 nm as light source for delivering light into the stimulated region of the mouse brain. We have also demonstrated light conversion from 470 nm to 590 nm by applying a silicate orange phosphor directly to the LED chip. The measured conversion efficiency is approximately 80% for ZIP595I phosphor. We discuss the properties of various forms of implant needles with respect to the ease of LED attachment and experimental validation of the constructed optogenetic implants.

  11. Primordial Germ Cells in Mice

    PubMed Central

    Saitou, Mitinori; Yamaji, Masashi

    2012-01-01

    Germ cell development creates totipotency through genetic as well as epigenetic regulation of the genome function. Primordial germ cells (PGCs) are the first germ cell population established during development and are immediate precursors for both the oocytes and spermatogonia. We here summarize recent findings regarding the mechanism of PGC development in mice. We focus on the transcriptional and signaling mechanism for PGC specification, potential pluripotency, and epigenetic reprogramming in PGCs and strategies for the reconstitution of germ cell development using pluripotent stem cells in culture. Continued studies on germ cell development may lead to the generation of totipotency in vitro, which should have a profound influence on biological science as well as on medicine. PMID:23125014

  12. Social reward among juvenile mice

    PubMed Central

    Panksepp, J B; Lahvis, G P

    2007-01-01

    Mammalian social relationships, such as mother–offspring attachments and pair bonds, can directly affect reproductive output. However, conspecifics approach one another in a comparatively broad range of contexts, so conceivably there are motivations for social congregation other than those underlying reproduction, parental care or territoriality. Here, we show that reward mediated by social contact is a fundamental aspect of juvenile mouse sociality. Employing a novel social conditioned place preference (SCPP) procedure, we demonstrate that social proximity is rewarding for juvenile mice from three inbred strains (A/J, C57BL/6J and DBA/2J), while mice from a fourth strain (BALB/cJ) are much less responsive to social contact. Importantly, this strain-dependent difference was not related to phenotypic variability in exploratory behavior or contextual learning nor influenced by the genetic background associated with maternal care or social conditioning. Furthermore, the SCPP phenotype was expressed early in development (postnatal day 25) and did not require a specific sex composition within the conditioning group. Finally, SCPP responses resulted from an interaction between two specifiable processes: one component of the interaction facilitated approach toward environments that were associated with social salience, whereas a second component mediated avoidance of environmental cues that predicted social isolation. We have thus identified a genetically prescribed process that can attribute value onto conditions predicting a general form of social contact. To our knowledge, this is the first definitive evidence to show that genetic variation can influence a form of social valuation not directly related to a reproductive behavior. PMID:17212648

  13. A protein-based smallpox vaccine protects mice from vaccinia and ectromelia virus challenges when given as a prime and single boost

    PubMed Central

    Xiao, Yuhong; Aldaz-Carroll, Lydia; Ortiz, Alexandra M.; Whitbeck, J. Charles; Alexander, Edward; Lou, Huan; Davis, J. Heather L.; Braciale, Thomas J.; Eisenberg, Roselyn J.; Cohen, Gary H.; Isaacs, Stuart N.

    2007-01-01

    The heightened concern about the intentional release of variola virus has led to the need to develop safer smallpox vaccines. While subunit vaccine strategies are safer than live virus vaccines, subunit vaccines have been hampered by the need for multiple boosts to confer optimal protection. Here we developed a protein-based subunit vaccine strategy that provides rapid protection in mouse models of orthopoxvirus infections after a prime and single boost. Mice vaccinated with vaccinia virus envelope proteins from the mature virus (MV) and extracellular virus (EV) adjuvanted with CpG-ODN and alum were protected from lethal intranasal challenge with vaccinia virus and the mouse-specific ectromelia virus. Organs from mice vaccinated with three proteins (A33, B5 and L1) and then sacrificed after challenge contained significantly lower titers of virus when compared to control groups of mice that were not vaccinated or that received sub-optimal formulations of the vaccine. Sera from groups of mice obtained prior to challenge had neutralizing activity against the MV and also inhibited comet formation indicating anti-EV activity. Long-term partial protection was also seen in mice challenged with vaccinia virus 6 months after initial vaccinations. Thus, this work represents a step toward the development of a practical subunit smallpox vaccine. PMID:17098336

  14. Evaluation of sulfur isotopic enrichment of urine metabolites for the differentiation of healthy and prostate cancer mice after the administration of 34S labelled yeast.

    PubMed

    Galilea San Blas, Oscar; Moreno Sanz, Fernando; Herrero Espílez, Pilar; Sainz Menéndez, Rosa María; Mayo Barallo, Juan Carlos; Marchante-Gayón, Juan Manuel; García Alonso, José Ignacio

    2017-01-01

    Sulfur isotopic enrichment of urine metabolites in healthy and prostate cancer mice using 34 S enriched yeast and High Performance Liquid Chromatography coupled to Multicollector Inductively Coupled Plasma Mass Spectrometry (HPLC-MC-ICP-MS) has been evaluated. A 30 weeks experiment (since the eleventh to the fortieth week of life) was carried out collecting the urine of three healthy mice and three transgenic mice with prostate cancer during 24h after a single oral administration of a 34 S enriched yeast slurry. The isotopic enrichment of different sulphur metabolites was monitored by coupling a C18 reverse phase HPLC column with a multicollector ICP-MS using a membrane desolvating system. Quantification of sulfur in the chromatographic peaks was carried out by post-column isotope dilution using a 33 S enriched spike. Differences between the 34 S enrichment in the urine metabolites of healthy and prostate cancer mice were found from the beginning of the disease. Both populations could be differentiated using a principal component analysis (PCA). Finally, 7 unknown mice were correctly classified in each population using a linear discriminant analysis. Copyright © 2016 Elsevier GmbH. All rights reserved.

  15. [Effects of sildenafil citrate on mice hearing].

    PubMed

    Luo, Xiaoqin; Guo, Xuyao; Chen, Lin; Chen, Xiaohong; Zhang, Xueyuan; Yuan, Wei

    2014-06-01

    The purpose of this investigation was to study the effects of the Sildenafil citrate on mice hearing. Seven-week-old adult male Kunming mice were used. The mice were randomly divided into four groups with 10 mice in each group.Sildenafil groups were orally administered daily with sildenafil [0.1 mg/(kg·d), 1 mg/(kg·d), 10 mg/(kg·d)] and control group was orally administered with normal saline. Then mice were tested for auditory brainstem response (ABR) to observe the changes of ABR's thresholds at before administration and 1, 5, 10, 15, 20 day afterwards. The mice basilar membrane samples were studied by immunofluorescent labeling.High performance liquid chromatography was used for determination the concentration of sildenafil in endolymph of mice cochlea. Statistical analysis was performed using SPSS 13.0. After 30 min following administration, the Sildenafil in endolymph of mice cochlear could be assayed by high performance liquid chromatography, and it was dose-related.Sildenafil increased the hearing thresholds with the time of administration. Hearing thresholds increased significantly in the sildenafil group at 20 d compared to the control group (P < 0.05). After administered high dose of Sildenafil, on the 20th day, the ABR thresholds average threshold was (60.0 ± 10.0) dBnHL, and the control group was (14.5 ± 6.0) dBnHL.Hair cells damages in the base ring of cochlea could be observed in experimental group in a concentration-dependent manner. Sildenafil can pass through blood-labyrinth barrier to the inner ear, and doses of sildenafil administration can induce hearing impairment in mice.

  16. Lethality In Mice Following Localized Photodynamic Therapy

    NASA Astrophysics Data System (ADS)

    Ferrario, Angela; Gomer, Charles J.; Murphree, A. L.

    1989-06-01

    Porphyrin photodynamic therapy directed specifically to the hind leg of various strains of mice was found to induce a high percentage of lethality at dosages which would be required to achieve cures in tumor bearing mice. Toxicity was observed in both pigmented and albino mouse strains. An inverse relationship between light dose rate and lethality was documented. Anti-coagulant drugs and anti-inflammatory agents which inhibit cyclo-oxygenase had protective effects. The response induced by localized PDT appears to mimic that of a classical traumatic shock syndrome and may be limited to PDT in small animals such as mice.

  17. Principles of Economic Rationality in Mice.

    PubMed

    Rivalan, Marion; Winter, York; Nachev, Vladislav

    2017-12-12

    Humans and non-human animals frequently violate principles of economic rationality, such as transitivity, independence of irrelevant alternatives, and regularity. The conditions that lead to these violations are not completely understood. Here we report a study on mice tested in automated home-cage setups using rewards of drinking water. Rewards differed in one of two dimensions, volume or probability. Our results suggest that mouse choice conforms to the principles of economic rationality for options that differ along a single reward dimension. A psychometric analysis of mouse choices further revealed that mice responded more strongly to differences in probability than to differences in volume, despite equivalence in return rates. This study also demonstrates the synergistic effect between the principles of economic rationality and psychophysics in making quantitative predictions about choices of healthy laboratory mice. This opens up new possibilities for the analyses of multi-dimensional choice and the use of mice with cognitive impairments that may violate economic rationality.

  18. Social transfer of pain in mice

    PubMed Central

    Smith, Monique L.; Hostetler, Caroline M.; Heinricher, Mary M.; Ryabinin, Andrey E.

    2016-01-01

    A complex relationship exists between the psychosocial environment and the perception and experience of pain, and the mechanisms of the social communication of pain have yet to be elucidated. The present study examined the social communication of pain and demonstrates that “bystander” mice housed and tested in the same room as mice subjected to inflammatory pain or withdrawal from morphine or alcohol develop corresponding hyperalgesia. Olfactory cues mediate the transfer of hyperalgesia to the bystander mice, which can be measured using mechanical, thermal, and chemical tests. Hyperalgesia in bystanders does not co-occur with anxiety or changes in corticosterone and cannot be explained by visually dependent emotional contagion or stress-induced hyperalgesia. These experiments reveal the multifaceted relationship between the social environment and pain behavior and support the use of mice as a model system for investigating these factors. In addition, these experiments highlight the need for proper consideration of how experimental animals are housed and tested. PMID:27774512

  19. RADIATION INDUCED AGING IN MICE

    SciTech Connect

    Curtis, H.J.; Gebhard, K.L.

    1958-10-31

    . Experiments were undertaken in an effort to determine the degree of similarity between natural and radiation induced aging, and to determine the causes for the latter. Several severe non-specific stresses were applied to mice either as single massive doses or as smaller doses administered over a large fraction of the life span of the animals. Stresses used included typhoid vaccine, tetanus toxin and tetanus toxoid and turpentine. None of these produced any premature aging comparable to that produced by radiation. The somatic mutation theory of aging and expecially radiationinduced aging has been tested by applying the chemical mutatgen, nitrogenmore » mustard, either as a massive single dose or as smaller single doses repeated over long periods of time. No shortening of the life span has been observed and it is concluded that the somatic mutation theory is untenable. Experiments designed to determine the organ system responsible for radiation induced aging have demonstrated that the hematopoietic system is not primarily involved in this phenomenon. (auth)« less

  20. Cytochrome P450 humanised mice

    PubMed Central

    2004-01-01

    Humans are exposed to countless foreign compounds, typically referred to as xenobiotics. These can include clinically used drugs, environmental pollutants, food additives, pesticides, herbicides and even natural plant compounds. Xenobiotics are metabolised primarily in the liver, but also in the gut and other organs, to derivatives that are more easily eliminated from the body. In some cases, however, a compound is converted to an electrophile that can cause cell toxicity and transformation leading to cancer. Among the most important xenobiotic-metabolising enzymes are the cytochromes P450 (P450s). These enzymes represent a superfamily of multiple forms that exhibit marked species differences in their expression and catalytic activities. To predict how humans will metabolise xenobiotics, including drugs, human liver extracts and recombinant P450s have been used. New humanised mouse models are being developed which will be of great value in the study of drug metabolism, pharmacokinetics and pharmacodynamics in vivo, and in carrying out human risk assessment of xenobiotics. Humanised mice expressing CYP2D6 and CYP3A4, two major drug-metabolising P450s, have revealed the feasibility of this approach. PMID:15588489

  1. Responses of Male C57BL/6N Mice to Observing the Euthanasia of Other Mice.

    PubMed

    Boivin, Gregory P; Bottomley, Michael A; Grobe, Nadja

    2016-01-01

    The AVMA Panel on Euthanasia recommends that sensitive animals should not be present during the euthanasia of others, especially of their own species, but does not provide guidelines on how to identify a sensitive species. To determine if mice are a sensitive species we reviewed literature on empathy in mice, and measured the cardiovascular and activity response of mice observing euthanasia of conspecifics. We studied male 16-wk-old C57BL/6N mice and found no increase in cardiovascular parameters or activity in the response of the mice to observing CO2 euthanasia. Mice observing decapitation had an increase in all values, but this was paralleled by a similar increase during mock decapitations in which no animals were handled or euthanized. We conclude that CO2 euthanasia of mice does not have an impact on other mice in the room, and that euthanasia by decapitation likely only has an effect due to the noise of the guillotine. We support the conceptual idea that mice are both a sensitive species and display empathy, but under the controlled circumstances of the euthanasia procedures used in this study there was no signaling of stress to witnessing inhabitants in the room.

  2. Responses of Male C57BL/6N Mice to Observing the Euthanasia of Other Mice

    PubMed Central

    Boivin, Gregory P; Bottomley, Michael A; Grobe, Nadja

    2016-01-01

    The AVMA Panel on Euthanasia recommends that sensitive animals should not be present during the euthanasia of others, especially of their own species, but does not provide guidelines on how to identify a sensitive species. To determine if mice are a sensitive species we reviewed literature on empathy in mice, and measured the cardiovascular and activity response of mice observing euthanasia of conspecifics. We studied male 16-wk-old C57BL/6N mice and found no increase in cardiovascular parameters or activity in the response of the mice to observing CO2 euthanasia. Mice observing decapitation had an increase in all values, but this was paralleled by a similar increase during mock decapitations in which no animals were handled or euthanized. We conclude that CO2 euthanasia of mice does not have an impact on other mice in the room, and that euthanasia by decapitation likely only has an effect due to the noise of the guillotine. We support the conceptual idea that mice are both a sensitive species and display empathy, but under the controlled circumstances of the euthanasia procedures used in this study there was no signaling of stress to witnessing inhabitants in the room. PMID:27423146

  3. Reduced immune responses in chimeric mice engrafted with bone marrow cells from mice with airways inflammation.

    PubMed

    Scott, Naomi M; Ng, Royce L X; McGonigle, Terence A; Gorman, Shelley; Hart, Prue H

    2015-11-01

    During respiratory inflammation, it is generally assumed that dendritic cells differentiating from the bone marrow are immunogenic rather than immunoregulatory. Using chimeric mice, the outcomes of airways inflammation on bone marrow progenitor cells were studied. Immune responses were analyzed in chimeric mice engrafted for >16 weeks with bone marrow cells from mice with experimental allergic airways disease (EAAD). Responses to sensitization and challenge with the allergen causing inflammation in the bone marrow-donor mice were significantly reduced in the chimeric mice engrafted with bone marrow cells from mice with EAAD (EAAD-chimeric). Responses to intranasal LPS and topical fluorescein isothiocyanate (non-specific challenges) were significantly attenuated. Fewer activated dendritic cells from the airways and skin of the EAAD-chimeric mice could be tracked to the draining lymph nodes, and may contribute to the significantly reduced antigen/chemical-induced hypertrophy in the draining nodes, and the reduced immune responses to sensitizing allergens. Dendritic cells differentiating in vitro from the bone marrow of >16 weeks reconstituted EAAD-chimeric mice retained an ability to poorly prime immune responses when transferred into naïve mice. Dendritic cells developing from bone marrow progenitors during airways inflammation are altered such that daughter cells have reduced antigen priming capabilities.

  4. Pharmacological aspects of metaldehyde poisoning in mice.

    PubMed

    Homeida, A M; Cooke, R G

    1982-03-01

    Metaldehyde, when administered orally to mice at a dose of 1 g kg-1, produced convulsions and death within 2 h. Brain concentrations of noradrenaline (NA) 5-hydroxytryptamie (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly reduced in these animals relative to controls. Treatment with either intraperitoneal clonidine or diazepam 20 min after administration of metaldehyde reduced the mortality rate and in mice surviving for 5 h, the decrease in brain NA and 5-HT concentrations were significantly reduced.

  5. Men and mice: Relating their ages.

    PubMed

    Dutta, Sulagna; Sengupta, Pallav

    2016-05-01

    Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the case when comparing the lifespan of mice versus humans taking the entire life at the same time without considering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be determined. Determining the age relation between mice and humans is necessary for setting up experimental murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome for humans of a specific age group, although current outcomes are based on mice of an approximate age. To fill this gap between approximation and accuracy, this review article is the first to establish a precise relation between mice age and human age, following our previous article, which explained the relation in ages of laboratory rats with humans in detail. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Plasminogen promotes macrophage phagocytosis in mice

    PubMed Central

    Ganapathy, Swetha; Settle, Megan; Plow, Edward F.

    2014-01-01

    The phagocytic function of macrophages plays a pivotal role in eliminating apoptotic cells and invading pathogens. Evidence implicating plasminogen (Plg), the zymogen of plasmin, in phagocytosis is extremely limited with the most recent in vitro study showing that plasmin acts on prey cells rather than on macrophages. Here, we use apoptotic thymocytes and immunoglobulin opsonized bodies to show that Plg exerts a profound effect on macrophage-mediated phagocytosis in vitro and in vivo. Plg enhanced the uptake of these prey by J774A.1 macrophage-like cells by 3.5- to fivefold Plg receptors and plasmin proteolytic activity were required for phagocytosis of both preys. Compared with Plg+/+ mice, Plg−/− mice exhibited a 60% delay in clearance of apoptotic thymocytes by spleen and an 85% reduction in uptake by peritoneal macrophages. Phagocytosis of antibody-mediated erythrocyte clearance by liver Kupffer cells was reduced by 90% in Plg−/− mice compared with Plg+/+ mice. A gene array of splenic and hepatic tissues from Plg−/− and Plg+/+ mice showed downregulation of numerous genes in Plg−/− mice involved in phagocytosis and regulation of phagocytic gene expression was confirmed in macrophage-like cells. Thus, Plg may play an important role in innate immunity by changing expression of genes that contribute to phagocytosis. PMID:24876560

  7. Hypothyroidism Compromises Hypothalamic Leptin Signaling in Mice

    PubMed Central

    Groba, Claudia; Mayerl, Steffen; van Mullem, Alies A.; Visser, Theo J.; Darras, Veerle M.; Habenicht, Andreas J.

    2013-01-01

    The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism. PMID:23518925

  8. Chronic Co-species Housing Mice and Rats Increased the Competitiveness of Male Mice.

    PubMed

    Liu, Ying-Juan; Li, Lai-Fu; Zhang, Yao-Hua; Guo, Hui-Fen; Xia, Min; Zhang, Meng-Wei; Jing, Xiao-Yuan; Zhang, Jing-Hua; Zhang, Jian-Xu

    2017-03-01

    Rats are predators of mice in nature. Nevertheless, it is a common practice to house mice and rats in a same room in some laboratories. In this study, we investigated the behavioral and physiological responsively of mice in long-term co-species housing conditions. Twenty-four male mice were randomly assigned to their original raising room (control) or a rat room (co-species-housed) for more than 6 weeks. In the open-field and light-dark box tests, the behaviors of the co-species-housed mice and controls were not different. In a 2-choice test of paired urine odors [rabbit urine (as a novel odor) vs. rat urine, cat urine (as a natural predator-scent) vs. rabbit urine, and cat urine vs. rat urine], the co-species-housed mice were more ready to investigate the rat urine odor compared with the controls and may have adapted to it. In an encounter test, the rat-room-exposed mice exhibited increased aggression levels, and their urines were more attractive to females. Correspondingly, the levels of major urinary proteins were increased in the co-species-housed mouse urine, along with some volatile pheromones. The serum testosterone levels were also enhanced in the co-species-housed mice, whereas the corticosterone levels were not different. The norepinephrine, dopamine, and 5-HT levels in the right hippocampus and striatum were not different between the 2. Our findings indicate that chronic co-species housing results in adaptation in male mice; furthermore, it appears that long-term rat-odor stimuli enhance the competitiveness of mice, which suggests that appropriate predator-odor stimuli may be important to the fitness of prey animals. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Demodex musculi Infestation in Genetically Immunomodulated Mice

    PubMed Central

    Smith, Peter C; Zeiss, Caroline J; Beck, Amanda P; Scholz, Jodi A

    2016-01-01

    Demodex musculi, a prostigmatid mite that has been reported infrequently in laboratory mice, has been identified with increasing frequency in contemporary colonies of immunodeficient mice. Here we describe 2 episodes of D. musculi infestation with associated clinical signs in various genetically engineered mouse strains, as well as treatment strategies and an investigation into transmissibility and host susceptibility. The first case involved D. musculi associated with clinical signs and pathologic lesions in BALB/c-Tg(DO11.10)Il13tm mice, which have a defect in type 2 helper T cell (Th2) immunity. Subsequent investigation revealed mite transmission to both parental strains (BALB/c-Tg[DO11.10] and BALB/c-Il13tm), BALB/c-Il13/Il4tm, and wild-type BALB/c. All Tg(DO11.10)Il13tm mice remained infested throughout the investigation, and D. musculi were recovered from all strains when they were cohoused with BALB/c-Tg(DO11.10)Il13tm index mice. However, only Il13tm and Il13/Il4tm mice demonstrated persistent infestation after index mice were removed. Only BALB/c-Tg(DO11.10)Il13tm showed clinical signs, suggesting that the phenotypic dysfunction of Th2 immunity is sufficient for persistent infestation, whereas clinical disease associated with D. musculi appears to be genotype-specific. This pattern was further exemplified in the second case, which involved NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and C;129S4 Rag2tm1.1Flv Il2rgtm1.1Flv/J mice with varying degrees of blepharitis, conjunctivitis, and facial pruritis. Topical amitraz decreased mite burden but did not eliminate infestation or markedly ameliorate clinical signs. Furthermore, mite burden began to increase by 1 mo posttreatment, suggesting that topical amitraz is an ineffective treatment for D. musculi. These experiences illustrate the need for vigilance regarding opportunistic and uncommon pathogens in rodent colonies, especially among mice with immunologic deficits. PMID:27538858

  10. Cardiac Function in Young and Old Little Mice

    PubMed Central

    Reddy, Anilkumar K.; Amador-Noguez, Daniel; Darlington, Gretchen J.; Scholz, Beth A.; Michael, Lloyd H.; Hartley, Craig J.; Entman, Mark L.; Taffet, George E.

    2009-01-01

    We studied cardiac function in young and old, wild-type (WT), and longer-living Little mice using cardiac flow velocities, echocardiographic measurements, and left ventricular (LV) pressure (P) to determine if enhanced reserves were in part responsible for longevity in these mice. Resting/baseline cardiac function, as measured by velocities, LV dimensions, +dP/dtmax, and −dP/dtmax, was significantly lower in young Little mice versus young WT mice. Fractional shortening (FS) increased significantly, and neither +dP/dtmax nor −dP/dtmax declined with age in Little mice. In contrast, old WT mice had no change in FS but had significantly lower +dP/dtmax and −dP/dtmax versus young WT mice. Significant decreases were observed in the velocity indices of old Little mice versus old WT mice, but other parameters were unchanged. The magnitude of dobutamine stress response remained unchanged with age in Little mice, while that in WT mice decreased. These data suggest that while resting cardiac function in Little mice versus WT mice is lower at young age, it is relatively unaltered with aging. Additionally, cardiac function in response to stress was maintained with age in Little mice but not in their WT counterparts. Thus, some mouse models of increased longevity may not be associated with enhanced reserves. PMID:18166681

  11. Antitumour activity of cordycepin in mice.

    PubMed

    Yoshikawa, Noriko; Nakamura, Kazuki; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

    2004-12-01

    1. The antitumour effect of orally administered cordycepin, a component isolated from water extracts of Cordyceps sinensis, was examined in mice inoculated with B16 melanoma (B16-BL6) cells. 2. B16-BL6 (1 x 10(6)) cells were inoculated subcutaneously into the right footpad of mice. At 2 weeks after the cell inoculation, the enlarged primary tumour lump was weighed. Cordycepin (0, 5 and 15 mg/kg per day) was administered orally to the mice for 2 weeks from the date of tumour inoculation. Cordycepin (15 mg/kg per day) significantly reduced by 36% the wet weight of the primary tumour lump compared to that of the untreated control mice, without any loss of bodyweight or systemic toxicity. 3. Cordycepin (15 mg/kg per day) administered orally for 2 weeks inhibited the tumour enlargement in the right thigh inoculated with B16-BL6 cells premixed with extracellular matrix (Matrigel). 4. These results indicate that orally administered cordycepin inhibits melanoma cell growth in mice with no adverse effects.

  12. Pion contamination in the MICE muon beam

    DOE PAGES

    Adams, D.; Alekou, A.; Apollonio, M.; ...

    2016-03-01

    Here, the international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240\\,MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less thanmore » $$\\sim$$1% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is $$f_\\pi < 1.4\\%$$ at 90% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling.« less

  13. Dehydration Parameters and Standards for Laboratory Mice

    PubMed Central

    Bekkevold, Christine M; Robertson, Kimberly L; Reinhard, Mary K; Battles, August H; Rowland, Neil E

    2013-01-01

    Water deprivation and restriction are common features of many physiologic and behavioral studies; however, there are no data-driven humane standards regarding mice on water deprivation or restriction studies to guide IACUC, investigators, and veterinarians. Here we acutely deprived outbred CD1 mice of water for as long as 48 h or restricted them to a 75% or 50% water ration; physical and physiologic indicators of dehydration were measured. With acute water deprivation, the appearance and attitude of mice deteriorated after 24 h, and weight loss exceeded 15%. Plasma osmolality was increased, and plasma volume decreased with each time interval. Plasma corticosterone concentration increased with duration of deprivation. There were no differences in any dehydration measures between mice housed in conventional static cages or ventilated racks. Chronic water restriction induced no significant changes compared with ad libitum availability. We conclude that acute water deprivation of as long as 24 h produces robust physiologic changes; however, deprivation in excess of 24 h is not recommended in light of apparent animal distress. Although clearly thirsty, mice adapt to chronic water restriction of as much as 50% of the ad libitum daily ration that is imposed over an interval of as long as 8 d. PMID:23849404

  14. Otolith Dysfunction Alters Exploratory Movement in Mice

    PubMed Central

    Blankenship, Philip A.; Cherep, Lucia A.; Donaldson, Tia N.; Brockman, Sarah N.; Trainer, Alexandria D.; Yoder, Ryan M.; Wallace, Douglas G.

    2017-01-01

    The organization of rodent exploratory behavior appears to depend on self-movement cue processing. As of yet, however, no studies have directly examined the vestibular system’s contribution to the organization of exploratory movement. The current study sequentially segmented open field behavior into progressions and stops in order to characterize differences in movement organization between control and otoconia-deficient tilted mice under conditions with and without access to visual cues. Under completely dark conditions, tilted mice exhibited similar distance traveled and stop times overall, but had significantly more circuitous progressions, larger changes in heading between progressions, and less stable clustering of home bases, relative to control mice. In light conditions, control and tilted mice were similar on all measures except for the change in heading between progressions. This pattern of results is consistent with otoconia-deficient tilted mice using visual cues to compensate for impaired self-movement cue processing. This work provides the first empirical evidence that signals from the otolithic organs mediate the organization of exploratory behavior, based on a novel assessment of spatial orientation. PMID:28235587

  15. Catalase deletion promotes prediabetic phenotype in mice.

    PubMed

    Heit, Claire; Marshall, Stephanie; Singh, Surrendra; Yu, Xiaoqing; Charkoftaki, Georgia; Zhao, Hongyu; Orlicky, David J; Fritz, Kristofer S; Thompson, David C; Vasiliou, Vasilis

    2017-02-01

    Hydrogen peroxide is produced endogenously and can be toxic to living organisms by inducing oxidative stress and cell damage. However, it has also been identified as a signal transduction molecule. By metabolizing hydrogen peroxide, catalase protects cells and tissues against oxidative damage and may also influence signal transduction mechanisms. Studies suggest that acatalasemic individuals (i.e., those with very low catalase activity) have a higher risk for the development of diabetes. We now report catalase knockout (Cat -/- ) mice, when fed a normal (6.5% lipid) chow, exhibit an obese phenotype that manifests as an increase in body weight that becomes more pronounced with age. The mice demonstrate altered hepatic and muscle lipid deposition, as well as increases in serum and hepatic triglycerides (TGs), and increased hepatic transcription and protein expression of PPARγ. Liver morphology revealed steatosis with inflammation. Cat -/- mice also exhibited pancreatic morphological changes that correlated with impaired glucose tolerance and increased fasting serum insulin levels, conditions consistent with pre-diabetic status. RNA-seq analyses revealed a differential expression of pathways and genes in Cat -/- mice, many of which are related to metabolic syndrome, diabetes, and obesity, such as Pparg and Cidec. In conclusion, the results of the present study show mice devoid of catalase develop an obese, pre-diabetic phenotype and provide compelling evidence for catalase (or its products) being integral in metabolic regulation. Copyright © 2016. Published by Elsevier Inc.

  16. Mice prefer draught-free housing.

    PubMed

    Krohn, T C; Hansen, A K

    2010-10-01

    An increasing number of rodents are housed in individually ventilated cage (IVC) systems, as these seem to be very effective for the protection of animals against infections, as well as protecting the staff against allergens. For the IVC systems to be properly ventilated, a huge amount of air has to be blown into the cage, which may cause a draught at animal level inside the cage. The aim of the present study was to evaluate the preferences of mice for differing levels of air speeds and air changes inside the cage. It has been concluded that mice do react to draughts, whereas they do not seem to be affected by a high number of air changes delivered without draught, which underlines the importance of applying draught-free IVC systems for mice.

  17. Magnetic biomineralisation in Huntington's disease transgenic mice

    NASA Astrophysics Data System (ADS)

    Beyhum, W.; Hautot, D.; Dobson, J.; Pankhurst, Q. A.

    2005-01-01

    The concentration levels of biogenic magnetite nanoparticles in transgenic R6/2 Huntington's disease (HD) mice have been investigated, using seven control and seven HD mice each from an 8 week-old litter and from a 12 week-old litter. Hysteresis and isothermal remnant magnetisation data were collected on a SQUID magnetometer, and analysed using a model comprising dia/paramagnetic, ferrimagnetic and superparamagnetic contributions, to extract the magnetite and ferritin concentrations present. It was found that magnetite was present in both superparamagnetic and blocked states. A larger spread and higher concentration of magnetite levels was found in the diseased mice for both the 8 week-old and 12 week-old batches, compared to the controls.

  18. Payload Processing for Mice Drawer System

    NASA Technical Reports Server (NTRS)

    Brown, Judy

    2007-01-01

    Experimental payloads flown to the International Space Station provide us with valuable research conducted in a microgravity environment not attainable on earth. The Mice Drawer System is an experiment designed by Thales Alenia Space Italia to study the effects of microgravity on mice. It is designed to fly to orbit on the Space Shuttle Utilization Logistics Flight 2 in October 2008, remain onboard the International Space Station for approximately 100 days and then return to earth on a following Shuttle flight. The experiment apparatus will be housed inside a Double Payload Carrier. An engineering model of the Double Payload Carrier was sent to Kennedy Space Center for a fit check inside both Shuttles, and the rack that it will be installed in aboard the International Space Station. The Double Payload Carrier showed a good fit quality inside each vehicle, and Thales Alenia Space Italia will now construct the actual flight model and continue to prepare the Mice Drawer System experiment for launch.

  19. Normal keratinized mucosa transplants in nude mice.

    PubMed

    Holmstrup, P; Dabelsteen, E; Reibel, J; Harder, F

    1981-01-01

    Two types of normal keratinized mucosa were transplanted to subcutaneous sites of nude mice of two different strains. 24 intact specimens of clinically normal human palatal mucosa were transplanted to nude mice of the strain nu/nu NC. The transplants were recovered after 42 d with a recovery rate of 96%. Moreover, 22 intact specimens of normal rat forestomach mucosa were transplanted to nude mice of the strain nu/nu BALB/c/BOM. These transplants were recovered after 21 d with a recovery rate of 63%. The histologic features of the transplants were essentially the same as those of the original tissues. However, epithelial outgrowths from the transplants differed with respect to the pattern of keratinization. The outgrowths of human palatal mucosa transplants were essentially unkeratinized, while the outgrowths of the rat forestomach transplants showed continued keratinization.

  20. Intermittent hypoxia induces hyperlipidemia in lean mice.

    PubMed

    Li, Jianguo; Thorne, Laura N; Punjabi, Naresh M; Sun, Cheuk-Kwan; Schwartz, Alan R; Smith, Philip L; Marino, Rafael L; Rodriguez, Annabelle; Hubbard, Walter C; O'Donnell, Christopher P; Polotsky, Vsevolod Y

    2005-09-30

    Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep(ob) mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.

  1. Quantification of alcohol drinking patterns in mice.

    PubMed

    Eisenhardt, Manuela; Leixner, Sarah; Spanagel, Rainer; Bilbao, Ainhoa

    2015-11-01

    The use of mice in alcohol research provides an excellent model system for a better understanding of the genetics and neurobiology of alcohol addiction. Almost 60 years ago, alcohol researchers began to test strains of mice for alcohol preference and intake. In particular, various voluntary alcohol drinking paradigms in the home cage were developed. In mouse models of voluntary oral alcohol consumption, animals have concurrent access to water and either one or several concentrated alcohol solutions in their home cages. Although these models have high face validity, many experimental conditions require a more precise monitoring of alcohol consumption in mice in order to capture the role of specific strains or genes, or any other manipulation on alcohol drinking behavior. Therefore, we have developed a fully automated, highly precise monitoring system for alcohol drinking in mice in the home cage. This system is now commercially available. We show that this drinkometer system allows for detecting differences in drinking behavior (i) in transgenic mice, (ii) following alcohol deprivation, and (iii) following stress applications that are usually not detected by classical home-cage drinking paradigms. In conclusion, our drinkometer system allows disturbance-free and high resolution monitoring of alcohol drinking behavior. In particular, micro-drinking and circadian drinking patterns can be monitored in genetically modified and inbred strains of mice after environmental and pharmacological manipulation, and therefore this system represents an improvement in measuring behavioral features that are of relevance for the development of alcohol use disorders. © 2015 Society for the Study of Addiction.

  2. Neurobehavioral toxicity of carbon nanotubes in mice.

    PubMed

    Gholamine, Babak; Karimi, Isaac; Salimi, Amir; Mazdarani, Parisa; Becker, Lora A

    2017-04-01

    The aim of this study was to evaluate neurobehavioral toxicity of single-walled (SWNTs) and multiwalled carbon nanotubes (MWNTs) in mice. Male NMRI mice were randomized into 5 groups ( n = 10 each): Normal control (NC) group was injected intraperitoneally (i.p.) with phosphate-buffered saline (PBS) solution (pH 7.8; ca. 1 mL), MW80 and MW800 groups were injected with either i.p. 80 or 800 mg kg -1 MWNTs suspended in 1 mL of PBS and SW80 and SW800 groups were injected with either i.p. 80 or 800 mg kg -1 SWNTs suspended in 1 mL of PBS. After 2 weeks, five mice from each group were evaluated for brain-derived neurotrophic factor (BDNF) messenger RNA expression and protein content of brain tissues. Locomotion, anxiety, learning and memory, and depression were measured by open field test (OFT), elevated plus-maze (EPM), object recognition test (ORT), and forced swimming test (FST), respectively. Ambulation time and center arena time in the OFT did not change among groups. In the EPM paradigm, SWNTs (800 mg kg -1 ) and MWNTs (80 and 800 mg kg -1 ) showed an anxiogenic effect. In ORT, MWNTs (80 mg kg -1 ) increased the discrimination ratio while in FST, MWNTs showed a depressant effect as compared to vehicle. The BDNF gene expression in mice treated with 80 and 800 mg kg -1 SWNTs or 80 mg kg -1 MWNTs decreased as compared to NC mice although BDNF gene expression increased in mice that were treated with 800 mg kg -1 MWNTs. The whole brain BDNF protein content did not change among groups. Our study showed that i.p. exposure to carbon nanotubes (CNTs) may result in behavioral toxicity linked with expression of depression or anxiety that depends on the type of CNTs. In addition, exposure to CNTs changed BDNF gene expression.

  3. Ocular Phenotype of Fbn2-Null Mice

    PubMed Central

    Shi, Yanrong; Tu, Yidong; Mecham, Robert P.; Bassnett, Steven

    2013-01-01

    Purpose. Fibrillin-2 (Fbn2) is the dominant fibrillin isoform expressed during development of the mouse eye. To test its role in morphogenesis, we examined the ocular phenotype of Fbn2−/− mice. Methods. Ocular morphology was assessed by confocal microscopy using antibodies against microfibril components. Results. Fbn2−/− mice had a high incidence of anterior segment dysgenesis. The iris was the most commonly affected tissue. Complete iridal coloboma was present in 37% of eyes. Dyscoria, corectopia and pseudopolycoria were also common (43% combined incidence). In wild-type (WT) mice, fibrillin-2-rich microfibrils are prominent in the pupillary membrane (PM) during development. In Fbn2-null mice, the absence of Fbn2 was partially compensated for by increased expression of fibrillin-1, although the resulting PM microfibrils were disorganized, compared with WTs. In colobomatous adult Fbn2−/− eyes, the PM failed to regress normally, especially beneath the notched region of the iris. Segments of the ciliary body were hypoplastic, and zonular fibers, although relatively plentiful, were unevenly distributed around the lens equator. In regions where the zonular fibers were particularly disturbed, the synchronous differentiation of the underlying lens fiber cells was affected. Conclusions. Fbn2 has an indispensable role in ocular morphogenesis in mice. The high incidence of iris coloboma in Fbn2-null animals implies a previously unsuspected role in optic fissure closure. The observation that fiber cell differentiation was disturbed in Fbn2−/− mice raises the possibility that the attachment of zonular fibers to the lens surface may help specify the equatorial margin of the lens epithelium. PMID:24130178

  4. Neurodegenerative Disease Transmission and Transgenesis in Mice.

    PubMed

    Dugger, Brittany N; Perl, Daniel P; Carlson, George A

    2017-11-01

    Although the discovery of the prion protein (PrP) resulted from its co-purification with scrapie infectivity in Syrian hamsters, work with genetically defined and genetically modified mice proved crucial for understanding the fundamental processes involved not only in prion diseases caused by PrP misfolding, aggregation, and spread but also in other, much more common, neurodegenerative brain diseases. In this review, we focus on methodological and conceptual approaches used to study scrapie and related PrP misfolding diseases in mice and how these approaches have advanced our understanding of related disorders including Alzheimer's and Parkinson's disease. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  5. Virulence of variola viruses for suckling mice.

    PubMed

    Huq, Farida; Dumbell, K R

    2003-01-01

    We report work done in 1971 to determine the quantitative virulence for suckling mice of 26 variola virus isolates from different countries and from cases of differing severity. Strains of recognized variola major and variola minor viruses differed up to 100-fold (expressed as the harmonic mean dose of inoculum which killed mice 2-4 d old, inoculated intracranially, in 5 d). Isolates from Indonesia and from East and West Africa gave intermediate values. Unlike tests on chick embryos, this test distinguished between African and Indonesian isolates.

  6. Active Viremia in Rotavirus-Infected Mice

    PubMed Central

    Blutt, Sarah E.; Fenaux, Martijn; Warfield, Kelly L.; Greenberg, Harry B.; Conner, Margaret E.

    2006-01-01

    Rotavirus circulates extraintestinally in animals used as models for rotavirus infection and in children. Rotavirus infection in mice was used to define host or viral factors that affect rotavirus viremia. Antigenemia was observed with homologous and heterologous rotaviruses, and neither age nor mouse strain genetics altered the occurrence of rotavirus antigenemia or viremia. Rotavirus RNA and infectious virus were present in sera and associated with the plasma fraction of blood in all infected mice. These findings indicate that antigenemia/viremia occurs routinely in rotavirus infections and imply that infectious rotavirus has access to any extraintestinal cell within contact of blood. PMID:16775359

  7. Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension.

    PubMed

    Kashyap, Sonu; Warner, Gina; Hu, Zeng; Gao, Feng; Osman, Mazen; Al Saiegh, Yousif; Lien, Karen R; Nath, Karl; Grande, Joseph P

    2017-01-01

    Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kidney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10-14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.

  8. Social and Sexual Behaivours of Mice in Partial Gravity

    NASA Astrophysics Data System (ADS)

    Aou, Shuji; Hasegawa, Katsuya; Kumei, Yasuhiro; Inoue, Katarzyna; Zeredo, Jorge; Narikiyo, Kimiya; Watanabe, Yuuki

    2012-07-01

    We examined social and sexual behaviours in normal ICR mice, C57BL mice and obese db/db mice lacking leptin receptors in low gravity conditions using parabolic-flight to generate graded levels of partial gravity. Although both normal and obese mice floated with vigorous limb and tail movements when a floor is smooth in microgravity but they were rather stable if a floor is cover by carpet. Obese mice were more stable and socially contacted longer with a partner in low-gravity conditions. When they returned to the home cage after parabolic flights, obese mice started to eat sooner without restless behaviour, while control mice showed restless behaviour without eating. Face grooming, an indicator of stress response, was found more often in the control mice than the obese mice. Obese mice returned to resting condition faster than the control. We also analysed sexual behaviour of ICR mice and C57BL mice but not db/db mice since they are sexually inactive. Social and sexual behaviour could be evaluated in partial gravity conditions to get basic data concerning whether rodents can communicate and reproduce in Moon, Mars and space or not. Supported by Grant-in-Aid for Exploratory Research (JSPS) to S Aou and FY2010 grants from JAXA and Japan Society for Promotion of Science to Y. Kumei.

  9. Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice.

    PubMed

    Leidinger, Charlotte; Herrmann, Felix; Thöne-Reineke, Christa; Baumgart, Nadine; Baumgart, Jan

    2017-03-06

    Establishing new refinement strategies in laboratory animal science is a central goal in fulfilling the requirements of Directive 2010/63/EU. Previous research determined a profound impact of gentle handling protocols on the well-being of laboratory mice. By introducing clicker training to the keeping of mice, not only do we promote the amicable treatment of mice, but we also enable them to experience cognitive enrichment. Clicker training is a form of positive reinforcement training using a conditioned secondary reinforcer, the "click" sound of a clicker, which serves as a time bridge between the strengthened behavior and an upcoming reward. The effective implementation of the clicker training protocol with a cohort of 12 BALB/c inbred mice of each sex proved to be uncomplicated. The mice learned rather quickly when challenged with tasks of the clicker training protocol, and almost all trained mice overcame the challenges they were given (100% of female mice and 83% of male mice). This study has identified that clicker training for mice strongly correlates with reduced fear in the mice during human-mice interactions, as shown by reduced anxiety-related behaviors (e.g., defecation, vocalization, and urination) and fewer depression-like behaviors (e.g., floating). By developing a reliable protocol that can be easily integrated into the daily routine of the keeping of laboratory mice, the lifetime experience of welfare in the mice can be improved substantially.

  10. Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice[S

    PubMed Central

    Babaev, Vladimir R.; Hebron, Katie E.; Wiese, Carrie B.; Toth, Cynthia L.; Ding, Lei; Zhang, Youmin; May, James M.; Fazio, Sergio; Vickers, Kasey C.; Linton, MacRae F.

    2014-01-01

    Macrophages play crucial roles in the formation of atherosclerotic lesions. Akt, a serine/threonine protein kinase B, is vital for cell proliferation, migration, and survival. Macrophages express three Akt isoforms, Akt1, Akt2, and Akt3, but the roles of Akt1 and Akt2 in atherosclerosis in vivo remain unclear. To dissect the impact of macrophage Akt1 and Akt2 on early atherosclerosis, we generated mice with hematopoietic deficiency of Akt1 or Akt2. After 8 weeks on Western diet, Ldlr−/− mice reconstituted with Akt1−/− fetal liver cells (Akt1−/−→Ldlr−/−) had similar atherosclerotic lesion areas compared with control mice transplanted with WT cells (WT→Ldlr−/−). In contrast, Akt2−/−→Ldlr−/− mice had dramatically reduced atherosclerotic lesions compared with WT→Ldlr−/− mice of both genders. Similarly, in the setting of advanced atherosclerotic lesions, Akt2−/−→Ldlr−/− mice had smaller aortic lesions compared with WT→Ldlr−/− and Akt1−/−→Ldlr−/− mice. Importantly, Akt2−/−→Ldlr−/− mice had reduced numbers of proinflammatory blood monocytes expressing Ly-6Chi and chemokine C-C motif receptor 2. Peritoneal macrophages isolated from Akt2−/− mice were skewed toward an M2 phenotype and showed decreased expression of proinflammatory genes and reduced cell migration. Our data demonstrate that loss of Akt2 suppresses the ability of macrophages to undergo M1 polarization reducing both early and advanced atherosclerosis. PMID:25240046

  11. [Anatomy and histology characteristics of lymph node in nude mice].

    PubMed

    Sun, R; Gao, B; Guo, C B

    2017-10-18

    To compare the differences of anatomical and histological characteristics of lymph nodes between BALB/c nude mice and BALB/c mice. Firstly, twenty BALB/c nude mice and twenty BALB/c mice were dissected by using a surgical microscope. Secondly, the differences of T cells and B cells at the lymph node were compared by the expressions of CD 3 and CD 20 immunohistochemistry dyes. There were, on average, 23 nodes per mouse contained within the large lymph node assembly in the BALB/c nude mouse. The anatomical features of the lymph node distribution in the nude mice were mainly found in the neck with relatively higher density. There were two lymph nodes both in the submandible lymph nodes group and in the superficial cervical lymph nodes group (the constituent ratios were 95% and 90%, respectively) in the BALB/c nude mice, but there were four lymph nodes (the constituent ratios were 95% and 90%, respectively) in the BALB/c mice. There were significant difference between the BALB/c nude mice and the BALB/c mice. Mostly there were two lymph nodes of deep cervical lymph nodes both in the BALB/c nude mice and the BALB/c mice (the constituent ratios were 95% and 100%, respectively). There were no significant difference between the BALB/c nude mice and the BALB/c mice. We confirmed that the number of CD 3 -positive T lymphocytes in lymph nodes of the nude mice decreased greatly as compared with the BALB/c mice. Expressions of CD3 in T cells were 95% and 100% in the BALB/c nude mice and in the BALB/c mice, respectively. There were significant differences between the BALB/c nude mice and the BALB/c mice. Expressions of CD20 in B cells were 95% and 100% in the BALB/c nude mice and in the BALB/c mice, respectively. There was no significant difference between the BALB/c nude mice and BALB/c mice. The anatomical pictures of lymph node distribution in the nude mouse will be benefit to those who are interested. The anatomical features of the lymph node local higher density in neck of

  12. Behavior of captive white-footed mice.

    PubMed

    Kavanau, J L

    1967-03-31

    Detailed studies of the behavior of captive white-footed mice have cast a number of old problems in new perspectives. Many responses of small captive mammals cannot be interpreted at face value because of severe distortions of behavior that are caused by depriving the wild animal of natural outlets for activity. Confined animals are likely to seize upon and repeatedly exercise virtually any opportunities to modify (and alter their relationships with) their surroundings. In addition they have a strong tendency to counteract nonvolitional and "unexpected" deviations from the status quo. As a result, their responses do not bear an immutable relationship to the nature of the stimulus or other variable being modified; stimuli and activities that are rewarding in certain circumstances are avoided in others. These aspects of behavior have been illustrated by studies of nest occupancy, running in motordriven wheels, and control of intensity of illumination. The results of the control-of-illumination studies suggest the complex interplay of tendencies to modify features of the environment, to avoid conditions imposed compulsorily, and to select preferred levels of illumination. The importance of split-second timing, coordination, and quick reflex actions in the running of activity wheels is indicated by the fact that experienced white-footed mice prefer running in square "wheels" and wheels with hurdles to running in plain round wheels. The relatively conservative behavior of these mice in selecting between multiple sources of food and water and different types of activity wheels suggests the need for careful experimental design in free-choice studies with inexperienced animals. The tendency of trained animals to give some so-called "incorrect" responses even after long experience can be interpreted most reasonably in terms of the adaptive value of a certain degree of variability of behavior in the wild. White-footed mice readily master complex regimes in which several

  13. CYTOGENETIC ANALYSES OF MICE EXPOSED TO DICHLOROMETHANE

    EPA Science Inventory

    Chromosome damage was studied in female B6C3F1 mice exposed to dichloromethane (DCM) by subcutaneous or inhalation treatments. o increase in either the frequencies of sister chromatid exchanges (SCEs) or chromosome aberrations (CAs) in bone marrow cells was observed after a singl...

  14. Protection of mice against Giardia muris infection.

    PubMed Central

    Roberts-Thomson, I C; Mitchell, G F

    1979-01-01

    Strains of mice showing relatively rapid (BALB/c) and defective (C3H/He) spontaneous elimination of Giardia muris displayed marked differences in the degree of resistance to infection induced by prior injection of trophozoites in Freund complete adjuvant. PMID:468385

  15. Prolonged longevity of hypopituitary dwarf mice.

    PubMed

    Bartke, A; Brown-Borg, H; Mattison, J; Kinney, B; Hauck, S; Wright, C

    2001-01-01

    In two types of mutant dwarf mice, congenital deficiencies in pituitary function are associated with remarkably increased life expectancy. In this review, we will describe the key phenotypic characteristics of these animals, the evidence that they exhibit delayed aging, and the mechanisms that are suspected to account for their prolonged longevity.

  16. Skeletal muscle weakness in osteogenesis imperfecta mice.

    PubMed

    Gentry, Bettina A; Ferreira, J Andries; McCambridge, Amanda J; Brown, Marybeth; Phillips, Charlotte L

    2010-09-01

    Exercise intolerance, muscle fatigue and weakness are often-reported, little-investigated concerns of patients with osteogenesis imperfecta (OI). OI is a heritable connective tissue disorder hallmarked by bone fragility resulting primarily from dominant mutations in the proα1(I) or proα2(I) collagen genes and the recently discovered recessive mutations in post-translational modifying proteins of type I collagen. In this study we examined the soleus (S), plantaris (P), gastrocnemius (G), tibialis anterior (TA) and quadriceps (Q) muscles of mice expressing mild (+/oim) and moderately severe (oim/oim) OI for evidence of inherent muscle pathology. In particular, muscle weight, fiber cross-sectional area (CSA), fiber type, fiber histomorphology, fibrillar collagen content, absolute, relative and specific peak tetanic force (P(o), P(o)/mg and P(o)/CSA respectively) of individual muscles were evaluated. Oim/oim mouse muscles were generally smaller, contained less fibrillar collagen, had decreased P(o) and an inability to sustain P(o) for the 300-ms testing duration for specific muscles; +/oim mice had a similar but milder skeletal muscle phenotype. +/oim mice had mild weakness of specific muscles but were less affected than their oim/oim counterparts which demonstrated readily apparent skeletal muscle pathology. Therefore muscle weakness in oim mice reflects inherent skeletal muscle pathology. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. A miniature mechanical ventilator for newborn mice.

    PubMed

    Kolandaivelu, K; Poon, C S

    1998-02-01

    Transgenic/knockout mice with pre-defined mutations have become increasingly popular in biomedical research as models of human diseases. In some instances, the resulting mutation may cause cardiorespiratory distress in the neonatal or adult animals and may necessitate resuscitation. Here we describe the design and testing of a miniature and versatile ventilator that can deliver varying ventilatory support modes, including conventional mechanical ventilation and high-frequency ventilation, to animals as small as the newborn mouse. With a double-piston body chamber design, the device circumvents the problem of air leakage and obviates the need for invasive procedures such as endotracheal intubation, which are particularly important in ventilating small animals. Preliminary tests on newborn mice as early as postnatal day O demonstrated satisfactory restoration of pulmonary ventilation and the prevention of respiratory failure in mutant mice that are prone to respiratory depression. This device may prove useful in the postnatal management of transgenic/knockout mice with genetically inflicted respiratory disorders.

  18. Effect of ammonia on Swiss albino mice

    NASA Technical Reports Server (NTRS)

    Hilado, C. J.; Casey, C. J.; Furst, A.

    1977-01-01

    Times to incapacitation and death and LC /50/ values were determined for Swiss albino male mice exposed to different concentrations of ammonia in a 4.2 liter hemispherical chamber. The LC/50/ for a 30 minute exposure was 21,430 ppm.

  19. Are mice eating up all the pine seeds?

    Treesearch

    Rafal Zwolak; Kerry Foresman; Elizabeth Crone; Dean Pearson; Yvette Ortega

    2008-01-01

    Wildlife, even miniscule mice, can play an important role in forest regeneration and composition by consuming seeds, seedlings, and saplings. Mice can, through sheer numbers, consume a tremendous number of seeds. We wanted to learn if deer mice could affect how ponderosa pine forests regenerate after fire.

  20. Neural Tube Defects In Mice Exposed To Tap Water

    PubMed Central

    Mallela, Murali K; Werre, Stephen R; Hrubec, Terry C

    2010-01-01

    In May of 2006 we suddenly began to observe neural tube defects (NTDs) in embryos of untreated control mice. We hypothesized the mice were being exposed unknowingly to a teratogenic agent and investigated the cause. Our results suggested that NTDs were not resulting from bedding material, feed, strain or source of the mice. Additionally, mice were negative for routine and comprehensive screens of pathogens. To further test whether the NTDs resulted from infectious or genetic cause localized to our facility, we obtained three strains of timed pregnant mice from commercial suppliers located in 4 different states. All strains and sources of mice arrived in our laboratory with NTDs, implying that commercially available mice were possibly exposed to a teratogen prior to purchase. Our investigation eventually concluded that exposure to tap water was causing the NTDs. The incidence of NTDs was greatest in purchased mice provided tap water and lowest in purchased mice provided distilled deionized water (DDI). Providing mice DDI water for two generations (F2-DDI) eliminated the NTDs. When F2-DDI mice were provided tap water from three different urban areas prior to breeding, their offspring again developed NTDs. Increased length of exposure to tap water significantly increased the incidence of NTDs. These results indicate that a contaminant in municipal tap water is likely causing NTDs in mice. The unknown teratogen appears to have a wide geographic distribution but has not yet been identified. Water analysis is currently underway to identify candidate contaminants that might be responsible for the malformations. PMID:20549630

  1. Inner ear dysfunction in caspase-3 deficient mice

    PubMed Central

    2011-01-01

    Background Caspase-3 is one of the most downstream enzymes activated in the apoptotic pathway. In caspase-3 deficient mice, loss of cochlear hair cells and spiral ganglion cells coincide closely with hearing loss. In contrast with the auditory system, details of the vestibular phenotype have not been characterized. Here we report the vestibular phenotype and inner ear anatomy in the caspase-3 deficient (Casp3-/-) mouse strain. Results Average ABR thresholds of Casp3-/- mice were significantly elevated (P < 0.05) compared to Casp3+/- mice and Casp3+/+ mice at 3 months of age. In DPOAE testing, distortion product 2F1-F2 was significantly decreased (P < 0.05) in Casp3-/- mice, whereas Casp3+/- and Casp3+/+ mice showed normal and comparable values to each other. Casp3-/- mice were hyperactive and exhibited circling behavior when excited. In lateral canal VOR testing, Casp3-/- mice had minimal response to any of the stimuli tested, whereas Casp3+/- mice had an intermediate response compared to Casp3+/+ mice. Inner ear anatomical and histological analysis revealed gross hypomorphism of the vestibular organs, in which the main site was the anterior semicircular canal. Hair cell numbers in the anterior- and lateral crista, and utricle were significantly smaller in Casp3-/- mice whereas the Casp3+/- and Casp3+/+ mice had normal hair cell numbers. Conclusions These results indicate that caspase-3 is essential for correct functioning of the cochlea as well as normal development and function of the vestibule. PMID:21988729

  2. The Mice Drawer System (MDS) experiment and the space endurance record-breaking mice.

    PubMed

    Cancedda, Ranieri; Liu, Yi; Ruggiu, Alessandra; Tavella, Sara; Biticchi, Roberta; Santucci, Daniela; Schwartz, Silvia; Ciparelli, Paolo; Falcetti, Giancarlo; Tenconi, Chiara; Cotronei, Vittorio; Pignataro, Salvatore

    2012-01-01

    The Italian Space Agency, in line with its scientific strategies and the National Utilization Plan for the International Space Station (ISS), contracted Thales Alenia Space Italia to design and build a spaceflight payload for rodent research on ISS: the Mice Drawer System (MDS). The payload, to be integrated inside the Space Shuttle middeck during transportation and inside the Express Rack in the ISS during experiment execution, was designed to function autonomously for more than 3 months and to involve crew only for maintenance activities. In its first mission, three wild type (Wt) and three transgenic male mice over-expressing pleiotrophin under the control of a bone-specific promoter (PTN-Tg) were housed in the MDS. At the time of launch, animals were 2-months old. MDS reached the ISS on board of Shuttle Discovery Flight 17A/STS-128 on August 28(th), 2009. MDS returned to Earth on November 27(th), 2009 with Shuttle Atlantis Flight ULF3/STS-129 after 91 days, performing the longest permanence of mice in space. Unfortunately, during the MDS mission, one PTN-Tg and two Wt mice died due to health status or payload-related reasons. The remaining mice showed a normal behavior throughout the experiment and appeared in excellent health conditions at landing. During the experiment, the mice health conditions and their water and food consumption were daily checked. Upon landing mice were sacrificed, blood parameters measured and tissues dissected for subsequent analysis. To obtain as much information as possible on microgravity-induced tissue modifications, we organized a Tissue Sharing Program: 20 research groups from 6 countries participated. In order to distinguish between possible effects of the MDS housing conditions and effects due to the near-zero gravity environment, a ground replica of the flight experiment was performed at the University of Genova. Control tissues were collected also from mice maintained on Earth in standard vivarium cages.

  3. Inhibition of autoimmune diabetes in NOD mice with serum from streptococcal preparation (OK-432)-injected mice.

    PubMed Central

    Seino, H; Satoh, J; Shintani, S; Takahashi, K; Zhu, X P; Masuda, T; Nobunaga, T; Saito, M; Terano, Y; Toyota, T

    1991-01-01

    We have recently reported that systemic and chronic administration of recombinant tumour necrosis factor alpha (TNF-alpha), as well as streptococcal preparation (OK-432), inhibits development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats, models of IDDM. In this study we examined whether serum containing endogenous TNF induced by OK-432 injection could inhibit IDDM in NOD mice. Treatment twice a week from 4 weeks of age with OK-432-injected mouse serum, which contained endogenous TNF (75U), but not IL-1, IL-2 and interferon-gamma (IFN-gamma) activity, reduced the intensity of insulitis and significantly inhibited the cumulative incidence of diabetes by 28 weeks of age in NOD mice, as compared with the incidence in non-treated mice (P less than 0.01) and in mice treated with control serum (P less than 0.02). This inhibitory effect of the serum was diminished, although not significantly, by neutralization of serum TNF activity with anti-mouse TNF antibody. In the mice treated with the serum from OK-432-injected mice, Thy-1.2+ or CD8+ spleen cells decreased (P less than 0.01) and surface-Ig+ (S-Ig+) cells increased (P less than 0.05), whereas the proliferative response of spleen cells to concanavalin A (P less than 0.01) and lipopolysaccharide (P less than 0.05) increased. The results indicate that the inhibition by OK-432 treatment of IDDM in NOD mice was partially mediated by serum factors including endogenous TNF. PMID:1747949

  4. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice.

    PubMed

    Murphy, Andrew J; Macdonald, Lynn E; Stevens, Sean; Karow, Margaret; Dore, Anthony T; Pobursky, Kevin; Huang, Tammy T; Poueymirou, William T; Esau, Lakeisha; Meola, Melissa; Mikulka, Warren; Krueger, Pamela; Fairhurst, Jeanette; Valenzuela, David M; Papadopoulos, Nicholas; Yancopoulos, George D

    2014-04-08

    Mice genetically engineered to be humanized for their Ig genes allow for human antibody responses within a mouse background (HumAb mice), providing a valuable platform for the generation of fully human therapeutic antibodies. Unfortunately, existing HumAb mice do not have fully functional immune systems, perhaps because of the manner in which their genetic humanization was carried out. Heretofore, HumAb mice have been generated by disrupting the endogenous mouse Ig genes and simultaneously introducing human Ig transgenes at a different and random location; KO-plus-transgenic humanization. As we describe in the companion paper, we attempted to make mice that more efficiently use human variable region segments in their humoral responses by precisely replacing 6 Mb of mouse Ig heavy and kappa light variable region germ-line gene segments with their human counterparts while leaving the mouse constant regions intact, using a unique in situ humanization approach. We reasoned the introduced human variable region gene segments would function indistinguishably in their new genetic location, whereas the retained mouse constant regions would allow for optimal interactions and selection of the resulting antibodies within the mouse environment. We show that these mice, termed VelocImmune mice because they were generated using VelociGene technology, efficiently produce human:mouse hybrid antibodies (that are rapidly convertible to fully human antibodies) and have fully functional humoral immune systems indistinguishable from those of WT mice. The efficiency of the VelocImmune approach is confirmed by the rapid progression of 10 different fully human antibodies into human clinical trials.

  5. Skin mites in mice (Mus musculus): high prevalence of Myobia sp. (Acari, Arachnida) in Robertsonian mice.

    PubMed

    Sastre, Natalia; Calvete, Oriol; Martínez-Vargas, Jessica; Medarde, Nuria; Casellas, Joaquim; Altet, Laura; Sánchez, Armand; Francino, Olga; Ventura, Jacint

    2018-07-01

    Myobia sp. and Demodex sp. are two skin mites that infest mice, particularly immunodeficient or transgenic lab mice. In the present study, wild house mice from five localities from the Barcelona Roberstonian system were analysed in order to detect skin mites and compare their prevalence between standard (2n = 40) and Robertsonian mice (2n > 40). We found and identified skin mites through real-time qPCR by comparing sequences from the mitochondrial 16S rRNA and the nuclear 18S rRNA genes since no sequences are available so far using the mitochondrial gene. Fourteen positive samples were identified as Myobia musculi except for a deletion of 296 bp out to 465 bp sequenced, and one sample was identified as Demodex canis. Sampling one body site, the mite prevalence in standard and Robertsonian mice was 0 and 26%, respectively. The malfunction of the immune system elicits an overgrowth of skin mites and consequently leads to diseases such as canine demodicosis in dogs or rosacea in humans. In immunosuppressed mice, the probability of developing demodicosis is higher than in healthy mice. Since six murine toll-like receptors (TLRs) are located in four chromosomes affected by Robertsonian fusions, we cannot dismiss that differences in mite prevalence could be the consequence of the interruption of TLR function. Although ecological and/or morphological factors cannot be disregarded to explain differences in mite prevalence, the detection of translocation breakpoints in TLR genes or the analysis of TLR gene expression are needed to elucidate how Robertsonian fusions affect the immune system in mice.

  6. The Mice Drawer System (MDS) Experiment and the Space Endurance Record-Breaking Mice

    PubMed Central

    Cancedda, Ranieri; Liu, Yi; Ruggiu, Alessandra; Tavella, Sara; Biticchi, Roberta; Santucci, Daniela; Schwartz, Silvia; Ciparelli, Paolo; Falcetti, Giancarlo; Tenconi, Chiara; Cotronei, Vittorio; Pignataro, Salvatore

    2012-01-01

    The Italian Space Agency, in line with its scientific strategies and the National Utilization Plan for the International Space Station (ISS), contracted Thales Alenia Space Italia to design and build a spaceflight payload for rodent research on ISS: the Mice Drawer System (MDS). The payload, to be integrated inside the Space Shuttle middeck during transportation and inside the Express Rack in the ISS during experiment execution, was designed to function autonomously for more than 3 months and to involve crew only for maintenance activities. In its first mission, three wild type (Wt) and three transgenic male mice over-expressing pleiotrophin under the control of a bone-specific promoter (PTN-Tg) were housed in the MDS. At the time of launch, animals were 2-months old. MDS reached the ISS on board of Shuttle Discovery Flight 17A/STS-128 on August 28th, 2009. MDS returned to Earth on November 27th, 2009 with Shuttle Atlantis Flight ULF3/STS-129 after 91 days, performing the longest permanence of mice in space. Unfortunately, during the MDS mission, one PTN-Tg and two Wt mice died due to health status or payload-related reasons. The remaining mice showed a normal behavior throughout the experiment and appeared in excellent health conditions at landing. During the experiment, the mice health conditions and their water and food consumption were daily checked. Upon landing mice were sacrificed, blood parameters measured and tissues dissected for subsequent analysis. To obtain as much information as possible on microgravity-induced tissue modifications, we organized a Tissue Sharing Program: 20 research groups from 6 countries participated. In order to distinguish between possible effects of the MDS housing conditions and effects due to the near-zero gravity environment, a ground replica of the flight experiment was performed at the University of Genova. Control tissues were collected also from mice maintained on Earth in standard vivarium cages. PMID:22666312

  7. SAHA Suppresses Peritoneal Fibrosis in Mice

    PubMed Central

    Io, Kumiko; Nishino, Tomoya; Obata, Yoko; Kitamura, Mineaki; Koji, Takehiko; Kohno, Shigeru

    2015-01-01

    ♦ Objective: Long-term peritoneal dialysis causes peritoneal fibrosis in submesothelial areas. However, the mechanism of peritoneal fibrosis is unclear. Epigenetics is the mechanism to induce heritable changes without any changes in DNA sequences. Among epigenetic modifications, histone acetylation leads to the transcriptional activation of genes. Recent studies indicate that histone acetylation is involved in the progression of fibrosis. Therefore, we examined the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on the progression of peritoneal fibrosis in mice. ♦ Methods: Peritoneal fibrosis was induced by the injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. SAHA, or a dimethylsulfoxide and saline vehicle, was administered subcutaneously every day from the start of the CG injections for 3 weeks. Morphologic peritoneal changes were assessed by Masson’s trichrome staining, and fibrosis-associated factors were assessed by immunohistochemistry. ♦ Results: In CG-injected mice, a marked thickening of the submesothelial compact zone was observed. In contrast, the administration of SAHA suppressed the progression of submesothelial thickening and type III collagen accumulation in CG-injected mice. The numbers of fibroblast-specific protein-1-positive cells and α-smooth muscle actin α-positive cells were significantly decreased in the CG + SAHA group compared to that of the CG group. The level of histone acetylation was reduced in the peritoneum of the CG group, whereas it was increased in the CG + SAHA group. ♦ Conclusions: Our results indicate that SAHA can suppress peritoneal thickening and fibrosis in mice through up-regulation of histone acetylation. These results suggest that SAHA may have therapeutic potential for treating peritoneal fibrosis. PMID:24584598

  8. Hypercholesterolemia Impairs Exercise Capacity in Mice

    PubMed Central

    Maxwell, Andrew J.; Niebauer, Josef; Lin, Patrick S.; Tsao, Philip S.; Bernstein, Daniel; Cooke, John P.

    2011-01-01

    Objective We previously reported an attenuation of both exercise hyperemia and measures of aerobic capacity in hypercholesterolemic mice. In this study we expanded upon the previous findings by examining the temporal and quantitative relationship of hypercholesterolemia to aerobic and anaerobic capacity and by exploring several potential mechanisms of dysfunction. Methods Eight-week old wild type (n=123) and apoE knockout (n=79) C57BL/6J mice were divided into groups with distinct cholesterol levels by feeding regular or high fat diets. At various ages the mice underwent treadmill ergospirometry. To explore mechanisms, aortic ring vasodilator function and nitrate (NOx) activity, urinary excretion of NOx, running muscle microvascular density and citrate synthase activity, as well as myocardial mass and histologic evidence of ischemia were measured. Results At 8 weeks of age, all mice had similar measures of exercise capacity. All indices of aerobic exercise capacity progressively declined at 12 and 20 weeks of age in the hypercholesterolemic mice as cholesterol levels increased while indices of anaerobic capacity remained unaffected. Across the 4 cholesterol groups, the degree of aerobic dysfunction was related to serum cholesterol levels; a relationship that was maintained after correcting for confounding factors. Associated with the deterioration in exercise capacity was a decline in measures of nitric oxide-mediated vascular function while there was no evidence of aberrations in functional or oxidative capacities or in other components of transport capacity. Conclusion Aerobic exercise dysfunction is observed in murine models of genetic and diet-induced hypercholesterolemia and is associated with a reduction in vascular nitric oxide production. PMID:19651675

  9. NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice

    PubMed Central

    Puchalapalli, Madhavi; Zeng, Xianke; Mu, Liang; Anderson, Aubree; Hix Glickman, Laura; Zhang, Ming; Sayyad, Megan R.; Mosticone Wangensteen, Sierra; Clevenger, Charles V.; Koblinski, Jennifer E.

    2016-01-01

    Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model. PMID:27662655

  10. Measurement of Sulfur Isotopic Composition (δ34S) by Multiple-Collector Thermal Ionization Mass Spectrometry (MC-TIMS) Using a 33S/36S Double Spike

    NASA Astrophysics Data System (ADS)

    Mann, J. L.; Kelly, W. R.

    2006-05-01

    A new analytical technique for the determination of δ34S will be described. The technique is based on the production of singularly charged arsenic sulfide molecular ions (AsS+) by thermal ionization using silica gel as an emitter and combines multiple-collector thermal ionization mass spectrometry (MC-TIMS) with a 33S/36S double spike to correct instrumental fractionation. Because the double spike is added to the sample before chemical processing, both the isotopic composition and sulfur concentration are measured simultaneously. The accuracy and precision of the double spike technique is comparable to or better than modern gas source mass spectrometry, but requires about a factor of 10 less sample. Δ33S effects can be determined directly in an unspiked sample without any assumptions about the value of k (mass dependent fractionation factor) which is currently required by gas source mass spectrometry. Three international sulfur standards (IAEA-S-1, IAEA-S-2, and IAEA-S-3) were measured to evaluate the precision and accuracy of the new technique and to evaluate the consensus values for these standards. Two different double spike preparations were used. The δ34S values (reported relative to Vienna Canyon Diablo Troilite (VCDT), (δ34S (‰) = 34S/32S)sample/(34S/32S)VCDT - 1) x 1000]), 34S/32SVCDT = 0.0441626) determined were -0.32‰ ± 0.04‰ (1σ, n=4) and -0.31‰ ± 0.13‰ (1σ, n=8) for IAEA-S-1, 22.65‰ ± 0.04‰ (1σ, n=7) and 22.60‰ ± 0.06‰ (1σ, n=5) for IAEA- S-2, and -32.47‰ ± 0.07‰ (1σ, n=8) for IAEA-S-3. The amount of natural sample used for these analyses ranged from 0.40 μmoles to 2.35 μmoles. Each standard showed less than 0.5‰ variability (IAEA-S-1 < 0.4‰, IAEA-S-2 < 0.2‰, and IAEA-S-3 < 0.2‰). Our values for S-1 and S-2 are in excellent agreement with the consensus values and the values reported by other laboratories using both SF6 and SO2. Our value for S-3 differs statistically from the Institute for Reference

  11. Oral lactoferrin protects against experimental candidiasis in mice

    PubMed Central

    Velliyagounder, Kabilan; Alsaedi, Wijdan; Alabdulmohsen, Waad; Markowitz, Kenneth; Fine, Daniel H.

    2015-01-01

    Aims To determine the role of lactoferrin in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO−/−) mice were compared to wild-type (WT) mice. We also determine the protective role of human lactoferrin in the LFKO−/− mice. Methods and Results Antibiotic treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0.3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO−/−I mice showed a 2 log (P=0.001) higher CFUs of C. albicans in the oral cavity compared to the WTI mice. LFKO−/−I mice given hLF had a 3 log (P=0.001) reduction in CFUs in the oral cavity compared to untreated LFKO−/−I mice. The severity of infection, observed by light microscopy revealed that the tongue of the LFKO−/−I mice showed more white patches compared to WTI and LFKO−/−I+hLF mice. Scanning electron microscopic observation revealed that more filiform papillae were destroyed in LFKO−/−I mice when compared to WTI or LFKO−/−I +hLF mice. Conclusions Human lactoferrin is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. Significance and Impact of the Study Human lactoferrin, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral health care products against C. albicans. PMID:25319508

  12. Oral lactoferrin protects against experimental candidiasis in mice.

    PubMed

    Velliyagounder, K; Alsaedi, W; Alabdulmohsen, W; Markowitz, K; Fine, D H

    2015-01-01

    To determine the role of human lactoferrin (hLF) in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO(-/-)) mice was compared to wild-type (WT) mice. We also aim to determine the protective role of hLF in LFKO(-/-) mice. Antibiotic-treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0·3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO(-/-) I mice showed a 2 log (P = 0·001) higher CFUs of C. albicans in the oral cavity compared to the WT mice infected with C. albicans (WTI). LFKO(-/-) I mice given hLF had a 3 log (P = 0·001) reduction in CFUs in the oral cavity compared to untreated LFKO(-/-) I mice. The severity of infection, observed by light microscopy, revealed that the tongue of the LFKO(-/-) I mice showed more white patches compared to WTI and LFKO(-/-) I + hLF mice. Scanning electron microscopic observations revealed that more filiform papillae were destroyed in LFKO(-/-) I mice when compared to WTI or LFKO(-/-) I + hLF mice. Human LF is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. Human LF, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral healthcare products against C. albicans. © 2014 The Society for Applied Microbiology.

  13. Suppression of oral tolerance by Lactococcus lactis in mice.

    PubMed

    Sakai, Tohru; Hirota, Yuko; Nakamoto, Mariko; Shuto, Emi; Hosaka, Toshio; Makino, Seiya; Ikegami, Shuji

    2011-01-01

    Although oral ovabumin (OVA) administration suppressed the antibody (Ab) response in OVA-immunized mice, Lactococcus lactis increased OVA-specific IgG2a in these mice. L. lactis increased the casein-specific IgG level in NC/Nga mice fed on a casein diet. The percentage of CD4(+)CD25(+) cells was increased in DO11.10 mice orally given OVA, but this increase of CD4(+)CD25(+) cells were suppressed in L. lactis-fed DO11.10 mice.

  14. Susceptibility of thermally injured mice to cytomegalovirus infection.

    PubMed

    Kobayashi, H; Kobayashi, M; Herndon, D N; Pollard, R B; Suzuki, F

    2001-11-01

    Thermally injured patients are very susceptible to infection with cytomegaloviruses. In this study a role of burn-associated type 2 T cell responses on the cytomegalovirus infection was examined in a mouse model of thermal injury. A predominance of type 2 T cell responses in splenic lymphocytes of thermally injured mice has been previously demonstrated. SCID mice inoculated with splenic T cells from thermally injured mice were susceptible to infection with a small amount (5 PFU/mouse) of murine cytomegalovirus (MCMV). Conversely, SCID mice inoculated with splenic T cells from normal mice were resistant to the same infection. High levels of IL-4 and IL-10, but not IFN-gamma and IL-2, were detected in sera of thermally injured mice (TI-mice) infected with MCMV when those were compared with sera of normal mice infected with MCMV. IL-4 and IL-10 (type 2 cytokines) were produced by splenic T cells from MCMV-infected TI-mice, when they were stimulated in vitro with anti-CD3 mAb. Type 1 cytokines (IFN-gamma and IL-2), however, were not produced by these T cells after the same stimulation. In contrast, splenic T cells from MCMV-infected normal mice produced type 1 cytokines by the stimulation with anti-CD3 mAb. These results suggest that the susceptibility of mice to MCMV infection is markedly influenced by burn-associated type 2 T cell responses.

  15. Comparison of neutrophil functions between two strains of inbred mice.

    PubMed

    Zhang, Xiaohuan; Zhao, Sainan; Sun, Luping; Li, Wenqing; Glogauer, Michael; Hu, Yan

    2016-12-01

    In this study, differences between two strains of inbred mice in aspects of neutrophil function, namely Rac1 expression, chemotaxis, nicotinamide adenine dinucleotide phosphate oxidase activity and formation of neutrophil extracellular traps (NETs), were determined. Neutrophils from CBA/CaH mice exhibited weaker Rac1 expression and a slower chemotactic gradient than BALB/c mice. Furthermore, PMA- or fMLP-stimulated neutrophils from CBA/CaH mice generated much less superoxide and NETs than similarly stimulated neutrophils from BALB/c mice. These findings suggest that neutrophils from BALB/c mice are functionally more efficient than those from CBA/CaH mice. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

  16. Innate resistance of mice to experimental infection with Naegleria fowleri.

    PubMed Central

    Haggerty, R M; John, D T

    1978-01-01

    The mouse system provides an excellent model for studying host resistance to Naegleria fowleri, the agent of primary amoebic meningoencephalitis. Innate resistance to infection with N. fowleri was examined with respect to infecting dose and the age, sex, and strain of mice. Intravenous inoculation with 10(7) amoebae per mouse produced 100% mortality in 9 days, whereas inoculation with fewer amoebae reduced the cumulative mortality. Male and female DUB/ICR mice of varying ages were inoculated intravenously with 2.5 X 10(5) N. fowleri per g of body weight. The youngest mice died first, with 100% mortality for both males and females, and mortality decreased with increasing age. Female mice were significantly more resistant to infection than males. Five strains of mice weighing approximately 20 g were inoculated intravenously with weight-adjusted doses; mortality ranged from 10% in C57BL/6 mice to 95% in A/HeCr mice. PMID:669800

  17. Propagation of Human Hepatocytes in uPA/SCID Mice: Producing Chimeric Mice with Humanized Liver.

    PubMed

    Ohshita, Hiroki; Tateno, Chise

    2017-01-01

    Primary or cryopreserved human hepatocytes (h-heps) have been used as the gold standard for in vitro metabolism and hepatotoxicity studies; however, the supply of h-heps is limited and they cannot grow in vitro. We achieved approximately 1000-fold propagation of h-heps in the liver of albumin promoter/enhancer-driven urokinase-type plasminogen activator transgenic/severe combined immunodeficiency disease (uPA/SCID) mice with genetically induced liver disease and immunodeficiency. When h-heps are transplanted into the uPA/SCID mouse liver via the spleen, the h-heps engraft in the mouse liver, resulting in its repopulation with h-heps. We have named this model "chimeric mouse with humanized liver, PXB-mouse ® ." Fresh h-heps can be isolated from the chimeric mice (PXB-cells ® ) and have been used for in vitro studies.The efficacy and safety of chemical entities for use in humans are estimated using experimental animals such as rats and mice. The drug development of many chemical entities has been halted because of metabolic differences between humans and animals during clinical studies. Therefore, chimeric mice with humanized liver have been used to predict human-type metabolism and safety conditions for h-heps. In addition, until recently there were no suitable hepatitis B or C virus (HBV or HCV) susceptible animal models aside from chimpanzees. Chimeric mice are the sole persistent infectious small animal model for HBV and HCV and they have been used to investigate the efficacy of new anti-HBV or HCV agents.In this chapter, we describe a method for producing chimeric mice with humanized liver using uPA/SCID mice.

  18. An alteration of the gut-liver axis drives pulmonary inflammation after intoxication and burn injury in mice

    PubMed Central

    Chen, Michael M.; Zahs, Anita; Brown, Mary M.; Ramirez, Luis; Turner, Jerrold R.; Choudhry, Mashkoor A.

    2014-01-01

    Approximately half of all adult burn patients are intoxicated at the time of their injury and have worse clinical outcomes than those without prior alcohol exposure. This study tested the hypothesis that intoxication alters the gut-liver axis, leading to increased pulmonary inflammation mediated by burn-induced IL-6 in the liver. C57BL/6 mice were given 1.2 g/kg ethanol 30 min prior to a 15% total body surface area burn. To restore gut barrier function, the specific myosin light chain kinase inhibitor membrane-permeant inhibitor of kinase (PIK), which we have demonstrated to reduce bacterial translocation from the gut, was administered 30 min after injury. Limiting bacterial translocation with PIK attenuated hepatic damage as measured by a 47% reduction in serum alanine aminotransferase (P < 0.05), as well as a 33% reduction in hepatic IL-6 mRNA expression (P < 0.05), compared with intoxicated and burn-injured mice without PIK. This mitigation of hepatic damage was associated with a 49% decline in pulmonary neutrophil infiltration (P < 0.05) and decreased alveolar wall thickening compared with matched controls. These results were reproduced by prophylactic reduction of the bacterial load in the intestines with oral antibiotics before intoxication and burn injury. Overall, these data suggest that the gut-liver axis is deranged when intoxication precedes burn injury and that limiting bacterial translocation in this setting attenuates hepatic damage and pulmonary inflammation. PMID:25104501

  19. Acute acetaminophen toxicity in transgenic mice with elevated hepatic glutathione.

    PubMed

    Rzucidlo, S J; Bounous, D I; Jones, D P; Brackett, B G

    2000-06-01

    Previous studies demonstrated that elevation of hepatic glutathione (GSH) concentrations protect against acetaminophen (APAP) hepatotoxicity in mice. Employing transgenic mice overexpressing glutathione synthetase, this study was conducted to determine if sustained elevation of hepatic GSH concentrations could ameliorate or prevent APAP toxicity. International Cancer Research transgenic mouse males and matched (ie same strain, sex, and age) control nontransgenic mice were pretreated ip with GSH synthetase substrate gamma-glutamylcysteinyl ethyl ester (gamma-GCE) or with saline. After a 16-h fast, mice received a single dose of 500 mg APAP/kg bw in saline ip and were sacrificed 4 h later. Other mice similarly pretreated were killed without APAP challenge. The elevated GSH concentrations in transgenic mice livers did not lessen APAP hepatotoxicity. Instead higher degrees of hepatotoxicity and nephrotoxicity were observed in transgenic mice than in controls as indicated by higher serum alanine aminotransferase activity and more severe histopathological lesions in transgenic mice livers and kidneys. Pretreatment with gamma-GCE did not affect either initial or post-APAP treatment tissue GSH concentrations or observed degrees of toxicity. Detection of a higher level of serum APAP in transgenic mice and the histopathological lesions found in transgenic mice kidneys together with no observable nephrotoxicity in control mice indicated early kidney damage in transgenic mice. Our findings suggest that high levels of GSH-APAP conjugates resulting from increased GSH concentrations in the livers of transgenic mice caused rapid kidney damage. Compromised excretory ability may have caused retention of APAP, which, in effect, elicited higher hepatotoxicity than that observed in nontransgenic mice.

  20. Methods to measure olfactory behavior in mice

    PubMed Central

    Zou, Junhui; Wang, Wenbin; Pan, Yung-Wei; Lu, Song; Xia, Zhengui

    2015-01-01

    Mice rely on the sense of olfaction to detect food sources, recognize social and mating partners, and avoid predators. Many behaviors of mice including learning and memory, social interaction, fear, and anxiety are closely associated with their function of olfaction, and behavior tasks designed to evaluate those brain functions may use odors as cues. Accurate assessment of olfaction is not only essential for the study of olfactory system but also critical for proper interpretation of various mouse behaviors especially learning and memory, emotionality and affect, and sociality. Here we describe a series of behavior experiments that offer multidimensional and quantitative assessments for mouse’s olfactory function, including olfactory habituation, discrimination, odor preference, odor detection sensitivity, and olfactory memory, to both social and nonsocial odors. PMID:25645244

  1. Nootropic activity of Albizzia lebbeck in mice.

    PubMed

    Chintawar, S D; Somani, R S; Kasture, Veena S; Kasture, S B

    2002-08-01

    The effect of saponin containing n-butanolic fraction (BF) extracted from dried leaves of Albizzia lebbeck on learning and memory was studied in albino mice using passive shock avoidance paradigm and the elevated plus maze. Significant improvement was observed in the retention ability of the normal and amnesic mice as compared to their respective controls. We have also studied the effects of BF on the behavior influenced by serotonin (5-HT), noradrenaline and dopamine. The brain levels of serotonin, gamma-aminobutyric acid (GABA) and dopamine were also estimated to correlate the behavior with neurotransmitter levels. The brain concentrations of GABA and dopamine were decreased, whereas the 5-HT level was increased. The data indicate the involvement of monoamine neurotransmitters in the nootropic action of BF of A. lebbeck.

  2. Galactose inhibition of ovulation in mice.

    PubMed

    Swartz, W J; Mattison, D R

    1988-03-01

    Clinical evidence suggests an association between galactosemia and premature ovarian failure. In the present study, adult female mice were fed a diet consisting of 50% galactose for either 2, 4, or 6 weeks. At all times there was a decrease in the normal ovulatory response, as evidenced by a reduction in the number of corpora lutea when compared with controls. Additionally, the exposure of galactose-treated mice to a superovulatory regimen of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) failed to induce an increased ovulatory response. Morphologic alterations, such as the increase in interstitial tissue and the appearance of lipofuscin, coupled with the failure to respond to exogenous gonadotropins, suggest that the reduced ovulatory response may be occurring at the level of the ovary. This effect, however, is reversible with cessation of galactose treatment.

  3. Effects of chronic centrifugation on mice

    NASA Technical Reports Server (NTRS)

    Janer, L.; Duke, J.

    1984-01-01

    Previous studies have shown that exposure to excess gravity in vitro alters the developmental sequence in embryonic mouse limbs and palates (Duke, Janer and Campbell, 1984; Duke, 1983). The effects of excess gravity on in vivo mammalian development was investigated using a small animal centrifuge. Four-week old female mice exposed to excess gravities of 1.8-3.5 G for eight weeks weighed significantly less than controls. Mice were mated after five weeks of adaptation to excess G, and sacrificed either at gestational day 12 or 18. There were fewer pregnancies in the centrifuged group (4/36) than in controls (9/31), and crown rump lengths (CRL) of embryos developing in the centrifuge were less than CRLs of 1-G embryos. These results show that although immersed in amniotic fluid, embryos are responsive to Delta-G.

  4. Hyperoxia Inhibits T Cell Activation in Mice

    NASA Astrophysics Data System (ADS)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    Background: The immune response is blunted in mice and humans in spaceflight. The effects of hyperoxia in mice alter expression of some of the same immune response genes. If these two conditions are additive, there could be an increased risk of infection in long duration missions. Immunosuppression is seen in healthy astronauts who have flown in space; however little is known about the mechanisms that cause the reduced immunity in spaceflight. Here we examine the role of oxidative stress on mice exposed to periods of high O2 levels mimicking pre-breathing protocols and extravehicular activity (EVA). To prevent decompression sickness, astronauts are exposed to elevated oxygen (hyperoxia) before and during EVA activities. Spaceflight missions may entail up to 24 hours of EVA per crewmember per week to perform construction and maintenance tasks. The effectiveness and success of these missions depends on designing EVA systems and protocols that maximize human performance and efficiency while minimizing health and safety risks for crewmembers. To our knowledge, no studies have been conducted on the immune system under 100% oxygen exposures to determine the potential for immune compromise due to prolonged and repeated EVAs. Methods: Animals were exposed to hyperoxic or control conditions for 8 hours per day over a period of 3 days, initiated 4 hours into the dark cycle (12h dark/12h light), using animal environmental control cabinets and oxygen controller (Biospherix, Lacona, NY). Experimental mice were exposed to 98-100% oxygen as a model for pre-breathing and EVA conditions, while control mice were maintained in chambers supplied with compressed air. These are ground control studies where we use real-time RTPCR (qRTPCR) to measure gene expression of the early immune gene expression during bead activation of splenocytes of normoxic and hyperoxic mice. All procedures were reviewed and approved by the IACUC at Ames Research Center. After the last 8h of hyperoxic exposure

  5. Guidelines for measuring cardiac physiology in mice

    PubMed Central

    Kassiri, Zamaneh; Virag, Jitka A. I.; de Castro Brás, Lisandra E.; Scherrer-Crosbie, Marielle

    2018-01-01

    Cardiovascular disease is a leading cause of death, and translational research is needed to understand better mechanisms whereby the left ventricle responds to injury. Mouse models of heart disease have provided valuable insights into mechanisms that occur during cardiac aging and in response to a variety of pathologies. The assessment of cardiovascular physiological responses to injury or insult is an important and necessary component of this research. With increasing consideration for rigor and reproducibility, the goal of this guidelines review is to provide best-practice information regarding how to measure accurately cardiac physiology in animal models. In this article, we define guidelines for the measurement of cardiac physiology in mice, as the most commonly used animal model in cardiovascular research. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/guidelines-for-measuring-cardiac-physiology-in-mice/. PMID:29351456

  6. Antidepressant Activity of Brahmi in Albino Mice

    PubMed Central

    Kadali, SLDV Ramana Murty; M.C., Das; Rao A.S.R., Srinivasa; Sri G, Karuna

    2014-01-01

    Context: In traditional system of medicine brahmi has been used to enhance memory. Recently it has been reported to have action in psychiatric disorders. With these backgrounds the work has been undertaken to study antidepressant activity of brahmi in albino mice. Aim: To evaluate antidepressant activity of brahmi in experimental models. Materials and Methods: The antidepressant activity was studied in albino mice using forced swimming test (FST), tail suspension test (TST) and shock induced depression (SID). Imipramine (10mg/kg), fluoxetine (30mg/kg) were used as standard drugs and brahmi (10, 20, 30mg/kg) was used as test drug. Results: Brahmi exhibited significant decrease in duration of immobility in FST and reduced the shock induced decrease in activity in SID models. It didn’t show any activity in the TST model. Conclusion: Brahmi has shown antidepressant activity in FST and SID. PMID:24783074

  7. The metabolic footprint of aging in mice.

    PubMed

    Houtkooper, Riekelt H; Argmann, Carmen; Houten, Sander M; Cantó, Carles; Jeninga, Ellen H; Andreux, Pénélope A; Thomas, Charles; Doenlen, Raphaël; Schoonjans, Kristina; Auwerx, Johan

    2011-01-01

    Aging is characterized by a general decline in cellular function, which ultimately will affect whole body homeostasis. Although DNA damage and oxidative stress all contribute to aging, metabolic dysfunction is a common hallmark of aging at least in invertebrates. Since a comprehensive overview of metabolic changes in otherwise healthy aging mammals is lacking, we here compared metabolic parameters of young and 2 year old mice. We systemically integrated in vivo phenotyping with gene expression, biochemical analysis, and metabolomics, thereby identifying a distinguishing metabolic footprint of aging. Among the affected pathways in both liver and muscle we found glucose and fatty acid metabolism, and redox homeostasis. These alterations translated in decreased long chain acylcarnitines and increased free fatty acid levels and a marked reduction in various amino acids in the plasma of aged mice. As such, these metabolites serve as biomarkers for aging and healthspan.

  8. The metabolic footprint of aging in mice

    PubMed Central

    Houtkooper, Riekelt H.; Argmann, Carmen; Houten, Sander M.; Cantó, Carles; Jeninga, Ellen H.; Andreux, Pénélope A.; Thomas, Charles; Doenlen, Raphaël; Schoonjans, Kristina; Auwerx, Johan

    2011-01-01

    Aging is characterized by a general decline in cellular function, which ultimately will affect whole body homeostasis. Although DNA damage and oxidative stress all contribute to aging, metabolic dysfunction is a common hallmark of aging at least in invertebrates. Since a comprehensive overview of metabolic changes in otherwise healthy aging mammals is lacking, we here compared metabolic parameters of young and 2 year old mice. We systemically integrated in vivo phenotyping with gene expression, biochemical analysis, and metabolomics, thereby identifying a distinguishing metabolic footprint of aging. Among the affected pathways in both liver and muscle we found glucose and fatty acid metabolism, and redox homeostasis. These alterations translated in decreased long chain acylcarnitines and increased free fatty acid levels and a marked reduction in various amino acids in the plasma of aged mice. As such, these metabolites serve as biomarkers for aging and healthspan. PMID:22355651

  9. STUDIES ON TRANSMISSIBLE LYMPHOID LEUCEMIA OF MICE.

    PubMed

    Furth, J; Strumia, M

    1931-04-30

    Lymphoid leucemia of the mouse is readily transmitted by intravenous inoculations. The majority of the mice inoculated successfully develop leucemic, a smaller number of them, aleucemic lymphadenosis. The data presented favor the view that leucemic and aleucemic lymphadenosis are essentially the same condition. Leucemia produced by transmission is preceded by an aleucemic stage, in which the lymph nodes and the spleen are uniformly enlarged, and the white blood count and the percentage of lymphocytes are within the normal range but immature lymphocytes are numerous in the circulating blood. Young as well as old mice may develop leucemia if leucotic material enters their circulation. Studies of transmissible leucemia favor the view that leucemia of mammals is a neoplastic disease. The basic problem of leucemia would seem to be determination of the factors that bring about a malignant transformation of lymphoid cells.

  10. STUDIES ON TRANSMISSIBLE LYMPHOID LEUCEMIA OF MICE

    PubMed Central

    Furth, J.; Strumia, M.

    1931-01-01

    Lymphoid leucemia of the mouse is readily transmitted by intravenous inoculations. The majority of the mice inoculated successfully develop leucemic, a smaller number of them, aleucemic lymphadenosis. The data presented favor the view that leucemic and aleucemic lymphadenosis are essentially the same condition. Leucemia produced by transmission is preceded by an aleucemic stage, in which the lymph nodes and the spleen are uniformly enlarged, and the white blood count and the percentage of lymphocytes are within the normal range but immature lymphocytes are numerous in the circulating blood. Young as well as old mice may develop leucemia if leucotic material enters their circulation. Studies of transmissible leucemia favor the view that leucemia of mammals is a neoplastic disease. The basic problem of leucemia would seem to be determination of the factors that bring about a malignant transformation of lymphoid cells. PMID:19869876

  11. Use of Wedge Absorbers in MICE

    SciTech Connect

    Neuffer, D.; Summers, D.; Mohayai, T.

    2017-03-01

    Wedge absorbers are needed to obtain longitudinal cooling in ionization cooling. They also can be used to obtain emittance exchanges between longitudinal and transverse phase space. There can be large exchanges in emittance, even with single wedges. In the present note we explore the use of wedge absorbers in the MICE experiment to obtain transverse–longitudinal emittance exchanges within present and future operational conditions. The same wedge can be used to explore “direct” and “reverse” emittance exchange dynamics, where direct indicates a configuration that reduces momentum spread and reverse is a configuration that increases momentum spread. Analytical estimated and ICOOL andmore » G4BeamLine simulations of the exchanges at MICE parameters are presented. Large exchanges can be obtained in both reverse and direct configurations.« less

  12. MICE data handling on the Grid

    NASA Astrophysics Data System (ADS)

    Martyniak, J.; Mice Collaboration

    2014-06-01

    The international Muon Ionisation Cooling Experiment (MICE) is designed to demonstrate the principle of muon ionisation cooling for the first time, for application to a future Neutrino factory or Muon Collider. The experiment is currently under construction at the ISIS synchrotron at the Rutherford Appleton Laboratory (RAL), UK. In this paper we present a system - the Raw Data Mover, which allows us to store and distribute MICE raw data - and a framework for offline reconstruction and data management. The aim of the Raw Data Mover is to upload raw data files onto a safe tape storage as soon as the data have been written out by the DAQ system and marked as ready to be uploaded. Internal integrity of the files is verified and they are uploaded to the RAL Tier-1 Castor Storage Element (SE) and placed on two tapes for redundancy. We also make another copy at a separate disk-based SE at this stage to make it easier for users to access data quickly. Both copies are check-summed and the replicas are registered with an instance of the LCG File Catalog (LFC). On success a record with basic file properties is added to the MICE Metadata DB. The reconstruction process is triggered by new raw data records filled in by the mover system described above. Off-line reconstruction jobs for new raw files are submitted to RAL Tier-1 and the output is stored on tape. Batch reprocessing is done at multiple MICE enabled Grid sites and output files are shipped to central tape or disk storage at RAL using a custom File Transfer Controller.

  13. Diabetes Associated Metabolomic Perturbations in NOD Mice

    PubMed Central

    Hwang, Jessica; Poudel, Ananta; Jo, Junghyo; Periwal, Vipul; Fiehn, Oliver; Hara, Manami

    2014-01-01

    Non-obese diabetic (NOD) mice are a widely-used model oftype1 diabetes (T1D). However, not all animals develop overt diabetes. This study examined the circulating metabolomic profiles of NOD mice progressing or not progressing to T1D. Total beta-cell mass was quantified in the intact pancreas using transgenic NOD mice expressinggreen fluorescent protein under the control of mouse insulin I promoter.While both progressor and non-progressor animals displayed lymphocyte infiltration and endoplasmic reticulum stress in the pancreas tissue;overt T1D did not develop until animals lost ~70% of the total beta-cell mass.Gas chromatography time of flight mass spectrometry (GC-TOF) was used to measure >470 circulating metabolites in male and female progressor and non-progressor animals (n=76) across a wide range of ages (neonates to >40-wk).Statistical and multivariate analyses were used to identify age and sex independent metabolic markers which best differentiated progressor and non-progressor animals’ metabolic profiles. Key T1D-associated perturbations were related with: (1) increased plasma glucose and reduced 1,5-anhydroglucitol markers of glycemic control; (2) increased allantoin, gluconic acid and nitric oxide-derived saccharic acid markers of oxidative stress; (3) reduced lysine, an insulin secretagogue; (4) increased branched-chain amino acids, isoleucine and valine; (5) reduced unsaturated fatty acids including arachidonic acid; and (6)perturbations in urea cycle intermediates suggesting increased arginine-dependent NO synthesis. Together these findings highlight the strength of the unique approach of comparing progressor and non-progressor NOD mice to identify metabolic perturbations involved in T1D progression. PMID:25755629

  14. A prototype molecular interactive collaborative environment (MICE).

    PubMed

    Bourne, P; Gribskov, M; Johnson, G; Moreland, J; Wavra, S; Weissig, H

    1998-01-01

    Illustrations of macromolecular structure in the scientific literature contain a high level of semantic content through which the authors convey, among other features, the biological function of that macromolecule. We refer to these illustrations as molecular scenes. Such scenes, if available electronically, are not readily accessible for further interactive interrogation. The basic PDB format does not retain features of the scene; formats like PostScript retain the scene but are not interactive; and the many formats used by individual graphics programs, while capable of reproducing the scene, are neither interchangeable nor can they be stored in a database and queried for features of the scene. MICE defines a Molecular Scene Description Language (MSDL) which allows scenes to be stored in a relational database (a molecular scene gallery) and queried. Scenes retrieved from the gallery are rendered in Virtual Reality Modeling Language (VRML) and currently displayed in WebView, a VRML browser modified to support the Virtual Reality Behavior System (VRBS) protocol. VRBS provides communication between multiple client browsers, each capable of manipulating the scene. This level of collaboration works well over standard Internet connections and holds promise for collaborative research at a distance and distance learning. Further, via VRBS, the VRML world can be used as a visual cue to trigger an application such as a remote MEME search. MICE is very much work in progress. Current work seeks to replace WebView with Netscape, Cosmoplayer, a standard VRML plug-in, and a Java-based console. The console consists of a generic kernel suitable for multiple collaborative applications and additional application-specific controls. Further details of the MICE project are available at http:/(/)mice.sdsc.edu.

  15. Nickel sensitisation in mice: a critical appraisal.

    PubMed

    Johansen, Pål; Wäckerle-Men, Ying; Senti, Gabriela; Kündig, Thomas M

    2010-06-01

    The market release of new domestic and industrial chemical and metal products requires certain safety certification, including testing for skin sensitisation. Although various official guidelines have described how such testing is to be done, the validity of the available test models are in part dubious, for which reason regulatory agencies and research aim to further improve and generalise the models for testing of skin sensitisation. We applied a recently published murine model of nickel allergy as to test its applicability in a regulatory setting and to study and better understand the events leading to type-IV hypersensitivity. Nickel was chosen as model hapten since it induces allergic contact dermatitis with high incidence in the general population. Typically, C57BL/6 mice were sensitised and challenged by intradermal applications of nickel, and cutaneous inflammation was analysed by the mouse ear-swelling test, by histology, and by lymphocyte reactivity in vitro. Surprisingly, the study suggested that the skin reactions observed were results of irritant reactions rather than of adaptive immune responses. Non-sensitised mice responded with cutaneous inflammation and in vitro lymphocyte reactivity which were comparable with nickel-sensitised mice. Furthermore, histological examinations as well as experiments in T-cell deficient mice demonstrated that lymphocytes were not involved and that nickel caused an irritant contact dermatitis rather a true allergic type-IV contact dermatitis. The authors question the validity of the described murine model of nickel allergy. Copyright 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  16. Health Evaluation of Experimental Laboratory Mice.

    PubMed

    Burkholder, Tanya; Foltz, Charmaine; Karlsson, Eleanor; Linton, C Garry; Smith, Joanne M

    2012-06-01

    Good science and good animal care go hand in hand. A sick or distressed animal does not produce the reliable results that a healthy and unstressed animal produces. This unit describes the essentials of assessing mouse health, colony health surveillance, common conditions, and determination of appropriate endpoints. Understanding the health and well-being of the mice used in research enables the investigator to optimize research results and animal care.

  17. Wound Healing in Mac-1 Deficient Mice

    DTIC Science & Technology

    2017-05-01

    36. Rosenkranz AR, Coxon A, Maurer M, Gurish MF, Austen KF, Friend DS, Galli SJ, Mayadas TN. Impaired mast cell development and innate immunity in Mac...genetically deficient mice. 3 INTRODUCTION Wound healing is a complex yet well-regulated process in which multiple resident cells ...recruited inflammatory cells , and stem cells interact to create an environment that supports the healing process. An optimal inflammatory response is a

  18. Mequindox Induced Genotoxicity and Carcinogenicity in Mice

    PubMed Central

    Liu, Qianying; Lei, Zhixin; Wu, Qin; Huang, Deyu; Xie, Shuyu; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

    2018-01-01

    Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice. PMID:29692735

  19. Mequindox Induced Genotoxicity and Carcinogenicity in Mice.

    PubMed

    Liu, Qianying; Lei, Zhixin; Wu, Qin; Huang, Deyu; Xie, Shuyu; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

    2018-01-01

    Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N -oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo , and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.

  20. A Wedge Absorber Experiment at MICE

    SciTech Connect

    Neuffer, David; Mohayai, Tanaz; Rogers, Chris

    2017-05-01

    Emittance exchange mediated by wedge absorbers is required for longitudinal ionization cooling and for final transverse emittance minimization for a muon collider. A wedge absorber within the MICE beam line could serve as a demonstration of the type of emittance exchange needed for 6-D cooling, including the configurations needed for muon colliders, as well as configurations for low-energy muon sources. Parameters for this test are explored in simulation and possible experimental configurations with simulated results are presented.

  1. Vestibular Evoked Myogenic Potentials in Normal Mice and Phex Mice With Spontaneous Endolymphatic Hydrops

    PubMed Central

    Sheykholeslami, Kianoush; Megerian, Cliff A.; Zheng, Qing Y.

    2010-01-01

    Objective and Background Vestibular evoked myogenic potentials (VEMPs) have been recorded from the neck musculature and the cervical spinal cord in humans and a limited number of laboratory animals in response to loud sound. However, the mouse VEMP has yet to be described. Evaluation of the sacculocollic pathway via VEMPs in mice can set the stage for future evaluations of mutant mice that now play an important role in research regarding human auditory and vestibular dysfunction. Materials and Methods Sound-evoked potentials were recorded from the neck extensor muscles and the cervical spinal cord in normal adult mice and in circling PhexHyp-Duk/y mice with known vestibular abnormalities, including endolymphatic hydrops (ELH). Results Biphasic potentials were recorded from all normal animals. The mean threshold of the VEMP response in normal adult mice was 60 dB normal hearing level with a mean peak latency of 6.25 ± 0.46 and 7.95 ± 0.42 milliseconds for p1 and n1 peaks, respectively. At the maximum sound intensity used (100 dB normal hearing level), 4 of 5 Phex mice did not exhibit VEMP responses, and 1 showed an elevated threshold, but normal response, with regard to peak latency and amplitude. The histologic findings in all of these Phex mice were consistent with distended membranous labyrinth, displaced Reissner membrane, ganglion cell loss, and ELH. Conclusion This is the first report of VEMP recordings in mice and the first report of abnormal VEMPs in a mouse model with ELH. The characteristics of these potentials such as higher response threshold in comparison to auditory brainstem response, myogenic nature of the response, and latency correlation with the cervical recording (accessory nerve nucleus) were similar to those of VEMPs in humans, guinea pigs, cats, and rats, suggesting that the mouse may be used as an animal model in the study of VEMPs. The simplicity and reliability of these recordings make the VEMP a uniquely informative test for assessing

  2. Critical period for acoustic preference in mice

    PubMed Central

    Yang, Eun-Jin; Lin, Eric W.; Hensch, Takao K.

    2012-01-01

    Preference behaviors are often established during early life, but the underlying neural circuit mechanisms remain unknown. Adapting a unique nesting behavior assay, we confirmed a “critical period” for developing music preference in C57BL/6 mice. Early music exposure between postnatal days 15 and 24 reversed their innate bias for silent shelter, which typically could not be altered in adulthood. Instead, exposing adult mice treated acutely with valproic acid or carrying a targeted deletion of the Nogo receptor (NgR−/−) unmasked a strong plasticity of preference consistent with a reopening of the critical period as seen in other systems. Imaging of cFos expression revealed a prominent neuronal activation in response to the exposed music in the prelimbic and infralimbic medial prefrontal cortex only under conditions of open plasticity. Neither behavioral changes nor selective medial prefrontal cortex activation was observed in response to pure tone exposure, indicating a music-specific effect. Open-field center crossings were increased concomitant with shifts in music preference, suggesting a potential anxiolytic effect. Thus, music may offer both a unique window into the emotional state of mice and a potentially efficient assay for molecular “brakes” on critical period plasticity common to sensory and higher order brain areas. PMID:23045690

  3. Critical period for acoustic preference in mice.

    PubMed

    Yang, Eun-Jin; Lin, Eric W; Hensch, Takao K

    2012-10-16

    Preference behaviors are often established during early life, but the underlying neural circuit mechanisms remain unknown. Adapting a unique nesting behavior assay, we confirmed a "critical period" for developing music preference in C57BL/6 mice. Early music exposure between postnatal days 15 and 24 reversed their innate bias for silent shelter, which typically could not be altered in adulthood. Instead, exposing adult mice treated acutely with valproic acid or carrying a targeted deletion of the Nogo receptor (NgR(-/-)) unmasked a strong plasticity of preference consistent with a reopening of the critical period as seen in other systems. Imaging of cFos expression revealed a prominent neuronal activation in response to the exposed music in the prelimbic and infralimbic medial prefrontal cortex only under conditions of open plasticity. Neither behavioral changes nor selective medial prefrontal cortex activation was observed in response to pure tone exposure, indicating a music-specific effect. Open-field center crossings were increased concomitant with shifts in music preference, suggesting a potential anxiolytic effect. Thus, music may offer both a unique window into the emotional state of mice and a potentially efficient assay for molecular "brakes" on critical period plasticity common to sensory and higher order brain areas.

  4. Acute toxicity of karlotoxins to mice

    PubMed Central

    Place, Allen R.; Munday, R.; Munday, J.S.

    2015-01-01

    Karlotoxins, polyketide derivatives produced by the dinoflagellate Karlodinium veneficum, are associated with fish kills in temperate estuaries world wide. In this study, the acute effects of 3 pure karlotoxin analogs (KmTx 1, KmTx 3 and KmTx 2) have been examined in mice. Transient lethargy and increased respiratory rates were observed soon after dosing with the karlotoxins by intraperitoneal injection, but no deaths were recorded in animals dosed with KmTx 2 at up to 500 μg/kg or with KmTx 1 or KmTx 3 at up to 4000 μg/kg. Animals dosed intraperitoneally with KmTx 1 and KmTx 3 at 4000 μg/kg showed a pronounced decrease in food and water intake, lasting 3–4 days after dosing, accompanied by a significant decrease in body weight. After this time, the lost body weight was regained and the behavior and appearance of the mice remained normal throughout the following 10 day observation period. No effects were seen in mice dosed orally with KmTx 1 or KmTx 3 at a dose of 4000 μg/kg. It is concluded that contamination of seafood if it were to occur with these karlotoxins is unlikely to pose a major risk of acute intoxication in consumers. PMID:25150200

  5. Parturition failure in mice lacking Mamld1

    PubMed Central

    Miyado, Mami; Miyado, Kenji; Katsumi, Momori; Saito, Kazuki; Nakamura, Akihiro; Shihara, Daizou; Ogata, Tsutomu; Fukami, Maki

    2015-01-01

    In mice, the onset of parturition is triggered by a rapid decline in circulating progesterone. Progesterone withdrawal occurs as a result of functional luteolysis, which is characterized by an increase in the enzymatic activity of 20α-hydroxysteroid dehydrogenase (20α-HSD) in the corpus luteum and is mediated by the prostaglandin F2α (PGF2α) signaling. Here, we report that the genetic knockout (KO) of Mamld1, which encodes a putative non-DNA-binding regulator of testicular steroidogenesis, caused defective functional luteolysis and subsequent parturition failure and neonatal deaths. Progesterone receptor inhibition induced the onset of parturition in pregnant KO mice, and MAMLD1 regulated the expression of Akr1c18, the gene encoding 20α-HSD, in cultured cells. Ovaries of KO mice at late gestation were morphologically unremarkable; however, Akr1c18 expression was reduced and expression of its suppressor Stat5b was markedly increased. Several other genes including Prlr, Cyp19a1, Oxtr, and Lgals3 were also dysregulated in the KO ovaries, whereas PGF2α signaling genes remained unaffected. These results highlight the role of MAMLD1 in labour initiation. MAMLD1 likely participates in functional luteolysis by regulating Stat5b and other genes, independent of the PGF2α signaling pathway. PMID:26435405

  6. Olfactory epithelium changes in germfree mice

    PubMed Central

    François, Adrien; Grebert, Denise; Rhimi, Moez; Mariadassou, Mahendra; Naudon, Laurent; Rabot, Sylvie; Meunier, Nicolas

    2016-01-01

    Intestinal epithelium development is dramatically impaired in germfree rodents, but the consequences of the absence of microbiota have been overlooked in other epithelia. In the present study, we present the first description of the bacterial communities associated with the olfactory epithelium and explored differences in olfactory epithelium characteristics between germfree and conventional, specific pathogen-free, mice. While the anatomy of the olfactory epithelium was not significantly different, we observed a thinner olfactory cilia layer along with a decreased cellular turn-over in germfree mice. Using electro-olfactogram, we recorded the responses of olfactory sensitive neuronal populations to various odorant stimulations. We observed a global increase in the amplitude of responses to odorants in germfree mice as well as altered responses kinetics. These changes were associated with a decreased transcription of most olfactory transduction actors and of olfactory xenobiotic metabolising enzymes. Overall, we present here the first evidence that the microbiota modulates the physiology of olfactory epithelium. As olfaction is a major sensory modality for most animal species, the microbiota may have an important impact on animal physiology and behaviour through olfaction alteration. PMID:27089944

  7. High tidal volume ventilation in infant mice.

    PubMed

    Cannizzaro, Vincenzo; Zosky, Graeme R; Hantos, Zoltán; Turner, Debra J; Sly, Peter D

    2008-06-30

    Infant mice were ventilated with either high tidal volume (V(T)) with zero end-expiratory pressure (HVZ), high V(T) with positive end-expiratory pressure (PEEP) (HVP), or low V(T) with PEEP. Thoracic gas volume (TGV) was determined plethysmographically and low-frequency forced oscillations were used to measure the input impedance of the respiratory system. Inflammatory cells, total protein, and cytokines in bronchoalveolar lavage fluid (BALF) and interleukin-6 (IL-6) in serum were measured as markers of pulmonary and systemic inflammatory response, respectively. Coefficients of tissue damping and tissue elastance increased in all ventilated mice, with the largest rise seen in the HVZ group where TGV rapidly decreased. BALF protein levels increased in the HVP group, whereas serum IL-6 rose in the HVZ group. PEEP keeps the lungs open, but provides high volumes to the entire lungs and induces lung injury. Compared to studies in adult and non-neonatal rodents, infant mice demonstrate a different response to similar ventilation strategies underscoring the need for age-specific animal models.

  8. Circadian Behaviour in Neuroglobin Deficient Mice

    PubMed Central

    Hundahl, Christian A.; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night. PMID:22496809

  9. Circadian behaviour in neuroglobin deficient mice.

    PubMed

    Hundahl, Christian A; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night.

  10. Novel transcranial magnetic stimulation coil for mice

    NASA Astrophysics Data System (ADS)

    March, Stephen; Stark, Spencer; Crowther, Lawrence; Hadimani, Ravi; Jiles, David

    2014-03-01

    Transcranial magnetic stimulation (TMS) shows potential for non-invasive treatment of various neurological disorders. Significant work has been performed on the design of coils used for TMS on human subjects but few reports have been made on the design of coils for use on the brains of animals such as mice. This work is needed as TMS studies utilizing mice can allow rapid preclinical development of TMS for human disorders but the coil designs developed for use on humans are inadequate for optimal stimulation of the much smaller mouse brain. A novel TMS coil has been developed with the goal of inducing strong and focused electric fields for the stimulation of small animals such as mice. Calculations of induced electric fields were performed utilizing an MRI derived inhomogeneous model of an adult male mouse. Mechanical and thermal analysis of this new TMS helmet-coil design have also been performed at anticipated TMS operating conditions to ensure mechanical stability of the new coil and establish expected linear attraction and rotational force values. Calculated temperature increases for typical stimulation periods indicate the helmet-coil system is capable of operating within established medical standards. A prototype of the coil has been fabricated and characterization results are presented.

  11. Mice lacking major brain gangliosides develop parkinsonism.

    PubMed

    Wu, Gusheng; Lu, Zi-Hua; Kulkarni, Neil; Amin, Ruchi; Ledeen, Robert W

    2011-09-01

    Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder that affects nearly 1% of the global population aged 65 and older. Whereas palliative treatments are in use, the goal of blocking progression of motor and cognitive disability remains unfulfilled. A better understanding of the basic pathophysiological mechanisms underlying PD would help to advance that goal. The present study provides evidence that brain ganglioside abnormality, in particular GM1, may be involved. This is based on use of the genetically altered mice with disrupted gene Galgt1 for GM2/GD2 synthase which depletes GM2/GD2 and all the gangliotetraose gangliosides that constitute the major molecular species of brain. These knockout mice show overt motor disability on aging and clear indications of motor impairment with appropriate testing at an earlier age. This disability was rectified by L-dopa administration. These mice show other characteristic symptoms of PD, including depletion of striatal dopamine (DA), loss of DA neurons of the substantia nigra pars compacta, and aggregation of alpha synuclein. These manifestations of parkinsonism were largely attenuated by administration of LIGA-20, a membrane permeable analog of GM1 that penetrates the blood brain barrier and enters living neurons. These results suggest that perturbation of intracellular mechanisms mediated by intracellular GM1 may be a contributing factor to PD.

  12. How do mice follow odor trails?

    NASA Astrophysics Data System (ADS)

    Zwicker, David; Trastour, Sophie; Mishra, Shruti; Mathis, Alexander; Murthy, Venkatesh; Brenner, Michael P.

    2015-11-01

    Mice are excellent at following odor trails e.g. to locate food or to find mates. However, it is not yet understood what navigation strategies they use. In principle, they could either evaluate temporal differences between sniffs or they could use concurrent input from the two nostrils. It is unknown to what extend these two strategies contribute to mice's performance. When mice follow trails, odors evaporate from the ground, are transported by flow in the air, and are then inhaled with the two nostrils. In order to differentiate between the two navigation strategies, we determine what information the mouse receives: first, we calculate the airflow by numerically solving the incompressible Navier-Stokes equations. We then determine the spatiotemporal odor concentration from the resulting advection-diffusion equations. Lastly, we determine the odor amount in each nostril by calculating the inhalation volumes using potential flow theory. Taken together, we determine the odor amount in each nostril during each sniff, allowing a detailed study of navigation strategies.

  13. A Chimera Analysis of Prestin Knockout Mice

    PubMed Central

    Cheatham, Mary Ann; Low-Zeddies, Sharon; Naik, Khurram; Edge, Roxanne; Zheng, Jing; Anderson, Charles T.; Dallos, Peter

    2009-01-01

    A chimera is a genetic composite containing a unique mix of cells derived from more than one zygote. This mouse model allows one to learn how cells of contrasting genotype functionally interact in vivo. Here we investigate the effect that different proportions of prestin-containing outer hair cells (OHC) have on cochlear amplification. In order to address this issue, we developed a prestin chimeric mouse in which both ROSA26 wildtype (WT) and prestin knockout (KO) genotypes are present in a single cochlea. The WT ROSA26 mice express a cell marker, allowing one to identify cells originating from the WT genome. Examination of cochlear tissue indicated that prestin chimeric mice demonstrate a mosaic in which mutant and normal OHCs interleave along the cochlear partition, similar to all other chimeric mouse models. The anatomical distribution of prestin-containing OHCs was compared with physiological data including thresholds and tuning curves for the compound action potential (CAP) recorded in anesthetized mice. Analysis of these measures did not reveal mixed phenotypes in which the distribution of prestin-containing OHCs impacted sensitivity and frequency selectivity to different degrees. However, by reducing the number of prestin-containing OHCs, phenotypes intermediate between WT and KO response patterns were obtained. Accordingly, we demonstrate a proportional reduction in sensitivity and in the tip length of CAP tuning curves as the number of OHCs derived from the KO genome increases, i.e., genotype ratio and phenotype are closely related. PMID:19776286

  14. Of mice and (Viking?) men: phylogeography of British and Irish house mice.

    PubMed

    Searle, Jeremy B; Jones, Catherine S; Gündüz, Islam; Scascitelli, Moira; Jones, Eleanor P; Herman, Jeremy S; Rambau, R Victor; Noble, Leslie R; Berry, R J; Giménez, Mabel D; Jóhannesdóttir, Fríoa

    2009-01-22

    The west European subspecies of house mouse (Mus musculus domesticus) has gained much of its current widespread distribution through commensalism with humans. This means that the phylogeography of M. m. domesticus should reflect patterns of human movements. We studied restriction fragment length polymorphism (RFLP) and DNA sequence variations in mouse mitochondrial (mt) DNA throughout the British Isles (328 mice from 105 localities, including previously published data). There is a major mtDNA lineage revealed by both RFLP and sequence analyses, which is restricted to the northern and western peripheries of the British Isles, and also occurs in Norway. This distribution of the 'Orkney' lineage fits well with the sphere of influence of the Norwegian Vikings and was probably generated through inadvertent transport by them. To form viable populations, house mice would have required large human settlements such as the Norwegian Vikings founded. The other parts of the British Isles (essentially most of mainland Britain) are characterized by house mice with different mtDNA sequences, some of which are also found in Germany, and which probably reflect both Iron Age movements of people and mice and earlier development of large human settlements. MtDNA studies on house mice have the potential to reveal novel aspects of human history.

  15. Of mice and (Viking?) men: phylogeography of British and Irish house mice

    PubMed Central

    Searle, Jeremy B.; Jones, Catherine S.; Gündüz, İslam; Scascitelli, Moira; Jones, Eleanor P.; Herman, Jeremy S.; Rambau, R. Victor; Noble, Leslie R.; Berry, R.J.; Giménez, Mabel D.; Jóhannesdóttir, Fríða

    2008-01-01

    The west European subspecies of house mouse (Mus musculus domesticus) has gained much of its current widespread distribution through commensalism with humans. This means that the phylogeography of M. m. domesticus should reflect patterns of human movements. We studied restriction fragment length polymorphism (RFLP) and DNA sequence variations in mouse mitochondrial (mt) DNA throughout the British Isles (328 mice from 105 localities, including previously published data). There is a major mtDNA lineage revealed by both RFLP and sequence analyses, which is restricted to the northern and western peripheries of the British Isles, and also occurs in Norway. This distribution of the ‘Orkney’ lineage fits well with the sphere of influence of the Norwegian Vikings and was probably generated through inadvertent transport by them. To form viable populations, house mice would have required large human settlements such as the Norwegian Vikings founded. The other parts of the British Isles (essentially most of mainland Britain) are characterized by house mice with different mtDNA sequences, some of which are also found in Germany, and which probably reflect both Iron Age movements of people and mice and earlier development of large human settlements. MtDNA studies on house mice have the potential to reveal novel aspects of human history. PMID:18826939

  16. Outbred CD1 mice are as suitable as inbred C57BL/6J mice in performing social tasks.

    PubMed

    Hsieh, Lawrence S; Wen, John H; Miyares, Laura; Lombroso, Paul J; Bordey, Angélique

    2017-01-10

    Inbred mouse strains have been used preferentially for behavioral testing over outbred counterparts, even though outbred mice reflect the genetic diversity in the human population better. Here, we compare the sociability of widely available outbred CD1 mice with the commonly used inbred C57BL/6J (C57) mice in the one-chamber social interaction test and the three-chamber sociability test. In the one-chamber task, intra-strain pairs of juvenile, non-littermate, male CD1 or C57 mice display a series of social and aggressive behaviors. While CD1 and C57 pairs spend equal amount of time socializing, CD1 pairs spend significantly more time engaged in aggressive behaviors than C57 mice. In the three-chamber task, sociability of C57 mice was less dependent on acclimation paradigms than CD1 mice. Following acclimation to all three chambers, both groups of age-matched male mice spent more time in the chamber containing a stranger mouse than in the empty chamber, suggesting that CD1 mice are sociable like C57 mice. However, the observed power suggests that it is easier to achieve statistical significance with C57 than CD1 mice. Because the stranger mouse could be considered as a novel object, we assessed for a novelty effect by adding an object. CD1 mice spend more time in the chamber with a stranger mouse than that a novel object, suggesting that their preference is social in nature. Thus, outbred CD1 mice are as appropriate as inbred C57 mice for studying social behavior using either the single or the three-chamber test using a specific acclimation paradigm. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Estrous Cyclicity of Mice During Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Moyer, Eric; Talyansky, Yuli; Scott, Ryan; Tash, Joseph; Christenson, Lane; Alwood, Joshua; Ronca, April

    2017-01-01

    Hindlimb unloading (HU) is a rodent model system used to simulate weightlessness experienced in space. However, some effects of this approach on rodent physiology are under-studied, specifically the effects on ovarian estrogen production which drives the estrous cycle. To resolve this deficiency, we conducted a ground-based validation study using the HU model, while monitoring estrous cycles in 16-weeks-old female C57BL6 mice. Animals were exposed to HU for 12 days following a 3 day HU cage acclimation period, and estrous cycling was analyzed in HU animals (n22), normally loaded HU Cage Pair-Fed controls (CPF; n22), and Vivarium controls fed ad libitum (VIV; n10). Pair feeding was used to control for potential nutritional deficits on ovarian function. Vaginal cells were sampled daily in all mice via saline lavage. Cells were dried and stained with crystal violet, and the smears evaluated using established vaginal cytology techniques by two individuals blinded to the animal treatment group. Estrous cyclicity was disrupted in nearly all HU and CPF mice, while those maintained in VIV had an average normal cycle length of 4.8 0.5 days, with all stages in the cycle visibly observed. CPF and HU animals arrested in the diestrous phase, which precedes the pre-ovulatory estrogen surge. Additionally, infection-like symptoms characterized by vaginal discharge and swelling arose in several HU animals, which we suspect was due to an inability of these mice to properly groom themselves, andor due to the change in the gravity vector relative to the vaginal opening, which prevented drainage of the lavage solution. Pair-feeding resulted in similar weight gains of HU and CPF (1.5 vs 3.0, respectively). The current results indicate that pair-feeding controlled weight gain and that the HU cage alone influenced estrous cyclicity. Thus, longer acclimation needs to be tested to determine if and when normal estrous cycling resumes in non-loaded mice in HU cages prior to HU testing. Future

  18. Estrous Cyclicity in Mice During Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Moyer, E. L.; Talyansky, Y.; Scott, R. T.; Tash, J. S.; Christenson, L. K.; Alwood, J. S.; Ronca, A. E.

    2017-01-01

    Hindlimb unloading (HU) is a rodent model system used to simulate weightlessness experienced in space. However, some effects of this approach on rodent physiology are under-studied, specifically the effects on ovarian estrogen production which drives the estrous cycle. To resolve this deficiency, we conducted a ground-based validation study using the HU model, while monitoring estrous cycles in 16-weeks-old female C57BL6 mice. Animals were exposed to HU for 12 days following a 3 day HU cage acclimation period, and estrous cycling was analyzed in HU animals (n=22), normally loaded HU Cage Pair-Fed controls (CPF; n=22), and Vivarium controls fed ad libitum (VIV; n=10). Pair feeding was used to control for potential nutritional deficits on ovarian function. Vaginal cells were sampled daily in all mice via saline lavage. Cells were dried and stained with crystal violet, and the smears evaluated using established vaginal cytology techniques by two individuals blinded to the animal treatment group. Estrous cyclicity was disrupted in nearly all HU and CPF mice, while those maintained in VIV had an average normal cycle length of 4.8+/- 0.5 days, with all stages in the cycle visibly observed. CPF and HU animals arrested in the diestrous phase, which precedes the pre-ovulatory estrogen surge. Additionally, infection-like symptoms characterized by vaginal discharge and swelling arose in several HU animals, which we suspect was due to an inability of these mice to properly groom themselves, and/or due to the change in the gravity vector relative to the vaginal opening, which prevented drainage of the lavage solution. Pair-feeding resulted in similar weight gains of HU and CPF (1.5% vs 3.0%, respectively). The current results indicate that pair-feeding controlled weight gain and that the HU cage alone influenced estrous cyclicity. Thus, longer acclimation needs to be tested to determine if and when normal estrous cycling resumes in non-loaded mice in HU cages prior to HU

  19. Antiorthostatic suspension stimulates profiles of macrophage activation in mice

    NASA Technical Reports Server (NTRS)

    Miller, E. S.; Bates, R. A.; Koebel, D. A.; Sonnenfeld, G.

    1999-01-01

    The antiorthostatic suspension model simulates certain physiological effects of spaceflight. We have previously reported BDF1 mice suspended by the tail in the antiorthostatic orientation for 4 days express high levels of resistance to virulent Listeria monocytogenesinfection. In the present study, we examined whether the increased resistance to this organism correlates with profiles of macrophage activation, given the role of the macrophage in killing this pathogen in vivo. We infected BDF1 mice with a lethal dose of virulent L. monocytogenes on day 4 of antiorthostatic suspension and 24 h later constructed profiles of macrophage activation. Viable listeria could not be detected in mice suspended in the antiorthostatic orientation 24 h after infection. Flow cytometric analysis revealed the numbers of granulocytes and mononuclear phagocytes in the spleen of infected mice were not significantly altered as a result of antiorthostatic suspension. Splenocytes from antiorthostatically suspended infected mice produced increased titers of IL-1. Serum levels of neopterin, a nucleotide metabolite secreted by activated macrophages, were enhanced in mice infected during antiorthostatic suspension, but not in antiorthostatically suspended naive mice. Splenic macrophages from mice infected on day 4 of suspension produced enhanced levels of lysozyme. In contrast to the results from antiorthostatically suspended infected mice, macrophages from antiorthostatically suspended uninfected mice did not express enhanced bactericidal activities. The collective results indicate that antiorthostatic suspension can stimulate profiles of macrophage activation which correlate with increased resistance to infection by certain classes of pathogenic bacteria.

  20. Intestinal microbiota modulates gluten-induced immunopathology in humanized mice.

    PubMed

    Galipeau, Heather J; McCarville, Justin L; Huebener, Sina; Litwin, Owen; Meisel, Marlies; Jabri, Bana; Sanz, Yolanda; Murray, Joseph A; Jordana, Manel; Alaedini, Armin; Chirdo, Fernando G; Verdu, Elena F

    2015-11-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility. Germ-free mice, clean specific-pathogen-free (SPF) mice colonized with a microbiota devoid of opportunistic pathogens and Proteobacteria, and conventional SPF mice that harbor a complex microbiota that includes opportunistic pathogens were used. Clean SPF mice had attenuated responses to gluten compared to germ-free and conventional SPF mice. Germ-free mice developed increased intraepithelial lymphocytes, markers of intraepithelial lymphocyte cytotoxicity, gliadin-specific antibodies, and a proinflammatory gliadin-specific T-cell response. Antibiotic treatment, leading to Proteobacteria expansion, further enhanced gluten-induced immunopathology in conventional SPF mice. Protection against gluten-induced immunopathology in clean SPF mice was reversed after supplementation with a member of the Proteobacteria phylum, an enteroadherent Escherichia coli isolated from a CD patient. The intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice. In subjects with moderate genetic susceptibility, intestinal microbiota changes may be a factor that increases CD risk. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  1. Supplementation with macular carotenoids improves visual performance of transgenic mice.

    PubMed

    Li, Binxing; Rognon, Gregory T; Mattinson, Ty; Vachali, Preejith P; Gorusupudi, Aruna; Chang, Fu-Yen; Ranganathan, Arunkumar; Nelson, Kelly; George, Evan W; Frederick, Jeanne M; Bernstein, Paul S

    2018-07-01

    Carotenoid supplementation can improve human visual performance, but there is still no validated rodent model to test their effects on visual function in laboratory animals. We recently showed that mice deficient in β-carotene oxygenase 2 (BCO2) and/or β-carotene oxygenase 1 (BCO1) enzymes can accumulate carotenoids in their retinas, allowing us to investigate the effects of carotenoids on the visual performance of mice. Using OptoMotry, a device to measure visual function in rodents, we examined the effect of zeaxanthin, lutein, and β-carotene on visual performance of various BCO knockout mice. We then transgenically expressed the human zeaxanthin-binding protein GSTP1 (hGSTP1) in the rods of bco2 -/- mice to examine if delivering more zeaxanthin to retina will improve their visual function further. The visual performance of bco2 -/- mice fed with zeaxanthin or lutein was significantly improved relative to control mice fed with placebo beadlets. β-Carotene had no significant effect in bco2 -/- mice but modestly improved cone visual function of bco1 -/- mice. Expression of hGSTP1 in the rods of bco2 -/- mice resulted in a 40% increase of retinal zeaxanthin and further improvement of visual performance. This work demonstrates that these "macular pigment mice" may serve as animal models to study carotenoid function in the retina. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. IL-4 Knock out Mice Display Anxiety-like Behavior

    PubMed Central

    Moon, Morgan L.; Joesting, Jennifer J.; Blevins, Neil A.; Lawson, Marcus A.; Gainey, Stephen J.; Towers, Albert E.; McNeil, Leslie K.; Freund, Gregory G.

    2015-01-01

    Inflammation is a recognized antecedent and coincident factor when examining the biology of anxiety. Little is known, however, about how reductions in endogenous anti-inflammatory mediators impact anxiety. Therefore, mood- cognition- and anxiety-associated/like behaviors were examined in IL-4 knock out (KO) mice and wild-type (WT) mice. In comparison to WT mice, IL-4 KO mice demonstrated decreased burrowing and increased social exploration. No differences were seen in forced swim or saccharine preference testing. IL-4 KO mice had similar performance to WT mice in the Morris water maze and during object location and novel object recognition. In the elevated zero-maze, IL-4 KO mice, in comparison to WT mice, demonstrated anxiety-like behavior. Anxiety-like behavior in IL-4 KO mice was not observed, however, during open-field testing. Taken together, these data indicate that IL-4 KO mice display state, but not trait, anxiety suggesting that reductions in endogenous anti-inflammatory bioactives can engender subtypes of anxiety. PMID:25772794

  3. Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized Mice

    PubMed Central

    Galipeau, Heather J.; McCarville, Justin L.; Huebener, Sina; Litwin, Owen; Meisel, Marlies; Jabri, Bana; Sanz, Yolanda; Murray, Joseph A.; Jordana, Manel; Alaedini, Armin; Chirdo, Fernando G.; Verdu, Elena F.

    2016-01-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility. Germ-free mice, clean specific-pathogen-free (SPF) mice colonized with a microbiota devoid of opportunistic pathogens and Proteobacteria, and conventional SPF mice that harbor a complex microbiota that includes opportunistic pathogens were used. Clean SPF mice had attenuated responses to gluten compared to germ-free and conventional SPF mice. Germ-free mice developed increased intraepithelial lymphocytes, markers of intraepithelial lymphocyte cytotoxicity, gliadin-specific antibodies, and a proinflammatory gliadin-specific T-cell response. Antibiotic treatment, leading to Proteobacteria expansion, further enhanced gluten-induced immunopathology in conventional SPF mice. Protection against gluten-induced immunopathology in clean SPF mice was reversed after supplementation with a member of the Proteobacteria phylum, an enteroadherent Escherichia coli isolated from a CD patient. The intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice. In subjects with moderate genetic susceptibility, intestinal microbiota changes may be a factor that increases CD risk. PMID:26456581

  4. IL-4 Knock Out Mice Display Anxiety-Like Behavior.

    PubMed

    Moon, Morgan L; Joesting, Jennifer J; Blevins, Neil A; Lawson, Marcus A; Gainey, Stephen J; Towers, Albert E; McNeil, Leslie K; Freund, Gregory G

    2015-07-01

    Inflammation is a recognized antecedent and coincident factor when examining the biology of anxiety. Little is known, however, about how reductions in endogenous anti-inflammatory mediators impact anxiety. Therefore, mood- cognition- and anxiety-associated/like behaviors were examined in IL-4 knock out (KO) mice and wild-type (WT) mice. In comparison to WT mice, IL-4 KO mice demonstrated decreased burrowing and increased social exploration. No differences were seen in forced swim or saccharine preference testing. IL-4 KO mice had similar performance to WT mice in the Morris water maze and during object location and novel object recognition. In the elevated zero-maze, IL-4 KO mice, in comparison to WT mice, demonstrated anxiety-like behavior. Anxiety-like behavior in IL-4 KO mice was not observed, however, during open-field testing. Taken together, these data indicate that IL-4 KO mice display state, but not trait, anxiety suggesting that reductions in endogenous anti-inflammatory bioactives can engender subtypes of anxiety.

  5. Adaptation and immunogenicity of Cryptosporidium parvum to immunocompetent mice.

    PubMed

    Matsuo, Tomohide; Tsuge, Yasuko; Umemiya-Shirafuji, Rika; Fujino, Takashi; Matsui, Toshihiro

    2014-03-01

    The adaptation and immunogenisity of Cryptosporidium parvum isolated from Siberian chipmunks (SC1 strain) in immunocompetent (ICR) mice were examined. The oocysts were received to the severe combined immunodeficiency (SCID) mice by repeated passage. The oocysts collected from the 18th SCID mice were inoculated to 5 ICR mice. The mice began to shed oocysts from 6 days after inoculation, the patency was 5 days, and the maximum oocysts per gram of feces (OPG) value was 10(4). The maximum of OPG value was gradually increased by successive passage, and finally that in the 22nd mice reached 10(6) (patency: 11 days). It is considered that these results indicate completion of their adaptation to ICR mice. To examine the immunogenicity of C. parvum to ICR mice, 8 groups of 5 mice each were inoculated with 1.3 × 10(6) oocysts of SC1 strain, which were collected after adaptation to SCID mice. All groups shed oocysts from 6th day, and their patency was from 8 to 12 days. On the 21st day after the primary infection, these mice were challenged with 1.3 × 10(6) oocysts. No oocysts shed from any groups, although 2 control groups shed oocysts from the 6th day, and their OPG values were more than 10(6). These results suggest that this strain has strong immunogenicity against ICR mice. Therefore, the immunological healthy mice were considered a useful experimental model to investigate immunological and drug treatments in the strain of C. parvum.

  6. Lipid metabolism and body composition in Gclm(-/-) mice

    SciTech Connect

    Kendig, Eric L.; Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267; Chen, Ying

    2011-12-15

    In humans and experimental animals, high fat diets (HFD) are associated with risk factors for metabolic diseases, such as excessive weight gain and adiposity, insulin resistance and fatty liver. Mice lacking the glutamate-cysteine ligase modifier subunit gene (Gclm(-/-)) and deficient in glutathione (GSH), are resistant to HFD-mediated weight gain. Herein, we evaluated Gclm-associated regulation of energy metabolism, oxidative stress, and glucose and lipid homeostasis. C57BL/6J Gclm(-/-) mice and littermate wild-type (WT) controls received a normal diet or an HFD for 11 weeks. HFD-fed Gclm(-/-) mice did not display a decreased respiratory quotient, suggesting that they are unable to process lipidmore » for metabolism. Although dietary energy consumption and intestinal lipid absorption were unchanged in Gclm(-/-) mice, feeding these mice an HFD did not produce excess body weight nor fat storage. Gclm(-/-) mice displayed higher basal metabolic rates resulting from higher activities of liver mitochondrial NADH-CoQ oxidoreductase, thus elevating respiration. Although Gclm(-/-) mice exhibited strong systemic and hepatic oxidative stress responses, HFD did not promote glucose intolerance or insulin resistance. Furthermore, HFD-fed Gclm(-/-) mice did not develop fatty liver, likely resulting from very low expression levels of genes encoding lipid metabolizing enzymes. We conclude that Gclm is involved in the regulation of basal metabolic rate and the metabolism of dietary lipid. Although Gclm(-/-) mice display a strong oxidative stress response, they are protected from HFD-induced excessive weight gain and adipose deposition, insulin resistance and steatosis. -- Highlights: Black-Right-Pointing-Pointer A high fat diet does not produce body weight and fat gain in Gclm(-/-) mice. Black-Right-Pointing-Pointer A high fat diet does not induce steatosis or insulin resistance in Gclm(-/-) mice. Black-Right-Pointing-Pointer Gclm(-/-) mice have high basal metabolism and

  7. Neuronal serotonin regulates growth of the intestinal mucosa in mice.

    PubMed

    Gross, Erica R; Gershon, Michael D; Margolis, Kara G; Gertsberg, Zoya V; Li, Zhishan; Cowles, Robert A

    2012-08-01

    The enteric abundance of serotonin (5-HT), its ability to promote proliferation of neural precursors, and reports that 5-HT antagonists affect crypt epithelial proliferation led us to investigate whether 5-HT affects growth and maintenance of the intestinal mucosa in mice. cMice that lack the serotonin re-uptake transporter (SERTKO mice) and wild-type mice were given injections of selective serotonin re-uptake inhibitors (gain-of-function models). We also analyzed mice that lack tryptophan hydroxylase-1 (TPH1KO mice, which lack mucosal but not neuronal 5-HT) and mice deficient in tryptophan hydroxylase-2 (TPH2KO mice, which lack neuronal but not mucosal 5-HT) (loss-of-function models). Wild-type and SERTKO mice were given ketanserin (an antagonist of the 5-HT receptor, 5-HT(2A)) or scopolamine (an antagonist of the muscarinic receptor). 5-HT(2A) receptors and choline acetyltransferase were localized by immunocytochemical analysis. Growth of the mucosa and proliferation of mucosal cells were significantly greater in SERTKO mice and in mice given selective serotonin re-uptake inhibitors than in wild-type mice, but were diminished in TPH2KO (but not in TPH1KO) mice. Ketanserin and scopolamine each prevented the ability of SERT knockout or inhibition to increase mucosal growth and proliferation. Cholinergic submucosal neurons reacted with antibodies against 5-HT(2A). 5-HT promotes growth and turnover of the intestinal mucosal epithelium. Surprisingly, these processes appear to be mediated by neuronal, rather than mucosal, 5-HT. The 5-HT(2A) receptor activates cholinergic neurons, which provide a muscarinic innervation to epithelial effectors. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice.

    PubMed

    Nakamura, Kazufumi; Miura, Daiji; Saito, Yukihiro; Yunoki, Kei; Koyama, Yasushi; Satoh, Minoru; Kondo, Megumi; Osawa, Kazuhiro; Hatipoglu, Omer F; Miyoshi, Toru; Yoshida, Masashi; Morita, Hiroshi; Ito, Hiroshi

    2017-01-01

    The klotho gene was identified as an "aging-suppressor" gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5% EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.

  9. Changes in the pharmacokinetics of digoxin in polyuria in streptozotocin-induced diabetic mice and lithium carbonate-treated mice.

    PubMed

    Ikarashi, Nobutomo; Kagami, Mai; Kobayashi, Yasushi; Ishii, Makoto; Toda, Takahiro; Ochiai, Wataru; Sugiyama, Kiyoshi

    2011-06-01

    In humans, digoxin is mainly eliminated through the kidneys unchanged, and renal clearance represents approximately 70% of the total clearance. In this study, we used the mouse models to examine digoxin pharmacokinetics in polyuria induced by diabetes mellitus and lithium carbonate (Li(2)CO(3)) administration, including mechanistic evaluation of the contribution of glomerular filtration, tubular secretion, and tubular reabsorption. After digoxin administration to streptozotocin (STZ)-induced diabetic mice, digoxin CL/F increased to approximately 2.2 times that in normal mice. After treatment with Li(2)CO(3) (0.2%) for 10 days, the CL/F increased approximately 1.1 times for normal mice and 1.6 times for STZ mice. Creatinine clearance (CLcr) and the renal mRNA expression levels of mdr1a did not differ significantly between the normal, STZ, and Li(2)CO(3)-treated mice. The urine volume of STZ mice was approximately 26 mL/day, 22 times that of normal mice. The urine volume of Li(2)CO(3)-treated mice increased approximately 7.3 times for normal mice and 2.3 times for STZ mice. These results suggest that the therapeutic effect of digoxin may be significantly reduced in the presence of polyuria either induced by diabetes mellitus or manifested as an adverse effect of Li(2)CO(3) in diabetic patients, along with increased urine volume.

  10. Knockout of Foxp2 disrupts vocal development in mice.

    PubMed

    Castellucci, Gregg A; McGinley, Matthew J; McCormick, David A

    2016-03-16

    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.

  11. Effect of Jiangzhi tablet on gastrointestinal propulsive function in mice

    NASA Astrophysics Data System (ADS)

    Wang, Xiangrong; Geng, Xiuli; Zhao, Jingsheng; Fan, Lili; Zhang, Zhengchen

    2018-04-01

    This paper aims to study the effect of lipid-lowering tablets on gastric emptying and small intestinal propulsion in mice. Mice were randomly divided into control group, Digestant Pill group, Jiangzhi tablet group, middle dose and small dose, the mice gastric emptying phenolsulfonphthalein, gastric residual rate of phenol red indicator to evaluate the gastric emptying rate, residual rate of detection in mouse stomach; small intestine propulsion and selection of carbon ink as the experimental index. Effects were observed to promote the function of normal mice gastric emptying and intestine. The gastric emptying and small intestinal motor function of normal mice were all promoted by each administration group, and the effect was most obvious in small dose group. The effect of reducing blood lipid on gastrointestinal motility of mice ware obviously enhanced.

  12. Diet-induced obese mice retain endogenous leptin action.

    PubMed

    Ottaway, Nickki; Mahbod, Parinaz; Rivero, Belen; Norman, Lee Ann; Gertler, Arieh; D'Alessio, David A; Perez-Tilve, Diego

    2015-06-02

    Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Behavioral Characteristics of Ubiquitin-Specific Peptidase 46-Deficient Mice

    PubMed Central

    Imai, Saki; Kano, Makoto; Nonoyama, Keiko; Ebihara, Shizufumi

    2013-01-01

    We have previously identified Usp46, which encodes for ubiquitin-specific peptidase 46, as a quantitative trait gene affecting the immobility time of mice in the tail suspension test (TST) and forced swimming test. The mutation that we identified was a 3-bp deletion coding for lysine (Lys 92), and mice with this mutation (MT mice), as well as Usp46 KO mice exhibited shorter TST immobility times. Behavioral pharmacology suggests that the gamma aminobutyric acid A (GABAA) receptor is involved in regulating TST immobility time. In order to understand how far Usp46 controls behavioral phenotypes, which could be related to mental disorders in humans, we subjected Usp46 MT and KO mice to multiple behavioral tests, including the open field test, ethanol preference test, ethanol-induced loss of righting reflex test, sucrose preference test, novelty-suppressed feeding test, marble burying test, and novel object recognition test. Although behavioral phenotypes of the Usp46 MT and KO mice were not always identical, deficiency of Usp46 significantly affected performance in all these tests. In the open field test, activity levels were lower in Usp46 KO mice than wild type (WT) or MT mice. Both MT and KO mice showed lower ethanol preference and shorter recovery times after ethanol administration. Compared to WT mice, Usp46 MT and KO mice exhibited decreased sucrose preference, took longer latency periods to bite pellets, and buried more marbles in the sucrose preference test, novelty-suppressed feeding test, and marble burying test, respectively. In the novel object recognition test, neither MT nor KO mice showed an increase in exploration of a new object 24 hours after training. These findings indicate that Usp46 regulates a wide range of behavioral phenotypes that might be related to human mental disorders and provides insight into the function of USP46 deubiquitinating enzyme in the neural system. PMID:23472206

  14. Zinc metabolism in genetically obese (ob/ob) mice

    SciTech Connect

    Kennedy, M.L.; Failla, M.L.

    1987-05-01

    Recent reports indicate that the concentrations and total amounts of several essential trace metals in various tissues of genetically obese rodents differ markedly from those in lean controls. In the present studies the absorption, retention and tissue distribution of zinc and constitutive levels of zinc-metallothionein (Zn-MT) in selected tissues were compared in obese (ob/ob) and lean (+/.) C57BL/6J mice. When 5-, 10- and 22-wk-old mice were administered 1.2 mumol /sup 65/Zn by stomach tube the apparent absorption of /sup 65/Zn by obese mice was 1.5, 2.2 and 3.9 times higher, respectively, than that in age-matched lean mice. Retention of orallymore » administered /sup 65/Zn after 96 h was also substantially higher in obese mice than in lean mice. To assess the possible influences of hyperphagia and intestinal hypertrophy on the enhanced apparent absorption of /sup 65/Zn by obese mice food intake by an additional group of obese mice was restricted to that of age-matched lean controls. When actual absorption of zinc was determined according to the method of Heth and Hoekstra, groups of ad libitum--fed obese, pair-fed obese and lean mice absorbed 38, 32 and 18% of administered /sup 65/Zn, respectively. In contrast, the rate of /sup 65/Zn excretion 2-6 d after oral or subcutaneous administration of the metal was similar for obese and lean mice. Unrestricted and pair-fed obese mice had significantly lower percentages of carcass /sup 65/Zn present in skin, muscle plus bone, spleen and testes and higher percentages present in liver, small intestine and adipose tissue than lean mice.« less

  15. Behavioral Characterization of the Hyperphagia Synphilin-1 Overexpressing Mice

    PubMed Central

    Moghadam, Alexander; Smith, Megan; Ofeldt, Erica; Yang, Dejun; Li, Tianxia; Tamashiro, Kellie; Choi, Pique; Moran, Timothy H.; Smith, Wanli W.

    2014-01-01

    Synphilin-1 is a cytoplasmic protein that has been shown to be involved in the control of energy balance. Previously, we reported on the generation of a human synphilin-1 transgenic mouse model (SP1), in which overexpression of human synphilin-1 resulted in hyperphagia and obesity. Here, behavioral measures in SP1 mice were compared with those of their age-matched controls (NTg) at two time points: when there was not yet a group body weight difference (“pre-obese”) and when SP1 mice were heavier (“obese”). At both time points, meal pattern analyses revealed that SP1 mice displayed higher daily chow intake than non-transgenic control mice. Furthermore, there was an increase in meal size in SP1 mice compared with NTg control mice at the obese stage. In contrast, there was no meal number change between SP1 and NTg control mice. In a brief-access taste procedure, both “pre-obese” and “obese“ SP1 mice displayed concentration-dependent licking across a sucrose concentration range similar to their NTg controls. However, at the pre-obese stage, SP1 mice initiated significantly more trials to sucrose across the testing sessions and licked more vigorously at the highest concentration presented, than the NTg counterparts. These group differences in responsiveness to sucrose were no longer apparent in obese SP1 mice. These results suggest that at the pre-obese stage, the increased trials to sucrose in the SP1 mice reflects increased appetitive behavior to sucrose that may be indicative of the behavioral changes that may contribute to hyperphagia and development of obesity in SP1 mice. These studies provide new insight into synphilin-1 contributions to energy homeostasis. PMID:24829096

  16. Behavioral characterization of the hyperphagia synphilin-1 overexpressing mice.

    PubMed

    Li, Xueping; Treesukosol, Yada; Moghadam, Alexander; Smith, Megan; Ofeldt, Erica; Yang, Dejun; Li, Tianxia; Tamashiro, Kellie; Choi, Pique; Moran, Timothy H; Smith, Wanli W

    2014-01-01

    Synphilin-1 is a cytoplasmic protein that has been shown to be involved in the control of energy balance. Previously, we reported on the generation of a human synphilin-1 transgenic mouse model (SP1), in which overexpression of human synphilin-1 resulted in hyperphagia and obesity. Here, behavioral measures in SP1 mice were compared with those of their age-matched controls (NTg) at two time points: when there was not yet a group body weight difference ("pre-obese") and when SP1 mice were heavier ("obese"). At both time points, meal pattern analyses revealed that SP1 mice displayed higher daily chow intake than non-transgenic control mice. Furthermore, there was an increase in meal size in SP1 mice compared with NTg control mice at the obese stage. In contrast, there was no meal number change between SP1 and NTg control mice. In a brief-access taste procedure, both "pre-obese" and "obese" SP1 mice displayed concentration-dependent licking across a sucrose concentration range similar to their NTg controls. However, at the pre-obese stage, SP1 mice initiated significantly more trials to sucrose across the testing sessions and licked more vigorously at the highest concentration presented, than the NTg counterparts. These group differences in responsiveness to sucrose were no longer apparent in obese SP1 mice. These results suggest that at the pre-obese stage, the increased trials to sucrose in the SP1 mice reflects increased appetitive behavior to sucrose that may be indicative of the behavioral changes that may contribute to hyperphagia and development of obesity in SP1 mice. These studies provide new insight into synphilin-1 contributions to energy homeostasis.

  17. Diacylglycerol Lipase α Knockout Mice Demonstrate Metabolic and Behavioral Phenotypes Similar to Those of Cannabinoid Receptor 1 Knockout Mice

    PubMed Central

    Powell, David R.; Gay, Jason P.; Wilganowski, Nathaniel; Doree, Deon; Savelieva, Katerina V.; Lanthorn, Thomas H.; Read, Robert; Vogel, Peter; Hansen, Gwenn M.; Brommage, Robert; Ding, Zhi-Ming; Desai, Urvi; Zambrowicz, Brian

    2015-01-01

    After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) similar to pair-fed WT mice, and adult Dagla KO mice had normal activity and VO2 levels, similar to Cnr1 KO mice. Our Dagla and Cnr1 KO mice also had low fasting insulin, triglyceride, and total cholesterol levels, and after glucose challenge had normal glucose but very low insulin levels. Dagla and Cnr1 KO mice also showed similar responses to a battery of behavioral tests. These data suggest: (1) the lean phenotype of young Dagla and Cnr1 KO mice is mainly due to hypophagia; (2) in pathways where ECs signal through Cnr1 to regulate food intake and other metabolic and behavioral phenotypes observed in Cnr1 KO mice, Dagla alone provides the 2-AG that serves as the EC signal; and (3) small molecule Dagla inhibitors with a pharmacokinetic profile similar to that of Cnr1 inverse agonists are likely to mirror the ability of these Cnr1 inverse agonists to lower BW and improve glycemic control in obese patients with type 2 diabetes, but may also induce undesirable neuropsychiatric side

  18. THC Prevents MDMA Neurotoxicity in Mice.

    PubMed

    Touriño, Clara; Zimmer, Andreas; Valverde, Olga

    2010-02-10

    The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4) were pretreated with THC (3 mg/kg x 4) at room (21 degrees C) and at warm (26 degrees C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1) receptor antagonist AM251 and the CB(2) receptor antagonist AM630, as well as in CB(1), CB(2) and CB(1)/CB(2) deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1) receptor antagonist AM251, neither in CB(1) and CB(1)/CB(2) knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2) cannabinoid antagonist and in CB(2) knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1) receptor, although CB(2) receptors may also contribute to

  19. SUPPRESSION OF IMMUNOGLOBULIN CLASS SYNTHESIS IN MICE

    PubMed Central

    Lawton, Alexander R.; Asofsky, Richard; Hylton, Martha B.; Cooper, Max D.

    1972-01-01

    Germfree BALB/c mice have been treated from birth with intraperitoneal injections of purified goat antibodies to mouse IgM. The treated mice, and controls which had received an equivalent amount of goat γ-globulin, were sacrificed at 8 or 13 wk of age. Compared to controls, mice given anti-µ (a) had very few germinal centers in spleen and lymph node, (b) had decreased numbers of mature plasma cells synthesizing IgM and IgG1 in spleen, and virtual absence of IgA-synthesizing plasma cells in the gut, (c) had greatly diminished numbers of B lymphocytes bearing membrane-bound immunoglobulins of the IgM, IgG1, IgG2, and IgA classes in spleen, (d) had reduced synthesis of IgM, IgG2, and IgA by in vitro spleen cultures, and (e) had significant decreases in serum levels of IgM, IgG1, IgG2, and IgA. The treated animals failed to make antibodies to ferritin after hyperimmunization, and lacked natural antibodies to sheep erythrocytes. These results indicate that cells ultimately committed to synthesis of IgG1, IgG2, and IgA immunoglobulins are derived from cells which have expressed IgM determinants at an earlier stage of differentiation. They are consistent with a proposed two-stage model for plasma cell differentiation. The first stage is antigen independent, involves sequential activation of Cµ, Cγ, and Cα genes by progeny of a single stem cell, and results in the formation of B lymphocytes bearing membrane-bound recognition antibodies of each class. The second, antigen-dependent, stage results in formation of mature plasmacytes and memory cells. PMID:4551216

  20. THC Prevents MDMA Neurotoxicity in Mice

    PubMed Central

    Touriño, Clara; Zimmer, Andreas; Valverde, Olga

    2010-01-01

    The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630, as well as in CB1, CB2 and CB1/CB2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB1 receptor antagonist AM251, neither in CB1 and CB1/CB2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB2 cannabinoid antagonist and in CB2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB1 receptor, although CB2 receptors may also contribute to attenuate neuroinflammation in this

  1. Social stress shortens lifespan in mice.

    PubMed

    Razzoli, Maria; Nyuyki-Dufe, Kewir; Gurney, Allison; Erickson, Connor; McCallum, Jacob; Spielman, Nicholas; Marzullo, Marta; Patricelli, Jessica; Kurata, Morito; Pope, Emily A; Touma, Chadi; Palme, Rupert; Largaespada, David A; Allison, David B; Bartolomucci, Alessandro

    2018-05-28

    Stress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age-related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early-stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  2. Partial Return Yoke for MICE Step IV and Final Step

    SciTech Connect

    Witte, Holger; Plate, Stephen; Berg, J.Scott

    2015-06-01

    This paper reports on the progress of the design and construction of a retro-fitted return yoke for the international Muon Ionization Cooling Experiment (MICE). MICE is a proof-of-principle experiment aiming to demonstrate ionization cooling experimentally. In earlier studies we outlined how a partial return yoke can be used to mitigate stray magnetic field in the experimental hall; we report on the progress of the construction of the partial return yoke for MICE Step IV. We also discuss an extension of the Partial Return Yoke for the final step of MICE; we show simulation results of the expected performance.

  3. Partial return yoke for MICE step IV and final step

    SciTech Connect

    Witte, H.; Plate, S.; Berg, J. S.

    2015-05-03

    This paper reports on the progress of the design and construction of a retro-fitted return yoke for the international Muon Ionization Cooling Experiment (MICE). MICE is a proof-of-principle experiment aiming to demonstrate ionization cooling experimentally. In earlier studies we outlined how a partial return yoke can be used to mitigate stray magnetic field in the experimental hall; we report on the progress of the construction of the partial return yoke for MICE Step IV. We also discuss an extension of the Partial Return Yoke for the final step of MICE; we show simulation results of the expected performance.

  4. [Effect of electromagnetic pulse irradiation on mice reproduction].

    PubMed

    Wang, Shui-ming; Wang, De-wen; Peng, Rui-yun; Chen, Hao-yu; Gao, Ya-bing; Cao, Xiao-zhe; Cui, Xue-mei; Zhao, Mei-lan

    2003-10-01

    To evaluate the effect of electromagnetic pulse (EMP) irradiation on mice reproduction. Female/male Kunming mice, 6 - 8 weeks old, prior to mating, or female after pregnancy were treated with whole body irradiation by 6 x 10(4) V/m electromagnetic pulse (EMP) for five times. The pregnant mice were killed on the 18th days, and teratological markers were analysed. EMP irradiation caused no significant changes in most of female organ weight and organ/body weight ratio. But it caused significant shortening in tail length of live foetus in the female mice before conception (prior to mating) or after pregnancy (P < 0.05), and obvious decrease in male offspring ratio (0.85 +/- 0.09 vs 1.09 +/- 0.17, P < 0.05). The male offspring ratio also significantly decreased (0.76 +/- 0.18 vs 1.09 +/- 0.17, P < 0.01) after male mice irradiated by EMP. The tail length of live foetus was shortened and male offspring sex ratio was increased after both male and female mice were irradiated by EMP. EMP irradiation also caused a significantly higher fetal death rate than normal control (P < 0.05). The embryo absorption rate was increased after irradiation except that was decreased in male mice. EMP irradiation has effect on pregnancy and offspring development in both male and female mice before mating and in female mice after pregnancy.

  5. Assessing cervical dislocation as a humane euthanasia method in mice.

    PubMed

    Carbone, Larry; Carbone, Elizabeth T; Yi, Elizabeth M; Bauer, Diana B; Lindstrom, Krista A; Parker, John M; Austin, Jamie A; Seo, Youngho; Gandhi, Anisha D; Wilkerson, James D

    2012-05-01

    Research investigators often choose to euthanize mice by cervical dislocation (CD) when other methods would interfere with the aims of a research project. Others choose CD to assure death in mice treated with injected or inhaled euthanasia agents. CD was first approved for mouse euthanasia in 1972 by the AVMA Panel on Euthanasia, although scientific assessment of its humaneness has been sparse. Here we compared 4 methods of spinal dislocation--3 targeting the cervical area (CD) and one the thoracic region--in regard to time to respiratory arrest in anesthetized mice. Of the 81 mice that underwent CD by 1 of the 3 methods tested, 17 (21%) continued to breathe, and euthanasia was scored as unsuccessful. Postmortem radiography revealed cervical spinal lesions in 5 of the 17 cases of unsuccessful CD euthanasia. In addition, 63 of the 64 successfully euthanized mice had radiographically visible lesions in the high cervical or atlantooccipital region. In addition, 50 of 64 (78%) mice euthanized successfully had radiographically visible thoracic or lumbar lesions or both. Intentionally creating a midthoracic dislocation in anesthetized mice failed to induce respiratory arrest and death in any of the 18 mice subjected to that procedure. We conclude that CD of mice holds the potential for unsuccessful euthanasia, that anesthesia could be valuable for CD skills training and assessment, and that postmortem radiography has minimal promise in quality-control assessments.

  6. Assessing Cervical Dislocation as a Humane Euthanasia Method in Mice

    PubMed Central

    Carbone, Larry; Carbone, Elizabeth T; Yi, Elizabeth M; Bauer, Diana B; Lindstrom, Krista A; Parker, John M; Austin, Jamie A; Seo, Youngho; Gandhi, Anisha D; Wilkerson, James D

    2012-01-01

    Research investigators often choose to euthanize mice by cervical dislocation (CD) when other methods would interfere with the aims of a research project. Others choose CD to assure death in mice treated with injected or inhaled euthanasia agents. CD was first approved for mouse euthanasia in 1972 by the AVMA Panel on Euthanasia, although scientific assessment of its humaneness has been sparse. Here we compared 4 methods of spinal dislocation–3 targeting the cervical area (CD) and one the thoracic region–in regard to time to respiratory arrest in anesthetized mice. Of the 81 mice that underwent CD by 1 of the 3 methods tested, 17 (21%) continued to breathe, and euthanasia was scored as unsuccessful. Postmortem radiography revealed cervical spinal lesions in 5 of the 17 cases of unsuccessful CD euthanasia. In addition, 63 of the 64 successfully euthanized mice had radiographically visible lesions in the high cervical or atlantooccipital region. In addition, 50 of 64 (78%) mice euthanized successfully had radiographically visible thoracic or lumbar lesions or both. Intentionally creating a midthoracic dislocation in anesthetized mice failed to induce respiratory arrest and death in any of the 18 mice subjected to that procedure. We conclude that CD of mice holds the potential for unsuccessful euthanasia, that anesthesia could be valuable for CD skills training and assessment, and that postmortem radiography has minimal promise in quality-control assessments. PMID:22776194

  7. Caloric restriction and spatial learning in old mice.

    PubMed

    Bellush, L L; Wright, A M; Walker, J P; Kopchick, J; Colvin, R A

    1996-08-01

    Spatial learning in old mice (19 or 24 months old), some of which had been calorically restricted beginning at 14 weeks of age, was compared to that of young mice, in two separate experiments using a Morris water maze. In the first experiment, only old mice reaching criterion performance on a cued learning task were tested in a subsequent spatial task. Thus, all old mice tested for spatial learning had achieved escape latencies equivalent to those of young controls. Despite equivalent swimming speeds, only about half the old mice in each diet group achieved criterion performance in the spatial task. In the second experiment, old and young mice all received the same number of training trials in a cued task and then in a spatial task. Immediately following spatial training, they were given a 60-s probe trial, with no platform in the pool. Both groups of old mice spent significantly less time in the quadrant where the platform had been and made significantly fewer direct crosses over the previous platform location than did the young control group. As in Experiment 1, calorie restriction failed to provide protection against aging-related deficits. However, in both experiments, some individual old mice evidenced performance in spatial learning indistinguishable from that of young controls. Separate comparisons of "age-impaired" and "age-unimpaired" old mice with young controls may facilitate the identification of neurobiological mechanisms underlying age-related cognitive decline.

  8. Preferences for paper bedding material of the laboratory mice.

    PubMed

    Ago, Akio; Gonda, Tatuo; Takechi, Mayumi; Takeuchi, Takashi; Kawakami, Kohei

    2002-04-01

    In order to identify indicators of the preferences for bedding materials, the paper bedding material preferences of laboratory mice were investigated in the present study. Four cages, each containing a different structure of paper bedding material were connected to allow free access to each cage. The preferences for paper bedding materials of laboratory mice were judged by the differences in the length of stay and sleep in each cage. The mice preferred the bedding material that allowed them to easily hide and build nests and was soft. We conclude that the comfort and well-being of laboratory mice can be increased through the appropriate selection of bedding material.

  9. Running promotes wakefulness and increases cataplexy in orexin knockout mice.

    PubMed

    España, Rodrigo A; McCormack, Sarah L; Mochizuki, Takatoshi; Scammell, Thomas E

    2007-11-01

    People with narcolepsy and mice lacking orexin/hypocretin have disrupted sleep/wake behavior and reduced physical activity. Our objective was to identify physiologic mechanisms through which orexin deficiency reduces locomotor activity. We examined spontaneous wheel running activity and its relationship to sleep/wake behavior in wild type (WT) and orexin knockout (KO) mice. Additionally, given that physical activity promotes alertness, we also studied whether orexin deficiency reduces the wake-promoting effects of exercise. Orexin KO mice ran 42% less than WT mice. Their ability to run appeared normal as they initiated running as often as WT mice and ran at normal speeds. However, their running bouts were considerably shorter, and they often had cataplexy or quick transitions into sleep after running. Wheel running increased the total amount of wakefulness in WT and orexin KO mice similarly, however, KO mice continued to have moderately fragmented sleep/wake behavior. Wheel running also doubled the amount of cataplexy by increasing the probability of transitioning into cataplexy. Orexin KO mice run significantly less than normal, likely due to sleepiness, imminent cataplexy, or a reduced motivation to run. Orexin is not required for the wake-promoting effects of wheel running given that both WT and KO mice had similar increases in wakefulness with running wheels. In addition, the clear increase in cataplexy with wheel running suggests the possibility that positive emotions or reward can trigger murine cataplexy, similar to that seen in people and dogs with narcolepsy.

  10. Hepatic Src Homology Phosphatase 2 Regulates Energy Balance in Mice

    PubMed Central

    Nagata, Naoto; Matsuo, Kosuke; Bettaieb, Ahmed; Bakke, Jesse; Matsuo, Izumi; Graham, James; Xi, Yannan; Liu, Siming; Tomilov, Alexey; Tomilova, Natalia; Gray, Susan; Jung, Dae Young; Ramsey, Jon J.; Kim, Jason K.; Cortopassi, Gino; Havel, Peter J.

    2012-01-01

    The Src homology 2 domain-containing protein-tyrosine phosphatase Src homology phosphatase 2 (Shp2) is a negative regulator of hepatic insulin action in mice fed regular chow. To investigate the role of hepatic Shp2 in lipid metabolism and energy balance, we determined the metabolic effects of its deletion in mice challenged with a high-fat diet (HFD). We analyzed body mass, lipid metabolism, insulin sensitivity, and glucose tolerance in liver-specific Shp2-deficient mice (referred to herein as LSHKO) and control mice fed HFD. Hepatic Shp2 protein expression is regulated by nutritional status, increasing in mice fed HFD and decreasing during fasting. LSHKO mice gained less weight and exhibited increased energy expenditure compared with control mice. In addition, hepatic Shp2 deficiency led to decreased liver steatosis, enhanced insulin-induced suppression of hepatic glucose production, and impeded the development of insulin resistance after high-fat feeding. At the molecular level, LSHKO exhibited decreased hepatic endoplasmic reticulum stress and inflammation compared with control mice. In addition, tyrosine and serine phosphorylation of total and mitochondrial signal transducer and activator of transcription 3 were enhanced in LSHKO compared with control mice. In line with this observation and the increased energy expenditure of LSHKO, oxygen consumption rate was higher in liver mitochondria of LSHKO compared with controls. Collectively, these studies identify hepatic Shp2 as a novel regulator of systemic energy balance under conditions of high-fat feeding. PMID:22619361

  11. MDMA reinstates cocaine-seeking behaviour in mice.

    PubMed

    Trigo, José Manuel; Orejarena, Maria Juliana; Maldonado, Rafael; Robledo, Patricia

    2009-06-01

    MDMA effects are mediated by monoaminergic systems, which seem to play a central role in cocaine craving and relapse. CD1 mice trained to self-administer cocaine (1 mg/kg/infusion) underwent an extinction procedure in which the cues contingent with drug self-administration remained present. Mice achieving extinction were injected with MDMA (10 mg/kg), d-amphetamine (1 and 2 mg/kg) or saline and tested for reinstatement. Acute MDMA, but not d-amphetamine or saline reinstated cocaine-seeking behaviour in mice in which cocaine self-administration and contingent cues were previously extinguished. Acute MDMA can reinstate cocaine-seeking behaviour in mice.

  12. Effects of anti-glare particles on sedation in mice

    NASA Astrophysics Data System (ADS)

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

    2018-04-01

    To investigate the effect of anti-glare particles on sedation of mice, 60 mice were randomly divided into 5 groups, were fed by Ant-dizzy Granule Suspension, saline, Yang Xue Qing Nao Granule suspension and the same volume of saline, and administered 1 times daily, for 7 days. The mice in the wilderness box, hang - 150W light bulbs in the box above, the light recording activities within 2 minutes. The wilderness box into the box after the number of mice, mice with limbs went to the 1 squares is around 1 in the same case, mouse location and method of wilderness case; each group was placed in the turn/bar with rotating speed of 40RPM, each time 5 Parallel experiment recorded the mouse stay time on the rotating rod, if the mouse fell within 2 minutes, immediately put it on the rotating rod to continue the experiment, recorded the mouse on the rotating rod accumulated stay time. If 10 minutes did not drop, press 10 minutes; eighty mice were divided into 5 groups. The number of each rat injected subthreshold dose of pentobarbital sodium in mice. The sleep recording liquid were recorded sleep latency and sleep time. The anti-vertigo granule can obviously reduce the spontaneous activity of mice (P<0.05), can significantly increase the residence time of mice on the rotating rod (P<0.05) have obvious synergistic effect (P<0.05). Anti-glare particles have good sedative effect.

  13. Factors Affecting Formation of Incomplete Vi Antibody in Mice

    PubMed Central

    Gaines, Sidney; Currie, Julius A.; Tully, Joseph G.

    1965-01-01

    Gaines, Sidney (Walter Reed Army Institute of Research, Washington, D.C.), Julius A. Currie, and Joseph G. Tully. Factors affecting formation of incomplete Vi antibody in mice. J. Bacteriol. 90:635–642. 1965.—Single immunizing doses of purified Vi antigen elicited complete and incomplete Vi antibodies in BALB/c mice, but only incomplete antibody in Cinnamon mice. Three of six other mouse strains tested responded like BALB/c mice; the remaining three, like Cinnamon mice. Varying the quantity of antigen injected or the route of administration failed to stimulate the production of detectable complete Vi antibody in Cinnamon mice. Such antibody was evoked in these animals by multiple injections of Vi antigen or by inoculating them with Vi-containing bacilli or Vi-coated erythrocytes. The early protection afforded by serum from Vi-immunized BALB/c mice coincided with the appearance of incomplete Vi antibody, 1 day prior to the advent of complete antibody. Persistence of incomplete as well as complete antibody in the serum of immunized mice was demonstrated for at least 56 days after injection of 10 μg of Vi antigen. Incomplete Vi antibody was shown to have blocking ability, in vitro bactericidal activity, and the capability of protecting mice against intracerebral as well as intraperitoneal challenge with virulent typhoid bacilli. Production of incomplete and complete Vi antibodies was adversely affected by immunization with partially depolymerized Vi antigens. PMID:16562060

  14. Gene doping: of mice and men.

    PubMed

    Azzazy, Hassan M E; Mansour, Mai M H; Christenson, Robert H

    2009-04-01

    Gene doping is the newest threat to the spirit of fair play in sports. Its concept stemmed out from legitimate gene therapy trials, but anti-doping authorities fear that they now may be facing a form of doping that is virtually undetectable and extremely appealing to athletes. This paper presents studies that generated mouse models with outstanding physical performance, by manipulating genes such as insulin-like growth factor 1 (IGF-1) or phosphoenolpyruvate carboxykinase (PEPCK), which are likely to be targeted for gene doping. The potential transition from super mice to super athletes will also be discussed, in addition to possible strategies for detection of gene doping.

  15. Testicular effects of acrylonitrile in mice.

    PubMed

    Tandon, R; Saxena, D K; Chandra, S V; Seth, P K; Srivastava, S P

    1988-07-01

    Daily oral administration of acrylonitrile (10 mg/kg body weight) to mice for a period of 60 days caused a significant decrease in the activity of testicular sorbitol dehydrogenase and acid phosphatase, and an increase in that of lactate dehydrogenase and beta-glucuronidase. Histopathological studies revealed degeneration of the seminiferous tubules. A decrease in the sperm counts of the epididymal spermatozoa was also observed in the animals of the acrylonitrile-exposed group. These observations suggest that acrylonitrile may affect the male reproductive function by causing testicular injury.

  16. Microangiography in Living Mice Using Synchrotron Radiation

    NASA Astrophysics Data System (ADS)

    Yuan, Falei; Wang, Yongting; Guan, Yongjing; Lu, Haiyan; Xie, Bohua; Tang, Yaohui; Xie, Honglan; Du, Guohao; Xiao, Tiqiao; Yang, Guo-Yuan

    2010-07-01

    Traditionally, there are no methods available to detect the fine morphologic changes of cerebrovasculature in small living animals such as rats and mice. Newly developed synchrotron radiation microangiography can achieve a fine resolution of several micrometers and had provided us with a powerful tool to study the cerebral vasculature in small animals. The purpose of this study is to identify the morphology of cerebrovasculature especially the structure of Lenticulostriate arteries (LSAs) in living mice using the synchrotron radiation source at Shanghai Synchrotron Radiation Facility (SSRF) in Shanghai, China. Adult CD-1 mice weighing 35-40 grams were anesthetized. Nonionic iodine (Omnipaque, 350 mg I /mL) was used as a contrast agent. The study was performed at the BL13W1 beam line at SSRF. The beam line was derived from a storage ring of electrons with an accelerated energy of 3.5 GeV and an average beam current of 200 mA. X-ray energy of 33.3 keV was used to produce the highest contrast image. Images were acquired every 172 ms by a x-ray camera (Photonic-Science VHR 1.38) with a resolution of 13 μm/pixel. The optimal dose of contrast agent is 100 μl per injection and the injecting rate is 33 μl/sec. The best position for imaging is to have the mouse lay on its right or left side, with ventral side facing the X-ray source. We observed the lenticulostriate artery for the first time in living mice. Our result show that there are 4 to 5 lenticulostriate branches originating from the root of middle cerebral artery in each hemisphere. LSAs have an average diameter of 43±6.8 μm. There were no differences between LSAs from the left and right hemisphere (p<0.05). These results suggest that synchrotron radiation may provide a unique tool for experimental stroke research.

  17. Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice

    PubMed Central

    2013-01-01

    Background Epidermolysis bullosa acquisita (EBA) is a rare skin blistering disease with a prevalence of 0.2/ million people. EBA is characterized by autoantibodies against type VII collagen. Type VII collagen builds anchoring fibrils that are essential for the dermal-epidermal junction. The pathogenic relevance of antibodies against type VII collagen subdomains has been demonstrated both in vitro and in vivo. Despite the multitude of clinical and immunological data, no information on metabolic changes exists. Methods We used an animal model of EBA to obtain insights into metabolomic changes during EBA. Sera from mice with immunization-induced EBA and control mice were obtained and metabolites were isolated by filtration. Proton nuclear magnetic resonance (NMR) spectra were recorded and analyzed by principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and random forest. Results The metabolic pattern of immunized mice and control mice could be clearly distinguished with PCA and PLS-DA. Metabolites that contribute to the discrimination could be identified via random forest. The observed changes in the metabolic pattern of EBA sera, i.e. increased levels of amino acid, point toward an increased energy demand in EBA. Conclusions Knowledge about metabolic changes due to EBA could help in future to assess the disease status during treatment. Confirming the metabolic changes in patients needs probably large cohorts. PMID:23800341

  18. Metabolite analysis distinguishes between mice with epidermolysis bullosa acquisita and healthy mice.

    PubMed

    Schönig, Sarah; Recke, Andreas; Hirose, Misa; Ludwig, Ralf J; Seeger, Karsten

    2013-06-26

    Epidermolysis bullosa acquisita (EBA) is a rare skin blistering disease with a prevalence of 0.2/ million people. EBA is characterized by autoantibodies against type VII collagen. Type VII collagen builds anchoring fibrils that are essential for the dermal-epidermal junction. The pathogenic relevance of antibodies against type VII collagen subdomains has been demonstrated both in vitro and in vivo. Despite the multitude of clinical and immunological data, no information on metabolic changes exists. We used an animal model of EBA to obtain insights into metabolomic changes during EBA. Sera from mice with immunization-induced EBA and control mice were obtained and metabolites were isolated by filtration. Proton nuclear magnetic resonance (NMR) spectra were recorded and analyzed by principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and random forest. The metabolic pattern of immunized mice and control mice could be clearly distinguished with PCA and PLS-DA. Metabolites that contribute to the discrimination could be identified via random forest. The observed changes in the metabolic pattern of EBA sera, i.e. increased levels of amino acid, point toward an increased energy demand in EBA. Knowledge about metabolic changes due to EBA could help in future to assess the disease status during treatment. Confirming the metabolic changes in patients needs probably large cohorts.

  19. [Mice are not Men and yet… how humanized mice inform us about human infectious diseases].

    PubMed

    Cachat, Anne; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Duc Dodon, Madeleine

    2012-01-01

    The study of human pathologies is often limited by the absence of animal models which are robust, cost-effective and reproduce the hallmarks of human infections. While mice have been frequently employed to study human diseases, many of important pathogens display unique human tropism. These last two decades the graft of human progenitor cells or tissues into -immunodeficient mice has allowed the elaboration of so called humanized mice. Humanized mouse technology has made rapid progress, and it is now possible to achieve high levels of human chimerism in various organs and tissues, particularly the immune system and the liver. The review briefly summarizes the different models of humanized mice available for in vivo experiments. With a focus on lymphotropic, monocytotropic and hepatotropic viruses, we here discuss the current status and future prospects of these models for studying the pathogenesis of infectious diseases. Furthermore, they provide a powerful tool for the development of innovative therapies. © 2012 médecine/sciences – Inserm / SRMS.

  20. Comparative toxicity of acephate in laboratory mice, white-footed mice, and meadow voles

    USGS Publications Warehouse

    Rattner, B.A.; Hoffman, D.J.

    1984-01-01

    The LD50 (95% confidence limits) of the organophosphorus insecticide acephate was estimated to be 351, 380, and 321 mg/kg (295?416, 280?516, and 266?388 mg/kg) for CD-1 laboratory mice (Mus musculus), white-footed mice (Peromyscus leucopus noveboracensis), and meadow voles (Microtus pennsylvanicus), respectively. In a second study, these species were provided mash containing 0, 25, 100, and 400 ppm acephate for five days. Brain and plasma cholinesterase activities were reduced in a dose-dependent manner to a similar extent in the three species (inhibition of brain acetyl-cholinesterase averaged for each species ranged from 13 to 22% at 25 ppm, 33 to 42% at 100 ppm, and 56 to 57% at 400 ppm). Mash intake, body or liver weight, plasma enzyme activities (alkaline phosphatase, alanine and aspartate aminotransferase), hepatic enzyme activities (aniline hydroxylase, 7-ethoxycoumarin O-deethylase, and glutathione S-transferase), and cytochrome content (P-450 and b5) were not affected by acephate ingestion, although values differed among species. In a third experiment, mice and voles received 400 ppm acephate for 5 days followed by untreated food for up to 2 weeks. Mean inhibition of brain acetylcholin-esterase for the three species ranged from 47 to 58% on day 5, but by days 12 and 19, activity had recovered to 66 to 76% and 81 to 88% of concurrent control values. These findings indicate that CD-1 laboratory mice, white-footed mice, and meadow voles are equally sensitive to acephate when maintained under uniform laboratory conditions. Several factors (e.g., behavior, food preference, habitat) could affect routes and degree of exposure in the field, thereby rendering some species of wild rodents ecologically more vulnerable to organophosphorus insecticides.

  1. Comparative toxicity of acephate in laboratory mice, white-footed mice and meadow voles

    USGS Publications Warehouse

    Rattner, B.A.; Hoffman, D.J.

    1983-01-01

    The LD50 (95% confidence limits) of the organophosphorus insecticide acephate was estimated to be 351, 380, and 321 mg/kg (295?416, 280?516, and 266?388 mg/kg) for CD-1 laboratory mice (Mus musculus), white-footed mice (Peromyscus leucopus noveboracensis), and meadow voles (Microtus pennsylvanicus), respectively. In a second study, these species were provided mash containing 0, 25, 100, and 400 ppm acephate for five days. Brain and plasma cholinesterase activities were reduced in a dose-dependent manner to a similar extent in the three species (inhibition of brain acetyl-cholinesterase averaged for each species ranged from 13 to 22% at 25 ppm, 33 to 42% at 100 ppm, and 56 to 57% at 400 ppm). Mash intake, body or liver weight, plasma enzyme activities (alkaline phosphatase, alanine and aspartate aminotransferase), hepatic enzyme activities (aniline hydroxylase, 7-ethoxycoumarin O-deethylase, and glutathione S-transferase), and cytochrome content (P-450 and b5) were not affected by acephate ingestion, although values differed among species. In a third experiment, mice and voles received 400 ppm acephate for 5 days followed by untreated food for up to 2 weeks. Mean inhibition of brain acetylcholin-esterase for the three species ranged from 47 to 58% on day 5, but by days 12 and 19, activity had recovered to 66 to 76% and 81 to 88% of concurrent control values. These findings indicate that CD-1 laboratory mice, white-footed mice, and meadow voles are equally sensitive to acephate when maintained under uniform laboratory conditions. Several factors (e.g., behavior, food preference, habitat) could affect routes and degree of exposure in the field, thereby rendering some species of wild rodents ecologically more vulnerable to organophosphorus insecticides.

  2. Analysis of Kalirin-7 Knockout Mice Reveals Different Effects in Female Mice

    PubMed Central

    Mazzone, Christopher M.; Larese, Taylor P.; Kiraly, Drew D.; Eipper, Betty A.

    2012-01-01

    Estradiol treatment of ovariectomized rodents is known to affect the morphology of dendritic spines and produce behavioral and cognitive effects. Kalirin-7 (Kal7), a postsynaptic density (PSD)-localized Rho-guanine nucleotide exchange factor, is important for dendritic spine formation and stability. Male Kal7 knockout [Kal7(KO)] mice exhibit a number of abnormal behavioral and biochemical phenotypes. Given that chronic 17β-estradiol (E2) replacement of ovariectomized rats enhanced Kal7 expression in the hippocampus and primary hippocampal cultures, we assessed the behavioral and biochemical effects of chronic E2 treatment of ovariectomized female wild-type and Kal7(KO) mice. Both intact and ovariectomized Kal7(KO) female mice exhibited decreased anxiety-like behavior compared with the corresponding wild type in the elevated zero maze and were unaffected by E2 treatment. Chronic E2 decreased locomotor activity in the open field and enhanced performance in a passive-avoidance fear conditioning task, which were both unaffected by genotype. Kal7(KO) female mice engaged in significantly more object exploration, both familiar and novel, than did wild-type females. E2 enhanced the acute locomotor response to cocaine, with no significant effect of genotype. Similar to Kal7(KO) males, Kal7(KO) females had decreased levels of N-methyl-d-aspartate receptor 2B in hippocampal PSD fractions with no effect of E2 treatment. The differing behavioral effects of Kal7 ablation in female and male mice may offer insight into the molecular underpinnings of these differences. PMID:22989522

  3. Staphylococcus-mediated T-cell activation and spontaneous natural killer cell activity in the absence of major histocompatibility complex class II molecules

    NASA Technical Reports Server (NTRS)

    Chapes, S. K.; Hoynowski, S. M.; Woods, K. M.; Armstrong, J. W.; Beharka, A. A.; Iandolo, J. J.; Spooner, B. S. (Principal Investigator)

    1993-01-01

    We used major histocompatibility complex class II antigen-deficient transgenic mice to show that in vitro natural killer cell cytotoxicity and T-cell activation by staphylococcal exotoxins (superantigens) are not dependent upon the presence of major histocompatibility complex class II molecules. T cells can be activated by exotoxins in the presence of exogenously added interleukin 1 or 2 or in the presence of specific antibody without exogenously added cytokines.

  4. Arginase inhibition promotes wound healing in mice.

    PubMed

    Kavalukas, Sandra L; Uzgare, Aarti R; Bivalacqua, Trinity J; Barbul, Adrian

    2012-02-01

    Arginase plays important regulatory roles in polyamine, ornithine, and nitric oxide syntheses. However, its role in the healing process has not been delineated. In this study, we used a highly potent and specific inhibitor of arginase, namely 2(S)-amino-6-boronohexanoic acid NH4 (ABH) to evaluate the role of arginase function in wound healing. ABH or saline was applied topically to full thickness, dorsal, excisional wounds in C57BL/6 mice every 8 hours for 14 days post surgery and the rate of wound closure was estimated planimetrically. Wound tissue was harvested from mice sacrificed on postoperative days 3 and 7 and examined histologically. The extent of epithelial, connective, and granulation tissue present within the wound area was estimated histomorphometrically. The effect of ABH on wound arginase activity, production of nitric oxide metabolites (NO(x)), and presence of smooth muscle actin positive cells (myofibroblasts) was evaluated. While arginase activity was inhibited in vivo, the rate of wound closure significantly increased 7 days post-surgery, (21 ± 4%: P < .01; Student t test) in ABH treated animals. This was accompanied by an early increase in wound granulation tissue and accumulation of NO(x) followed by enhanced re-epithelialization and localization of myofibroblasts beneath the wound epithelium. Arginase inhibition improves excisional wound healing and may be used to develop therapeutics for early wound closure. Copyright © 2012 Mosby, Inc. All rights reserved.

  5. Molecular Hydrogen Attenuates Neuropathic Pain in Mice

    PubMed Central

    Kawaguchi, Masanori; Satoh, Yasushi; Otsubo, Yukiko; Kazama, Tomiei

    2014-01-01

    Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting. PMID:24941001

  6. Scurfy mice: A model for autoimmune disease

    SciTech Connect

    Godfrey, V.L.

    1993-01-01

    Autoimmune disease-the condition in which the body attacks its own tissue-has been an object of public concern recently. Former President George Bush and his wife Barbara both are afflicted with Graves' disease in which the body's own immune system attakcs the thyroid gland. The safety of breast implants was called into question because of evidence that some recipients had developed autoimmune disorders such a rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. Women, the media pointed out, have a higher-than-average incidence of many autoimmune disorders. These events suggest the need to know more about what makes the immune system work somore » well and what makes it go awry. At ORNL's Biology Division, progress is being in understanding the underlying causes of immune disease by studying mice having a disease that causes them to be underdeveloped; to have scaly skin, small ears, and large spleens; to open their eyes late; and to die early. These [open quotes]scurfy[close quotes]mice are helping us better understand the role of the thymus gland in autoimmune disease.« less

  7. Dedicated low-field MRI in mice

    NASA Astrophysics Data System (ADS)

    Choquet, P.; Breton, E.; Goetz, C.; Marin, C.; Constantinesco, A.

    2009-09-01

    The rationale of this work is to point out the relevance of in vivo MR images of mice obtained using a dedicated low-field system. For this purpose a small 0.1 T water-cooled electro-magnet and solenoidal radio frequency (RF) transmit-receive coils were used. All MR images were acquired in three-dimensional (3D) mode. An isolation cell was designed allowing easy placement of the RF coils and simple delivery of gaseous anesthesia as well as warming of the animal. Images with and without contrast agent were obtained in total acquisition times on the order of half an hour to four hours on normal mice as well as on animals bearing tumors. Typical in plane pixel dimensions range from 200 × 200 to 500 × 500 µm2 with slice thicknesses ranging between 0.65 and 1.50 mm. This work shows that, besides light installation and low cost, dedicated low-field MR systems are suitable for small rodents imaging, opening this technique even to small research units.

  8. Magnolol inhibits venous remodeling in mice.

    PubMed

    Kuk, Hanna; Arnold, Caroline; Meyer, Ralph; Hecker, Markus; Korff, Thomas

    2017-12-19

    Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context - a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti-oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins.

  9. Radioprotective Effects of Gallic Acid in Mice

    PubMed Central

    Nair, Gopakumar Gopinathan

    2013-01-01

    Radioprotecting ability of the natural polyphenol, gallic acid (3,4,5-trihydroxybenzoic acid, GA), was investigated in Swiss albino mice. Oral administration of GA (100 mg/kg body weight), one hour prior to whole body gamma radiation exposure (2–8 Gy; 6 animals/group), reduced the radiation-induced cellular DNA damage in mouse peripheral blood leukocytes, bone marrow cells, and spleenocytes as revealed by comet assay. The GA administration also prevented the radiation-induced decrease in the levels of the antioxidant enzyme, glutathione peroxidise (GPx), and nonprotein thiol glutathione (GSH) and inhibited the peroxidation of membrane lipids in these animals. Exposure of mice to whole body gamma radiation also caused the formation of micronuclei in blood reticulocytes and chromosomal aberrations in bone marrow cells, and the administration of GA resulted in the inhibition of micronucleus formation and chromosomal aberrations. In irradiated animals, administration of GA elicited an enhancement in the rate of DNA repair process and a significant increase in endogenous spleen colony formation. The administration of GA also prevented the radiation-induced weight loss and mortality in animals (10 animals/group) exposed to lethal dose (10 Gy) of gamma radiation. (For every experiment unirradiated animals without GA administration were taken as normal control; specific dose (Gy) irradiated animals without GA administration serve as radiation control; and unirradiated GA treated animals were taken as drug alone control). PMID:24069607

  10. Heart rate reduction and longevity in mice.

    PubMed

    Gent, Sabine; Kleinbongard, Petra; Dammann, Philip; Neuhäuser, Markus; Heusch, Gerd

    2015-03-01

    Heart rate correlates inversely with life span across all species, including humans. In patients with cardiovascular disease, higher heart rate is associated with increased mortality, and such patients benefit from pharmacological heart rate reduction. However, cause-and-effect relationships between heart rate and longevity, notably in healthy individuals, are not established. We therefore prospectively studied the effects of a life-long pharmacological heart rate reduction on longevity in mice. We hypothesized, that the total number of cardiac cycles is constant, and that a 15% heart rate reduction might translate into a 15% increase in life span. C57BL6/J mice received either placebo or ivabradine at a dose of 50 mg/kg/day in drinking water from 12 weeks to death. Heart rate and body weight were monitored. Autopsy was performed on all non-autolytic cadavers, and parenchymal organs were evaluated macroscopically. Ivabradine reduced heart rate by 14% (median, interquartile range 12-15%) throughout life, and median life span was increased by 6.2% (p = 0.01). Body weight and macroscopic findings were not different between placebo and ivabradine. Life span was not increased to the same extent as heart rate was reduced, but nevertheless significantly prolonged by 6.2%.

  11. Ghrelin reverses experimental diabetic neuropathy in mice

    SciTech Connect

    Kyoraku, Itaru; Shiomi, Kazutaka; Kangawa, Kenji

    Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic micemore » and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin {alpha}, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.« less

  12. Deletion of ultraconserved elements yields viable mice

    SciTech Connect

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel

    2007-07-15

    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lackingmore » these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.« less

  13. MDMA attenuates THC withdrawal syndrome in mice.

    PubMed

    Touriño, Clara; Maldonado, Rafael; Valverde, Olga

    2007-07-01

    3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition, and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet. In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Delta(9)-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration. Both chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA. The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.

  14. Angiostatin inhibits experimental liver fibrosis in mice.

    PubMed

    Vogten, J Mathys; Drixler, Tamas A; te Velde, Elisabeth A; Schipper, Marguerite E; van Vroonhoven, Theo J M V; Voest, Emile E; Borel Rinkes, Inne H M

    2004-07-01

    Liver fibrosis is a response to chronic hepatic damage, which ultimately leads to liver failure and necessitates liver transplantation. A characteristic of fibrosis is pathological vessel growth. This type of angiogenesis may contribute to the disturbance of hepatocyte perfusion dynamics and lead to aggravation of disease. We hypothesized that angiostatin can inhibit pathological vessel growth and, consequently, the development of hepatic fibrosis. Hepatic fibrosis was induced by injection of carbon tetrachloride for 5 weeks. Angiostatin mice received carbon tetrachloride for 5 weeks and angiostatin during weeks 4 and 5. After 5 weeks, immunohistochemistry for endothelial cell marker von Willebrand factor and for cell proliferation was performed. Angiogenesis was quantified by counting the number of immunopositive microvessels. Also, the relative fibrotic surface was determined using Sirius Red histostaining and computer image analysis. Immunohistochemistry revealed increased expression for von Willebrand factor in fibrotic livers. Immunopositive microvessels were localized in fibrotic areas surrounding larger vessels and in emerging fibrotic septa. Angiostatin reduced the number of immunopositive microvessels by 69% (p<0.001). In addition, angiostatin reduced the relative fibrotic area in the liver by 63+/-0.1% (p<0.001). Finally, angiostatin treatment was not associated with differences in cell proliferation. Angiostatin inhibits the development of pathological angiogenesis and liver fibrosis in mice. These results warrant further evaluation of angiostatin as an antifibrotic agent, potentially contributing to the deferment of liver transplantation and reduced recurrence of fibrotic disease in the transplanted liver.

  15. Cancer dormancy: from mice to man.

    PubMed

    Marches, Radu; Scheuermann, Richard; Uhr, Jonathan

    2006-08-01

    In this review, we focused on our studies of cancer dormancy in a murine B cell lymphoma and human breast cancer. Lifelong dormancy was induced in syngeneic mice by prior immunization to the idiotype of the tumor cell (TC) Ig before TC challenge. The mice maintained approximately 10(6) lymphoma cells in their spleen throughout their lifetime despite replication of the TCs at a reduced rate. Recurrences occurred randomly. Because of the balance between replication and cell death, we hypothesized that a similar balance might occur in long-term survivors of breast cancer when the risk of recurrences is very low. We developed a sensitive assay for circulating tumor cells (CTCs) which none were found in normal age-matched women. One third of patients, 7-22 years after mastectomy and without any evidence of disease, had CTCs. The half-life of these CTCs could be deduced from other studies as probably 2-3 hours. Hence, there was a precise balance between replication of TCs (presumably from micrometastases) and cell death. Therefore, a major population of clinically cured breast cancer patients have a chronic disease controlled by their own physiological mechanisms. We speculate on underlying mechanisms based both on studies in experimental models and clinical trials.

  16. Arctigenin Efficiently Enhanced Sedentary Mice Treadmill Endurance

    PubMed Central

    Chen, Jing; Yu, Liang; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2011-01-01

    Physical inactivity is considered as one of the potential risk factors for the development of type 2 diabetes and other metabolic diseases, while endurance exercise training could enhance fat oxidation that is associated with insulin sensitivity improvement in obesity. AMP-activated protein kinase (AMPK) as an energy sensor plays pivotal roles in the regulation of energy homeostasis, and its activation could improve glucose uptake, promote mitochondrial biogenesis and increase glycolysis. Recent research has even suggested that AMPK activation contributed to endurance enhancement without exercise. Here we report that the natural product arctigenin from the traditional herb Arctium lappa L. (Compositae) strongly increased AMPK phosphorylation and subsequently up-regulated its downstream pathway in both H9C2 and C2C12 cells. It was discovered that arctigenin phosphorylated AMPK via calmodulin-dependent protein kinase kinase (CaMKK) and serine/threonine kinase 11(LKB1)-dependent pathways. Mice treadmill based in vivo assay further indicated that administration of arctigenin improved efficiently mice endurance as reflected by the increased fatigue time and distance, and potently enhanced mitochondrial biogenesis and fatty acid oxidation (FAO) related genes expression in muscle tissues. Our results thus suggested that arctigenin might be used as a potential lead compound for the discovery of the agents with mimic exercise training effects to treat metabolic diseases. PMID:21887385

  17. Gene therapy improves dental manifestations in hypophosphatasia model mice.

    PubMed

    Okawa, R; Iijima, O; Kishino, M; Okawa, H; Toyosawa, S; Sugano-Tajima, H; Shimada, T; Okada, T; Ozono, K; Ooshima, T; Nakano, K

    2017-06-01

    Hypophosphatasia is a rare inherited skeletal disorder characterized by defective bone mineralization and deficiency of tissue non-specific alkaline phosphatase (TNSALP) activity. The disease is caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL) encoding TNSALP. Early exfoliation of primary teeth owing to disturbed cementum formation, periodontal ligament weakness and alveolar bone resorption are major complications encountered in oral findings, and discovery of early loss of primary teeth in a dental examination often leads to early diagnosis of hypophosphatasia. Although there are no known fundamental treatments or effective dental approaches to prevent early exfoliation of primary teeth in affected patients, several possible treatments have recently been described, including gene therapy. Gene therapy has also been applied to TNSALP knockout mice (Alpl -/- ), which phenocopy the infantile form of hypophosphatasia, and improved their systemic condition. In the present study, we investigated whether gene therapy improved the dental condition of Alpl -/- mice. Following sublethal irradiation (4 Gy) at the age of 2 d, Alpl -/- mice underwent gene therapy using bone marrow cells transduced with a lentiviral vector expressing a bone-targeted form of TNSALP injected into the jugular vein (n = 3). Wild-type (Alpl +/+ ), heterozygous mice (Alpl +/- ) and Alpl -/- mice were analyzed at 9 d of age (n = 3 of each), while Alpl +/+ mice and treated or untreated Alpl -/- mice were analyzed at 1 mo of age (n = 3 of each), and Alpl +/- mice and Alpl -/- mice with gene therapy were analyzed at 3 mo of age (n = 3 of each). A single mandibular hemi-section obtained at 1 mo of age was analyzed using a small animal computed tomography machine to assess alveolar bone formation. Other mandibular hemi-sections obtained at 9 d, 1 mo and 3 mo of age were subjected to hematoxylin and eosin staining and immunohistochemical analysis of osteopontin, a marker of

  18. Masking responses to light in period mutant mice.

    PubMed

    Pendergast, Julie S; Yamazaki, Shin

    2011-10-01

    Masking is an acute effect of an external signal on an overt rhythm and is distinct from the process of entrainment. In the current study, we investigated the phase dependence and molecular mechanisms regulating masking effects of light pulses on spontaneous locomotor activity in mice. The circadian genes, Period1 (Per1) and Per2, are necessary components of the timekeeping machinery and entrainment by light appears to involve the induction of the expression of Per1 and Per2 mRNAs in the suprachiasmatic nuclei (SCN). We assessed the roles of the Per genes in regulating masking by assessing the effects of light pulses on nocturnal locomotor activity in C57BL/6J Per mutant mice. We found that Per1(-/-) and Per2(-/-) mice had robust negative masking responses to light. In addition, the locomotor activity of Per1(-/-)/Per2(-/-) mice appeared to be rhythmic in the light-dark (LD) cycle, and the phase of activity onset was advanced (but varied among individual mice) relative to lights off. This rhythm persisted for 1 to 2 days in constant darkness in some Per1(-/-)/Per2(-/-) mice. Furthermore, Per1(-/-)/Per2(-/-) mice exhibited robust negative masking responses to light. Negative masking was phase dependent in wild-type mice such that maximal suppression was induced by light pulses at zeitgeber time 14 (ZT14) and gradually weaker suppression occurred during light pulses at ZT16 and ZT18. By measuring the phase shifts induced by the masking protocol (light pulses were administered to mice maintained in the LD cycle), we found that the phase responsiveness of Per mutant mice was altered compared to wild-types. Together, our data suggest that negative masking responses to light are robust in Per mutant mice and that the Per1(-/-)/Per2(-/-) SCN may be a light-driven, weak/damping oscillator.

  19. Ketamine-xylazine anesthesia causes hyperopic refractive shift in mice

    PubMed Central

    Tkatchenko, Tatiana V.; Tkatchenko, Andrei V.

    2010-01-01

    Mice have increasingly been used as a model for studies of myopia. The key to successful use of mice for myopia research is the ability to obtain accurate measurements of refractive status of their eyes. In order to obtain accurate measurements of refractive errors in mice, the refraction needs to be performed along the optical axis of the eye. This represents a particular challenge, because mice are very difficult to immobilize. Recently, ketamine-xylazine anesthesia has been used to immobilize mice before measuring refractive errors, in combination with tropicamide ophthalmic solution to induce mydriasis. Although these drugs have increasingly been used while refracting mice, their effects on the refractive state of the mouse eye have not yet been investigated. Therefore, we have analyzed the effects of tropicamide eye drops and ketamine-xylazine anesthesia on refraction in P40 C57BL/6J mice. We have also explored two alternative methods to immobilize mice, i.e. the use of a restraining platform and pentobarbital anesthesia. We found that tropicamide caused a very small, but statistically significant, hyperopic shift in refraction. Pentobarbital did not have any substantial effect on refractive status, whereas ketamine-xylazine caused a large and highly significant hyperopic shift in refraction. We also found that the use of a restraining platform represents good alternative for immobilization of mice prior to refraction. Thus, our data suggest that ketamine-xylazine anesthesia should be avoided in studies of refractive development in mice and underscore the importance of providing appropriate experimental conditions when measuring refractive errors in mice. PMID:20813132

  20. Perfluorocarbon emulsion therapy attenuates pneumococcal infection in sickle cell mice.

    PubMed

    Helmi, Nawal; Andrew, Peter W; Pandya, Hitesh C

    2015-05-15

    Impaired immunity and tissue hypoxia-ischemia are strongly linked with Streptococcus pneumoniae pathogenesis in patients with sickle cell anemia. Perfluorocarbon emulsions (PFCEs) have high O2-dissolving capacity and can alleviate tissue hypoxia. Here, we evaluate the effects of intravenous PFCE therapy in transgenic sickle cell (HbSS) mice infected with S. pneumoniae. HbSS and C57BL/6 (control) mice intravenously infected with S. pneumoniae were treated intravenously with PFCE or phosphate-buffered saline (PBS) and then managed in either air/O2 (FiO2 proportion, 50%; hereafter referred to as the PFCE-O2 and PBS-O2 groups) or air only (hereafter, the PFCE-air and PBS-air groups) gas mixtures. Lungs were processed for leukocyte and bacterial counts and cytokine measurements. HbSS mice developed severe pneumococcal infection significantly faster than C57BL/6 mice (Kaplan-Maier analysis, P < .05). PFCE-O2-treated HbSS mice had significantly better survival at 72 hours than HBSS mice treated with PFCE-air, PBS-O2, or PBS-air (P < .05). PFCE-O2-treated HbSS mice also had significantly lower pulmonary leukocyte counts, lower interleukin 1β and interferon γ levels, and higher interleukin 10 levels than PFCE-air-treated HbSS mice. Clearance of S. pneumoniae from lungs of HbSS mice or C57BL/6 mice was not altered by PFCE treatment. Improved survival of PFCE-O₂-treated HbSS mice infected with S. pneumoniae is associated with altered pulmonary inflammation but not enhanced bacterial clearance. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

    PubMed Central

    Stapleton, David I.; Lau, Xianzhong; Flores, Marcelo; Trieu, Jennifer; Gehrig, Stefan M.; Chee, Annabel; Naim, Timur; Lynch, Gordon S.; Koopman, René

    2014-01-01

    Background Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice. Results Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01)). Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001). Glycogen synthase activity was 12% higher (P<0.05) but glycogen branching enzyme activity was 70% lower (P<0.01) in mdx compared with wild-type mice. The rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01) in mdx mice resulting from a 24% reduction in PKA activity (P<0.01). In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001) together with starch-binding domain protein 1 (219% higher; P<0.01). In addition, mdx mice were glucose intolerant (P<0.01) and had 30% less liver glycogen (P<0.05) compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05) as a possible cause of this phenotype. Conclusion We identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen. PMID:24626262

  2. NAPHTHALENE TOXICITY IN CD-1 MICE: GENERAL TOXICOLOGY AND IMMUNOTOXICOLOGY

    EPA Science Inventory

    The purpose of this study was to evaluate the acute and subchronic toxicity, and effects on immune function, of naphthalene (NAP) in random-bred CD-1 mice. The acute oral LD50 of this compound was 533 and 710 mg/kg in male and female mice, respectively. Fourteen- and ninety-day d...

  3. Pirt contributes to uterine contraction-induced pain in mice.

    PubMed

    Wang, Changming; Wang, Zhongli; Yang, Yan; Zhu, Chan; Wu, Guanyi; Yu, Guang; Jian, Tunyu; Yang, Niuniu; Shi, Hao; Tang, Min; He, Qian; Lan, Lei; Liu, Qin; Guan, Yun; Dong, Xinzhong; Duan, Jinao; Tang, Zongxiang

    2015-09-17

    Uterine contraction-induced pain (UCP) represents a common and severe form of visceral pain. Nerve fibers that innervate uterine tissue express the transient receptor potential vanilloid channel 1 (TRPV1), which has been shown to be involved in the perception of UCP. The phosphoinositide-interacting regulator of TRP (Pirt) may act as a regulatory subunit of TRPV1. The intraperitoneal injection of oxytocin into female mice after a 6-day priming treatment with estradiol benzoate induces writhing responses, which reflect the presence of UCP. Here, we first compared writhing response between Pirt (+/+) and Pirt (-/-) mice. Second, we examined the innervation of Pirt-expressing nerves in the uterus of Pirt (-/-) mice by immunofluorescence and two-photon microscopy. Third, we identified the soma of dorsal root ganglion (DRG) neurons that innerve the uterus using retrograde tracing and further characterized the neurochemical properties of these DRG neurons. Finally, we compared the calcium response of capsaicin between DRG neurons from Pirt (+/+) and Pirt (-/-) mice. We found that the writhing responses were less intensive in Pirt (-/-) mice than in Pirt (+/+) mice. We also observed Pirt-expressing nerve fibers in the myometrium of the uterus, and that retrograde-labeled cells were small-diameter, unmyelinated, and Pirt-positive DRG neurons. Additionally, we found that the number of capsaicin-responding neurons and the magnitude of evoked calcium response were markedly reduced in DRG neurons from Pirt (-/-) mice. Taken together, we speculate that Pirt plays an important role in mice uterine contraction-induced pain.

  4. Voluntary running enhances glymphatic influx in awake behaving, young mice.

    PubMed

    von Holstein-Rathlou, Stephanie; Petersen, Nicolas Caesar; Nedergaard, Maiken

    2018-01-01

    Vascular pathology and protein accumulation contribute to cognitive decline, whereas exercise can slow vascular degeneration and improve cognitive function. Recent investigations suggest that glymphatic clearance measured in aged mice while anesthetized is enhanced following exercise. We predicted that exercise would also stimulate glymphatic activity in awake, young mice with higher baseline glymphatic function. Therefore, we assessed glymphatic function in young female C57BL/6J mice following five weeks voluntary wheel running and in sedentary mice. The active mice ran a mean distance of 6km daily. We injected fluorescent tracers in cisterna magna of awake behaving mice and in ketamine/xylazine anesthetized mice, and later assessed tracer distribution in coronal brain sections. Voluntary exercise consistently increased CSF influx during wakefulness, primarily in the hypothalamus and ventral parts of the cortex, but also in the middle cerebral artery territory. While glymphatic activity was higher under ketamine/xylazine anesthesia, we saw a decrease in glymphatic function during running in awake mice after five weeks of wheel running. In summary, daily running increases CSF flux in widespread areas of the mouse brain, which may contribute to the pro-cognitive effects of exercise. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Oxygen effects on mortality of mice infected with Diplococcus pneumoniae

    NASA Technical Reports Server (NTRS)

    Angrick, E. J.; Somerson, N. L.; Weiss, H. S.

    1974-01-01

    Mice infected by intraperitoneal injection of Diplococcus pneumoniae were held at 1 atm in either hypoxic (12%), hyperoxic (75%), or a normal (21%) oxygen environment. Mortality rates indicated prolongation of survival in hypoxia and shortened survival in hyperoxia. Exposure of mice to the experimental gas mixtures prior to inoculation did not alter the results.

  6. Torticollis in Mice Intravenously Infected with Mycobacterium tuberculosis

    PubMed Central

    Magden, Elizabeth R; Weiner, Cristina M; Gilliland, Janet C; DeGroote, Mary Ann; Lenaerts, Anne J; Kendall, Lon V

    2011-01-01

    Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 106 cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin–pyrazinamide or moxifloxacin–rifampin–pyrazinamide. Torticollis did not develop in mice receiving isoniazid–rifampin–pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice. Affected mice were euthanized, and complete necropsy evaluation was performed on 4 mice. Gross necropsy evaluation revealed typical tuberculosis lesions in lungs of infected mice. Histologic evaluation of tissues revealed granulomatous otitis media with intralesional acid-fast bacilli consistent with Mycobacterium tuberculosis. These cases represent an unusual finding specific to the intravenous mouse model of Mycobacterium tuberculosis and may represent a model of a similar condition in humans that is known as tuberculous otitis media. PMID:21439219

  7. Torticollis in mice intravenously infected with Mycobacterium tuberculosis.

    PubMed

    Magden, Elizabeth R; Weiner, Cristina M; Gilliland, Janet C; DeGroote, Mary Ann; Lenaerts, Anne J; Kendall, Lon V

    2011-03-01

    Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 10(6) cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin-pyrazinamide or moxifloxacin-rifampin-pyrazinamide. Torticollis did not develop in mice receiving isoniazid- rifampin-pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice. Affected mice were euthanized, and complete necropsy evaluation was performed on 4 mice. Gross necropsy evaluation revealed typical tuberculosis lesions in lungs of infected mice. Histologic evaluation of tissues revealed granulomatous otitis media with intralesional acid-fast bacilli consistent with Mycobacterium tuberculosis. These cases represent an unusual finding specific to the intravenous mouse model of Mycobacterium tuberculosis and may represent a model of a similar condition in humans that is known as tuberculous otitis media.

  8. REVIEW - Thermal Physiology of Laboratory Mice: Defining Thermoneutrality

    EPA Science Inventory

    In terms of total number of publications, the laboratory mouse (Mus musculus) has emerged as the most popular test subject in biomedical research. Mice are used as models to study obesity, diabetes, eNS diseases and variety of other pathologies. Mice are classified as homeotherms...

  9. Phenytoin promotes Th2 type immune response in mice

    PubMed Central

    Okada, K; Sugiura, T; Kuroda, E; Tsuji, S; Yamashita, U

    2001-01-01

    The effects of chronic administration of phenytoin, a common anticonvulsive drug, on immune responses were studied in mice. Anti-keyhole limpet haemocyanin (KLH) IgE antibody response after KLH-immunization was enhanced in phenytoin-treated mice. Proliferative responses of spleen cells induced with KLH, concanavalin A (ConA), lipopolysaccharide and anti-CD3 antibody were reduced in phenytoin-treated mice. Accessory function of spleen adherent cells on ConA-induced T cell proliferative response was reduced in phenytoin-treated mice. KLH-induced IL-4 production of spleen cells was enhanced, while IFN-γ production was reduced in phenytoin-treated mice. In addition, production of IL-1α, but not IL-6 and IL-12 by spleen adherent cells from phenytoin-treated mice was reduced. Natural killer cell activity was reduced in phenytoin-treated mice. These results suggest that phenytoin treatment preferentially induces a Th2 type response. We also observed that plasma ACTH and corticosterone levels were increased in phenytoin-treated mice, and speculated that phenytoin might act directly and indirectly, through HPA axis activation, on the immune system to modulate Th1/Th2 balance. PMID:11472401

  10. Antistress, Adoptogenic Activity of Sida cordifolia Roots in Mice.

    PubMed

    Sumanth, Meera; Mustafa, S S

    2009-05-01

    Ethanol extract of roots of Sida cordifolia was evaluated for antistress, adaptogenic activity using cold restraint stress and swim endurance in mice. Mice pretreated with extract of Sida cordifolia showed significant improvement in the swim duration and reduced the elevated WBC, blood glucose and plasma cortisone.

  11. Antistress, Adoptogenic Activity of Sida cordifolia Roots in Mice

    PubMed Central

    Sumanth, Meera; Mustafa, S. S.

    2009-01-01

    Ethanol extract of roots of Sida cordifolia was evaluated for antistress, adaptogenic activity using cold restraint stress and swim endurance in mice. Mice pretreated with extract of Sida cordifolia showed significant improvement in the swim duration and reduced the elevated WBC, blood glucose and plasma cortisone. PMID:20490305

  12. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice.

    PubMed

    Pan, Qiong; Sun, Yiming; Jin, Qili; Li, Qixiang; Wang, Qing; Liu, Hao; Zhao, Surong

    2016-11-01

    To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

  13. Molecular Determinants of Influenza Virus Pathogenesis in Mice

    PubMed Central

    Katz, Jaqueline M.; York, Ian A.

    2015-01-01

    Mice are widely used for studying influenza virus pathogenesis and immunology because of their low cost, the wide availability of mouse-specific reagents, and the large number of mouse strains available, including knockout and transgenic strains. However, mice do not fully recapitulate the signs of influenza infection of humans: transmission of influenza between mice is much less efficient than in humans, and influenza viruses often require adaptation before they are able to efficiently replicate in mice. In the process of mouse adaptation, influenza viruses acquire mutations that enhance their ability to attach to mouse cells, replicate within the cells, and suppress immunity, among other functions. Many such mouse-adaptive mutations have been identified, covering all 8 genomic segments of the virus. Identification and analysis of these mutations have provided insight into the molecular determinants of influenza virulence and pathogenesis, not only in mice but also in humans and other species. In particular, several mouse-adaptive mutations of avian influenza viruses have proved to be general mammalian-adaptive changes that are potential markers of pre-pandemic viruses. As well as evaluating influenza pathogenesis, mice have also been used as models for evaluation of novel vaccines and anti-viral therapies. Mice can be a useful animal model for studying influenza biology as long as differences between human and mice infections are taken into account. PMID:25038937

  14. The gut microbiota regulates bone mass in mice

    PubMed Central

    Sjögren, Klara; Engdahl, Cecilia; Henning, Petra; Lerner, Ulf H; Tremaroli, Valentina; Lagerquist, Marie K; Bäckhed, Fredrik; Ohlsson, Claes

    2012-01-01

    The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4+ T cells and CD11b+/GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis. © 2012 American Society for Bone and Mineral Research. PMID:22407806

  15. Bacterial infection causes stress-induced memory dysfunction in mice.

    PubMed

    Gareau, Mélanie G; Wine, Eytan; Rodrigues, David M; Cho, Joon Ho; Whary, Mark T; Philpott, Dana J; Macqueen, Glenda; Sherman, Philip M

    2011-03-01

    The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.

  16. Bone growth and turnover in progesterone receptor knockout mice.

    SciTech Connect

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda

    2008-05-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bonesmore » of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.« less

  17. Metabolic effects of intra-abdominal fat in GHRKO mice

    PubMed Central

    Masternak, Michal M.; Bartke, Andrzej; Wang, Feiya; Spong, Adam; Gesing, Adam; Fang, Yimin; Salmon, Adam B.; Hughes, Larry F.; Liberati, Teresa; Boparai, Ravneet; Kopchick, John J.; Westbrook, Reyhan

    2011-01-01

    SUMMARY Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are GH resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity. Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice. Some of the examined parameters were altered by VFR in opposite directions in GHRKO and normal mice, others were affected in only one genotype or exhibited significant genotype × treatment interactions. Functional differences between visceral fat of GHRKO and normal mice were confirmed by measurements of adipokine secretion, lipolysis and expression of genes related to fat metabolism. We conclude that in the absence of GH signaling the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals. PMID:22040032

  18. Consequences of neonatal thymectomy in New Zealand black mice

    PubMed Central

    East, June; de Sousa, Maria A. B.; Parrott, Delphine M. V.; Jaquet, H.

    1967-01-01

    The possible role of the thymus in autoimmune disease was studied by comparing the effects of neonatal thymectomy on New Zealand Black (NZB) mice (which develop a Coombs positive haemolytic anaemia) and on C3H/Bi, F1 (C57BL × C3H/Bi), C57BL and TO mice. The neonatally thymectomized NZB mice, in common with those of other strains, showed lethal wasting, a lymphocyte deficit in their lymphoid organs and blood, their packed cell volume was reduced and some had liver lesions associated with the hepatotrophic virus MHV-1. As in C3H/Bi and hybrid mice, thymectomy had little effect on the levels of immunoglobulins (IgG, IgA, IgM) present in their sera. Removing the thymus from NZB mice did not prevent and could precipitate Coombs positive reactions; thymectomized mice of the other strains were Coombs negative. Although germinal centres develop and plasma cells occur in the lymphoid organs of most thymectomized mice, the striking feature of the NZB mice was the large number, size and activity of the germinal centres that persisted after thymectomy. ImagesFig. 3Fig. 4 PMID:4166241

  19. Delayed stabilization of dendritic spines in fragile X mice.

    PubMed

    Cruz-Martín, Alberto; Crespo, Michelle; Portera-Cailliau, Carlos

    2010-06-09

    Fragile X syndrome (FXS) causes mental impairment and autism through transcriptional silencing of the Fmr1 gene, resulting in the loss of the RNA-binding protein fragile X mental retardation protein (FMRP). Cortical pyramidal neurons in affected individuals and Fmr1 knock-out (KO) mice have an increased density of dendritic spines. The mutant mice also show defects in synaptic and experience-dependent circuit plasticity, which are known to be mediated in part by dendritic spine dynamics. We used in vivo time-lapse imaging with two-photon microscopy through cranial windows in male and female neonatal mice to test the hypothesis that dynamics of dendritic protrusions are altered in KO mice during early postnatal development. We find that layer 2/3 neurons from wild-type mice exhibit a rapid decrease in dendritic spine dynamics during the first 2 postnatal weeks, as immature filopodia are replaced by mushroom spines. In contrast, KO mice show a developmental delay in the downregulation of spine turnover and in the transition from immature to mature spine subtypes. Blockade of metabotropic glutamate receptor (mGluR) signaling, which reverses some adult phenotypes of KO mice, accentuated this immature protrusion phenotype in KO mice. Thus, absence of FMRP delays spine stabilization and dysregulated mGluR signaling in FXS may partially normalize this early synaptic defect.

  20. Neurturin-deficient mice develop dry eye and keratoconjunctivitis sicca.

    PubMed

    Song, Xiu Jun; Li, De-Quan; Farley, William; Luo, Li Hui; Heuckeroth, Robert O; Milbrandt, Jeffrey; Pflugfelder, Stephen C

    2003-10-01

    Neurturin has been identified as a neurotrophic factor for parasympathetic neurons. Neurturin-deficient (NRTN(-/-)) mice have defective parasympathetic innervation of their lacrimal glands. This study was conducted to evaluate tear function and ocular surface phenotype in NRTN(-/-) mice. Determined by tail genomic DNA PCR, 25 NRTN(-/-) mice and 17 neurturin-normal (NRTN(+/+)) mice aged 6 weeks to 4 months were evaluated. Aqueous tear production, tear fluorescein clearance and corneal sensation were serially measured. Corneal permeability to AlexaFluor dextran (AFD; Molecular Probes, Eugene, OR) was measured by a fluorometric assay at 485 nm excitation and 530 nm emission. Histology was evaluated in PAS-stained sections. Mucin and HLA class II (IA) antigen were assessed by immunofluorescent staining. Tear IL-1beta was measured by ELISA, and tear matrix metalloproteinase (MMP)-9 by zymography. Gene expression in the corneal epithelia was analyzed by semiquantitative RT-PCR. In comparison to that in age-matched NRTN(+/+) mice, aqueous tear production, tear fluorescein clearance, and corneal sensation were significantly reduced in NRTN(-/-) mice, whereas corneal permeability to AFD was significantly increased. Immunoreactive MUC-4 and -5AC mucin and goblet cell density (P < 0.001) in the conjunctiva of NRTN(-/-) mice were lower than in NRTN(+/+) mice. The expression of MUC-1 and -4 mRNA by the corneal epithelium was reduced in NRTN(-/-) mice. There were a significantly greater number of IA antigen-positive conjunctival epithelial cells in NRTN(-/-) mice than NRTN(+/+) mice. Tear fluid IL-1beta and MMP-9 concentrations and the expression of IL-1beta, TNF-alpha, macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant (KC), and MMP-9 mRNA by the corneal epithelia were significantly increased in NRTN(-/-) mice, compared with NRTN(+/+) mice. Neurturin-deficient mice show phenotypic changes and ocular surface inflammation that mimic human

  1. Paintings discrimination by mice: Different strategies for different paintings.

    PubMed

    Watanabe, Shigeru

    2017-09-01

    C57BL/6 mice were trained on simultaneous discrimination of paintings with multiple exemplars, using an operant chamber with a touch screen. The number of exemplars was successively increased up to six. Those mice trained in Kandinsky/Mondrian discrimination showed improved learning and generalization, whereas those trained in Picasso/Renoir discrimination showed no improvements in learning or generalization. These results suggest category-like discrimination in the Kandinsky/Mondrian task, but item-to-item discrimination in the Picasso/Renoir task. Mice maintained their discriminative behavior in a pixelization test with various paintings; however, mice in the Picasso/Renoir task showed poor performance in a test that employed scrambling processing. These results do not indicate that discrimination strategy for any Kandinsky/Mondrian combinations differed from that for any Picasso/Monet combinations but suggest the mice employed different strategies of discrimination tasks depending upon stimuli. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Neutrino Factory Targets and the MICE Beam

    SciTech Connect

    Walaron, Kenneth Andrew

    2007-01-01

    The future of particle physics in the next 30 years must include detailed study of neutrinos. The first proof of physics beyond the Standard Model of particle physics is evident in results from recent neutrino experiments which imply that neutrinos have mass and flavour mixing. The Neutrino Factory is the leading contender to measure precisely the neutrino mixing parameters to probe beyond the Standard Model physics. Significantly, one must look to measure the mixing angle θ 13 and investigate the possibility of leptonic CP violation. If found this may provide a key insight into the origins of the matter/anti- mattermore » asymmetry seen in the universe, through the mechanism of leptogenesis. The Neutrino Factory will be a large international multi-billion dollar experiment combining novel new accelerator and long-baseline detector technology. Arguably the most important and costly features of this facility are the proton driver and cooling channel. This thesis will present simulation work focused on determining the optimal proton driver energy to maximise pion production and also simulation of the transport of this pion °ux through some candidate transport lattices. Bench-marking of pion cross- sections calculated by MARS and GEANT4 codes to measured data from the HARP experiment is also presented. The cooling channel aims to reduce the phase-space volume of the decayed muon beam to a level that can be e±ciently injected into the accelerator system. The Muon Ionisation Cooling Experiment (MICE) hosted by the Rutherford Appleton laboratory, UK is a proof-of-principle experiment aimed at measuring ionisation cooling. The experiment will run parasitically to the ISIS accelerator and will produce muons from pion decay. The MICE beamline provides muon beams of variable emittance and momentum to the MICE experiment to enable measurement of cooling over a wide range of beam conditions. Simulation work in the design of this beamline is presented in this thesis as are

  3. Microbiota-Derived Metabolic Factors Reduce Campylobacteriosis in Mice.

    PubMed

    Sun, Xiaolun; Winglee, Kathryn; Gharaibeh, Raad Z; Gauthier, Josee; He, Zhen; Tripathi, Prabhanshu; Avram, Dorina; Bruner, Steven; Fodor, Anthony; Jobin, Christian

    2018-05-01

    Campylobacter jejuni, a prevalent foodborne bacterial pathogen, exploits the host innate response to induce colitis. Little is known about the roles of microbiota in C jejuni-induced intestinal inflammation. We investigated interactions between microbiota and intestinal cells during C jejuni infection of mice. Germ-free C57BL/6 Il10 -/- mice were colonized with conventional microbiota and infected with a single dose of C jejuni (10 9 colony-forming units/mouse) via gavage. Conventional microbiota were cultured under aerobic, microaerobic, or anaerobic conditions and orally transplanted into germ-free Il10 -/- mice. Colon tissues were collected from mice and analyzed by histology, real-time polymerase chain reaction, and immunoblotting. Fecal microbiota and bile acids were analyzed with 16S sequencing and high-performance liquid chromatography with mass spectrometry, respectively. Introduction of conventional microbiota reduced C jejuni-induced colitis in previously germ-free Il10 -/- mice, independent of fecal load of C jejuni, accompanied by reduced activation of mammalian target of rapamycin. Microbiota transplantation and 16S ribosomal DNA sequencing experiments showed that Clostridium XI, Bifidobacterium, and Lactobacillus were enriched in fecal samples from mice colonized with microbiota cultured in anaerobic conditions (which reduce colitis) compared with mice fed microbiota cultured under aerobic conditions (susceptible to colitis). Oral administration to mice of microbiota-derived secondary bile acid sodium deoxycholate, but not ursodeoxycholic acid or lithocholic acid, reduced C jejuni-induced colitis. Depletion of secondary bile acid-producing bacteria with antibiotics that kill anaerobic bacteria (clindamycin) promoted C jejuni-induced colitis in specific pathogen-free Il10 -/- mice compared with the nonspecific antibiotic nalidixic acid; colitis induction by antibiotics was associated with reduced level of luminal deoxycholate. We identified a

  4. Comprehensive Behavioral Analysis of Activating Transcription Factor 5-Deficient Mice

    PubMed Central

    Umemura, Mariko; Ogura, Tae; Matsuzaki, Ayako; Nakano, Haruo; Takao, Keizo; Miyakawa, Tsuyoshi; Takahashi, Yuji

    2017-01-01

    Activating transcription factor 5 (ATF5) is a member of the CREB/ATF family of basic leucine zipper transcription factors. We previously reported that ATF5-deficient (ATF5-/-) mice demonstrated abnormal olfactory bulb development due to impaired interneuron supply. Furthermore, ATF5-/- mice were less aggressive than ATF5+/+ mice. Although ATF5 is widely expressed in the brain, and involved in the regulation of proliferation and development of neurons, the physiological role of ATF5 in the higher brain remains unknown. Our objective was to investigate the physiological role of ATF5 in the higher brain. We performed a comprehensive behavioral analysis using ATF5-/- mice and wild type littermates. ATF5-/- mice exhibited abnormal locomotor activity in the open field test. They also exhibited abnormal anxiety-like behavior in the light/dark transition test and open field test. Furthermore, ATF5-/- mice displayed reduced social interaction in the Crawley’s social interaction test and increased pain sensitivity in the hot plate test compared with wild type. Finally, behavioral flexibility was reduced in the T-maze test in ATF5-/- mice compared with wild type. In addition, we demonstrated that ATF5-/- mice display disturbances of monoamine neurotransmitter levels in several brain regions. These results indicate that ATF5 deficiency elicits abnormal behaviors and the disturbance of monoamine neurotransmitter levels in the brain. The behavioral abnormalities of ATF5-/- mice may be due to the disturbance of monoamine levels. Taken together, these findings suggest that ATF5-/- mice may be a unique animal model of some psychiatric disorders. PMID:28744205

  5. Salty taste deficits in CALHM1 knockout mice.

    PubMed

    Tordoff, Michael G; Ellis, Hillary T; Aleman, Tiffany R; Downing, Arnelle; Marambaud, Philippe; Foskett, J Kevin; Dana, Rachel M; McCaughey, Stuart A

    2014-07-01

    Genetic ablation of calcium homeostasis modulator 1 (CALHM1), which releases adenosine triphosphate from Type 2 taste cells, severely compromises the behavioral and electrophysiological responses to tastes detected by G protein-coupled receptors, such as sweet and bitter. However, the contribution of CALHM1 to salty taste perception is less clear. Here, we evaluated several salty taste-related phenotypes of CALHM1 knockout (KO) mice and their wild-type (WT) controls: 1) In a conditioned aversion test, CALHM1 WT and KO mice had similar NaCl avoidance thresholds. 2) In two-bottle choice tests, CALHM1 WT mice showed the classic inverted U-shaped NaCl concentration-preference function but CALHM1 KO mice had a blunted peak response. 3) In brief-access tests, CALHM1 KO mice showed less avoidance than did WT mice of high concentrations of NaCl, KCl, NH(4)Cl, and sodium lactate (NaLac). Amiloride further ameliorated the NaCl avoidance of CALHM1 KO mice, so that lick rates to a mixture of 1000 mM NaCl + 10 µM amiloride were statistically indistinguishable from those to water. 4) Relative to WT mice, CALHM1 KO mice had reduced chorda tympani nerve activity elicited by oral application of NaCl, NaLac, and sucrose but normal responses to HCl and NH(4)Cl. Chorda tympani responses to NaCl and NaLac were amiloride sensitive in WT but not KO mice. These results reinforce others demonstrating that multiple transduction pathways make complex, concentration-dependent contributions to salty taste perception. One of these pathways depends on CALHM1 to detect hypertonic NaCl in the mouth and signal the aversive taste of concentrated salt. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  6. [Development of a hepatitis B virus carrier transgenic mice model].

    PubMed

    Caner, Müge; Arat, Sezen; Bircan, Rifat

    2008-01-01

    The studies for the development of transgenic mice models which provide important profits for the studies concerning immunopathogenesis of hepatitis B virus (HBV) infections are in progress since 20 years. For this purpose different lineages bearing whole HBV genome or selected viral genes have been developed and their usage in clarifying the HBV replication and pathogenesis mechanisms have been emphasized. The aim of this study was to develop and breed a HBV carrier mice model. In the study the full HBV genome has been transferred to mouse embryos by microinjection procedure. Following transgenic manipulation, the HBV carriers among the daughter mice have been detected by molecular methods in which HBV-DNA replication and expression have been shown. The manipulations for transgene transfers have been performed in TUBITAK Marmara Research Center Transgene Laboratory, Gebze, Istanbul. The HBV-DNA carrier mice have been demonstrated by polymerase chain reaction (PCR) using the DNA samples obtained from tail tissues and also by dot-blot hybridization of the mice sera. Integrated HBV-DNA has been detected by applying in-situ hybridization to the liver tissue sections. HBV-DNA expression has been shown by reverse transcriptase PCR method with total RNA molecules that have been isolated from the liver tissues of the HBV-DNA carrier mice. HBsAg has been detected in the liver by immunohistochemical method, and HBsAg and HBeAg have additionally been demonstrated by ELISA. HBV genome, expression of the genome and the expression products have been determined in approximately 10% of the mice of which HBV-DNA have been transferred. By inbreeding heterozygote carrier mice, homozygote HBV transgenic mice line have been obtained. These HBV transgenic mice are the first lineages developed in our country. It is hopefully thought that this HBV carrier transgenic mouse model may contribute to the studies on the pathogenesis of HBV infections which are important health problems in the

  7. Probiotics Protect Mice from Ovariectomy-Induced Cortical Bone Loss

    PubMed Central

    Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H.; Farman, Helen H.; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

    2014-01-01

    The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice. PMID:24637895

  8. Probiotics protect mice from ovariectomy-induced cortical bone loss.

    PubMed

    Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H; Farman, Helen H; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

    2014-01-01

    The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice.

  9. Salty Taste Deficits in CALHM1 Knockout Mice

    PubMed Central

    Ellis, Hillary T.; Aleman, Tiffany R.; Downing, Arnelle; Marambaud, Philippe; Foskett, J. Kevin; Dana, Rachel M.; McCaughey, Stuart A.

    2014-01-01

    Genetic ablation of calcium homeostasis modulator 1 (CALHM1), which releases adenosine triphosphate from Type 2 taste cells, severely compromises the behavioral and electrophysiological responses to tastes detected by G protein–coupled receptors, such as sweet and bitter. However, the contribution of CALHM1 to salty taste perception is less clear. Here, we evaluated several salty taste–related phenotypes of CALHM1 knockout (KO) mice and their wild-type (WT) controls: 1) In a conditioned aversion test, CALHM1 WT and KO mice had similar NaCl avoidance thresholds. 2) In two-bottle choice tests, CALHM1 WT mice showed the classic inverted U-shaped NaCl concentration-preference function but CALHM1 KO mice had a blunted peak response. 3) In brief-access tests, CALHM1 KO mice showed less avoidance than did WT mice of high concentrations of NaCl, KCl, NH4Cl, and sodium lactate (NaLac). Amiloride further ameliorated the NaCl avoidance of CALHM1 KO mice, so that lick rates to a mixture of 1000mM NaCl + 10 µM amiloride were statistically indistinguishable from those to water. 4) Relative to WT mice, CALHM1 KO mice had reduced chorda tympani nerve activity elicited by oral application of NaCl, NaLac, and sucrose but normal responses to HCl and NH4Cl. Chorda tympani responses to NaCl and NaLac were amiloride sensitive in WT but not KO mice. These results reinforce others demonstrating that multiple transduction pathways make complex, concentration-dependent contributions to salty taste perception. One of these pathways depends on CALHM1 to detect hypertonic NaCl in the mouth and signal the aversive taste of concentrated salt. PMID:24846212

  10. [Role of acetylcholine in gelsenicine-induced death in mice].

    PubMed

    Lai, Zhou-Yi; Wang, Hai-Bo; Lv, Rui-Ling; Tan, Qiu-Chan; Deng, Zhi-Qin; Wang, Yuan; Sun, Xiao-Xue; Wu, Jia-Bao; Zhu, Lin-Yan; Wang, Lei; Chen, Li-Xin; Ye, Wen-Cai; Wang, Li-Wei

    2016-06-25

    The aim of this study was to investigate the relationship between the acetylcholine concentration in the blood and gelsenicine-induced death in mice. Kunming mice were given intraperitoneal injections of normal saline, gelsenicine or different doses of acetylcholine chloride. Atropine was given to the mice which received gelsenicine or medium dose acetylcholine chloride injection. The blood was sampled immediately when the mice died or survived for 20 min after injection. The acetylcholine concentration and acetylcholinesterase activity in the blood were measured by the testing kits, and the mortality was calculated and analyzed. The results showed that half lethal dose of gelsenicine (0.15 mg/kg) reduced the acetylcholinesterase activity and increased the blood acetylcholine concentration. The blood acetylcholine concentration of the dead mice in the gelsenicine group was increased to 43.0 μg/mL (from 31.1 μg/mL in the control), which was lower than that (53.9 μg/mL) of the dead mice in the medium dose acetylcholine chloride group, but almost equal to that (42.7 μg/mL) of the survival mice in the medium dose acetylcholine chloride group. Atropine could successfully rescue the mice from acetylcholine poisoning, but its efficiency of rescuing the mice from gelsenicine intoxication was weak. These results suggest that gelsenicine can inhibit acetylcholinesterase activity and increase blood acetylcholine concentration, but the accumulation of acetylcholine may not be the only or main cause of the death induced by gelsenicine in mice.

  11. Running Promotes Wakefulness and Increases Cataplexy in Orexin Knockout Mice

    PubMed Central

    España, Rodrigo A.; McCormack, Sarah L.; Mochizuki, Takatoshi; Scammell, Thomas E.

    2007-01-01

    Study Objective: People with narcolepsy and mice lacking orexin/hypocretin have disrupted sleep/wake behavior and reduced physical activity. Our objective was to identify physiologic mechanisms through which orexin deficiency reduces locomotor activity. Design: We examined spontaneous wheel running activity and its relationship to sleep/wake behavior in wild type (WT) and orexin knockout (KO) mice. Additionally, given that physical activity promotes alertness, we also studied whether orexin deficiency reduces the wake-promoting effects of exercise. Measurements and Results: Orexin KO mice ran 42% less than WT mice. Their ability to run appeared normal as they initiated running as often as WT mice and ran at normal speeds. However, their running bouts were considerably shorter, and they often had cataplexy or quick transitions into sleep after running. Wheel running increased the total amount of wakefulness in WT and orexin KO mice similarly, however, KO mice continued to have moderately fragmented sleep/wake behavior. Wheel running also doubled the amount of cataplexy by increasing the probability of transitioning into cataplexy. Conclusions: Orexin KO mice run significantly less than normal, likely due to sleepiness, imminent cataplexy, or a reduced motivation to run. Orexin is not required for the wake-promoting effects of wheel running given that both WT and KO mice had similar increases in wakefulness with running wheels. In addition, the clear increase in cataplexy with wheel running suggests the possibility that positive emotions or reward can trigger murine cataplexy, similar to that seen in people and dogs with narcolepsy. Citation: España RA; McCormack SL; Mochizuki T; Scammell TE. Running promotes wakefulness and increases cataplexy in orexin knockout mice. SLEEP 2007;30(11):1417-1425. PMID:18041476

  12. Acetaminophen-induced acute liver injury in HCV transgenic mice

    SciTech Connect

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wildmore » type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.« less

  13. Mechanical Forces Exacerbate Periodontal Defects in Bsp-null Mice

    PubMed Central

    Soenjaya, Y.; Foster, B.L.; Nociti, F.H.; Ao, M.; Holdsworth, D.W.; Hunter, G.K.; Somerman, M.J.

    2015-01-01

    Bone sialoprotein (BSP) is an acidic phosphoprotein with collagen-binding, cell attachment, and hydroxyapatite-nucleating properties. BSP expression in mineralized tissues is upregulated at onset of mineralization. Bsp-null (Bsp-/-) mice exhibit reductions in bone mineral density, bone turnover, osteoclast activation, and impaired bone healing. Furthermore, Bsp-/- mice have marked periodontal tissue breakdown, with a lack of acellular cementum leading to periodontal ligament detachment, extensive alveolar bone and tooth root resorption, and incisor malocclusion. We hypothesized that altered mechanical stress from mastication contributes to periodontal destruction observed in Bsp-/- mice. This hypothesis was tested by comparing Bsp-/- and wild-type mice fed with standard hard pellet diet or soft powder diet. Dentoalveolar tissues were analyzed using histology and micro–computed tomography. By 8 wk of age, Bsp-/- mice exhibited molar and incisor malocclusion regardless of diet. Bsp-/- mice with hard pellet diet exhibited high incidence (30%) of severe incisor malocclusion, 10% lower body weight, 3% reduced femur length, and 30% elevated serum alkaline phosphatase activity compared to wild type. Soft powder diet reduced severe incisor malocclusion incidence to 3% in Bsp-/- mice, supporting the hypothesis that occlusal loading contributed to the malocclusion phenotype. Furthermore, Bsp-/- mice in the soft powder diet group featured normal body weight, long bone length, and serum alkaline phosphatase activity, suggesting that tooth dysfunction and malnutrition contribute to growth and skeletal defects reported in Bsp-/- mice. Bsp-/- incisors also erupt at a slower rate, which likely leads to the observed thickened dentin and enhanced mineralization of dentin and enamel toward the apical end. We propose that the decrease in eruption rate is due to a lack of acellular cementum and associated defective periodontal attachment. These data demonstrate the importance of BSP

  14. Voluntary Exercise Produces Antidepressant and Anxiolytic Behavioral Effects in Mice

    PubMed Central

    Duman, Catharine H.; Schlesinger, Lee; Russell, David S.; Duman, Ronald S.

    2008-01-01

    Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment. PMID:18267317

  15. Angiopoietin-1 deficiency increases tumor metastasis in mice.

    PubMed

    Michael, Iacovos P; Orebrand, Martina; Lima, Marta; Pereira, Beatriz; Volpert, Olga; Quaggin, Susan E; Jeansson, Marie

    2017-08-11

    Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Studies have shown that Angiopoietin-1 counteracts permeability induced by a number of stimuli. Here, we test the hypothesis that loss of Angiopoietin-1/Tek signaling in the vasculature would increase metastasis. Angiopoietin-1 was deleted in mice just before birth using floxed Angiopoietin-1 and Tek mice crossed to doxycycline-inducible bitransgenic ROSA-rtTA/tetO-Cre mice. By crossing Angiopoietin-1 knockout mice to the MMTV-PyMT autochthonous mouse breast cancer model, we investigated primary tumor growth and metastasis to the lung. Furthermore, we utilized B16F10 melanoma cells subcutaneous and experimental lung metastasis models in Angiopoietin-1 and Tek knockout mice. We found that primary tumor growth in MMTV-PyMT mice was unaffected, while metastasis to the lung was significantly increased in Angiopoietin-1 knockout MMTV-PyMT mice. In addition, angiopoietin-1 deficient mice exhibited a significant increase in lung metastasis of B16F10 melanoma cells, compared to wild type mice 3 weeks after injection. Additional experiments showed that this was likely an early event due to increased attachment or extravasation of tumor cells, since seeding of tumor cells was significantly increased 4 and 24 h post tail vein injection. Finally, using inducible Tek knockout mice, we showed a significant increase in tumor cell seeding to the lung, suggesting that Angiopoietin-1/Tek signaling is important for vascular integrity to limit metastasis. This study show that loss of the Angiopoietin-1/Tek vascular growth factor system leads to increased metastasis without affecting primary tumor growth.

  16. Energy metabolism in BPH/2J genetically hypertensive mice.

    PubMed

    Jackson, Kristy L; Nguyen-Huu, Thu-Phuc; Davern, Pamela J; Head, Geoffrey A

    2014-05-01

    Recent evidence indicates that genetic hypertension in BPH/2J mice is sympathetically mediated, but these mice also have lower body weight (BW) and elevated locomotor activity compared with BPN/3J normotensive mice, suggestive of metabolic abnormalities. The aim of the present study was to determine whether hypertension in BPH/2J mice is associated with metabolic differences. Whole-body metabolic and cardiovascular parameters were measured over 24 h by indirect calorimetry and radiotelemetry respectively, in conscious young (10-13 weeks) and older (22-23 weeks) BPH/2J, normotensive BPN/3J and C57Bl6 mice. Blood pressure (BP) was greater in BPH/2J compared with both normotensive strains at both ages (P<0.01). Metabolic rate was greater in young BPH/2J compared with BPN/3J mice (P<0.01) but similar to C57Bl6 mice indicating that high metabolic rate is not necessarily related to the hypertension per say. The slope of the BP-metabolic rate relationship was comparable between BPH/2J and normotensive mice when adjusted for activity (P>0.1) suggesting differences in this relationship are not responsible for hypertension. EchoMRI revealed that percentage body composition was comparable in BPN/3J and BPH/2J mice (P>0.1) and both strains gained weight similarly with age (P=0.3). Taken together, the present findings indicate that hypertension in BPH/2J mice does not appear to be related to altered energy metabolism.

  17. Intestinal IgA responses to Giardia muris in mice depleted of helper T lymphocytes and in immunocompetent mice.

    PubMed

    Heyworth, M F

    1989-04-01

    Immunocompetent mice infected with Giardia muris generate an intestinal antibody response to this parasite and clear G. muris infection. Previous work has shown that G. muris infection is prolonged in mice that have been depleted of helper (CD4+) T lymphocytes by treatment with a monoclonal antibody (mAb) directed against the murine CD4 antigen. The aim of the present study was to compare the intestinal anti-Giardia antibody response in immunocompetent mice and in mice depleted of helper T (Th) lymphocytes by treatment with anti-CD4 mAb. Immunocompetent mice generated an IgA response to G. muris, as judged by the presence of IgA on Giardia trophozoites harvested from the intestine of these animals more than 10 days after the start of the infection. The anti-Giardia IgA response was impaired in mice depleted of Th lymphocytes, as judged by virtual absence of immunofluorescent staining of trophozoites from these animals for surface-bound IgA. Clearance of G. muris infection was impaired by treatment of mice with anti-CD4 mAb. The results suggest that Th (CD4+) lymphocytes are important for the generation of a local IgA response against G. muris trophozoites in the mouse intestine and that IgA anti-trophozoite antibody may contribute to the clearance of G. muris from the intestine of immunocompetent mice.

  18. Caudal dysgenesis in islet-1 transgenic mice

    PubMed Central

    Muller, Yunhua Li; Yueh, Yir Gloria; Yaworsky, Paul J.; Salbaum, J. Michael; Kappen, Claudia

    2014-01-01

    Maternal diabetes during pregnancy is responsible for the occurrence of diabetic embryopathy, a spectrum of birth defects that includes heart abnormalities, neural tube defects, and caudal dysgenesis syndromes. Here, we report that mice transgenic for the homeodomain transcription factor Isl-1 develop profound caudal growth defects that resemble human sacral/caudal agenesis. Isl-1 is normally expressed in the pancreas and is required for pancreas development and endocrine cell differentiation. Aberrant regulation of this pancreatic transcription factor causes increased mesodermal cell death, and the severity of defects is dependent on transgene dosage. Together with the finding that mutation of the pancreatic transcription factor HLXB9 causes sacral agenesis, our results implicate pancreatic transcription factors in the pathogenesis of birth defects associated with diabetes. PMID:12738808

  19. Heart Rate and Electrocardiography Monitoring in Mice

    PubMed Central

    Ho, David; Zhao, Xin; Gao, Shumin; Hong, Chull; Vatner, Dorothy E.; Vatner, Stephen F.

    2011-01-01

    The majority of current cardiovascular research involves studies in genetically engineered mouse models. The measurement of heart rate is central to understanding cardiovascular control under normal conditions, with altered autonomic tone, superimposed stress or disease states, both in wild type mice as well as those with altered genes. Electrocardiography (ECG) is the “gold standard” using either hard wire or telemetry transmission. In addition, heart rate is measured or monitored from the frequency of the arterial pressure pulse or cardiac contraction, or by pulse oximetry. For each of these techniques, discussions of materials and methods, as well as advantages and limitations are covered. However, only the direct ECG monitoring will determine not only the precise heart rates but also whether the cardiac rhythm is normal or not. PMID:21743842

  20. Quench anaylsis of MICE spectrometer superconducting solenoid

    SciTech Connect

    Kashikhin, Vladimir; Bross, Alan; /Fermilab

    MICE superconducting spectrometer solenoids fabrication and tests are in progress now. First tests of the Spectrometer Solenoid discovered some issues which could be related to the chosen passive quench protection system. Both solenoids do not have heaters and quench propagation relied on the 'quench back' effect, cold diodes, and shunt resistors. The solenoids have very large inductances and stored energy which is 100% dissipated in the cold mass during a quench. This makes their protection a challenging task. The paper presents the quench analysis of these solenoids based on 3D FEA solution of coupled transient electromagnetic and thermal problems. Themore » simulations used the Vector Fields QUENCH code. It is shown that in some quench scenarios, the quench propagation is relatively slow and some areas can be overheated. They describe ways of improving the solenoids quench protection in order to reduce the risk of possible failure.« less

  1. Metformin improves healthspan and lifespan in mice

    PubMed Central

    Martin-Montalvo, Alejandro; Mercken, Evi M.; Mitchell, Sarah J.; Palacios, Hector H.; Mote, Patricia L.; Scheibye-Knudsen, Morten; Gomes, Ana P.; Ward, Theresa M.; Minor, Robin K.; Blouin, Marie-José; Schwab, Matthias; Pollak, Michael; Zhang, Yongqing; Yu, Yinbing; Becker, Kevin G.; Bohr, Vilhelm A.; Ingram, Donald K.; Sinclair, David A.; Wolf, Norman S.; Spindler, Stephen R.; Bernier, Michel; de Cabo, Rafael

    2013-01-01

    Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging. PMID:23900241

  2. Metformin improves healthspan and lifespan in mice.

    PubMed

    Martin-Montalvo, Alejandro; Mercken, Evi M; Mitchell, Sarah J; Palacios, Hector H; Mote, Patricia L; Scheibye-Knudsen, Morten; Gomes, Ana P; Ward, Theresa M; Minor, Robin K; Blouin, Marie-José; Schwab, Matthias; Pollak, Michael; Zhang, Yongqing; Yu, Yinbing; Becker, Kevin G; Bohr, Vilhelm A; Ingram, Donald K; Sinclair, David A; Wolf, Norman S; Spindler, Stephen R; Bernier, Michel; de Cabo, Rafael

    2013-01-01

    Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.

  3. Can we use mice to study schizophrenia?

    PubMed

    Canetta, Sarah; Kellendonk, Christoph

    2018-03-19

    The validity of rodent models for the study of psychiatric disorders is controversial. Despite great efforts from academic institutions and pharmaceutical companies, as of today, no major therapeutic intervention has been developed for the treatment of psychiatric disorders based on mechanistic insights from rodent models. Here, we argue that despite these historical shortcomings, rodent studies are nevertheless instrumental for identifying neuronal circuit mechanisms underlying behaviours that are affected in psychiatric disorders. Focusing on schizophrenia, we will give four examples of rodent models that were generated based on genetic and environmental risk factors or pathophysiological evidence as entry points. We will then discuss how circuit analysis in these specific examples can be used for testing hypotheses about neuronal mechanisms underlying symptoms of schizophrenia, which will then guide the development of new therapies.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'. © 2018 The Author(s).

  4. [Hepatic allopurinol oxidizing enzyme in mice].

    PubMed

    Huh, K; Iwata, H; Yamamoto, I

    1975-03-01

    The relationship between allopurinol oxidizing enzyme and aldehyde oxidase was investaged in mice. The oxidation of both N-methylnicotinamide and allopurinol appears to be catalized by a single enzyme, aldehyde oxidase (aldehyde-oxygen oxidoreductase EC, 1.2.3.1.). This conclusion is based on the following evidence; The postnatal changes of allopurinol and N-methylnicotinamide oxidizing activities were similar during growth and the levels of both activities increased in a parallel fashion upon the attainment of sexual maturity. The rates of loss of the activities of both enzymes by heat denaturation as well as dexamethasone administration were similar. The inhibitors of allopurinol oxidizing enzyme also suppressed N-methylnicotinamide oxidation. Competition of N-methylnicotineamide and allopurinol for oxidation was demonstrated. The rate of increase of the activities in both enzymes was almost parallel during each step of the purification from mouse liver supernatant. It was ascertained that xanthine oxidase in the enzyme preparation does not influence allopurinol oxidation.

  5. Nanowire arrays restore vision in blind mice.

    PubMed

    Tang, Jing; Qin, Nan; Chong, Yan; Diao, Yupu; Yiliguma; Wang, Zhexuan; Xue, Tian; Jiang, Min; Zhang, Jiayi; Zheng, Gengfeng

    2018-03-06

    The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices.

  6. Autophagy is essential for hearing in mice.

    PubMed

    Fujimoto, Chisato; Iwasaki, Shinichi; Urata, Shinji; Morishita, Hideaki; Sakamaki, Yuriko; Fujioka, Masato; Kondo, Kenji; Mizushima, Noboru; Yamasoba, Tatsuya

    2017-05-11

    Hearing loss is the most frequent sensory disorder in humans. Auditory hair cells (HCs) are postmitotic at late-embryonic differentiation and postnatal stages, and their damage is the major cause of hearing loss. There is no measurable HC regeneration in the mammalian cochlea, and the maintenance of cell function is crucial for preservation of hearing. Here we generated mice deficient in autophagy-related 5 (Atg5), a gene essential for autophagy, in the HCs to investigate the effect of basal autophagy on hearing acuity. Deletion of Atg5 resulted in HC degeneration and profound congenital hearing loss. In autophagy-deficient HCs, polyubiquitinated proteins and p62/SQSTM1, an autophagy substrate, accumulated as inclusion bodies during the first postnatal week, and these aggregates increased in number. These findings revealed that basal autophagy has an important role in maintenance of HC morphology and hearing acuity.

  7. Closed-Loop Optogenetic Intervention in Mice

    PubMed Central

    Oijala, Mikko; Soltesz, Ivan

    2014-01-01

    Optogenetic interventions offer novel ways of probing, in a temporally specific manner, the roles of specific cell types in neuronal network functions of awake, behaving animals. Despite the unique potential for temporally specific optogenetic interventions in disease states, a major hurdle in its broad application to unpredictable brain states in a laboratory setting is constructing a real-time responsive system. We recently created a closed-loop system for stopping spontaneous seizures in chronically epileptic mice using optogenetic intervention. This system performs with very high sensitivity and specificity, and the strategy is relevant not only to epilepsy, but can also be used to react in real time, with optogenetic or other interventions, to diverse brain states. The protocol presented here is highly modular and requires variable time to perform. We describe the basic construction of a complete system, and include our downloadable custom closed-loop detection software which can be employed for this purpose. PMID:23845961

  8. Chronic Activation of FXR in Transgenic Mice Caused Perinatal Toxicity and Sensitized Mice to Cholesterol Toxicity

    PubMed Central

    Cheng, Qiuqiong; Inaba, Yuka; Lu, Peipei; Xu, Meishu; He, Jinhan; Zhao, Yueshui; Guo, Grace L.; Kuruba, Ramalinga; de la Vega, Rona; Evans, Rhobert W.; Li, Song

    2015-01-01

    The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage. PMID:25719402

  9. Silibinin attenuates allergic airway inflammation in mice

    SciTech Connect

    Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu

    Highlights: Black-Right-Pointing-Pointer Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. Black-Right-Pointing-Pointer Silibinin reduces the levels of various cytokines into the lung of allergic mice. Black-Right-Pointing-Pointer Silibinin prevents the development of airway hyperresponsiveness in allergic mice. Black-Right-Pointing-Pointer Silibinin suppresses NF-{kappa}B transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-{kappa}B) pathway. Because NF-{kappa}B activation plays a pivotal role in the pathogenesismore » of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-{kappa}B activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-{kappa}B activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.« less

  10. Mucosal immunogenicity of plant lectins in mice

    PubMed Central

    Lavelle, E C; Grant, G; Pusztai, A; Pfüller, U; O’Hagan, D T

    2000-01-01

    The mucosal immunogenicity of a number of plant lectins with different sugar specificities was investigated in mice. Following intranasal (i.n.) or oral administration, the systemic and mucosal antibody responses elicited were compared with those induced by a potent mucosal immunogen (cholera toxin; CT) and a poorly immunogenic protein (ovalbumin; OVA). After three oral or i.n. doses of CT, high levels of specific serum antibodies were measured and specific IgA was detected in the serum, saliva, vaginal wash, nasal wash and gut wash of mice. Immunization with OVA elicited low titres of serum IgG but specific IgA was not detected in mucosal secretions. Both oral and i.n. delivery of all five plant lectins investigated [Viscum album (mistletoe lectin 1; ML‐1), Lycospersicum esculentum (tomato lectin; LEA), Phaseolus vulgaris (PHA), Triticum vulgaris (wheat germ agglutinin (WGA), Ulex europaeus I (UEA‐1)] stimulated the production of specific serum IgG and IgA antibody after three i.n. or oral doses. Immunization with ML‐1 induced high titres of serum IgG and IgA in addition to specific IgA in mucosal secretions. The response to orally delivered ML‐1 was comparable to that induced by CT, although a 10‐fold higher dose was administered. Immunization with LEA also induced high titres of serum IgG, particularly after i.n. delivery. Low specific IgA titres were also detected to LEA in mucosal secretions. Responses to PHA, WGA and UEA‐1 were measured at a relatively low level in the serum, and little or no specific mucosal IgA was detected. PMID:10651938

  11. Quantitative cumulative biodistribution of antibodies in mice

    PubMed Central

    Yip, Victor; Palma, Enzo; Tesar, Devin B; Mundo, Eduardo E; Bumbaca, Daniela; Torres, Elizabeth K; Reyes, Noe A; Shen, Ben Q; Fielder, Paul J; Prabhu, Saileta; Khawli, Leslie A; Boswell, C Andrew

    2014-01-01

    The neonatal Fc receptor (FcRn) plays an important and well-known role in antibody recycling in endothelial and hematopoietic cells and thus it influences the systemic pharmacokinetics (PK) of immunoglobulin G (IgG). However, considerably less is known about FcRn’s role in the metabolism of IgG within individual tissues after intravenous administration. To elucidate the organ distribution and gain insight into the metabolism of humanized IgG1 antibodies with different binding affinities FcRn, comparative biodistribution studies in normal CD-1 mice were conducted. Here, we generated variants of herpes simplex virus glycoprotein D-specific antibody (humanized anti-gD) with increased and decreased FcRn binding affinity by genetic engineering without affecting antigen specificity. These antibodies were expressed in Chinese hamster ovary cell lines, purified and paired radiolabeled with iodine-125 and indium-111. Equal amounts of I-125-labeled and In-111-labeled antibodies were mixed and intravenously administered into mice at 5 mg/kg. This approach allowed us to measure both the real-time IgG uptake (I-125) and cumulative uptake of IgG and catabolites (In-111) in individual tissues up to 1 week post-injection. The PK and distribution of the wild-type IgG and the variant with enhanced binding for FcRn were largely similar to each other, but vastly different for the rapidly cleared low-FcRn-binding variant. Uptake in individual tissues varied across time, FcRn binding affinity, and radiolabeling method. The liver and spleen emerged as the most concentrated sites of IgG catabolism in the absence of FcRn protection. These data provide an increased understanding of FcRn’s role in antibody PK and catabolism at the tissue level. PMID:24572100

  12. The gut microbiota modulates host energy and lipid metabolism in mice[S

    PubMed Central

    Velagapudi, Vidya R.; Hezaveh, Rahil; Reigstad, Christopher S.; Gopalacharyulu, Peddinti; Yetukuri, Laxman; Islam, Sama; Felin, Jenny; Perkins, Rosie; Borén, Jan; Orešič, Matej; Bäckhed, Fredrik

    2010-01-01

    The gut microbiota has recently been identified as an environmental factor that may promote metabolic diseases. To investigate the effect of gut microbiota on host energy and lipid metabolism, we compared the serum metabolome and the lipidomes of serum, adipose tissue, and liver of conventionally raised (CONV-R) and germ-free mice. The serum metabolome of CONV-R mice was characterized by increased levels of energy metabolites, e.g., pyruvic acid, citric acid, fumaric acid, and malic acid, while levels of cholesterol and fatty acids were reduced. We also showed that the microbiota modified a number of lipid species in the serum, adipose tissue, and liver, with its greatest effect on triglyceride and phosphatidylcholine species. Triglyceride levels were lower in serum but higher in adipose tissue and liver of CONV-R mice, consistent with increased lipid clearance. Our findings show that the gut microbiota affects both host energy and lipid metabolism and highlights its role in the development of metabolic diseases. PMID:20040631

  13. Integration of QTL and bioinformatic tools to identify candidate genes for triglycerides in mice[S

    PubMed Central

    Leduc, Magalie S.; Hageman, Rachael S.; Verdugo, Ricardo A.; Tsaih, Shirng-Wern; Walsh, Kenneth; Churchill, Gary A.; Paigen, Beverly

    2011-01-01

    To identify genetic loci influencing lipid levels, we performed quantitative trait loci (QTL) analysis between inbred mouse strains MRL/MpJ and SM/J, measuring triglyceride levels at 8 weeks of age in F2 mice fed a chow diet. We identified one significant QTL on chromosome (Chr) 15 and three suggestive QTL on Chrs 2, 7, and 17. We also carried out microarray analysis on the livers of parental strains of 282 F2 mice and used these data to find cis-regulated expression QTL. We then narrowed the list of candidate genes under significant QTL using a “toolbox” of bioinformatic resources, including haplotype analysis; parental strain comparison for gene expression differences and nonsynonymous coding single nucleotide polymorphisms (SNP); cis-regulated eQTL in livers of F2 mice; correlation between gene expression and phenotype; and conditioning of expression on the phenotype. We suggest Slc25a7 as a candidate gene for the Chr 7 QTL and, based on expression differences, five genes (Polr3 h, Cyp2d22, Cyp2d26, Tspo, and Ttll12) as candidate genes for Chr 15 QTL. This study shows how bioinformatics can be used effectively to reduce candidate gene lists for QTL related to complex traits. PMID:21622629

  14. Experimental study on acute toxicity of Qingnao tablet to mice

    NASA Astrophysics Data System (ADS)

    Xie, Guoqi; Wang, Huamin; Ma, Zhenzhen; Hao, Shaojun; Li, Jun; Wang, Hongyu; Wen, Zhonghua; Zhang, Zhengchen

    2018-04-01

    To investigate the effect of Qingnao tablets on acute toxicity in mice. Forty mice, half male and half female, were randomly divided into normal saline group and Qingnao tablet group. After fasting for 12 hours, the mice were given 0. 4 ml / 10 g in maximum volume. In 1st, the rats were perfused 3 times (every 8 hours). The rats in the saline group were perfused with the same volume of saline in the same way. The mice were observed continuously within 3 hours and then every hour. The mice were given a normal diet for 14 consecutive days, and the changes of autonomous activity, reaction, diet, stool, secretion, eye and nose were observed daily. The mice fasted on the 13th day and weighed on the 14th day. And then put the mice to death, The changes of the liver, heart, spleen, lung, kidney, stomach, intestines, and brain were observed by the naked eye. There was no obvious abnormality in normal saline group. The autonomous activity of mice in the administration group decreased after initial administration, and gradually returned to normal after 2 hours of administration. On the day of administration, the stool of the mice became dark brown, and the feces returned to normal after 1.1 days of normal urination. No other mice had abnormal secretion, reaction, eye nose, diet, etc. On the 14th day, there were no visible heart, liver, spleen, lung, kidney, gastrointestinal tract in normal saline group and Qingnao tablet group. Abnormal changes in brain and other organs (edema, color, etc.). In the normal saline group and Qingnao tablet group, the initial weight of the mice was: 21.70 ± 0.97N 21.71 ± 1.13, and the weight of the mice on the 7th day was 29.70 ± 2.4c28.65 ± 3.11. On the 14th day, the body weight was 32.38 ± 3.40, 33.77 ± 3.82. Qingnao tablet has no obvious toxicity to the main organs of mice, so it can be considered safe in clinical use.

  15. Reward-seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors.

    PubMed

    Nemirovsky, Sergio I; Avale, M Elena; Brunner, Daniela; Rubinstein, Marcelo

    2009-11-01

    The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information. Because participation of D4Rs in executive learning is largely unknown, we challenged D4R knockout mice (Drd4(-/-)) and their wild-type (WT) littermates, neonatally treated with 6-hydroxydopamine (6-OHDA; icv) or vehicle in two operant learning paradigms. A continuous reinforcement task, in which one food-pellet was delivered after every lever press, showed that 6-OHDA-treated mice (hypodopaminergic) WT mice pressed the reinforcing lever at much lower rates than normodopaminergic WT mice. In contrast, Drd4(-/-) mice displayed increased lever pressing rates, regardless of their dopamine content. In another study, mice were trained to solve an operant two-choice task in which a first showing lever was coupled to the delivery of one food pellet only after a second lever emerged. Interval between presentation of both levers was initially 12 s and progressively shortened to 6, 2, and finally 0.5 s. Normodopaminergic WT mice obtained a pellet reward in more than 75% of the trials at 12, 6, and 2 s, whereas hypodopaminergic WT mice were severely impaired to select the reward-paired lever. Absence of D4Rs was not detrimental in this task. Moreover, hypodopaminergic Drd4(-/-) mice were as efficient as their normodopaminergic Drd4(-/-) siblings in selecting the reward-paired lever. In summary, hypodopaminergic mice exhibit severe impairments to retrieve rewards in two operant positive reinforcement tasks, but these deleterious effects are totally prevented in the absence of functional D4Rs.

  16. Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles

    SciTech Connect

    Gustafsson, Åsa, E-mail: asa.gustafsson@foi.se; Dept of Public Health and Clinical Medicine, Umeå University; Bergström, Ulrika

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 andmore » 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. - Highlights: • Hematite NPs induce differential responses in airways of healthy and allergic mice. • Hematite induced an airway inflammation in healthy mice. • Hematite induced cellular reduction in the alveolus and lymph nodes of allergic mice. • Cell death is possible due to extensive pro-oxidative environment in allergic mice. • It is important to include sensitive individuals when valuing health effects of NPs.« less

  17. Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma

    PubMed Central

    Miller, Cassandra L.; Muthupalani, Sureshkumar; Shen, Zeli; Drees, Frauke; Ge, Zhongming; Feng, Yan; Chen, Xiaowei; Gong, Guanyu; Nagar, Karan K.; Wang, Timothy C.; Gertler, Frank B.; Fox, James G.

    2016-01-01

    During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma. PMID:27045955

  18. Chronic social stress leads to altered sleep homeostasis in mice.

    PubMed

    Olini, Nadja; Rothfuchs, Iru; Azzinnari, Damiano; Pryce, Christopher R; Kurth, Salome; Huber, Reto

    2017-06-01

    Disturbed sleep and altered sleep homeostasis are core features of many psychiatric disorders such as depression. Chronic uncontrollable stress is considered an important factor in the development of depression, but little is known on how chronic stress affects sleep regulation and sleep homeostasis. We therefore examined the effects of chronic social stress (CSS) on sleep regulation in mice. Adult male C57BL/6 mice were implanted for electrocortical recordings (ECoG) and underwent either a 10-day CSS protocol or control handling (CON). Subsequently, ECoG was assessed across a 24-h post-stress baseline, followed by a 4-h sleep deprivation, and then a 20-h recovery period. After sleep deprivation, CSS mice showed a blunted increase in sleep pressure compared to CON mice, as measured using slow wave activity (SWA, electroencephalographic power between 1-4Hz) during non-rapid eye movement (NREM) sleep. Vigilance states did not differ between CSS and CON mice during post-stress baseline, sleep deprivation or recovery, with the exception of CSS mice exhibiting increased REM sleep during recovery sleep. Behavior during sleep deprivation was not affected by CSS. Our data provide evidence that CSS alters the homeostatic regulation of sleep SWA in mice. In contrast to acute social stress, which results in a faster SWA build-up, CSS decelerates the homeostatic build up. These findings are discussed in relation to the causal contribution of stress-induced sleep disturbance to depression. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Sensitivity of inbred and selectively bred mice to ethanol.

    PubMed

    Smolen, A; Smolen, T N; van de Kamp, J L

    1987-01-01

    The Long-Sleep (LS) and Short-Sleep (SS) mice were bred for differences in sensitivity to ethanol as measured by duration of loss of the righting response (sleep time). The foundation population was a heterogeneous stock (HS) which was derived from a cross of eight inbred strains. Ethanol-induced sleep time and waking blood and brain ethanol levels were measured in the eight inbred strains, LS, SS and HS mice. The C3H and ISBI strains were quite resistant to ethanol as measured by sleep time, and only one, RIII, was very sensitive. Waking ethanol concentrations were similar for all of the inbreds, implying a narrow range of central nervous system sensitivity to ethanol. The HS mice had relatively short sleep times and blood ethanol levels equal to most of the inbred. The LS mice were significantly more, and the SS mice significantly less sensitive to ethanol than any of the inbreds or HS mice. These studies suggest that the extremes of CNS sensitivities to ethanol manifested by the LS and SS mice cannot be traced to any of the inbred strains, and must have arisen through the selection process by changes in allelic frequencies of those genes conferring ethanol sensitivity and resistance.

  20. Assessment of Dental Fluorosis in Mmp20+/− Mice

    PubMed Central

    Sharma, R.; Tye, C.E.; Arun, A.; MacDonald, D.; Chatterjee, A.; Abrazinski, T.; Everett, E.T.; Whitford, G.M.; Bartlett, J.D.

    2011-01-01

    The molecular mechanisms that underlie dental fluorosis are poorly understood. The retention of enamel proteins hallmarking fluorotic enamel may result from impaired hydrolysis and/or removal of enamel proteins. Previous studies have suggested that partial inhibition of Mmp20 expression is involved in the etiology of dental fluorosis. Here we ask if mice expressing only one functional Mmp20 allele are more susceptible to fluorosis. We demonstrate that Mmp20+/− mice express approximately half the amount of MMP20 as do wild-type mice. The Mmp20 heterozygous mice have normal-appearing enamel, with Vickers microhardness values similar to those of wild-type control enamel. Therefore, reduced MMP20 expression is not solely responsible for dental fluorosis. With 50-ppm-fluoride (F−) treatment ad libitum, the Mmp20+/− mice had F− tissue levels similar to those of Mmp20+/+ mice. No significant difference in enamel hardness was observed between the F−-treated heterozygous and wild-type mice. Interestingly, we did find a small but significant difference in quantitative fluorescence between these two groups, which may be attributable to slightly higher protein content in the Mmp20+/− mouse enamel. We conclude that MMP20 plays a nominal role in dental enamel fluorosis. PMID:21386097

  1. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice

    PubMed Central

    Mazagova, Magdalena; Wang, Lirui; Anfora, Andrew T.; Wissmueller, Max; Lesley, Scott A.; Miyamoto, Yukiko; Eckmann, Lars; Dhungana, Suraj; Pathmasiri, Wimal; Sumner, Susan; Westwater, Caroline; Brenner, David A.; Schnabl, Bernd

    2015-01-01

    Translocation of bacteria and their products across the intestinal barrier is common in patients with liver disease, and there is evidence that experimental liver fibrosis depends on bacterial translocation. The purpose of our study was to investigate liver fibrosis in conventional and germ-free (GF) C57BL/6 mice. Chronic liver injury was induced by administration of thioacetamide (TAA) in the drinking water for 21 wk or by repeated intraperitoneal injections of carbon tetrachloride (CCl4). Increased liver fibrosis was observed in GF mice compared with conventional mice. Hepatocytes showed more toxin-induced oxidative stress and cell death. This was accompanied by increased activation of hepatic stellate cells, but hepatic mediators of inflammation were not significantly different. Similarly, a genetic model using Myd88/Trif-deficient mice, which lack downstream innate immunity signaling, had more severe fibrosis than wild-type mice. Isolated Myd88/Trif-deficient hepatocytes were more susceptible to toxin-induced cell death in culture. In conclusion, the commensal microbiota prevents fibrosis upon chronic liver injury in mice. This is the first study describing a beneficial role of the commensal microbiota in maintaining liver homeostasis and preventing liver fibrosis.—Mazagova, M., Wang, L., Anfora, A. T., Wissmueller, M., Lesley, S. A., Miyamoto, Y., Eckmann, L., Dhungana, S., Pathmasiri, W., Sumner, S., Westwater, C., Brenner, D. A., Schnabl, B. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. PMID:25466902

  2. Effects of Hindlimb Unweighting on Arterial Contractile Responses in Mice

    NASA Technical Reports Server (NTRS)

    Ma, Jia; Ren, Xin-Ling; Purdy, Ralph E.

    2003-01-01

    The aim of this work was to determine if hindlimb unweighting in mice alters arterial contractile responses. Sixteen male C57B/6 mice and 16 male Chinese Kunming mice were divided into control and 3 weeks hindlimb unweighting groups, respectively. Using isolated arterial rings from different arteries of mouse, effects of 3 weeks hindlimb unweighting on arterial contractile responsiveness were examined in vitro. The results showed that, in arterial rings from both C57B/6 and Chinese Kunming mice, maximum isometric contractile tensions evoked by either KCl or phenylephrine were significantly lower in abdominal aortic, mesenteric arterial and femoral arterial rings from hindlimb unweighting, compared to control mice. However, the maximal contractile responses of common carotid rings to KCl and PE were not significantly different between control and hindlimb unweighting groups. The sensitivity (EC(sub 50)) of all arteries to KCl or PE showed no significant differences between control and hindlimb unweighting mice. These data indicated that 3 weeks hindlimb unweighting results in a reduced capacity of the arterial smooth muscle of the hindquarter to develop tension. In addition, the alterations in arterial contractile responses caused by hindlimb unweighting in mice are similar as those in rats. Our work suggested that hindlimb unweighting mouse model may be used as a model for the study of postflight cardiovascular deconditioning.

  3. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

    PubMed Central

    Trammell, Samuel A.J.; Weidemann, Benjamin J.; Chadda, Ankita; Yorek, Matthew S.; Holmes, Amey; Coppey, Lawrence J.; Obrosov, Alexander; Kardon, Randy H.; Yorek, Mark A.; Brenner, Charles

    2016-01-01

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

  4. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

    PubMed

    Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita; Yorek, Matthew S; Holmes, Amey; Coppey, Lawrence J; Obrosov, Alexander; Kardon, Randy H; Yorek, Mark A; Brenner, Charles

    2016-05-27

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

  5. Impaired Vibration of Auditory Ossicles in Osteopetrotic Mice

    PubMed Central

    Kanzaki, Sho; Takada, Yasunari; Niida, Shumpei; Takeda, Yoshihiro; Udagawa, Nobuyuki; Ogawa, Kaoru; Nango, Nobuhito; Momose, Atsushi; Matsuo, Koichi

    2011-01-01

    In the middle ear, a chain of three tiny bones (ie, malleus, incus, and stapes) vibrates to transmit sound from the tympanic membrane to the inner ear. Little is known about whether and how bone-resorbing osteoclasts play a role in the vibration of auditory ossicles. We analyzed hearing function and morphological features of auditory ossicles in osteopetrotic mice, which lack osteoclasts because of the deficiency of either cytokine RANKL or transcription factor c-Fos. The auditory brainstem response showed that mice of both genotypes experienced hearing loss, and laser Doppler vibrometry revealed that the malleus behind the tympanic membrane failed to vibrate. Histological analysis and X-ray tomographic microscopy using synchrotron radiation showed that auditory ossicles in osteopetrotic mice were thicker and more cartilaginous than those in control mice. Most interestingly, the malleal processus brevis touched the medial wall of the tympanic cavity in osteopetrotic mice, which was also the case for c-Src kinase–deficient mice (with normal numbers of nonresorbing osteoclasts). Osteopetrotic mice showed a smaller volume of the tympanic cavity but had larger auditory ossicles compared with controls. These data suggest that osteoclastic bone resorption is required for thinning of auditory ossicles and enlargement of the tympanic cavity so that auditory ossicles vibrate freely. PMID:21356377

  6. Loss of CDKL5 disrupts respiratory function in mice.

    PubMed

    Lee, Kun-Ze; Liao, Wenlin

    2018-01-01

    Cyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serine-threonine kinase that is highly expressed in the central nervous system. Mutations in CDKL5 cause neurological and psychiatric symptoms, including early-onset seizures, motor dysfunction, autistic features and sleep breathing abnormalities in patients. It remains to be addressed whether loss of CDKL5 causes respiratory dysfunction in mice. Here, we examined the respiratory pattern of male Cdkl5 -/y mice at 1-3 months of age during resting breathing and respiratory challenge (i.e., hypoxia and hypercapnia) via whole body plethysmography. The results demonstrated that the resting respiratory frequency and tidal volume of Cdkl5 -/y mice was unaltered compared to that of WT mice at 1 month of age. However, these mutant mice exhibit transient reduction in tidal volume during respiratory challenge even the reduction was restored at 2 months of age. Notably, the sigh-breathing pattern was changed in Cdkl5 -/y mice, showing a transient reduction in sigh volume at 1-2 month of age and long-term attenuation of peak expiratory airflow from 1 to 3 month of age. Therefore, loss of CDKL5 causes breathing deficiency, supporting a CDKL5-mediated regulation of respiratory function in mice. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Hypercholesterolemia induces T cell expansion in humanized immune mice.

    PubMed

    Proto, Jonathan D; Doran, Amanda C; Subramanian, Manikandan; Wang, Hui; Zhang, Mingyou; Sozen, Erdi; Rymond, Christina C; Kuriakose, George; D'Agati, Vivette; Winchester, Robert; Sykes, Megan; Yang, Yong-Guang; Tabas, Ira

    2018-06-01

    Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.

  8. VDR deficiency affects alveolar bone and cementum apposition in mice.

    PubMed

    Zhang, Xueming; Rahemtulla, Firoz; Zhang, Ping; Thomas, Huw F

    2011-07-01

    To compare the mineralisation density (MD), morphology and histology of alveolar bone and cementum amongst VDR +/+, VDR -/-, and VDR -/- groups supplemented with a diet TD 96348, containing 20% lactose, 2.0% calcium and 1.25% phosphorous. Four groups of mice (6 mice/group) were identified by genotyping: VDR +/+ mice (VDR wild type), VDR -/- mice (VDR deficient), VDR -/- offsprings derived from VDR -/- parents receiving a supplemental diet (early rescued), and VDR -/- mice fed with a supplemental diet beginning at age one month (late rescued). All mice were sacrificed at age 70.5 days. Micro-CT was used to compare MD and morphology of alveolar bone and cementum. H-E and Toluidine blue staining was used to examine the ultrastructure of the alveolar bone and cementum at matched locations. In VDR -/- group, alveolar bone and cementum failed to mineralise normally. Early rescue increased MD of alveolar bone in VDR -/- mice with excessive alveolar bone formation, but which not observed in late rescue group. MD and morphology of cementum-dentine complex in both early and late rescue groups were comparable with VDR +/+ group when feeding with high-calcium rescue diet. VDR affects alveolar bone mineralisation and formation systemically and locally. However, cementum apposition and mineralisation is mainly regulated by calcium concentrations in serum. Copyright © 2010 Elsevier Ltd. All rights reserved.

  9. Cytokine expression profile over time in burned mice.

    PubMed

    Finnerty, Celeste C; Przkora, Rene; Herndon, David N; Jeschke, Marc G

    2009-01-01

    The persistent inflammatory response induced by a severe burn increases patient susceptibility to infections and sepsis, potentially leading to multi-organ failure and death. In order to use murine models to develop interventions that modulate the post-burn inflammatory response, the response in mice and the similarities to the human response must first be determined. Here, we present the temporal serum cytokine expression profiles in burned mice in comparison to sham mice and human burn patients. Male C57BL/6 mice were randomized to control (n=47) or subjected to a 35% TBSA scald burn (n=89). Mice were sacrificed 3, 6, 9, 12, 24, and 48 h and 7, 10, and 14 days post-burn; cytokines were measured by multi-plex array. Following the burn injury, IL-6, IL-1beta, KC, G-CSF, TNF, IL-17, MIP-1alpha, RANTES, and GM-CSF were increased, p<0.05. IL-2, IL-3, and IL-5 were decreased, p<0.05. IL-10, IFN-gamma, and IL-12p70 were expressed in a biphasic manner, p<0.05. This temporal cytokine expression pattern elucidates the pathogenesis of the inflammatory response in burned mice. Expression of 11 cytokines were similar in mice and children, returning to lowest levels by post-burn day 14, confirming the utility of the burned mouse model for development of therapeutic interventions to attenuate the post-burn inflammatory response.

  10. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.

    PubMed

    Toth, Peter; Tucsek, Zsuzsanna; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2014-12-01

    Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.

  11. Lung Function Changes in Mice Sensitized to Ammonium ...

    EPA Pesticide Factsheets

    Occupational exposure to halogenated platinum salts can trigger the development of asthma. The risk to the general population that may result from the use of platinum in catalytic converters and its emerging use as a diesel fuel additive is unclear. To investigate pulmonary responses to platinum, we developed a mouse model of platinum hypersensitivity. Mice were sensitized through application of ammonium hexachloroplatinate (AHCP) to the shaved back on days 0, 5 and 19, and to each ear on days 10, 11 and 12. On days 24 and 29, mice were challenged by oropharyngeal aspiration with AHCP in saline. Before and immediately after challenge, pulmonary responses were assessed using whole body plethysmography (WBP). A dose-dependentincrease in immediate responses was observed in AHCP-sensitized and challenged mice. On days 26 and 31, changes in ventilatory responses to methacholine (Mch) aerosol were assessed by WBP; dose-dependent increases in Mch responsiveness occurred in sensitized mice. Lymph node cell counts indicate a proliferative response in lymph nodes drainng the sites of application. Bronchoalveolar lavage fluid harvested from sensitized mice contained an average of 5% eosinophils compared to less than 0.5% in non-sensitized mice (p < 0.05); significant increases in total serum immunoglobulin E were observed for all sensitized mice. Although a second airway challenge on day 29 affected some results, only one airway challenge was needed to observe changes in l

  12. Impaired olfaction in mice lacking aquaporin-4 water channels

    PubMed Central

    Lu, Daniel C.; Zhang, Hua; Zador, Zsolt; Verkman, A. S.

    2008-01-01

    Aquaporin-4 (AQP4) is a water-selective transport protein expressed in glial cells throughout the central nervous system. AQP4 deletion in mice produces alterations in several neuroexcitation phenomena, including hearing, vision, epilepsy, and cortical spreading depression. Here, we report defective olfaction and electroolfactogram responses in AQP4-null mice. Immunofluorescence indicated strong AQP4 expression in supportive cells of the nasal olfactory epithelium. The olfactory epithelium in AQP4-null mice had identical appearance, but did not express AQP4, and had ∼12-fold reduced osmotic water permeability. Behavioral analysis showed greatly impaired olfaction in AQP4-null mice, with latency times of 17 ± 0.7 vs. 55 ± 5 s in wild-type vs. AQP4-null mice in a buried food pellet test, which was confirmed using an olfactory maze test. Electroolfactogram voltage responses to multiple odorants were reduced in AQP4-null mice, with maximal responses to triethylamine of 0.80 ± 0.07 vs. 0.28 ± 0.03 mV. Similar olfaction and electroolfactogram defects were found in outbred (CD1) and inbred (C57/bl6) mouse genetic backgrounds. Our results establish AQP4 as a novel determinant of olfaction, the deficiency of which probably impairs extracellular space K+ buffering in the olfactory epithelium.—Lu, D. C., Zhang, H., Zador, Z., Verkman, A. S. Impaired olfaction in mice lacking aquaporin-4 water channels. PMID:18511552

  13. Telmisartan regresses left ventricular hypertrophy in caveolin-1 deficient mice

    PubMed Central

    Kreiger, Marta H; Di Lorenzo, Annarita; Teutsch, Christine; Kauser, Katalin; Sessa, William C.

    2011-01-01

    The role of angiotensin II (Ang II) in promoting cardiac hypertrophy is well known, however the role of the Ang II in a spontaneous model of hypertrophy in mice lacking the protein caveolin-1 (Cav- KO) has not been explored. In this study, WT and Cav-1 KO mice were treated with angiotensin receptor blocker (ARB), telmisartan, and cardiac function assessed by echocardiography. Treatment of Cav-1 KO mice with telmisartan significantly improved cardiac function compared to age-matched, vehicle treated Cav-1 KO mice, while telmisartan did not affected cardiac function in WT mice. Both left ventricular (LV) weight to body weight ratios and LV to tibial length ratios were also reverted by telmisartan in Cav-1 KO but not WT mice. LV hypertrophy was associated with increased expression of natriuretic peptides-A and –B, β-myosin heavy chain and TGF-β and telmisartan treatment normalized the expression of these genes. Telmisartan reduced the expression of collagen genes (Col1A and Col3A) and associated perivascular fibrosis in intramyocardial vessels in Cav-1 KO mice. In conclusion, telmisartan treatment reduces indexes of cardiac hypertrophy in this unique genetic model of spontaneous LV hypertrophy. PMID:20585312

  14. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates.

    PubMed

    Cheal, Sarah M; Xu, Hong; Guo, Hong-Fen; Lee, Sang-Gyu; Punzalan, Blesida; Chalasani, Sandhya; Fung, Edward K; Jungbluth, Achim; Zanzonico, Pat B; Carrasquillo, Jorge A; O'Donoghue, Joseph; Smith-Jones, Peter M; Wittrup, K Dane; Cheung, Nai-Kong V; Larson, Steven M

    2016-05-01

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens (177)Lu-or (86)Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq (177)Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten (86)Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.

  15. Effects of Social Defeat Stress on Sleep in Mice.

    PubMed

    Henderson, Fiona; Vialou, Vincent; El Mestikawy, Salah; Fabre, Véronique

    2017-01-01

    Stress plays a key role in the development of psychiatric disorders and has a negative impact on sleep integrity. In mice, chronic social defeat stress (CSDS) is an ethologically valid model of stress-related disorders but little is known about its effects on sleep regulation. Here, we investigated the immediate and long-term effects of 10 consecutive days of social defeat (SD) on vigilance states in C57Bl/6J male mice. Social behavior was assessed to identify susceptible mice, i.e., mice that develop long-lasting social avoidance, and unsusceptible mice. Sleep-wake stages in mice of both groups were analyzed by means of polysomnographic recordings at baseline, after the first, third, and tenth stress sessions and on the 5th recovery day (R5) following the 10-day CSDS. In susceptible mice, each SD session produced biphasic changes in sleep-wake states that were preserved all along 10-day CSDS. These sessions elicited a short-term enhancement of wake time while rapid eye-movement (REM) sleep was strongly inhibited. Concomitantly, delta power was increased during non REM (NREM) sleep. During the following dark period, an increase in total sleep time, as well as wake fragmentation, were observed after each analyzed SD session. Similar changes were observed in unsusceptible mice. At R5, elevated high-frequency EEG activity, as observed in insomniacs, emerged during NREM sleep in both susceptible and unsusceptible groups suggesting that CSDS impaired sleep quality. Furthermore, susceptible but not unsusceptible mice displayed stress-anticipatory arousal during recovery, a common feature of anxiety disorders. Altogether, our findings show that CSDS has profound impacts on vigilance states and further support that sleep is tightly regulated by exposure to stressful events. They also revealed that susceptibility to chronic psychological stress is associated with heightened arousal, a physiological feature of stress vulnerability.

  16. Procedures for Behavioral Experiments in Head-Fixed Mice

    PubMed Central

    Guo, Zengcai V.; Hires, S. Andrew; Li, Nuo; O'Connor, Daniel H.; Komiyama, Takaki; Ophir, Eran; Huber, Daniel; Bonardi, Claudia; Morandell, Karin; Gutnisky, Diego; Peron, Simon; Xu, Ning-long; Cox, James; Svoboda, Karel

    2014-01-01

    The mouse is an increasingly prominent model for the analysis of mammalian neuronal circuits. Neural circuits ultimately have to be probed during behaviors that engage the circuits. Linking circuit dynamics to behavior requires precise control of sensory stimuli and measurement of body movements. Head-fixation has been used for behavioral research, particularly in non-human primates, to facilitate precise stimulus control, behavioral monitoring and neural recording. However, choice-based, perceptual decision tasks by head-fixed mice have only recently been introduced. Training mice relies on motivating mice using water restriction. Here we describe procedures for head-fixation, water restriction and behavioral training for head-fixed mice, with a focus on active, whisker-based tactile behaviors. In these experiments mice had restricted access to water (typically 1 ml/day). After ten days of water restriction, body weight stabilized at approximately 80% of initial weight. At that point mice were trained to discriminate sensory stimuli using operant conditioning. Head-fixed mice reported stimuli by licking in go/no-go tasks and also using a forced choice paradigm using a dual lickport. In some cases mice learned to discriminate sensory stimuli in a few trials within the first behavioral session. Delay epochs lasting a second or more were used to separate sensation (e.g. tactile exploration) and action (i.e. licking). Mice performed a variety of perceptual decision tasks with high performance for hundreds of trials per behavioral session. Up to four months of continuous water restriction showed no adverse health effects. Behavioral performance correlated with the degree of water restriction, supporting the importance of controlling access to water. These behavioral paradigms can be combined with cellular resolution imaging, random access photostimulation, and whole cell recordings. PMID:24520413

  17. Low-dose ethanol aggravates allergic dermatitis in mice.

    PubMed

    Sakazaki, Fumitoshi; Ogino, Hirofumi; Arakawa, Tomohiro; Okuno, Tomofumi; Ueno, Hitoshi

    2014-08-01

    Alcohol injures dendritic cells and suppresses cellular immunity, while some evidence indicates that drinking alcohol aggravates allergic asthma. This study investigated the effect of low doses of ethanol in enhancing allergic reactions in the skin of mice. Liquid food containing alcohol was administered to conventional NC/Nga mice to induce alcoholic hepatic steatosis, and spontaneous dermatitis was evaluated. BALB/c mice were administered approximately 1 g/kg body weight of ethanol by gavage, and contact hypersensitivity (CHS) or active cutaneous anaphylaxis (ACA) was induced. Spleens were collected 24 h after the elicitation of CHS and mRNA expressions of interferon (IFN)-γ, interleukin (IL)-4, IL-6, IL-10, and IL-18 were measured by quantitative RT-PCR. Alcohol-containing diet exaggerated spontaneous dermatitis in conventional NC/Nga mice and contact hypersensitivity in BALB/c mice. Ethanol administered by gavage for 5 days enhanced contact hypersensitivity in BALB/c mice. Ethanol administration with gavage also enhanced ACA of BALB/c mice. Ethanol did not affect mRNA expression of IFN-γ and IL-4, but did enhance IL-6, IL-10, and IL-18 mRNA expression. Histological evaluation revealed an absence of hepatic steatosis in mice administered ethanol by gavage for 5 days. In ethanol-administered mice, inflamed areas presented as lesions or a local extreme accumulation of mononuclear cells in the epidermis. These findings suggest that ethanol enhances the expression of inflammatory cytokines independently from T helper (Th)1/Th2 cytokine phenotypes, causing abnormalities in the epidermis resulting in exacerbated allergic reactivity. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Elevated body temperature during sleep in orexin knockout mice

    PubMed Central

    Mochizuki, Takatoshi; Klerman, Elizabeth B.; Sakurai, Takeshi; Scammell, Thomas E.

    2008-01-01

    Core body temperature (Tb) is influenced by many physiological factors, including behavioral state, locomotor activity, and biological rhythms. To determine the relative roles of these factors, we examined Tb in orexin knockout (KO) mice, which have a narcolepsy-like phenotype with severe sleep-wake fragmentation. Because orexin is thought to promote heat production during wakefulness, we hypothesized that orexin KO mice would have lower Tb while awake. Surprisingly, the Tb of orexin KO mice was 0.4°C higher than wild-type (WT) littermates during the dark period. Orexin KO mice had normal diurnal variations in Tb, but the ultradian rhythms of Tb, locomotor activity, and wakefulness were markedly reduced. During sustained wakefulness, Tb was the same in both groups. During the first 15 min of spontaneous sleep, the Tb of WT mice decreased by 1.0°C, but Tb in orexin KO mice decreased only 0.4°C. Even during intense recovery sleep after 8 hr of sleep deprivation, the Tb of orexin KO mice remained 0.7°C higher than in WT mice. This blunted fall in Tb during sleep may be due to inadequate activation of heat loss mechanisms or sustained activity in heat-generating systems. These observations reveal an unexpected role for orexin in thermoregulation. In addition, because heat loss is an essential aspect of sleep, the blunted fall in Tb of orexin KO mice may provide an explanation for the fragmented sleep of narcolepsy. PMID:16556901

  19. Feeding-elicited cataplexy in orexin knockout mice

    PubMed Central

    Clark, Erika L.; Baumann, Christian R.; Cano, Georgina; Scammell, Thomas E.; Mochizuki, Takatoshi

    2009-01-01

    Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad lib regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 hr after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more cataplexy during the food-anticipation period and more cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy. PMID:19362119

  20. Saw palmetto extract induces nuclear heterogeneity in mice.

    PubMed

    Trinachartvanit, Wachareeporn; Francis, Bettina M; Rayburn, A Lane

    2009-01-01

    Saw palmetto (SW), a phytotherapeutic compound used in the treatment of prostate disease, was examined for potential nuclear effects. SW extract was incorporated into a complete casein-based semisynthetic rodent chow at 0%, 0.1% and 1% SW. SW was fed to mice for 6 weeks, after which the mice received a single i/p injection of either the known genotoxic agent methyl methanesulfonate (MMS) in saline or just saline. Forty-eight hours after injection, blood and bone marrow were collected for flow cytometric analysis. A significant effect of MMS was observed in both male and female mice with respect to: an increase in nuclear heterogeneity in bone marrow cells as measured by the coefficient of variation of the G1 peak in a flow histogram (6.32 versus 4.8 in male mice, 7.0 versus 4.9 in female mice) and an increase in the number of micronucleated blood cells (3.4% versus 0.56% male mice, 3.1% versus 0.6 in female mice) indicating a positive genotoxic response. SW also appears to increase the heterogeneity of bone marrow nuclei in a dose dependent manner (0-5.1%, 0.1-5.5% and 1-5.7% in male mice, 0-5.7%, 0.1-6.0% and 1-6.2% in female mice) without a concomitant increase in blood cell micronuclei. These results indicate that SW is not genotoxic with respect to physical DNA damage and that the changes observed in the bone marrow are due to chromatin conformation modifications in the nuclei of in vivo treated mouse cells. Copyright © 2008 Elsevier B.V. All rights reserved.

  1. Chronic rapamycin treatment causes diabetes in male mice

    PubMed Central

    Schindler, Christine E.; Partap, Uttara; Patchen, Bonnie K.

    2014-01-01

    Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes. PMID:24965794

  2. Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice.

    PubMed

    Zhang, Zhuan; Hong, Juan; Zhang, Suyun; Zhang, Tingting; Sha, Sha; Yang, Rong; Qian, Yanning; Chen, Ling

    2016-04-01

    Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU(+) and BrdU(+)/NeuN(+) cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU(+) cells were increased in HSP mice and OVX/EB mice; and the density of DCX(+) fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU(+) cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU(+) cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX(+) fibers in HSP mice without the reduction of 28-day-old BrdU(+) cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Effects of social isolation, re-socialization and age on cognitive and aggressive behaviors of Kunming mice and BALB/c mice.

    PubMed

    An, Dong; Chen, Wei; Yu, De-Qin; Wang, Shi-Wei; Yu, Wei-Zhi; Xu, Hong; Wang, Dong-Mei; Zhao, Dan; Sun, Yi-Ping; Wu, Jun-Cheng; Tang, Yi-Yuan; Yin, Sheng-Ming

    2017-05-01

    Both Kunming (KM) mice and BALB/c mice have been widely used as rodent models to investigate stress-associated mental diseases. However, little is known about the different behaviors of KM mice and BALB/c mice after social isolation, particularly cognitive and aggressive behaviors. In this study, the behaviors of KM and BALB/c mice isolated for 2, 4 and 8 weeks and age-matched controls were evaluated using object recognition, object location and resident-intruder tests. The recovery of behavioral deficits by re-socialization was also examined for the isolated mice in adolescence. Our study showed that isolation for 2, 4 and 8 weeks led to cognitive deficits and increased aggressiveness for both KM and BALB/c mice. An important finding is that re-socialization could completely recover spatial/non-spatial cognitive deficits resulted from social isolation for both KM and BALB/c mice. In addition, age only impacted aggressiveness of KM mice. Moreover, isolation duration showed different impacts on cognitive and aggressive behaviors for both KM and BALB/c mice. Furthermore, BALB/c mice showed weak spatial/non-spatial memory and low aggressiveness when they were at the same age and isolation duration, compared to KM mice. In conclusion, KM mice and BALB/c mice behaved characteristically under physiology and isolation conditions. © 2016 Japanese Society of Animal Science.

  4. Rodent models of depression: learned helplessness induced in mice.

    PubMed

    Anisman, H; Merali, Z

    2001-05-01

    Uncontrollable stressors induce a variety of behavioral disturbances that are in many ways reminiscent of the symptoms that characterize clinical depression. These deficits are evident across a range of species, including mice. Given the increasing focus on genetic techniques involving mice to identify the mechanisms subserving these behavioral disturbances (e.g., recombinant, knockout, and transgenic strains), it is of particular interest to provide a detailed description of the method to induce behavioral deficits in response to uncontrollable stressors. This unit describes the procedure used to assess the effects of controllable and uncontrollable shock on subsequent shock escape performance in mice using an escape-delay procedure.

  5. Coping with parvovirus infections in mice: health surveillance and control.

    PubMed

    Janus, Lydia M; Bleich, Andre

    2012-01-01

    Parvoviruses of mice, minute virus of mice (MVM) and mouse parvovirus (MPV), are challenging pathogens to eradicate from laboratory animal facilities. Due to the impediment on rodent-based research, recent studies have focused on the assessment of re-derivation techniques and parvoviral potential to induce persistent infections. Summarizing recent data, this review gives an overview on studies associated with parvoviral impact on research, diagnostic methods, parvoviral persistence and re-derivation techniques, demonstrating the complex nature of parvovirus infection in mice and unfolding the challenge of controlling parvovirus infections in laboratory animal facilities.

  6. Production of alpha 1,3-galactosyltransferase gene-deficient pigs by somatic cell nuclear transfer: a novel selection method for gal alpha 1,3-Gal antigen-deficient cells.

    PubMed

    Fujimura, Tatsuya; Takahagi, Yoichi; Shigehisa, Tamotsu; Nagashima, Hiroshi; Miyagawa, Shuji; Shirakura, Ryota; Murakami, Hiroshi

    2008-09-01

    The objective of the present study was to isolate alpha 1,3-galactosyltransferase (GalGT)-gene double knockout (DKO) cells using a novel simple method of cell selection method. To obtain GalGT-DKO cells, GalGT-gene single knockout (SKO) fetal fibroblast cells were cultured for three to nine passages and GalGT-null cells were separated using a biotin-labeled IB4 lectin attached to streptavidin-coated magnetic beads. After 15-17 days of additional cultivation, seven GalGT-DKO cell colonies were obtained from a total of 2.5 x 10(7) GalGT-SKO cells. A total of 926 somatic nuclear transferred embryos reconstructed with the DKO cells were transferred into eight recipient pigs, producing four farrowed, three liveborns, and six stillborns. Absence of GalGT gene in the cloned pigs was confirmed by PCR and Southern blotting. Flow cytometric analysis revealed that alphaGal antigens were not present in the cells of the cloned DKO pigs.

  7. Repertoire of BALB/c Mice Natural Anti-Carbohydrate Antibodies: Mice vs. Humans Difference, and Otherness of Individual Animals

    PubMed Central

    Bello-Gil, Daniel; Khasbiullina, Nailya; Shilova, Nadezhda; Bovin, Nicolai; Mañez, Rafael

    2017-01-01

    One of the most common genetic backgrounds for mice used as a model to investigate human diseases is the inbred BALB/c strain. This work is aimed to characterize the pattern of natural anti-carbohydrate antibodies present in the serum of 20 BALB/c mice by printed glycan array technology and to compare their binding specificities with that of human natural anti-carbohydrate antibodies. Natural antibodies (NAbs) from the serum of BALB/c mice interacted with 71 glycans from a library of 419 different carbohydrate structures. However, only seven of these glycans were recognized by the serum of all the animals studied, and other five glycans by at least 80% of mice. The pattern of the 12 glycans mostly recognized by the circulating antibodies of BALB/c mice differed significantly from that observed with natural anti-carbohydrate antibodies in humans. This lack of identical repertoires of natural anti-carbohydrate antibodies between individual inbred mice, and between mice and humans, should be taken into consideration when mouse models are intended to be used for investigation of NAbs in biomedical research. PMID:29163519

  8. 42 CFR 136a.33 - Grace period.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... explanation of their appeal rights as provided in § 36a.14 of the part. These patients shall be offered... ending September 16, 1988. During this grace period such individual's eligibility will continue to be...

  9. 42 CFR 136a.33 - Grace period.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... explanation of their appeal rights as provided in § 36a.14 of the part. These patients shall be offered... ending September 16, 1988. During this grace period such individual's eligibility will continue to be...

  10. 42 CFR 136a.33 - Grace period.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... explanation of their appeal rights as provided in § 36a.14 of the part. These patients shall be offered... ending September 16, 1988. During this grace period such individual's eligibility will continue to be...

  11. 42 CFR 136a.33 - Grace period.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... explanation of their appeal rights as provided in § 36a.14 of the part. These patients shall be offered... ending September 16, 1988. During this grace period such individual's eligibility will continue to be...

  12. 42 CFR 136a.33 - Grace period.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... explanation of their appeal rights as provided in § 36a.14 of the part. These patients shall be offered... ending September 16, 1988. During this grace period such individual's eligibility will continue to be...

  13. 8 CFR 245a.33 - Filing.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS ADJUSTMENT OF STATUS TO THAT OF PERSONS ADMITTED FOR LAWFUL TEMPORARY OR PERMANENT RESIDENT STATUS UNDER SECTION 245A OF THE IMMIGRATION AND... notice to appear until 90 days from the date of the initial denial, to allow the alien the opportunity to...

  14. CHARACTERISTICS OF IMMUNOLOGICAL MEMORY IN MICE

    PubMed Central

    Black, S. J.; Inchley, C. J.

    1974-01-01

    The kinetics of the generation of primed IgM and IgG antibody-forming cell precursors, and of helper T-cell populations, were analyzed in mice whose primary responses to high and low doses of SRBC were arrested at intervals by the immunosuppressive agents cyclophosphamide monohydrate and specific antibody. The extent to which immunological memory was established in these animals before blockade of the primary response was assessed by the hemolytic plaque assay following challenge 12 wk after priming. The presence of IgG B-memory cells and T-memory cells in suppressed mice was further investigated by the transfer into these animals of syngeneic SRBC-stimulated thymocytes or anti-θ-treated spleen cells. It was found that the progenitors of secondary IgM-synthesizing cells were primed almost immediately after injection of antigen, and that early blockade of the primary response resulted in a raised IgM response after challenge. On the other hand, priming for a secondary IgG response took at least 4 days, and was dose-dependent, although helper T populations for a secondary IgG response appeared 3 days after antigen injection. It appeared that both IgM and IgG memory cells may be considered as Y cells in terms of the X-Y-Z scheme of lymphocyte activation, but that the two populations are generated at different times after exposure to antigen. The size of either Y-cell population at any given time is dependent upon the amount of antigen available to provoke differentiation to antibody-forming Z cells, and the IgM Y-cell population in particular is likely to be depleted during the course of a normal 1° response. When IgM Y cells were maintained for long periods as a result of immunosuppression, their secondary antibody response was independent of the primed T cells necessary for a secondary IgG response. PMID:4602981

  15. Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA-uPA/SCID Mice

    PubMed Central

    Tateno, Chise; Kawase, Yosuke; Tobita, Yoshimi; Hamamura, Satoko; Ohshita, Hiroki; Yokomichi, Hiroshi; Sanada, Harumi; Kakuni, Masakazu; Shiota, Akira; Kojima, Yuha; Ishida, Yuji; Shitara, Hiroshi; Wada, Naoko A.; Tateishi, Hiromi; Sudoh, Masayuki; Nagatsuka, Shin-ichiro; Jishage, Kou-ichi; Kohara, Michinori

    2015-01-01

    We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression—not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for

  16. Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA-uPA/SCID Mice.

    PubMed

    Tateno, Chise; Kawase, Yosuke; Tobita, Yoshimi; Hamamura, Satoko; Ohshita, Hiroki; Yokomichi, Hiroshi; Sanada, Harumi; Kakuni, Masakazu; Shiota, Akira; Kojima, Yuha; Ishida, Yuji; Shitara, Hiroshi; Wada, Naoko A; Tateishi, Hiromi; Sudoh, Masayuki; Nagatsuka, Shin-Ichiro; Jishage, Kou-Ichi; Kohara, Michinori

    2015-01-01

    We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression-not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for

  17. Effects of Sleep Deprivation and Aging on Long-Term and Remote Memory in Mice

    ERIC Educational Resources Information Center

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a…

  18. CD34 EXPRESSION BY HAIR FOLLICLE STEM CELLS IS REQUIRED FOR SKIN TUMOR DEVELOPMENT IN MICE

    EPA Science Inventory

    We used knockout mice to show that a cell surface protein called CD34 is required for skin tumor formation in mice. Wild type mice treated with 7-12-Dimethylbenz(a)anthracene (DMBA) and a tumor promoter developed papillomas. When we treated CD34 knockout (KO) mice the same way, n...

  19. Body Temperature Measurements for Metabolic Phenotyping in Mice

    PubMed Central

    Meyer, Carola W.; Ootsuka, Youichirou; Romanovsky, Andrej A.

    2017-01-01

    Endothermic organisms rely on tightly balanced energy budgets to maintain a regulated body temperature and body mass. Metabolic phenotyping of mice, therefore, often includes the recording of body temperature. Thermometry in mice is conducted at various sites, using various devices and measurement practices, ranging from single-time probing to continuous temperature imaging. Whilst there is broad agreement that body temperature data is of value, procedural considerations of body temperature measurements in the context of metabolic phenotyping are missing. Here, we provide an overview of the various methods currently available for gathering body temperature data from mice. We explore the scope and limitations of thermometry in mice, with the hope of assisting researchers in the selection of appropriate approaches, and conditions, for comprehensive mouse phenotypic analyses. PMID:28824441

  20. Refinement of habituation procedures in diet-induced obese mice.

    PubMed

    Kärrberg, L; Andersson, L; Kastenmayer, R J; Ploj, K

    2016-10-01

    Orogastric gavage, while a common method for delivering experimental substances in mice, has been shown to induce stress. To minimize the associated stress with this procedure, sham gavage prior to the start of experiment is a common method for habiutating mice. We investigated whether handling and restraint could replace sham treatment in the acclimatization protocol. Mice were either undisturbed, hand-restrained for 10 s or sham-gavaged daily for six days prior to eight days of twice daily gavage. The results showed that repetitive restraint and gavage had no differences in body weight after eight days of treatment compared with the body weights at the start of treatment, whereas animals left undisturbed lost significant weight once treatment began. These data suggest that procedure refinement by replacing sham treatment with hand restraint is sufficient to acclimatize mice to the stress associated with gavage. © The Author(s) 2016.

  1. Operant ethanol self-administration in ethanol dependent mice.

    PubMed

    Lopez, Marcelo F; Becker, Howard C

    2014-05-01

    While rats have been predominantly used to study operant ethanol self-administration behavior in the context of dependence, several studies have employed operant conditioning procedures to examine changes in ethanol self-administration behavior as a function of chronic ethanol exposure and withdrawal experience in mice. This review highlights some of the advantages of using operant conditioning procedures for examining the motivational effects of ethanol in animals with a history of dependence. As reported in rats, studies using various operant conditioning procedures in mice have demonstrated significant escalation of ethanol self-administration behavior in mice rendered dependent via forced chronic ethanol exposure in comparison to nondependent mice. This paper also presents a summary of these findings, as well as suggestions for future studies. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Social factors modulate restraint stress induced hyperthermia in mice.

    PubMed

    Watanabe, Shigeru

    2015-10-22

    Stress-induced hyperthermia (SIH) was examined in three different social conditions in mice by thermographic measurement of the body surface temperature. Placing animals in cylindrical holders induced restraint stress. I examined the effect of the social factors in SIH using the thermograph (body surface temperature). Mice restrained in the holders alone showed SIH. Mice restrained in the holders at the same time as other similarly restrained cage mates (social equality condition) showed less hyperthermia. Interestingly, restrained mice with free moving cage mates (social inequality condition) showed the highest hyperthermia. These results are consistent with a previous experiment measuring the memory-enhancing effects of stress and the stress-induced elevation of corticosterone, and suggest that social inequality enhances stress. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. DEVELOPMENTAL TOXICOGENOMIC STUDIES OF PFOA AND PFOS IN MICE.

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are developmentally toxic in rodents. To better understand the mechanism(s) associated with this toxicity, we have conducted transcript profiling in mice. In an initial study, pregnant animals were dosed througho...

  4. Biglycan Overexpression on Tooth Enamel Formation in Transgenic Mice

    PubMed Central

    Wen, Xin; Zou, YanMing; Luo, Wen; Goldberg, Michel; Moats, Rex; Conti, Peter S.; Snead, Malcolm L.; Paine, Michael L.

    2008-01-01

    Previously it was shown that the volume of forming enamel of molar teeth in biglycan-null mice was greater than in genetically matched wild-type mice. This phenotypic change appeared to result from an increase in amelogenin expression, implying that biglycan directly influences amelogenin synthesis. To determine whether biglycan over-expression resulted in decreased amelogenin expression, we engineered transgenic mice to over-express biglycan in the enamel organ epithelium. Biglycan over-expression did not significantly affect the amelogenin expression in incisor and molar teeth in 3-day transgenic mice. In the transgenic animals we observed that the immature and mature enamel appeared normal. These results suggested that increasing the biglycan expression, in the cells that synthesize the precursor protein matrix for enamel, has a negligible influence on amelogenesis. PMID:18727043

  5. Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice

    PubMed Central

    Lee, Jaehoon; Kim, Hye Jin; Moon, Jung Ah; Sung, Young Hoon; Baek, In-Jeoung; Roh, Jae-il; Ha, Na Young; Kim, Seung-Yeon; Bahk, Young Yil; Lee, Jong Eun; Yoo, Tae Hyun; Lee, Han-Woong

    2011-01-01

    p23 is a cochaperone of heat shock protein 90 and also interacts functionally with numerous steroid receptors and kinases. However, the in vivo roles of p23 remain unclear. To explore its in vivo function, we generated the transgenic (TG) mice ubiquitously overexpressing p23. The p23 TG mice spontaneously developed kidney abnormalities closely resembling human hydronephrosis. Consistently, kidney functions deteriorate significantly in the p23 TG mice compared to their wild-type (WT) littermates. Furthermore, the expression of target genes for aryl hydrocarbon receptor (AhR), such as cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (Cyp1B1), were induced in the kidneys of the p23 TG mice. These results indicate that the overexpression of p23 contributes to the development of hydronephrosis through the upregulation of the AhR pathway in vivo. PMID:21323770

  6. Multiple ovarian transplants to rescue a transgenic line of mice.

    PubMed

    Dawes, Joyce; Liu, Bowen; Mars, Wendy; Michalopoulos, George; Khillan, Jaspal S

    2010-06-01

    Transgenic mice are useful tools for studying gene function and regulation but can be difficult to successfully breed. To 'rescue' transgenic lines that are difficult to propagate, researchers use a variety of techniques. One method is ovarian transplant, in which researchers remove ovaries from a donor transgenic mouse, cryopreserve the ovarian tissue, transplant this tissue into histocompatible female mice and breed these recipient females. Though it is a useful technique, cryopreservation can potentially damage ovarian tissue, which could reduce fertility. In this article, the authors describe how they carried out ovarian transplants without cryopreservation to rescue a line of transgenic C57BL/6 mice. Other researchers who have experience with mouse reproductive surgery should be able to use this technique to rescue infertile transgenic lines of mice.

  7. Broad protection against influenza infection by vectored immunoprophylaxis in mice

    PubMed Central

    Balazs, Alejandro B.; Bloom, Jesse D.; Hong, Christin M.; Rao, Dinesh S.; Baltimore, David

    2014-01-01

    Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines. PMID:23728362

  8. Increased atherosclerosis in mice with increased vascular biglycan content.

    PubMed

    Thompson, Joel C; Tang, Tao; Wilson, Patricia G; Yoder, Meghan H; Tannock, Lisa R

    2014-07-01

    The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4-12 weeks. LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. Published by Elsevier Ireland Ltd.

  9. Transgenic and gene knockout mice in gastric cancer research

    PubMed Central

    Jiang, Yannan; Yu, Yingyan

    2017-01-01

    Mouse models are useful tool for carcinogenic study. They will greatly enrich the understanding of pathogenesis and molecular mechanisms for gastric cancer. However, only few of mice could develop gastric cancer spontaneously. With the development and improvement of gene transfer technology, investigators created a variety of transgenic and knockout/knockin mouse models of gastric cancer, such as INS-GAS mice and gastrin knockout mice. Combined with helicobacter infection and carcinogens treatment, these transgenic/knockout/knockin mice developed precancerous or cancerous lesions, which are proper for gene function study or experimental therapy. Here we review the progression of genetically engineered mouse models on gastric cancer research, and emphasize the effects of chemical carcinogens or infectious factors on carcinogenesis of genetically modified mouse. We also emphasize the histological examination on mouse stomach. We expect to provide researchers with some inspirations on this field. PMID:27713138

  10. What Gene Mutations Affect Serotonin in Mice?

    PubMed

    Tenpenny, Richard C; Commons, Kathryn G

    2017-05-17

    Although serotonin neurotransmission has been implicated in several neurodevelopmental and psychological disorders, the factors that drive dysfunction of the serotonin system are poorly understood. Current research regarding the serotonin system revolves around its dysfunction in neuropsychiatric disorders, but there is no database collating genetic mutations that result in serotonin abnormalities. To bridge this gap, we developed a list of genes in mice that, when perturbed, result in altered levels of serotonin either in brain or blood. Due to the intrinsic limitations of search, the current list should be considered a preliminary subset of all relevant cases. Nevertheless, it offered an opportunity to gain insight into what types of genes have the potential to impact serotonin by using gene ontology (GO). This analysis found that genes associated with monoamine metabolism were more often associated with increases in brain serotonin than decreases. Speculatively, this could be because several pathways (and therefore many genes) are responsible for the clearance and metabolism of serotonin whereas only one pathway (and therefore fewer genes) is directly involved in the synthesis of serotonin. Another contributor could be cross talk between monoamine systems such as dopamine. In contrast, genes that were associated with decreases in brain serotonin were more likely linked to a developmental process. Sensitivity of serotonin neurons to developmental perturbations could be due to their complicated neuroanatomy or possibly they may be negatively regulated by dysfunction of their innervation targets. Thus, these observations suggest hypotheses regarding the mechanisms underlying the vulnerability of brain serotonin neurotransmission.

  11. Herbkines increases physical stamina in mice.

    PubMed

    Koo, Hyun-Na; Lee, Jai-Kyoo; Hong, Seung-Heon; Kim, Hyung-Min

    2004-01-01

    Herbkines has been used for the purpose of development of physical strength. In the present study, we investigated the effect of Herbkines on performance of the forced swimming test (FST) and on blood biochemical parameters related to fatigue: blood urea nitrogen (BUN), creatine kinase (CK), lactic dehydrogenase (LDH), glucose (Glc), and total protein (TP). Herbkines were orally administered to mice, 10 ml/kg, continuously once per day for 2 weeks using a feeding atraumatic needle. After 2 d, on FST, the immobility time was decreased in the Herbkines-fed group (178+/-8.2 s) in comparison with the control group (189+/-22 s); however, the statistical difference was very weak (p=0.596). After 2 weeks, the immobility time was significantly decreased in the Herbkines-fed group (196+/-4.5 s) in comparison with the control group (221+/-6.2 s). In addition, the content of BUN in the blood serum was significantly decreased. However, the levels of CK, LDH, Glc, and TP did not show a significant change. The results predict a potential benefit of Herbkines as an anti-fatigue treatment and for improving physical stamina.

  12. Thermoneutrality, Mice, and Cancer: A Heated Opinion.

    PubMed

    Hylander, Bonnie L; Repasky, Elizabeth A

    2016-04-01

    The 'mild' cold stress caused by standard sub-thermoneutral housing temperatures used for laboratory mice in research institutes is sufficient to significantly bias conclusions drawn from murine models of several human diseases. We review the data leading to this conclusion, discuss the implications for research and suggest ways to reduce problems in reproducibility and experimental transparency caused by this housing variable. We have found that these cool temperatures suppress endogenous immune responses, skewing tumor growth data and the severity of graft versus host disease, and also increase the therapeutic resistance of tumors. Owing to the potential for ambient temperature to affect energy homeostasis as well as adrenergic stress, both of which could contribute to biased outcomes in murine cancer models, housing temperature should be reported in all publications and considered as a potential source of variability in results between laboratories. Researchers and regulatory agencies should work together to determine whether changes in housing parameters would enhance the use of mouse models in cancer research, as well as for other diseases. Finally, for many years agencies such as the National Cancer Institute (NCI) have encouraged the development of newer and more sophisticated mouse models for cancer research, but we believe that, without an appreciation of how basic murine physiology is affected by ambient temperature, even data from these models is likely to be compromised. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Narcosis studies and oxygen poisoning of mice

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The research for a mechanism by which narcotic gases alter metabolism is reported. Possible sites of action by narcotic and anesthetic gases in isolated electron transport particles were explored. Using the relative activities of the NADH-oxygen, NADH-ferricyanide, succinate-cytochrome C and succinate-NAD oxidoreductase systems as parameters, the relative potency of volatile anesthetics were tested. Testing the relative ability of human subjects to contract and repay an oxygen debt while in the narcotic versus alert state, it was found that narcosis induced by 33% nitrous oxide increased the size of the oxygen debt contracted and the amount of oxygen required to repay it during recovery. Mice acclimatized to sea level (760 mm Hg), 5000 feet (632 mm Hg) or 15,000 feet 437 mm Hg) for from one to eight weeks were found to be more susceptible to convulsion and death as a function of altitude acclimatization when tested in hyperoxic environments. There were no reasonable explanations for the connection between hypoxia and oxygen poisoning but several practical implications for persons living at altitude are discussed.

  14. Placental effects of lead in mice.

    PubMed

    Fuentes, M; Torregrosa, A; Mora, R; Götzens, V; Corbellla, J; Domingo, J L

    1996-01-01

    Although a number of studies in animal models have shown embryolethal and teratogenic lead effects when this element is administered by a parenteral route, the mechanism of the embryonary changes is well not established. In this study, the embryonic effects of parenteral lead exposure on day 9 of gestation were assessed in the Swiss mouse. Lead acetate trihydrate was injected intraperitoneally at 14, 28, 56 and 112 mg/kg. There was no maternal toxicity evidenced by death, reduced body weight gain or reduced food consumption. However, absolute placental weight at 112 mg/kg and relative placental weight at 14, 56 and 112 mg/kg were diminished significantly. The number of total implants, live and dead fetuses, sex ratio and fetal body weight were unaffected by lead exposure. Most sections of placenta showed vascular congestion, an increase of intracellular spaces and deposits of hyaline material of perivascular predominance. Trophoblast hyperplasia was also observed, whereas there was a reinforcement of the fibrovascular network in the labyrinth. It is concluded that the trophoblast hyperplasia observed in the placenta of pregnant mice after parenteral lead exposure at doses that are not toxic for the dam could act as a repairing mechanism of the extraembryonary tissues.

  15. Photic Resetting and Entrainment in CLOCK-Deficient Mice

    PubMed Central

    Dallmann, Robert; DeBruyne, Jason P.; Weaver, David R.

    2012-01-01

    Mice lacking CLOCK protein have a relatively subtle circadian phenotype, including a slightly shorter period in constant darkness, differences in phase resetting after 4-hr light pulses in the early and late night, and a variably advanced phase angle of entrainment in a light-dark (LD) cycle (DeBruyne et al., Neuron 50:465–477, 2006). The present series of experiments was conducted to more fully characterize the circadian phenotype of Clock−/− mice under various lighting conditions. A phase-response curve (PRC) to 4-hour light pulses in free-running mice was conducted; the results confirm that Clock−/− mice exhibit very large phase advances after 4 hrs light pulses in the late subjective night, but have relatively normal responses to light at other phases. The abnormal shape of the PRC to light may explain the tendency of CLOCK-deficient mice to begin activity before lights-out when housed in a 12 hrs light: 12 hrs dark lighting schedule. To assess this relationship further, Clock−/− and wild-type control mice were entrained to skeleton lighting cycles (1L:23D, and 1L:10D:1L:12D). Comparing entrainment under the two types of skeleton photoperiods revealed that exposure to 1 hr light in the morning leads to a phase advance of activity onset (expressed the following afternoon) in Clock−/− mice, but not in the controls. Constant light typically causes an intensity-dependent increase in circadian period in mice, but this did not occur in CLOCK-deficient mice. The failure of Clock−/− mice to respond to the period-lengthening effect of constant light likely results from the increased functional impact of light falling in the phase advance zone of the PRC. Collectively, these experiments reveal that alterations in the response of CLOCK-deficient mice to light in several paradigms are likely due to an imbalance in the shape of the PRC to light. PMID:21921293

  16. Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice

    PubMed Central

    Wang, Xianfeng; Buechler, Nancy L.; Martin, Ayana; Wells, Jonathan; Yoza, Barbara; McCall, Charles E.; Vachharajani, Vidula

    2016-01-01

    Objective Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. Methods Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a “second-hit” (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. Results We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65. Conclusion SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may

  17. Hepatic delta 6-desaturase activity in lean and genetically obese ob/ob mice.

    PubMed Central

    Hughes, S; York, D A

    1985-01-01

    Hepatic delta 6-desaturase activity is primarily located in the mitochondrial fraction in mice. Both delta 6- and delta 5-desaturase activities are increased in the liver of young (6-week-old) obese mice. The increase in hepatic delta 6-desaturase activity in obese mice does not occur until weaning. Neither restriction of food intake nor hyperinsulinaemia normalize hepatic delta 6-desaturase activity of obese mice. Both cold acclimation and tri-iodothyronine (30 micrograms/day per kg) decreased hepatic delta 6-desaturase activity of obese mice to levels observed in lean mice, whereas the increase in activity in obese mice was still maintained after the induction of hypothyroidism. PMID:3977836

  18. Age, experience and genetic background influence treadmill walking in mice

    PubMed Central

    Wooley, Christine M.; Xing, Shuqin; Burgess, Robert W.; Cox, Gregory A.; Seburn, Kevin L.

    2009-01-01

    WOOLEY, C.M., S. XING, R.W. BURGESS, G.A. COX, AND K.L. SEBURN. Age, experience and genetic background influence treadmill walking in mice. PHYSIOL. BEHAV. XX(X), XXX-XXX, 2008 – The use of a treadmill to gather data for gait analysis in mice is a convenient, sensitive method to evaluate motor performance. However, evidence from several species, including mice, shows that treadmill locomotion is a novel task that is not equivalent to over ground locomotion and that may be particularly sensitive to the test environment and protocol. We investigated the effects of age, genetic background and repeated trials on treadmill walking in mice and show that these factors are important considerations in the interpretation of gait data. Specifically we report that as C57BL/6J (B6) mice age, the animals use progressively longer, less frequent strides to maintain the same walking speed. The increase is most rapid between 1 and 6 months of age and is explained, in part, by changes in size and weight. We also extended previous findings showing that repeat trials cause mice to modify their treadmill gait pattern. In general, B6 mice tend to take shorter, more frequent steps and adopt a wider dynamic stance with repeated walking trials. The nature and extent of the response changes with both the number and timing of the trials and was observed with inter-trial intervals as long as 3 months. Finally, we compared the gait pattern of an additional seven inbred strains of mice and found significant variation in the length and frequency of strides used to maintain the same walking speed. The combined results offer the bases for further mechanistic studies and can be used to guide optimal experimental design. PMID:19027767

  19. Effects of prenatal cocaine exposure on social development in mice.

    PubMed

    Kabir, Zeeba D; Kennedy, Bruce; Katzman, Aaron; Lahvis, Garet P; Kosofsky, Barry E

    2014-01-01

    Prenatal cocaine exposure (PCE) in humans and animals has been shown to impair social development. Molecules that mediate synaptic plasticity and learning in the medial prefrontal cortex (mPFC), specifically brain-derived neurotrophic factor (BDNF) and its downstream signaling molecule, early growth response protein 1 (egr1), have been shown to affect the regulation of social interactions (SI). In this study we determined the effects of PCE on SI and the corresponding ultrasonic vocalizations (USVs) in developing mice. Furthermore, we studied the PCE-induced changes in the constitutive expression of BDNF, egr1 and their transcriptional regulators in the mPFC as a possible molecular mechanism mediating the altered SI. In prenatal cocaine-exposed (PCOC) mice we identified increased SI and USV production at postnatal day (PD) 25, and increased SI but not USVs at PD35. By PD45 the expression of both social behaviors normalized in PCOC mice. At the molecular level, we found increased BDNF exon IV and egr1 mRNA in the mPFC of PCOC mice at PD30 that normalized by PD45. This was concurrent with increased EGR1 protein in the mPFC of PCOC mice at PD30, suggesting a role of egr1 in the enhanced SI observed in juvenile PCOC mice. Additionally, by measuring the association of acetylation of histone 3 at lysine residues 9 and 14 (acH3K9,14) and MeCP2 at the promoters of BDNF exons I and IV and egr1, our results provide evidence of promoter-specific alterations in the mPFC of PCOC juvenile mice, with increased association of acH3K9,14 only at the BDNF exon IV promoter. These results identify a potential PCE-induced molecular alteration as the underlying neurobiological mechanism mediating the altered social development in juvenile mice. © 2014 S. Karger AG, Basel.

  20. Gender Affects Skin Wound Healing in Plasminogen Deficient Mice

    PubMed Central

    Rønø, Birgitte; Engelholm, Lars Henning; Lund, Leif Røge; Hald, Andreas

    2013-01-01

    The fibrinolytic activity of plasmin plays a fundamental role in resolution of blood clots and clearance of extravascular deposited fibrin in damaged tissues. These vital functions of plasmin are exploited by malignant cells to accelerate tumor growth and facilitate metastases. Mice lacking functional plasmin thus display decreased tumor growth in a variety of cancer models. Interestingly, this role of plasmin has, in regard to skin cancer, been shown to be restricted to male mice. It remains to be clarified whether gender also affects other phenotypic characteristics of plasmin deficiency or if this gender effect is restricted to skin cancer. To investigate this, we tested the effect of gender on plasmin dependent immune cell migration, accumulation of hepatic fibrin depositions, skin composition, and skin wound healing. Gender did not affect immune cell migration or hepatic fibrin accumulation in neither wildtype nor plasmin deficient mice, and the existing differences in skin composition between males and females were unaffected by plasmin deficiency. In contrast, gender had a marked effect on the ability of plasmin deficient mice to heal skin wounds, which was seen as an accelerated wound closure in female versus male plasmin deficient mice. Further studies showed that this gender effect could not be reversed by ovariectomy, suggesting that female sex-hormones did not mediate the accelerated skin wound healing in plasmin deficient female mice. Histological examination of healed wounds revealed larger amounts of fibrotic scars in the provisional matrix of plasmin deficient male mice compared to female mice. These fibrotic scars correlated to an obstruction of cell infiltration of the granulation tissue, which is a prerequisite for wound healing. In conclusion, the presented data show that the gender dependent effect of plasmin deficiency is tissue specific and may be secondary to already established differences between genders, such as skin thickness and

  1. Peptide YY induces characteristic meal patterns of aged mice.

    PubMed

    Mogami, Sachiko; Yamada, Chihiro; Fujitsuka, Naoki; Hattori, Tomohisa

    2017-11-01

    Changes in eating behavior occur in the elderly due to oral and swallowing dysfunctions. We aimed to clarify the difference between basal meal patterns of young and aged mice in relation to appetite regulating hormones. Thirty two of young (7-week-old) and aged (23-25-month-old) C57BL/6 male mice were acclimated to a single housing and then transferred to a highly sensitive automated feeding monitoring device. Feeding behavior was monitored from the onset of the dark phase after habituation to the device. Plasma peptide YY (PYY) levels were assessed under the several feeding status or after treatment of PYY. PYY and its receptor (NPY Y2 receptor, Y2R) antagonist were intraperitoneally administered 30min before the monitoring. Although the basal 24-h meal amounts did not differ by age, the total meal time and frequency of minimum feeding activity (bout) were significantly increased and the average bout size and time per bout were significantly decreased in aged mice. PYY dynamics were abnormal and the temporal reduction in food intake by exogenous PYY was more prominent in aged mice than in young mice. PYY administration to young mice induced aged-like meal patterns, and Y2R antagonist administration to aged mice induced young-like meal patterns. Aged mice exhibited characteristic meal patterns probably due to PYY metabolism dysfunction and/or enhanced PYY-Y2R signaling, suggesting a novel method for assessing eating difficulties in aged animals and a potential target for the remedy. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

    PubMed Central

    Berger, Katja; Schulte, Kevin; Boor, Peter; Kuppe, Christoph; van Kuppevelt, Toin H.; Floege, Jürgen; Smeets, Bart

    2014-01-01

    Previously, we showed that some podocytes in juvenile mice are recruited from cells lining Bowman’s capsule, suggesting that parietal epithelial cells (PECs) are a progenitor cell population for podocytes. To investigate whether PECs also replenish podocytes in adult mice, PECs were genetically labeled in an irreversible fashion in 5-week-old mice. No significant increase in labeled podocytes was observed, even after 18 months. To accelerate a potential regenerative mechanism, progressive glomerular hypertrophy was induced by progressive partial nephrectomies. Again, no significant podocyte replenishment was observed. Rather, labeled PECs exclusively invaded segments of the tuft affected by glomerulosclerosis, consistent with our previous findings. We next reassessed PEC recruitment in juvenile mice using a different reporter mouse and confirmed significant recruitment of labeled PECs onto the glomerular tuft. Moreover, some labeled cells on Bowman’s capsule expressed podocyte markers, and cells on Bowman’s capsule were also directly labeled in juvenile podocyte-specific Pod-rtTA transgenic mice. In 6-week-old mice, however, cells on Bowman’s capsule no longer expressed podocyte-specific markers. Similarly, in human kidneys, some cells on Bowman’s capsule expressed the podocyte marker synaptopodin from 2 weeks to 2 years of age but not at 7 years of age. In summary, podocyte regeneration from PECs could not be detected in aging mice or models of glomerular hypertrophy. We propose that a small fraction of committed podocytes reside on Bowman’s capsule close to the vascular stalk and are recruited onto the glomerular tuft during infancy to adolescence in mice and humans. PMID:24408873

  3. Helicobacter Infection Significantly Alters Pregnancy Success in Laboratory Mice.

    PubMed

    Bracken, Tara C; Cooper, Caitlin A; Ali, Zil; Truong, Ha; Moore, Julie M

    2017-05-01

    Helicobacter spp. are gram-negative, helically shaped bacteria that cause gastric and enterohepatic infections in mammalian species. Although Helicobacter infection frequently is implicated to interfere with reproductive success, few experimental data support these claims. We therefore retrospectively investigated the effect of Helicobacter infection on murine pregnancy outcome after the identification of endemic Helicobacter infection in an animal research facility. Multiplex conventional PCR analysis was used to characterize Helicobacter infection status in one inbred and 2 transgenic strains of mice in 2 self-contained rooms assigned to the same investigator. Outcomes of timed-mating experiments were compared among Helicobacter spp.-infected and uninfected mice of the same strain; Helicobacter infection was eradicated from the colony through fostering with uninfected dams. Although Helicobacter infection affected fecundity in only one strain of transgenic mouse, the total number of embryos per gravid uterus was significantly reduced in C57BL/6J mice that were infected with a single Helicobacter species, H. typhlonius. Helicobacter infection was also associated with a significant increase in the number of resorbing embryos per uterus and significant decreases in pregnancy-associated weight gain relative to uninfected mice in C57BL6/J mice and one transgenic strain. Helicobacter spp.-infected mice of all tested strains exhibited higher frequency of intrauterine hemorrhaging relative to uninfected mice. These results indicate that naturally-acquired Helicobacter infection not only reduces the productivity of a research animal breeding colony, but also negatively impacts embryo health. Despite these deleterious effects, these data suggest that colonies can be rederived to be Helicobacter-free by Cesarean section and fostering with uninfected dams. This paper provides the first evidence that H. typhlonius infection is sufficient to interfere with reproductive success

  4. Evaluate the Influence of Eupatorium adenophorum Extract with Mice Organ

    NASA Astrophysics Data System (ADS)

    Nong, Xiang; Yang, Can; Yang, Yaojun; Liang, Zi; Hu, Qiang; Zhang, Ting

    2018-01-01

    In order to study the influence of extract from Eupatorium adenophorum in mice organs, this experiment will be the basis of further study that make Eupatorium adenophorum become Phyto contraceptive, this experiment take the feeding respectively way after the completion of the 1D, 5D, 10d, 15d of Eupatorium adenophorum mice by intragastrical administration of levonorgestrel group and blank control group. After the same operation in different periods of small rat heart and kidney the uterus, testis, and other organs were observed. The results showed that after extraction of E. adenophorum changes in female mice uterus shape was perfused significantly, showed swelling larger. Data analysis of each viscera coefficient was found E. adenophorum had No obvious effect on the heart, kidneys and testicles of mice. but there are obvious differences date between the treatment group and the blank group. (5d: F=10. 800 P=0. 043 cases) from tissue sections we can see female mice uterus cell morphology changes significantly, there was a similar appearance change in the uterus of the female mice with the estradiol For a male mouse testis of E.adenophorum gavage had No obvious effect. And it is found that the heart, the treated mice kidney, testis, ovary and other organs were observed in each period of time the organization had No obvious change; only female mice uterus tissue sections of individual cells became larger, and the organization of the gap larger. This research shows that E.adenophorum extract has the potential to develop botanical contraceptives, we will conduct in-depth study.

  5. Ghrelin treatment prevents development of activity based anorexia in mice.

    PubMed

    Legrand, Romain; Lucas, Nicolas; Breton, Jonathan; Azhar, Saïda; do Rego, Jean-Claude; Déchelotte, Pierre; Coëffier, Moïse; Fetissov, Sergueï O

    2016-06-01

    Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1nM) together or not with total IgG (1nM) from obese ob/ob or lean mice before access to food during 8 days of 3h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  6. Surgery plus anesthesia induces loss of attention in mice

    PubMed Central

    Ren, Quan; Peng, Mian; Dong, Yuanlin; Zhang, Yiying; Chen, Ming; Yin, Ning; Marcantonio, Edward R.; Xie, Zhongcong

    2015-01-01

    There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium. PMID:26441522

  7. Surgery plus anesthesia induces loss of attention in mice.

    PubMed

    Ren, Quan; Peng, Mian; Dong, Yuanlin; Zhang, Yiying; Chen, Ming; Yin, Ning; Marcantonio, Edward R; Xie, Zhongcong

    2015-01-01

    There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium.

  8. THE INFECTION OF MICE WITH SWINE INFLUENZA VIRUS.

    PubMed

    Shope, R E

    1935-09-30

    The experiments confirm the earlier observation of Andrewes, Laidlaw and Smith that the swine influenza virus is pathogenic for white mice when administered intranasally. Two field strains of the swine influenza virus were found to differ in their initial pathogenicity for mice. One strain was apparently fully pathogenic even in its 1st mouse passage while the other required 2 or 3 mouse passages to acquire full virulence for this species. Both strains, however, were initially infectious for mice, without the necessity of intervening ferret passages. There is no evidence that bacteria play any significant rôle in the mouse disease though essential in that of swine, and fatal pneumonias can be produced in mice by pure virus infections. Mice surviving the virus disease are immune to reinfection for at least a month. In mice the disease is not contagious though it is notably so in swine. The virus, while regularly producing fatal pneumonias when administered intranasally to mice, appears to be completely innocuous when given subcutaneously or intraperitoneally. Prolonged serial passage of the virus in mice does not influence its infectivity or virulence for swine or ferrets. It is a stable virus so far as its infectivity is concerned, and can be transferred at will from any one of its three known susceptible hosts to any other. In discussing these facts the stability of the swine influenza virus has been contrasted with the apparent instability of freshly isolated strains of the human influenza virus. Though the mouse is an un-natural host for the virus it is, nevertheless, useful for the study of those aspects of swine influenza which have to do with the virus only.

  9. Differences in Susceptibility of Inbred Mice to Bacillus anthracis

    DTIC Science & Technology

    1985-04-26

    dilutions of the mixture were prepared and injected into A/J and CBA/J mice via the tail vein, as described by Ezzell et al. (9). Five mice per strain were...xylazine (Rompun, Miles Laboratories, Shawnee, Kansas) in 50 pl, and were dissected iwnmediately. Gross pathological changes were noted, heart blood and...anthracis; a histopathological study of skin lesions produced by B. anthracis in susceptible and resistant animal species. J. Infect. Dis. 80:1-13. 9. Ezzell

  10. Antibiotic administration in the drinking water of mice.

    PubMed

    Marx, James O; Vudathala, Daljit; Murphy, Lisa; Rankin, Shelley; Hankenson, F Claire

    2014-05-01

    Although antibiotics frequently are added to the drinking water of mice, this practice has not been tested to confirm that antibiotics reach therapeutic concentrations in the plasma of treated mice. In the current investigation, we 1) tested the stability of enrofloxacin and doxycycline in the drinking water of adult, female C57BL/6 mice; 2) measured the mice's consumption of water treated with enrofloxacin, doxycycline, amoxicillin, or trimethoprim-sulfamethoxazole; and 3) used HPLC to measure plasma antibiotic concentrations in mice that had ingested treated water for 1 wk. Plasma concentrations of antibiotic were measured 1 h after the start of both the light and dark cycle. The main findings of the study were that both enrofloxacin and nonpharmaceutical, chemical-grade doxycycline remained relatively stable in water for 1 wk. In addition, mice consumed similar volumes of antibiotic-treated and untreated water. The highest plasma antibiotic concentrations measured were: enrofloxacin, 140.1 ± 10.4 ng/mL; doxycycline, 56.6 ± 12.5 ng/mL; amoxicillin, 299.2 ± 64.1 ng/mL; and trimethoprim-sulfamethoxazole, 5.9 ± 1.2 ng/mL. Despite the stability of the antibiotics in the water and predictable water consumption by mice, the plasma antibiotic concentrations were well below the concentrations required for efficacy against bacterial pathogens, except for those pathogens that are exquisitely sensitive to the antibiotic. The findings of this investigation prompt questions regarding the rationale of the contemporary practice of adding antibiotics to the drinking water of mice for systemic antibacterial treatments.

  11. Mapping Mammary Epithelial Cell Transformation in BRCA1 Mutant Mice

    DTIC Science & Technology

    2006-07-01

    Transformation in BRCA1 Mutant Mice PRINCIPAL INVESTIGATOR: Gerburg M. Wulf CONTRACTING ORGANIZATION: Beth Israel Deaconess Medical...REPORT NUMBER Beth Israel Deaconess Medical Center Boston, MA 02215 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES...and whether it allowed us to analyze the early steps of tumor formation. For this purpose transgenic and conditional knock-out mice (mutant p53 or

  12. Betacellulin ameliorates hyperglycemia in obese diabetic db/db mice.

    PubMed

    Oh, Yoon Sin; Shin, Seungjin; Li, Hui Ying; Park, Eun-Young; Lee, Song Mi; Choi, Cheol Soo; Lim, Yong; Jung, Hye Seung; Jun, Hee-Sook

    2015-11-01

    We found that administration of a recombinant adenovirus (rAd) expressing betacellulin (BTC) into obese diabetic db/db mice ameliorated hyperglycemia. Exogenous glucose clearance was significantly improved, and serum insulin levels were significantly higher in rAd-BTC-treated mice than rAd-β-gal-treated control mice. rAd-BTC treatment increased insulin/bromodeoxyuridine double-positive cells in the islets, and islets from rAd-BTC-treated mice exhibited a significant increase in the level of G1-S phase-related cyclins as compared with control mice. In addition, BTC treatment increased messenger RNA (mRNA) and protein levels of these cyclins and cyclin-dependent kinases in MIN-6 cells. BTC treatment induced intracellular Ca(2+) levels through phospholipase C-γ1 activation, and upregulated calcineurin B (CnB1) levels as well as calcineurin activity. Upregulation of CnB1 by BTC treatment was observed in isolated islet cells from db/db mice. When treated with CnB1 small interfering RNA (siRNA) in MIN-6 cells and isolated islets, induction of cell cycle regulators by BTC treatment was blocked and consequently reduced BTC-induced cell viability. As well as BTC's effects on cell survival and insulin secretion, our findings demonstrate a novel pathway by which BTC controls beta-cell regeneration in the obese diabetic condition by regulating G1-S phase cell cycle expression through Ca(2+) signaling pathways. Administration of BTC to db/db mice results in amelioration of hyperglycemia. BTC stimulates beta-cell proliferation in db/db mice. Ca(2+) signaling was involved in BTC-induced beta-cell proliferation. BTC has an anti-apoptotic effect and potentiates glucose-stimulated insulin secretion.

  13. Raloxifen prevents bone loss in castrated male mice.

    PubMed

    Broulík, P D; Broulíková, K

    2007-01-01

    Raloxifen is a selective estrogen receptor modulator which prevents bone loss in ovariectomized female mice in a fashion similar to estrogens. Since testosterone-deficient male mice also lose bone mass, we were interested in testing the effects of raloxifen on bones in intact and castrated male mice. Bone density was significantly reduced in castrated animals (1.36+/-0.04 g/ml) as compared to intact animals (1.42+/-0.03 g/ml) (p<0.01). When castrated mice with extraordinarily low concentrations of testosterone and with reduced weight of seminal vesicles were treated with raloxifen, the changes in bone density and bone minerals resulting from castration (1.36+/-0.04 g/ml) were entirely prevented (1.40+/-0.01 g/ml). Cortical bone was lost in orchidectomized mice, and this decrease in cortical thickness of the femur was prevented by raloxifen administration. Raloxifen in a dose used in humans for treatment of osteoporosis decreased the weight of seminal vesicles, an organ which is highly sensitive to the androgenic effect, decreased the concentration of testosterone (12.5+/-2.8 micromol/l) (p<0.01) but not to the same level as in the case of castrated animals (0.6+/-0.3 micromol/l), and did not have any effect on bone density or mineral content in intact mice. The results of the present study may thus be interpreted as supporting the hypothesis that raloxifen is an effective agent against the deleterious effects of castration-induced osteopenia in male mice and also support the hypothesis that estrogens may have physiological skeletal effects in male mice.

  14. Crybb2 deficiency impairs fertility in female mice

    SciTech Connect

    Gao, Qian; Sun, Li-Li; Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433

    Highlights: • Crybb2 deletion impaired female fertility. • Crybb2 deletion dramatically affected the production of reproduction-related hormones and hormone response. • Crybb2 deletion impaired follicular development and inhibited the proliferation of granulosa cells. • Crybb2 deletion promoted follicular atresia and apoptosis in granulosa cells. - Abstract: Beta-B2-crystallin (CRYBB2), encoded by Crybb2 gene, is a major protein in the mammalian eye lens that plays an important role in maintaining the transparency of the ocular lens. However, CRYBB2 also plays important roles in many extra-lenticular tissues and organs such as the retina, brain and testis. Our previous studies demonstrated that male Crybb2more » deficient (Crybb2{sup −/−}) mice have reduced fertility compared with wild-type (WT) mice, while female Crybb2{sup −/−} mice exhibited reduced ovary weights and shorter estrous cycle percentages. Here we specifically investigated the role of CRYBB2 in the female reproductive system. Our studies revealed that ovaries from female Crybb2{sup −/−} mice exhibited significantly reduced numbers of primordial, secondary and pre-ovulatory follicles when compared with WT mice, while the rate of atretic follicles was also increased. Additionally, fewer eggs were collected from the oviduct of Crybb2{sup −/−} female mice after superovulation. Estrogen levels were higher in the metestrus and diestrus cycles of female Crybb2{sup −/−} mice, while progesterone levels were lower in diestrus cycles. Furthermore, the expression of survival and cell cycle genes, Bcl-2, Cdk4 and Ccnd2, were significantly decreased in granulosa cells isolated from female Crybb2{sup −/−} mice, consistent with the predominant expression of CRYBB2 in ovarian granulosa cells. Our results reveal a critical role for CRYBB2 in female fertility and specific effects on the proliferation and survival status of ovarian granulosa cells.« less

  15. Effects of Subretinal Electrical Stimulation in Mer-KO Mice

    PubMed Central

    Mocko, Julie A.; Kim, Moon; Faulkner, Amanda E.; Cao, Yang; Ciavatta, Vincent T.

    2011-01-01

    Purpose. Subretinal electrical stimulation (SES) from microphotodiode arrays protects photoreceptors in the RCS rat model of retinitis pigmentosa. The authors examined whether merkd mice, which share a Mertk mutation with RCS rats, showed similar neuroprotective effects from SES. Methods. Merkd mice were implanted with a microphotodiode array at postnatal day (P) 14. Weekly electroretinograms (ERGs) followed by retinal histology at week 4 were compared with those of age-matched controls. RT-PCR for fibroblast growth factor beta (Fgf2), ciliary nerve trophic factor (Cntf), glial-derived neurotrophic factor (Gdnf), insulin growth factor 1 (Igf1), and glial fibrillary acidic protein (Gfap) was performed on retinas at 1 week after surgery. Rates of degeneration using ERG parameters were compared between merkd mice and RCS rats from P28 to P42. Results. SES-treated merkd mice showed no differences in ERG a- and b-wave amplitudes or photoreceptor numbers compared with controls. However, the expression of Fgf2 and Cntf was greater (6.5 ± 1.9- and 2.5 ± 0.5-fold, respectively; P < 0.02) in SES-treated merkd retinas. Rates of degeneration were faster for dark-adapted maximal b-wave, log σ, and oscillatory potentials in merkd mice than in RCS rats. Conclusions. Although SES upregulated Fgf2 in merkd retinas, as reported previously for RCS retinas, this was not accompanied by neuroprotection of photoreceptors. Comparisons of ERG responses from merkd mice and RCS rats across different ages showed inner retinal dysfunction in merkd mice but not in RCS rats. This inner retinal dysfunction and the faster rate of degeneration in merkd mice may produce a retinal environment that is not responsive to neuroprotection from SES. PMID:21467171

  16. Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice

    PubMed Central

    Calhoun, Gabriela; Wang, Li; Almeida, Luis E.F.; Kenyon, Nicholas; Afsar, Nina; Nouraie, Mehdi; Finkel, Julia C.; Quezado, Zenaide M.N.

    2015-01-01

    Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickling, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickling and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickling and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickling compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients. PMID:25724786

  17. Energy homeostasis in leptin deficient Lepob/ob mice.

    PubMed

    Skowronski, Alicja A; Ravussin, Yann; Leibel, Rudolph L; LeDuc, Charles A

    2017-01-01

    Maintenance of reduced body weight is associated both with reduced energy expenditure per unit metabolic mass and increased hunger in mice and humans. Lowered circulating leptin concentration, due to decreased fat mass, provides a primary signal for this response. However, leptin deficient (Lepob/ob) mice (and leptin receptor deficient Zucker rats) reduce energy expenditure following weight reduction by a necessarily non-leptin dependent mechanisms. To identify these mechanisms, Lepob/ob mice were fed ad libitum (AL group; n = 21) or restricted to 3 kilocalories of chow per day (CR group, n = 21). After losing 20% of initial weight (in approximately 2 weeks), the CR mice were stabilized at 80% of initial body weight for two weeks by titrated refeeding, and then released from food restriction. CR mice conserved energy (-17% below predicted based on body mass and composition during the day; -52% at night); and, when released to ad libitum feeding, CR mice regained fat and lean mass (to AL levels) within 5 weeks. CR mice did so while their ad libitum caloric intake was equal to that of the AL animals. While calorically restricted, the CR mice had a significantly lower respiratory exchange ratio (RER = 0.89) compared to AL (0.94); after release to ad libitum feeding, RER was significantly higher (1.03) than in the AL group (0.93), consistent with their anabolic state. These results confirm that, in congenitally leptin deficient animals, leptin is not required for compensatory reduction in energy expenditure accompanying weight loss, but suggest that the hyperphagia of the weight-reduced state is leptin-dependent.

  18. Behavioural characterization of vitamin D receptor knockout mice.

    PubMed

    Burne, Thomas H J; McGrath, John J; Eyles, Darryl W; Mackay-Sim, Alan

    2005-02-28

    Vitamin D (calcitriol) is a nuclear transcription regulator acting via a nuclear hormone receptor (VDR). In addition to its role in the regulation of calcium and phosphate homeostasis and in bone formation, Vitamin D is also thought to be involved in brain function. The aim of this study was to behaviourally phenotype VDR knockout mice. We characterized the behaviour of VDR null mutant mice and wildtype littermate controls by subjecting them to a range of tests including a primary behavioural screen (using the SHIRPA protocol), rotarod, gait analysis, Y-maze, marble burying test, bedding test, holeboard test, elevated plus maze, open field test and prepulse inhibition of the acoustic startle response. There were no effects of genotype on most of the scores from the SHIRPA protocol except that VDR -/- mice had alopecia, were shorter and weighed less than VDR +/+ mice. VDR -/- mice had a shorter gait as well as impairments on the rotarod, in the bedding test and impaired habituation in both the open field and on the acoustic startle response. The VDR -/- mice had normal acoustic startle responses but had impaired PPI at long (256 ms) but not short (64 ms) prepulse to pulse intervals. The VDR -/- mice were less active in the open field and buried fewer marbles in the marble burying test. However, there were no differences in the time spent on the open arms of the elevated plus maze or in working memory as assessed by repeat arm entries on the Y-maze. Therefore, it appears that VDR -/- mice have muscular and motor impairments that significantly affects locomotor behaviour but seemingly no impairments in cognition as indicated by exploration, working memory or anxiety.

  19. RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice.

    PubMed

    Madigan, Laura A; Wong, Gordon S; Gordon, Elizabeth M; Chen, Wei-Sheng; Balenga, Nariman; Koziol-White, Cynthia J; Panettieri, Reynold A; Levine, Stewart J; Druey, Kirk M

    2018-01-01

    A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5-deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma.

  20. Gender differences in hypoxic acclimatization in cyclooxygenase-2-deficient mice.

    PubMed

    Xu, Kui; Sun, Xiaoyan; Benderro, Girriso F; Tsipis, Constantinos P; LaManna, Joseph C

    2017-02-01

    The aim of this study was to determine the effect of cyclooxygenase-2 (COX-2) gene deletion on the adaptive responses during prolonged moderate hypobaric hypoxia. Wild-type (WT) and COX-2 knockout (KO) mice of both genders (3 months old) were exposed to hypobaric hypoxia (~0.4 ATM) or normoxia for 21 days and brain capillary densities were determined. Hematocrit was measured at different time intervals; brain hypoxia-inducible factor -1 α (HIF-1 α ), angiopoietin 2 (Ang-2), brain erythropoietin (EPO), and kidney EPO were measured under normoxic and hypoxic conditions. There were no gender differences in hypoxic acclimatization in the WT mice and similar adaptive responses were observed in the female KO mice. However, the male KO mice exhibited progressive vulnerability to prolonged hypoxia. Compared to the WT and female KO mice, the male COX-2 KO mice had significantly lower survival rate and decreased erythropoietic and polycythemic responses, diminished cerebral angiogenesis, decreased brain accumulation of HIF-1 α , and attenuated upregulation of VEGF, EPO, and Ang-2 during hypoxia. Our data suggest that there are physiologically important gender differences in hypoxic acclimatization in COX-2-deficient mice. The COX-2 signaling pathway appears to be required for acclimatization in oxygen-limiting environments only in males, whereas female COX-2-deficient mice may be able to access COX-2-independent mechanisms to achieve hypoxic acclimatization. © 2017 Case Western Reserve University. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  1. Antibiotic Administration in the Drinking Water of Mice

    PubMed Central

    Marx, James O; Vudathala, Daljit; Murphy, Lisa; Rankin, Shelley; Hankenson, F Claire

    2014-01-01

    Although antibiotics frequently are added to the drinking water of mice, this practice has not been tested to confirm that antibiotics reach therapeutic concentrations in the plasma of treated mice. In the current investigation, we 1) tested the stability of enrofloxacin and doxycycline in the drinking water of adult, female C57BL/6 mice; 2) measured the mice's consumption of water treated with enrofloxacin, doxycycline, amoxicillin, or trimethoprim–sulfamethoxazole; and 3) used HPLC to measure plasma antibiotic concentrations in mice that had ingested treated water for 1 wk. Plasma concentrations of antibiotic were measured 1 h after the start of both the light and dark cycle. The main findings of the study were that both enrofloxacin and nonpharmaceutical, chemical-grade doxycycline remained relatively stable in water for 1 wk. In addition, mice consumed similar volumes of antibiotic-treated and untreated water. The highest plasma antibiotic concentrations measured were: enrofloxacin, 140.1 ± 10.4 ng/mL; doxycycline, 56.6 ± 12.5 ng/mL; amoxicillin, 299.2 ± 64.1 ng/mL; and trimethoprim–sulfamethoxazole, 5.9 ± 1.2 ng/mL. Despite the stability of the antibiotics in the water and predictable water consumption by mice, the plasma antibiotic concentrations were well below the concentrations required for efficacy against bacterial pathogens, except for those pathogens that are exquisitely sensitive to the antibiotic. The findings of this investigation prompt questions regarding the rationale of the contemporary practice of adding antibiotics to the drinking water of mice for systemic antibacterial treatments. PMID:24827573

  2. Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice.

    PubMed

    Mahbod, Parinaz; Smith, Eric P; Fitzgerald, Maureen E; Morano, Rachel L; Packard, Benjamin A; Ghosal, Sriparna; Scheimann, Jessie R; Perez-Tilve, Diego; Herman, James P; Tong, Jenny

    2018-01-01

    Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism, and emotionality (stress, anxiety, and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or, in an acylated form, acyl ghrelin (AG), through the actions of ghrelin O-acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hormone secretagogue receptor (GHSR) 1a. We investigated the role of endogenous AG, DAG, and GHSR1a signaling on anxiety and stress responses using ghrelin knockout (Ghr KO), GOAT KO, and Ghsr stop-floxed (Ghsr null) mice. Behavioral and hormonal responses were tested in the elevated plus maze and light/dark (LD) box. Mice lacking both AG and DAG (Ghr KO) increased anxiety-like behaviors across tests, whereas anxiety reactions were attenuated in DAG-treated Ghr KO mice and in mice lacking AG (GOAT KO). Notably, loss of GHSR1a (Ghsr null) did not affect anxiety-like behavior in any test. Administration of AG and DAG to Ghr KO mice with lifelong ghrelin deficiency reduced anxiety-like behavior and decreased phospho-extracellular signal-regulated kinase phosphorylation in the Edinger-Westphal nucleus in wild-type mice, a site normally expressing GHSR1a and involved in stress- and anxiety-related behavior. Collectively, our data demonstrate distinct roles for endogenous AG and DAG in regulation of anxiety responses and suggest that the behavioral impact of ghrelin may be context dependent. Copyright © 2018 Endocrine Society.

  3. Fish oil concentrate delays sensitivity to thermal nociception in mice

    PubMed Central

    Veigas, Jyothi M.; Williams, Paul J.; Halade, Ganesh; Rahman, Mizanur M.; Yoneda, Toshiyuki; Fernandes, Gabriel

    2011-01-01

    Fish oil has been used to alleviate pain associated with inflammatory conditions such as rheumatoid arthritis. The anti-inflammatory property of fish oil is attributed to the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid. Contrarily, vegetable oils such as safflower oil are rich in n-6 fatty acids which are considered to be mediators of inflammation. This study investigates the effect of n-3 and n-6 fatty acids rich oils as dietary supplements on the thermally induced pain sensitivity in healthy mice. C57Bl/6J mice were fed diet containing regular fish oil, concentrated fish oil formulation (CFO) and safflower oil (SO) for 6 months. Pain sensitivity was measured by plantar test and was correlated to the expression of acid sensing ion channels (ASICs), transient receptor potential vanilloid 1 (TRPV1) and c-fos in dorsal root ganglion cells. Significant delay in sensitivity to thermal nociception was observed in mice fed CFO compared to mice fed SO (p<0.05). A significant diminution in expression of ion channels such as ASIC1a (64%), ASIC13 (37%) and TRPV1 (56%) coupled with reduced expression of c-fos, a marker of neuronal activation, was observed in the dorsal root ganglion cells of mice fed CFO compared to that fed SO. In conclusion, we describe here the potential of fish oil supplement in reducing sensitivity to thermal nociception in normal mice. PMID:21345372

  4. [Synapse maturation and autism: learning from neuroligin model mice].

    PubMed

    Tabuchi, Katsuhiko; Chang, WenHsin; Hang, WenHsin; Asgar, Nur Farehan; Asgar, Nur Farehan Mohamed; Pramanik, Gopal

    2014-02-01

    Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer II/III pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.

  5. Perioperative haemostatic management of haemophilic mice using normal mouse plasma.

    PubMed

    Tatsumi, K; Ohashi, K; Kanegae, K; Shim, I K; Okano, T

    2013-11-01

    Intense haemostatic interventions are required to avoid bleeding complications when surgical procedures are performed on haemophilia patients. The objective of this study was to establish an appropriate protocol for perioperative haemostatic management of haemophilic mice. We assessed the prophylactic haemostatic effects of normal mouse plasma (NMP) on haemophilia B (HB) mice for both a skin flap procedure and a laparotomy. When 500 μL of NMP was administered to the mice, plasma factor IX (FIX:C) levels peaked at 15.1% immediately after intravenous (IV) administration, at 6.1% 2 h after intraperitoneal (IP) administration and at 2.7% 6 h after subcutaneous administration. Administering 500 μL of NMP via IP or IV 30 min in advance enabled the skin flap procedure to be performed safely without any complications. After the laparotomy procedure, several mice in the IP administration group exhibited lethal bleeding, but all mice survived in the IV administration group. Anti-mouse FIX inhibitors did not develop, even after repetitive administrations of NMP. However, human FIX concentrates, especially plasma-derived concentrates, elicited the anti-human FIX inhibitors. The results show that administering 500 μL of NMP via IV or IP 30 min in advance enables surgical procedures to be safely performed on HB mice, and that IV administration is more desirable than IP if the procedure requires opening of the abdominal wall. © 2013 John Wiley & Sons Ltd.

  6. Impaired receptivity and decidualization in DHEA-induced PCOS mice

    PubMed Central

    Li, Shu-Yun; Song, Zhuo; Song, Min-Jie; Qin, Jia-Wen; Zhao, Meng-Long; Yang, Zeng-Ming

    2016-01-01

    Polycystic ovary syndrome (PCOS), a complex endocrine disorder, is a leading cause of female infertility. An obvious reason for infertility in PCOS women is anovulation. However, success rate with high quality embryos selected by assisted reproduction techniques in PCOS patients still remain low with a high rate of early clinical pregnancy loss, suggesting a problem in uterine receptivity. Using a dehydroepiandrosterone-induced mouse model of PCOS, some potential causes of decreased fertility in PCOS patients were explored. In our study, ovulation problem also causes sterility in PCOS mice. After blastocysts from normal mice are transferred into uterine lumen of pseudopregnant PCOS mice, the rate of embryo implantation was reduced. In PCOS mouse uteri, the implantation-related genes are also dysregulated. Additionally, artificial decidualization is severely impaired in PCOS mice. The serum estrogen level is significantly higher in PCOS mice than vehicle control. The high level of estrogen and potentially impaired LIF-STAT3 pathway may lead to embryo implantation failure in PCOS mice. Although there are many studies about effects of PCOS on endometrium, both embryo transfer and artificial decidualization are applied to exclude the effects from ovulation and embryos in our study. PMID:27924832

  7. Oxytocin in the Treatment of Dystocia in Mice

    PubMed Central

    Narver, Heather L

    2012-01-01

    Physicians and veterinarians often prescribe oxytocin to treat dystocia. However, oxytocin administration to pregnant women or animals is not without risk. In the venue of laboratory animal medicine, the use of oxytocin may present confounding variables to research. Although oxytocin has been studied extensively, many of its physiologic effects and interactions with other hormones remain unclear. Investigator concerns about adverse and confounding effects of oxytocin in their research mice prompted the current review of oxytocin and its use to treat murine dystocia. Well-controlled studies of oxytocin in dystocic mice have not been conducted. However, in humans and other animals, inconsistent and adverse effects are well-documented. Limited knowledge of the complex physiologic and molecular mechanisms of action of oxytocin and scant support for the efficacy of oxytocin in dystocic mice fail to meet the standards of evidence-based veterinary medical practice. The administration of oxytocin is contraindicated in many cases of dystocia in research mice, and its use in dystocic mice may be unfounded. A brief review of oxytocin and the physiologic mechanisms of parturition are provided to support this conclusion. Alternative treatments for murine dystocia are discussed, and a holistic approach is advocated to better serve animal welfare and to safeguard the integrity of valuable research. Laboratory animal veterinarians overseeing the development of guidelines or standard operating procedures for technician or investigator treatment of dystocic mice should understand the effects of oxytocin administration in light of relevant research. PMID:22330862

  8. Immunosuppressive activity of tilmicosin on the immune responses in mice.

    PubMed

    Guan, Shuang; Song, Yu; Guo, Weixiao; Chu, Xiao; Zhang, Xiaozhe; Wang, Dacheng; Lu, Jing; Deng, Xuming

    2011-06-01

    Tilmicosin, a semi-synthetic macrolide antibiotic that is only used in the veterinary clinic, was evaluated for its immunosuppressive activity on the immune responses to ovalbumin (OVA) in mice. Tilmicosin suppressed concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated splenocyte proliferation in vitro. BALB/c mice were immunized subcutaneously with OVA on day 1 and 4. Beginning on the day of boosting immunization, the mice were administered intraperitoneally with tilmicosin at a single dose of 10, 30, and 90 mg/kg for 10 consecutive days. On day 14, blood samples were collected for measuring specific total-immunoglobulin G (total-IgG), IgG1, IgG2b, and splenocytes were harvested for determining lymphocyte proliferation and interleukin-2 (IL-2), interferon-γ (IFN-γ), IL-4 production. The results demonstrated that tilmicosin could significantly suppress Con A-induced splenocyte proliferation in a dose-dependent manner, decrease LPS-and OVA-induced splenocyte proliferation only at high concentration, produced less IL-2, IL-4, and IFN-γ as compared to the control in the OVA-immunized mice. Moreover, the OVA-specific IgG, IgG1, and IgG2b levels in the OVA-immunized mice were reduced by tilmicosin. These results suggest that tilmicosin could suppress the cellular and humoral immune response in mice.

  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. Stevia and Saccharin Preferences in Rats and Mice

    PubMed Central

    Bahrani, Mahsa; Zukerman, Steven; Ackroff, Karen

    2010-01-01

    Use of natural noncaloric sweeteners in commercial foods and beverages has expanded recently to include compounds from the plant Stevia rebaudiana. Little is known about the responses of rodents, the animal models for many studies of taste systems and food intake, to stevia sweeteners. In the present experiments, preferences of female Sprague–Dawley rats and C57BL/6J mice for different stevia products were compared with those for the artificial sweetener saccharin. The stevia component rebaudioside A has the most sweetness and least off-tastes to human raters. In ascending concentration tests (48-h sweetener vs. water), rats and mice preferred a high-rebaudioside, low-stevioside extract as strongly as saccharin, but the extract stimulated less overdrinking and was much less preferred to saccharin in direct choice tests. Relative to the extract, mice drank more pure rebaudioside A and showed stronger preferences but still less than those for saccharin. Mice also preferred a commercial mixture of rebaudioside A and erythritol (Truvia). Similar tests of sweet receptor T1R3 knockout mice and brief-access licking tests with normal mice suggested that the preferences were based on sweet taste rather than post-oral effects. The preference response of rodents to stevia sweeteners is notable in view of their minimal response to some other noncaloric sweeteners (aspartame and cyclamate). PMID:20413452

  11. Potential Role for ADAM15 in Pathological Neovascularization in Mice

    PubMed Central

    Horiuchi, Keisuke; Weskamp, Gisela; Lum, Lawrence; Hammes, Hans-Peter; Cai, Hui; Brodie, Thomas A.; Ludwig, Thomas; Chiusaroli, Riccardo; Baron, Roland; Preissner, Klaus T.; Manova, Katia; Blobel, Carl P.

    2003-01-01

    ADAM15 (named for a disintegrin and metalloprotease 15, metargidin) is a membrane-anchored glycoprotein that has been implicated in cell-cell or cell-matrix interactions and in the proteolysis of molecules on the cell surface or extracellular matrix. To characterize the potential roles of ADAM15 during development and in adult mice, we analyzed its expression pattern by mRNA in situ hybridization and generated mice carrying a targeted deletion of ADAM15 (adam15−/− mice). A high level of expression of ADAM15 was found in vascular cells, the endocardium, hypertrophic cells in developing bone, and specific areas of the hippocampus and cerebellum. However, despite the pronounced expression of ADAM15 in these tissues, no major developmental defects or pathological phenotypes were evident in adam15−/− mice. The elevated levels of ADAM15 in endothelial cells prompted an evaluation of its role in neovascularization. In a mouse model for retinopathy of prematurity, adam15−/− mice had a major reduction in neovascularization compared to wild-type controls. Furthermore, the size of tumors resulting from implanted B16F0 mouse melanoma cells was significantly smaller in adam15−/− mice than in wild-type controls. Since ADAM15 does not appear to be required for developmental angiogenesis or for adult homeostasis, it may represent a novel target for the design of inhibitors of pathological neovascularization. PMID:12897135

  12. Stevia and saccharin preferences in rats and mice.

    PubMed

    Sclafani, Anthony; Bahrani, Mahsa; Zukerman, Steven; Ackroff, Karen

    2010-06-01

    Use of natural noncaloric sweeteners in commercial foods and beverages has expanded recently to include compounds from the plant Stevia rebaudiana. Little is known about the responses of rodents, the animal models for many studies of taste systems and food intake, to stevia sweeteners. In the present experiments, preferences of female Sprague-Dawley rats and C57BL/6J mice for different stevia products were compared with those for the artificial sweetener saccharin. The stevia component rebaudioside A has the most sweetness and least off-tastes to human raters. In ascending concentration tests (48-h sweetener vs. water), rats and mice preferred a high-rebaudioside, low-stevioside extract as strongly as saccharin, but the extract stimulated less overdrinking and was much less preferred to saccharin in direct choice tests. Relative to the extract, mice drank more pure rebaudioside A and showed stronger preferences but still less than those for saccharin. Mice also preferred a commercial mixture of rebaudioside A and erythritol (Truvia). Similar tests of sweet receptor T1R3 knockout mice and brief-access licking tests with normal mice suggested that the preferences were based on sweet taste rather than post-oral effects. The preference response of rodents to stevia sweeteners is notable in view of their minimal response to some other noncaloric sweeteners (aspartame and cyclamate).

  13. Severe pulmonary metastasis in obese and diabetic mice.

    PubMed

    Mori, Akinori; Sakurai, Hiroaki; Choo, Min-Kyung; Obi, Ryosuke; Koizumi, Keiichi; Yoshida, Chiho; Shimada, Yutaka; Saiki, Ikuo

    2006-12-15

    Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. Copyright 2006 Wiley-Liss, Inc.

  14. Stress conditioning in mice: alterations in immunity and tumor growth.

    PubMed

    Benaroya-Milshtein, Noa; Hollander, Nurit; Apter, Alan; Yaniv, Isaac; Pick, Chaim G

    2011-05-01

    The neuroendocrine and autonomic nervous systems are known regulators of brain-immune interaction. However, the functional significance of this interaction under stress is not fully understood. We investigated the effect of a stress paradigm by applying electric foot shock followed by three reminders, on behavior, immune parameters, and lymphoma tumor growth. Male C3H mice were divided into two groups: Group 1-exposed to electric foot shock followed by three reminders, and Group 2-untreated (controls). Sets of mice underwent the elevated plus maze, staircase, and hot plate tests. After foot shock, natural killer (NK) cell activity, and lymphocyte proliferation were measured. In addition, sets of mice were either vaccinated twice with B-cell lymphoma 38C-13 immunoglobulin for determination of anti-idiotype (Id) antibodies in sera, or inoculated with tumor cells and monitored for tumor development and survival time. Mice exposed to electric foot shock followed by the three reminders had higher NK cell activity, levels of anti-Id antibodies, and a higher proliferation rate of splenocytes in response to mitogens, than the control mice. The exposed mice also showed attenuated tumor growth. Thus, the stress paradigm inhibited tumor development and lead to some immune changes that were not accompanied by behavioral changes.

  15. Neuroinflammation and cognitive function in aged mice following minor surgery

    PubMed Central

    Rosczyk, H.A.; Sparkman, N. L.; Johnson, R.W.

    2009-01-01

    Following surgery, elderly patients often suffer from postoperative cognitive dysfunction (POCD) which can persist long after physical recovery. It is known that surgery-induced tissue damage activates the peripheral innate immune system resulting in the release of inflammatory mediators. Compared to adults, aged animals demonstrate increased neuroinflammation and microglial priming that leads to an exaggerated proinflammatory cytokine response following activation of the peripheral immune system. Therefore, we sought to determine if the immune response to surgical trauma results in increased neuroinflammation and cognitive impairment in aged mice. Adult and aged mice underwent minor abdominal surgery and 24 h later hippocampal cytokines were measured and working memory was assessed in a reversal learning version of the Morris water maze. While adult mice showed no signs of neuroinflammation following surgery, aged mice had significantly increased levels of IL-1β mRNA in the hippocampus. Minor surgery did not result in severe cognitive impairment although aged mice that underwent surgery did tend to perseverate in the old target during reversal testing suggesting reduced cognitive flexibility. Overall these results suggest that minor surgery leads to an exaggerated neuroinflammatory response in aged mice but does not result in significantly impaired performance in the Morris water maze. PMID:18602982

  16. An evaluation of analgesic regimens for abdominal surgery in mice.

    PubMed

    Hayes, K E; Raucci, J A; Gades, N M; Toth, L A

    2000-11-01

    This study was designed to evaluate the efficacy of several analgesic regimens for use after intraperitoneal implantation of telemetry transmitters in mice. The lengths of time required for postoperative recovery of food and water intake, locomotor activity, and core temperature of mice that did not receive postsurgical analgesic medication were compared to those of mice that were given either an analgesic in the drinking water or buprenorphine injections. Many measured variables were not substantially altered by analgesic medications. However, ibuprofen-treated mice demonstrated significantly greater locomotor activity on days 2 through 5 after surgery and a more rapid return to stable postsurgical levels of activity and water intake as compared to those in untreated mice. These changes are consistent with potential analgesic efficacy of the ibuprofen treatment regimen. Buprenorphine injections elicited hyperactivity, hyperthermia, and reduced food and water intake during both the immediate postsurgical recovery period and after apparent recuperation from surgery, as compared to effects observed in saline-treated mice. Evaluating the effect of analgesic regimens on postsurgical changes in physiologic and behavioral variables can be useful in assessing the efficacy of analgesic treatments, but some changes may indicate pharmacologic effects that do not reflect pain relief.

  17. TAM receptor knockout mice are susceptible to retinal autoimmune induction.

    PubMed

    Ye, Fei; Li, Qiutang; Ke, Yan; Lu, Qingjun; Han, Lixia; Kaplan, Henry J; Shao, Hui; Lu, Qingxian

    2011-06-16

    TAM receptors are expressed mainly by dendritic cells and macrophages in the immune system, and mice lacking TAM receptors develop systemic autoimmune diseases because of inefficient negative control of the cytokine signaling in those cells. This study aims to test the susceptibility of the TAM triple knockout (tko) mice to the retina-specific autoantigen to develop experimental autoimmune uveoretinitis (EAU). TAM tko mice that were or were not immunized with interphotoreceptor retinoid-binding protein (IRBP) peptides were evaluated for retinal infiltration of the macrophages and CD3(+) T cells by immunohistochemistry, spontaneous activation of CD4(+) T cells, and memory T cells by flow cytometry and proliferation of IRBP-specific CD4(+) T cells by [(3)H]thymidine incorporation assay. Ocular inflammation induced by IRBP peptide immunization and specific T cell transfer were observed clinically by funduscopy and confirmed by histology. Tko mice were found to have less naive, but more activated, memory T cells, among which were exhibited high sensitivity to ocular IRBP autoantigens. Immunization with a low dose of IRBP and adoptive transfer of small numbers of IRBP-specific T cells from immunized tko mice caused the infiltration of lymphocytes, including CD3(+) T cells, into the tko retina. Mice without TAM receptor spontaneously develop IRBP-specific CD4(+) T cells and are more susceptible to retinal autoantigen immunization. This TAM knockout mouse line provides an animal model with which to study the role of antigen-presenting cells in the development of T cell-mediated uveitis.

  18. [Establishment of endometriosis subcutaneous model in immunodeficient nude mice].

    PubMed

    Ni, H J; Zhang, Z; Dai, Y D; Zhang, S Y

    2016-09-06

    Objective: To establish a model of endometriosis in immunodeficient nude mice and compare the outcome of the model construction between two different techniques. Methods: Eighteen nude mice were divided into 2 groups, with 9 mice in each group. All nude mice received a subcutaneous transplantation of endometrial fragments, followed by sutured the wounded skin (sutured group) or not (no-sutured group). Then the success rate of the model construction, inflammation of the wounds and the animal survival rate in the two groups were analyzed. Result: In no-sutured group, the survival rate of animal and the success rate of the model construction were 9/9 and 8/9 respectively, with 8/9 survival rate and 7/9 success rate in sutured group. No significant difference was found between the two groups. And no obvious inflammation was presented in the wounds for both groups. Conclusion: It is an effective method to establish animal model of endometriosis by subcutaneous transplantation in nude mice. After transplantation, it does not affect the outcome of the survival rate of the animal and the success rate of the model construction whether we suture the wounded skin. Considering the shorter operation time, we found it's a simpler and time saving method to establish endometriosis by subcutaneously transplanting endometrial fragments in nude mice with no skin-sutured. And this model is worth of promotion.

  19. Impaired receptivity and decidualization in DHEA-induced PCOS mice.

    PubMed

    Li, Shu-Yun; Song, Zhuo; Song, Min-Jie; Qin, Jia-Wen; Zhao, Meng-Long; Yang, Zeng-Ming

    2016-12-07

    Polycystic ovary syndrome (PCOS), a complex endocrine disorder, is a leading cause of female infertility. An obvious reason for infertility in PCOS women is anovulation. However, success rate with high quality embryos selected by assisted reproduction techniques in PCOS patients still remain low with a high rate of early clinical pregnancy loss, suggesting a problem in uterine receptivity. Using a dehydroepiandrosterone-induced mouse model of PCOS, some potential causes of decreased fertility in PCOS patients were explored. In our study, ovulation problem also causes sterility in PCOS mice. After blastocysts from normal mice are transferred into uterine lumen of pseudopregnant PCOS mice, the rate of embryo implantation was reduced. In PCOS mouse uteri, the implantation-related genes are also dysregulated. Additionally, artificial decidualization is severely impaired in PCOS mice. The serum estrogen level is significantly higher in PCOS mice than vehicle control. The high level of estrogen and potentially impaired LIF-STAT3 pathway may lead to embryo implantation failure in PCOS mice. Although there are many studies about effects of PCOS on endometrium, both embryo transfer and artificial decidualization are applied to exclude the effects from ovulation and embryos in our study.

  20. Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

    PubMed Central

    Gainetdinov, Raul R.; Mohn, Amy R.; Bohn, Laura M.; Caron, Marc G.

    2001-01-01

    In the brain, dopamine exerts an important modulatory influence over behaviors such as emotion, cognition, and affect as well as mechanisms of reward and the control of locomotion. The dopamine transporter (DAT), which reuptakes the released neurotransmitter into presynaptic terminals, is a major determinant of the intensity and duration of the dopaminergic signal. Knockout mice lacking the dopamine transporter (DAT-KO mice) display marked changes in dopamine homeostasis that result in elevated dopaminergic tone and pronounced locomotor hyperactivity. A feature of DAT-KO mice is that their hyperactivity can be inhibited by psychostimulants and serotonergic drugs. The pharmacological effect of these drugs occurs without any observable changes in dopaminergic parameters, suggesting that other neurotransmitter systems in addition to dopamine might contribute to the control of locomotion in these mice. We report here that the hyperactivity of DAT-KO mice can be markedly further enhanced when N-methyl-d-aspartate receptor-mediated glutamatergic transmission is blocked. Conversely, drugs that enhance glutamatergic transmission, such as positive modulators of l-α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of DAT-KO mice. Interestingly, blockade of N- methyl-d-aspartate receptors prevented the inhibitory effects of both psychostimulant and serotonergic drugs on hyperactivity. These findings support the concept of a reciprocal functional interaction between dopamine and glutamate in the basal ganglia and suggest that agents modulating glutamatergic transmission may represent an approach to manage conditions associated with dopaminergic dysfunction. PMID:11572967

  1. Mitochondrial oxidative metabolism during respiratory infection in riboflavin deficient mice.

    PubMed

    Brijlal, S; Lakshmi, A V; Bamji, M S

    1999-12-01

    Studies in children and mice have shown that respiratory infection alters riboflavin metabolism, resulting in increased urinary loss of this vitamin. This could be due to mobilization of riboflavin from the liver to blood because liver Flavin adenine dinucleotide (FAD) levels were lowered in the mice during infection. To understand the functional implications of lowered hepatic FAD levels during respiratory infection, flavoprotein functions such as oxidative phosphorylation and beta-oxidation of the liver mitochondria were examined during infection in mice. Weanling mice were fed either riboflavin-restricted or control diet for 18 days and then injected with a sublethal dose of Klebsiella pneumoniae. During infection, the state 3 respiratory rate with palmitoyl-L-carnitine and glutamate were significantly lowered (27-29%) in the riboflavin-restricted group, whereas in the control group 10% reduction was observed with palmitoyl-L-carnitine as substrate. A 22% reduction in the respiratory control ratio with palmitoyl-L-carnitine as substrate was observed during infection in the riboflavin-restricted group. The beta-oxidation of palmitoyl-L-carnitine was significantly lowered (29%) in the riboflavin-restricted infected group. The results of the study suggest that the effects of infection on vital physiologic functions were more pronounced in the riboflavin-restricted mice than in the control mice. (c) Elsevier Science Inc. 1999.

  2. PLAG1 deficiency impairs spermatogenesis and sperm motility in mice.

    PubMed

    Juma, Almas R; Grommen, Sylvia V H; O'Bryan, Moira K; O'Connor, Anne E; Merriner, D Jo; Hall, Nathan E; Doyle, Stephen R; Damdimopoulou, Pauliina E; Barriga, Daniel; Hart, Adam H; Van de Ven, Wim J M; De Groef, Bert

    2017-07-13

    Deficiency in pleomorphic adenoma gene 1 (PLAG1) leads to reduced fertility in male mice, but the mechanism by which PLAG1 contributes to reproduction is unknown. To investigate the involvement of PLAG1 in testicular function, we determined (i) the spatial distribution of PLAG1 in the testis using X-gal staining; (ii) transcriptomic consequences of PLAG1 deficiency in knock-out and heterozygous mice compared to wild-type mice using RNA-seq; and (iii) morphological and functional consequences of PLAG1 deficiency by determining testicular histology, daily sperm production and sperm motility in knock-out and wild-type mice. PLAG1 was sparsely expressed in germ cells and in Sertoli cells. Genes known to be involved in spermatogenesis were downregulated in the testes of knock-out mice, as well as Hsd17b3, which encodes a key enzyme in androgen biosynthesis. In the absence of Plag1, a number of genes involved in immune processes and epididymis-specific genes were upregulated in the testes. Finally, loss of PLAG1 resulted in significantly lowered daily sperm production, in reduced sperm motility, and in several animals, in sloughing of the germinal epithelium. Our results demonstrate that the subfertility seen in male PLAG1-deficient mice is, at least in part, the result of significantly reduced sperm output and sperm motility.

  3. Astaxanthin affects oxidative stress and hyposalivation in aging mice

    PubMed Central

    Kuraji, Manatsu; Matsuno, Tomonori; Satoh, Tazuko

    2016-01-01

    Oral dryness, a serious problem for the aging Japanese society, is induced by aging-related hyposalivation and causes dysphagia, dysgeusia, inadaptation of dentures, and growth of oral Candida albicans. Oxidative stress clearly plays a role in decreasing saliva secretion and treatment with antioxidants such astaxanthin supplements may be beneficial. Therefore, we evaluated the effects of astaxanthin on the oral saliva secretory function of aging mice. The saliva flow increased in astaxanthin-treated mice 72 weeks after administration while that of the control decreased by half. The plasma d-ROMs values of the control but not astaxanthin-treated group measured before and 72 weeks after treatment increased. The diacron-reactive oxygen metabolites (d-ROMs) value of astaxanthin-treated mice 72 weeks after treatment was significantly lower than that of the control group was. The plasma biological antioxidative potential (BAP) values of the control but not astaxanthin-treated mice before and 72 weeks after treatment decreased. Moreover, the BAP value of the astaxanthin-treated group 72 weeks after treatment was significantly higher than that of the control was. Furthermore, the submandibular glands of astaxanthin-treated mice had fewer inflammatory cells than the control did. Specifically, immunofluorescence revealed a significantly large aquaporin-5 positive cells in astaxanthin-treated mice. Our results suggest that astaxanthin treatment may prevent age-related decreased saliva secretion. PMID:27698533

  4. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  5. Vitamin D3 analogs stimulate hair growth in nude mice.

    PubMed

    Vegesna, Vijaya; O'Kelly, James; Uskokovic, Milan; Said, Jonathan; Lemp, Nathan; Saitoh, Takayuki; Ikezoe, Takayuki; Binderup, Lise; Koeffler, H Phillip

    2002-11-01

    The active form of vitamin D3 can regulate epidermal keratinization by inducing terminal differentiation; and mice lacking the vitamin D receptor display defects leading to postnatal alopecia. These observations implicate the vitamin D3 pathway in regulation of hair growth. We tested the ability of 1,25 dihydroxyvitamin D3 and its synthetic analogs to stimulate hair growth in biege/nude/xid (BNX) nu/nu (nude) mice exhibiting congenital alopecia. Nude mice were treated with different vitamin D3 analogs at doses that we had previously found to be the highest dose without inducing toxicity (hypercalcemia). The mice were monitored for hair growth and were scored according to a defined scale. Skin samples were taken for histological observation of hair follicles and for extraction of RNA and protein. Vitamin D3 analogs dramatically stimulated the hair growth of nude mice, although parental 1,25 dihydroxyvitamin D3 had no effect. Hair growth occurred in a cyclical pattern, accompanied by formation of normal hair follicles and increased expression of certain keratins (Ha7, Ha8, and Hb3). Vitamin D3 analogs seem to act on keratinocytes to initiate hair follicle cycling and stimulate hair growth in mice that otherwise do not grow hair.

  6. Effects of Lizhong Tang on gastrointestinal motility in mice.

    PubMed

    Lee, Min Cheol; Ha, Wooram; Park, Jinhyeong; Kim, Junghoon; Jung, Yunjin; Kim, Byung Joo

    2016-09-14

    To investigate the effects of Lizhong Tang, a traditional Chinese medicine formula, on gastrointestinal motility in mice. The in vivo effects of Lizhong Tang on GI motility were investigated by measuring the intestinal transit rates (ITRs) and gastric emptying (GE) values in normal mice and in mice with experimentally induced GI motility dysfunction (GMD). In normal ICR mice, the ITR and GE values were significantly and dose-dependently increased by Lizhong Tang (ITR values: 54.4% ± 1.9% vs 65.2% ± 1.8%, P < 0.01 with 0.1 g/kg Lizhong Tang and 54.4% ± 1.9% vs 83.8% ± 1.9%, P < 0.01 with 1 g/kg Lizhong Tang; GE values: 60.7% ± 1.9% vs 66.8% ± 2.1%, P < 0.05 with 0.1 g/kg Lizhong Tang and 60.7% ± 1.9% vs 72.5% ± 1.7%, P < 0.01 with 1 g/kg Lizhong Tang). The ITRs of the GMD mice were significantly reduced compared with those of the normal mice, which were significantly and dose-dependently reversed by Lizhong Tang. Additionally, in loperamide- and cisplatin-induced models of GE delay, Lizhong Tang administration reversed the GE deficits. These results suggest that Lizhong Tang may be a novel candidate for development as a prokinetic treatment for the GI tract.

  7. Suspended animation-like state protects mice from lethal hypoxia.

    PubMed

    Blackstone, Eric; Roth, Mark B

    2007-04-01

    Joseph Priestley observed the high burn rate of candles in pure oxygen and wondered if people would "live out too fast" if we were in the same environment. We hypothesize that sulfide, a natural reducer of oxygen that is made in many cell types, acts as a buffer to prevent unrestricted oxygen consumption. To test this, we administered sulfide in the form of hydrogen sulfide (H2S) to mice (Mus musculus). As we have previously shown, H2S decreases the metabolic rate of mice by approximately 90% and induces a suspended animation-like state. Mice cannot survive for longer than 20 min when exposed to 5% oxygen. However, if mice are first put into a suspended animation-like state by a 20-min pretreatment with H2S and then are exposed to low oxygen, they can survive for more than 6.5 h in 5% oxygen with no apparent detrimental effects. In addition, if mice are exposed to a 20-min pretreatment with H2S followed by 1 h at 5% oxygen, they can then survive for several hours at oxygen tensions as low as 3%. We hypothesize that prior exposure to H2S reduces oxygen demand, therefore making it possible for the mice to survive with low oxygen supply. These results suggest that H2S may be useful to prevent damage associated with hypoxia.

  8. Maladaptive defensive behaviours in monoamine oxidase A-deficient mice.

    PubMed

    Godar, Sean C; Bortolato, Marco; Frau, Roberto; Dousti, Mona; Chen, Kevin; Shih, Jean C

    2011-10-01

    Rich evidence indicates that monoamine oxidase (MAO) A, the major enzyme catalysing the degradation of monoamine neurotransmitters, plays a key role in emotional regulation. Although MAOA deficiency is associated with reactive aggression in humans and mice, the involvement of this enzyme in defensive behaviour remains controversial and poorly understood. To address this issue, we tested MAOA knockout (KO) mice in a spectrum of paradigms and settings associated with variable degrees of threat. The presentation of novel inanimate objects induced a significant reduction in exploratory approaches and increase in defensive behaviours, such as tail-rattling, biting and digging. These neophobic responses were context-dependent and particularly marked in the home cage. In the elevated plus- and T-mazes, MAOA KO mice and wild-type (WT) littermates displayed equivalent locomotor activity and time in closed and open arms; however, MAOA KO mice featured significant reductions in risk assessment, as well as unconditioned avoidance and escape. No differences between genotypes were observed in the defensive withdrawal and emergence test. Conversely, MAOA KO mice exhibited a dramatic reduction of defensive and fear-related behaviours in the presence of predator-related cues, such as predator urine or an anaesthetized rat, in comparison with those observed in their WT littermates. The behavioural abnormalities in MAOA KO mice were not paralleled by overt alterations in sensory and microvibrissal functions. Collectively, these results suggest that MAOA deficiency leads to a general inability to appropriately assess contextual risk and attune defensive and emotional responses to environmental cues.

  9. Caloric restriction enhances fear extinction learning in mice.

    PubMed

    Riddle, Megan C; McKenna, Morgan C; Yoon, Yone J; Pattwell, Siobhan S; Santos, Patricia Mae G; Casey, B J; Glatt, Charles E

    2013-05-01

    Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.

  10. Myostatin gene mutated mice induced with tale nucleases.

    PubMed

    Zhou, Fangfang; Sun, Ruilin; Chen, Hongyan; Fei, Jian; Lu, Daru

    2015-01-01

    Myostain gene (MSTN) is expressed primarily in skeletal muscle, and negatively regulates skeletal muscle mass; it has been suggested that mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. Therefore, it is important to establish a fast and effective gene editing method. In this report, we established the myostatin mutated-mouse model by microinjection of Transcription Activator-Like Effector Nucleases (TALENs) mRNA within the mouse fertilized oocytes and achieved high rates of mutagenesis of the mouse MSTN in C57BL/6J. Six of 45 born mice carried target mutations and we appointed one as the parental mating with wild mouse to produce the F1 and backcross to produce the F2 generation. All the mutations of the mice were examined quickly and efficiently by high-resolution melting curve analysis (HRMA) and then verified by direct sequencing. We obtained the homozygous of the F2 generation which transmitted the mutant alleles to the progeny with 100% efficiency. Mutant mice exhibited increases in muscle mass comparable to those observed in wild-type mice. Therefore, combining TALEN-mediated gene targeting with HRMA technology is a superior method of constructing genetically modified mice through microinjection in the mouse fertilized oocytes with high efficiency and short time of selection.

  11. Doppler velocity measurements from large and small arteries of mice

    PubMed Central

    Reddy, Anilkumar K.; Madala, Sridhar; Entman, Mark L.; Michael, Lloyd H.; Taffet, George E.

    2011-01-01

    With the growth of genetic engineering, mice have become increasingly common as models of human diseases, and this has stimulated the development of techniques to assess the murine cardiovascular system. Our group has developed nonimaging and dedicated Doppler techniques for measuring blood velocity in the large and small peripheral arteries of anesthetized mice. We translated technology originally designed for human vessels for use in smaller mouse vessels at higher heart rates by using higher ultrasonic frequencies, smaller transducers, and higher-speed signal processing. With these methods one can measure cardiac filling and ejection velocities, velocity pulse arrival times for determining pulse wave velocity, peripheral blood velocity and vessel wall motion waveforms, jet velocities for the calculation of the pressure drop across stenoses, and left main coronary velocity for the estimation of coronary flow reserve. These noninvasive methods are convenient and easy to apply, but care must be taken in interpreting measurements due to Doppler sample volume size and angle of incidence. Doppler methods have been used to characterize and evaluate numerous cardiovascular phenotypes in mice and have been particularly useful in evaluating the cardiac and vascular remodeling that occur following transverse aortic constriction. Although duplex ultrasonic echo-Doppler instruments are being applied to mice, dedicated Doppler systems are more suitable for some applications. The magnitudes and waveforms of blood velocities from both cardiac and peripheral sites are similar in mice and humans, such that much of what is learned using Doppler technology in mice may be translated back to humans. PMID:21572013

  12. Genistein treatment increases bone mass in obese, hyperglycemic mice

    PubMed Central

    Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

    2016-01-01

    Background Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. Methods In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Results Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Conclusion Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight. PMID:27042131

  13. Genistein treatment increases bone mass in obese, hyperglycemic mice.

    PubMed

    Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

    2016-01-01

    Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight.

  14. Microglial K+ Channel Expression in Young Adult and Aged Mice

    PubMed Central

    Schilling, Tom; Eder, Claudia

    2015-01-01

    The K+ channel expression pattern of microglia strongly depends on the cells' microenvironment and has been recognized as a sensitive marker of the cells' functional state. While numerous studies have been performed on microglia in vitro, our knowledge about microglial K+ channels and their regulation in vivo is limited. Here, we have investigated K+ currents of microglia in striatum, neocortex and entorhinal cortex of young adult and aged mice. Although almost all microglial cells exhibited inward rectifier K+ currents upon membrane hyperpolarization, their mean current density was significantly enhanced in aged mice compared with that determined in young adult mice. Some microglial cells additionally exhibited outward rectifier K+ currents in response to depolarizing voltage pulses. In aged mice, microglial outward rectifier K+ current density was significantly larger than in young adult mice due to the increased number of aged microglial cells expressing these channels. Aged dystrophic microglia exhibited outward rectifier K+ currents more frequently than aged ramified microglia. The majority of microglial cells expressed functional BK-type, but not IK- or SK-type, Ca2+-activated K+ channels, while no differences were found in their expression levels between microglia of young adult and aged mice. Neither microglial K+ channel pattern nor K+ channel expression levels differed markedly between the three brain regions investigated. It is concluded that age-related changes in microglial phenotype are accompanied by changes in the expression of microglial voltage-activated, but not Ca2+-activated, K+ channels. PMID:25472417

  15. Impaired olfaction in mice lacking aquaporin-4 water channels.

    PubMed

    Lu, Daniel C; Zhang, Hua; Zador, Zsolt; Verkman, A S

    2008-09-01

    Aquaporin-4 (AQP4) is a water-selective transport protein expressed in glial cells throughout the central nervous system. AQP4 deletion in mice produces alterations in several neuroexcitation phenomena, including hearing, vision, epilepsy, and cortical spreading depression. Here, we report defective olfaction and electroolfactogram responses in AQP4-null mice. Immunofluorescence indicated strong AQP4 expression in supportive cells of the nasal olfactory epithelium. The olfactory epithelium in AQP4-null mice had identical appearance, but did not express AQP4, and had approximately 12-fold reduced osmotic water permeability. Behavioral analysis showed greatly impaired olfaction in AQP4-null mice, with latency times of 17 +/- 0.7 vs. 55 +/- 5 s in wild-type vs. AQP4-null mice in a buried food pellet test, which was confirmed using an olfactory maze test. Electroolfactogram voltage responses to multiple odorants were reduced in AQP4-null mice, with maximal responses to triethylamine of 0.80 +/- 0.07 vs. 0.28 +/- 0.03 mV. Similar olfaction and electroolfactogram defects were found in outbred (CD1) and inbred (C57/bl6) mouse genetic backgrounds. Our results establish AQP4 as a novel determinant of olfaction, the deficiency of which probably impairs extracellular space K(+) buffering in the olfactory epithelium.

  16. Generating Chimeric Mice by Using Embryos from Nonsuperovulated BALB/c Mice Compared with Superovulated BALB/c and Albino C57BL/6 Mice.

    PubMed

    Esmail, Michael Y; Qi, Peimin; Connor, Aurora Burds; Fox, James G; García, Alexis

    2016-01-01

    The reliable generation of high-percentage chimeras from gene-targeted C57BL/6 embryonic stem cells has proven challenging, despite optimization of cell culture and microinjection techniques. To improve the efficiency of this procedure, we compared the generation of chimeras by using 3 different inbred, albino host, embryo-generating protocols: BALB/cAnNTac (BALB/c) donor mice superovulated at 4 wk of age, 12-wk-old BALB/c donor mice without superovulation, and C57BL/6NTac-Tyr(tm1Arte) (albino B6) mice superovulated at 4 wk of age. Key parameters measured included the average number of injectable embryos per donor, the percentage of live pups born from the total number of embryos transferred to recipients, and the number of chimeric pups with high embryonic-stem-cell contribution by coat color. Although albino B6 donors produced significantly more injectable embryos than did BALB/c donors, 12-wk-old BALB/c donor produced high-percentage (at least 70%) chimeras more than 2.5 times as often as did albino B6 mice and 20 times more efficiently than did 4-wk-old BALB/c donors. These findings clearly suggest that 12-wk-old BALB/c mice be used as blastocyst donors to reduce the number of mice used to generate each chimera, reduce the production of low-percentage chimeras, and maximize the generation of high-percentage chimeras from C57BL/6 embryonic stem cells.

  17. Persistence of polyomavirus in mice infected as adults differs from that observed in mice infected as newborns.

    PubMed Central

    Berke, Z; Dalianis, T

    1993-01-01

    By using the polymerase chain reaction (PCR) technique, a technique more sensitive than Southern analysis, which allows detection of polyomavirus DNA only in newborn and nude adult mice, it has now been possible to monitor the persistence pattern of polyomavirus DNA after infection of normal adult CBA mice for the first time. Viral signs appeared gradually, showing variations in time course and organ distribution between mice, and reached a peak activity after 2 to 3 weeks, when they could be found in bone, heart, gonads, lymph node, and skin, but disappeared by 2 to 5 months. No virus DNA was detected in the kidneys or lungs, which is in contrast to what is observed after infection of newborn mice. This finding suggests that the persistence pattern of polyomavirus is age dependent. PMID:8389934

  18. [Breeding of transgenic mice expressing human tau isoform with P301L mutation and identification of homozygous transgenic mice].

    PubMed

    Wang, Yan-yan; Chen, Ru-zhui; Zhu, Xiao-nani; Liu, Jing; Li, Zhi-hui; Liu, Xiu-juan; Li, Zhi-hui; Na, Xin; Liang, Shan-shan; Qiu, Guo-guang; Zhang, Wei; Wang, Hai; Wang, Xue-lan

    2012-05-01

    To establish homozygous transgenic mouse strain expressing human tau isoform with P301L mutation. Five transgenic mice expressing human tau isoform with P301L mutation were obtained by microinjection into male nuclei. Homozygote and hemizygote were identified by PCR and real-time fluorescent quantitative PCR. Ninety five homozygous transgenic mice were selected, and the results indicated that homozygous transgenic mice were superior to hemizygote in simulating the changes of biological characteristics. Exogenous gene tau is able to stably transmit to next generation and the combination of SYBR Green real-time fluorescent quantitative PCR with the traditional mating is a fast, reliable and economical way to screen homozygous and hemizygous transgenic mice.

  19. Grating acuity at different luminances in wild-type mice and in mice lacking rod or cone function.

    PubMed

    Schmucker, Christine; Seeliger, Mathias; Humphries, Pete; Biel, Martin; Schaeffel, Frank

    2005-01-01

    The mouse eye has become an important model in vision research. However, it is not known how visual acuity changes with luminance. Therefore, grating acuity of mice was measured at different luminances in an automated optomotor paradigm. Furthermore, mutant mice lacking either rods (RHO-/- and CNGB1-/-) or cones (CNGA3-/-), or both, were studied to determine the rod and cone contribution to visual acuity. Freely ranging individual mice were automatically tracked at a 25-Hz sampling rate with a self-programmed video system in a large rotating optomotor drum. The drum had a square-wave grating inside with adjustable spatial frequency. The angular speed of the mice with respect to the center of the drum and the angular orientation of the snout-tail body axis were analyzed. In addition, the motor activity of the wild-type mice was recorded at different luminances. The optomotor drum provided reliable data on visual input to the mouse's behavior and was convenient to use, since the experimenter's had only to place the mice individually in a Perspex cylinder. Optomotor grating acuity of the wild-type mice was limited to 0.3 to 0.4 cyc/deg. Maximum optomotor responses were obtained at 0.1 to 0.2 cyc/deg. The importance of visual input declined monotonically with decreasing luminance (30 cd/m2, 100%; 0.1 cd/m2, 76.4%; 0.005 cd/m2, 45.9%; and darkness, -9%). Mice lacking functional rods were able to resolve gratings up to 0.1 cyc/deg at 30 cd/m2. Surprisingly, mice lacking functional cones had an optomotor acuity that was similar to the wild-type. Double-knockout mice without rods and cones had no detectable grating acuity. Because the visual system of the mouse is more responsive at bright luminances, experiments in which visual input is important should be performed in photopic conditions (30 cd/m2 or even more). Apparently, spatial vision is governed by the rod system, which is not saturated in the mesopic or low photopic range. Mice lacking both rods and cones have no

  20. Evidence for Persistence of Ectromelia Virus in Inbred Mice, Recrudescence Following Immunosuppression and Transmission to Naïve Mice.

    PubMed

    Sakala, Isaac G; Chaudhri, Geeta; Scalzo, Anthony A; Eldi, Preethi; Newsome, Timothy P; Buller, Robert M; Karupiah, Gunasegaran

    2015-12-01

    Orthopoxviruses (OPV), including variola, vaccinia, monkeypox, cowpox and ectromelia viruses cause acute infections in their hosts. With the exception of variola virus (VARV), the etiological agent of smallpox, other OPV have been reported to persist in a variety of animal species following natural or experimental infection. Despite the implications and significance for the ecology and epidemiology of diseases these viruses cause, those reports have never been thoroughly investigated. We used the mouse pathogen ectromelia virus (ECTV), the agent of mousepox and a close relative of VARV to investigate virus persistence in inbred mice. We provide evidence that ECTV causes a persistent infection in some susceptible strains of mice in which low levels of virus genomes were detected in various tissues late in infection. The bone marrow (BM) and blood appeared to be key sites of persistence. Contemporaneous with virus persistence, antiviral CD8 T cell responses were demonstrable over the entire 25-week study period, with a change in the immunodominance hierarchy evident during the first 3 weeks. Some virus-encoded host response modifiers were found to modulate virus persistence whereas host genes encoded by the NKC and MHC class I reduced the potential for persistence. When susceptible strains of mice that had apparently recovered from infection were subjected to sustained immunosuppression with cyclophosphamide (CTX), animals succumbed to mousepox with high titers of infectious virus in various organs. CTX treated index mice transmitted virus to, and caused disease in, co-housed naïve mice. The most surprising but significant finding was that immunosuppression of disease-resistant C57BL/6 mice several weeks after recovery from primary infection generated high titers of virus in multiple tissues. Resistant mice showed no evidence of a persistent infection. This is the strongest evidence that ECTV can persist in inbred mice, regardless of their resistance status.

  1. Socially Isolated Mice Exhibit a Blunted Homeostatic Sleep Response to Acute Sleep Deprivation Compared to Socially Paired Mice

    PubMed Central

    Kaushal, Navita; Nair, Deepti; Gozal, David; Ramesh, Vijay

    2012-01-01

    Sleep is an important physiological process underlying maintenance of physical, mental and emotional health. Consequently, sleep deprivation (SD) is associated with adverse consequences and increases the risk for anxiety, immune, and cognitive disorders. SD is characterized by increased energy expenditure responses and sleep rebound upon recovery that are regulated by homeostatic processes, which in turn are influenced by stress. Since all previous studies on SD were conducted in a setting of social isolation, the impact of the social contextual setting is unknown. Therefore, we used a relatively stress-free SD paradigm in mice to assess the impact of social isolation on sleep, wakefulness and delta electroencephalogram (EEG) power during non-rapid eye movement (NREM) sleep. Paired or isolated C57BL/6J adult chronically-implanted male mice were exposed to SD for 6 hours and telemetric polygraphic recordings were conducted, including 18 hours recovery. Recovery from SD in the paired group showed a significant decrease in wake and significant increase in NREM sleep and rapid eye movement (REM), and a similar, albeit less robust response occurred in the isolated mice. Delta power during NREM sleep was increased in both groups immediately following SD, but paired mice exhibited significantly higher delta power throughout the dark period. The increase in body temperature and gross motor activity observed during the SD procedure was decreased during the dark period. In both open field and elevated plus maze tests, socially isolated mice showed significantly higher anxiety than paired mice. The homeostatic processes altered by SD are differentially affected in paired and isolated mice, suggesting that the social context of isolation stress may adversely affect the quantity and quality of sleep in mice. PMID:22498175

  2. Trehalose Dimycolate Enhances Survival of Fission Neutron-Irradiated Mice and Klebsiella pneumoniae-Challenged Irradiated Mice

    DTIC Science & Technology

    1990-01-01

    SR90-5 Trehalose Dimycolate Enhances Survival of Fission Neutron-Irradiated Mice and Kiebsiella pneumoniae-Challenged Irradiated Mice 1’ 2 D. (. M...doses kines and immunomodulators of nonspecific resistance to of fission neutron radiation is increased when trehalose dimycol- infection might have... trehalose day before exposure to radiation. TDM in an emulsion of squa- dimycolate (TDM) have been shown to be effective in in- lene. Tween 80, and saline

  3. Microbiological survey of mice (Mus musculus) purchased from commercial pet shops in Kanagawa and Tokyo, Japan.

    PubMed

    Hayashimoto, Nobuhito; Morita, Hanako; Ishida, Tomoko; Uchida, Ritsuki; Tanaka, Mai; Ozawa, Midori; Yasuda, Masahiko; Itoh, Toshio

    2015-01-01

    Information regarding the prevalence of infectious agents in mice in pet shops in Japan is scarce. This information is particularly useful for minimizing the risk of potential transmission of infections to laboratory mice. Therefore, we surveyed infectious agents in mice from pet shops in Kanagawa and Tokyo, Japan. The survey was conducted in 28 mice from 5 pet shops to screen for 47 items (17 viruses, 22 bacteria and fungi, 10 parasites) using culture tests, serology, PCR, and microscopy. The most common viral agent detected was murine norovirus (17 mice; 60.7%), followed by Theiler's murine encephalomyelitis virus (13 mice; 46.4%), and mouse hepatitis virus (12 mice; 42.8%). The most common agent amongst the bacteria and fungi was Pasteurella pneumotropica (10 mice; 35.7%), followed by Helicobacter ganmani and Pneumocystis murina (8 mice; 28.5%, for both). Tritrichomonas muris was the most common parasite (19 mice; 67.8%), followed by Spironucleus muris (13 mice; 46.4%), Aspiculuris tetraptera, and Syphacia obvelata (8 mice each; 28.5%). Remarkably, a zoonotic agent, Hymenolepis nana, was found in 7 mice (25%). Given these results, we suggest that the workers in laboratory animal facilities should recognize again the potential risks of mice outside of the laboratory animal facilities as an infectious source, and avoid keeping mice as pets or as feed for carnivorous reptiles as much as possible for risk management.

  4. RU486 did not exacerbate cytokine release in mice challenged with LPS nor in db/db mice

    PubMed Central

    Yang, Baichun; Trump, Ryan P; Shen, Ying; McNulty, Judi A; Clifton, Lisa G; Stimpson, Stephen A; Lin, Peiyuan; Pahel, Greg L

    2008-01-01

    Background Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFα levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice. Results Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFα in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFα and further increased serum corticosterone. Conclusion RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFα release, possibly due to the increased release of glucocorticoids. PMID:18474108

  5. A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice.

    PubMed

    Subbanna, Shivakumar; Nagre, Nagaraja N; Shivakumar, Madhu; Basavarajappa, Balapal S

    2016-12-01

    The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5-Azacytidine (5-AzaC), a DNA methyltransferase inhibitor, on neurobehavioral abnormalities in mice. Our findings suggest that the 5-AzaC treatment significantly inhibited DNA methylation, impaired extracellular signal-regulated kinase (ERK1/2) activation and reduced expression of the activity-regulated cytoskeleton-associated protein (Arc). These events lead to the activation of caspase-3 (a marker for neurodegeneration) in several brain regions, including the hippocampus and cortex, two brain areas that are essential for memory formation and memory storage, respectively. 5-AzaC treatment of P7 mice induced significant deficits in spatial memory, social recognition, and object memory in adult mice and deficits in long-term potentiation (LTP) in adult hippocampal slices. Together, these data demonstrate that the inhibition of DNA methylation by 5-AzaC treatment in P7 mice causes neurodegeneration and impairs ERK1/2 activation and Arc protein expression in neonatal mice and induces behavioral abnormalities in adult mice. DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function. Published by Elsevier Inc.

  6. Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles.

    PubMed

    Gustafsson, Åsa; Bergström, Ulrika; Ågren, Lina; Österlund, Lars; Sandström, Thomas; Bucht, Anders

    2015-10-01

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Effects of intra-abdominal sepsis on atherosclerosis in mice.

    PubMed

    Kaynar, Ata Murat; Yende, Sachin; Zhu, Lin; Frederick, Daniel R; Chambers, Robin; Burton, Christine L; Carter, Melinda; Stolz, Donna Beer; Agostini, Brittani; Gregory, Alyssa D; Nagarajan, Shanmugam; Shapiro, Steven D; Angus, Derek C

    2014-09-03

    Sepsis and other infections are associated with late cardiovascular events. Although persistent inflammation is implicated, a causal relationship has not been established. We tested whether sepsis causes vascular inflammation and accelerates atherosclerosis. We performed prospective, randomized animal studies at a university research laboratory involving adult male ApoE-deficient (ApoE-/-) and young C57B/L6 wild-type (WT) mice. In the primary study conducted to determine whether sepsis accelerates atherosclerosis, we fed ApoE-/- mice (N = 46) an atherogenic diet for 4 months and then performed cecal ligation and puncture (CLP), followed by antibiotic therapy and fluid resuscitation or a sham operation. We followed mice for up to an additional 5 months and assessed atheroma in the descending aorta and root of the aorta. We also exposed 32 young WT mice to CLP or sham operation and followed them for 5 days to determine the effects of sepsis on vascular inflammation. ApoE-/- mice that underwent CLP had reduced activity during the first 14 days (38% reduction compared to sham; P < 0.001) and sustained weight loss compared to the sham-operated mice (-6% versus +9% change in weight after CLP or sham surgery to 5 months; P < 0.001). Despite their weight loss, CLP mice had increased atheroma (46% by 3 months and 41% increase in aortic surface area by 5 months; P = 0.03 and P = 0.004, respectively) with increased macrophage infiltration into atheroma as assessed by immunofluorescence microscopy (0.52 relative fluorescence units (rfu) versus 0.97 rfu; P = 0.04). At 5 months, peritoneal cultures were negative; however, CLP mice had elevated serum levels of interleukin 6 (IL-6) and IL-10 (each at P < 0.05). WT mice that underwent CLP had increased expression of intercellular adhesion molecule 1 in the aortic lumen versus sham at 24 hours (P = 0.01) that persisted at 120 hours (P = 0.006). Inflammatory and adhesion genes (tumor necrosis factor α, chemokine (C-C motif) ligand 2

  8. Behavioral and Electrophysiological Characterization of Dyt1 Heterozygous Knockout Mice

    PubMed Central

    Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C.; Campbell, Susan L.; Roper, Steven N.; Sweatt, J. David; Li, Yuqing

    2015-01-01

    DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinAΔE). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinAΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia. PMID:25799505

  9. Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

    PubMed

    Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C; Campbell, Susan L; Roper, Steven N; Sweatt, J David; Li, Yuqing

    2015-01-01

    DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

  10. Retinal degeneration increases susceptibility to myopia in mice

    PubMed Central

    Park, Hanna; Tan, Christopher C.; Faulkner, Amanda; Jabbar, Seema B.; Schmid, Gregor; Abey, Jane; Iuvone, P. Michael

    2013-01-01

    Purpose Retinal diseases are often associated with refractive errors, suggesting the importance of normal retinal signaling during emmetropization. For instance, retinitis pigmentosa, a disease characterized by severe photoreceptor degeneration, is associated with myopia; however, the underlying link between these conditions is not known. This study examines the influence of photoreceptor degeneration on refractive development by testing two mouse models of retinitis pigmentosa under normal and form deprivation visual conditions. Dopamine, a potential stop signal for refractive eye growth, was assessed as a potential underlying mechanism. Methods Refractive eye growth in mice that were homozygous for a mutation in Pde6b, Pde6brd1/rd1 (rd1), or Pde6brd10/rd10 (rd10) was measured weekly from 4 to 12 weeks of age and compared to age-matched wild-type (WT) mice. Refractive error was measured using an eccentric infrared photorefractor, and axial length was measured with partial coherence interferometry or spectral domain ocular coherence tomography. A cohort of mice received head-mounted diffuser goggles to induce form deprivation from 4 to 6 weeks of age. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured with high-performance liquid chromatography in each strain after exposure to normal or form deprivation conditions. Results The rd1 and rd10 mice had significantly greater hyperopia relative to the WT controls throughout normal development; however, axial length became significantly longer only in WT mice starting at 7 weeks of age. After 2 weeks of form deprivation, the rd1 and rd10 mice demonstrated a faster and larger myopic shift (−6.14±0.62 and −7.38±1.46 diopter, respectively) compared to the WT mice (−2.41±0.47 diopter). Under normal visual conditions, the DOPAC levels and DOPAC/dopamine ratios, a measure of dopamine turnover, were significantly lower in the rd1 and rd10 mice compared to the WT mice, while the dopamine levels were

  11. Necrostatin-1 rescues mice from lethal irradiation.

    PubMed

    Huang, Zhentai; Epperly, Michael; Watkins, Simon C; Greenberger, Joel S; Kagan, Valerian E; Bayır, Hülya

    2016-04-01

    There is an emerging need in new medical products that can mitigate and/or treat the short- and long-term consequences of radiation exposure after a radiological or nuclear terroristic event. The direct effects of ionizing radiation are realized primarily via apoptotic death pathways in rapidly proliferating cells within the initial 1-2days after the exposure. However later in the course of the radiation disease necrotic cell death may ensue via direct and indirect pathways from increased generation of pro-inflammatory cytokines. Here we evaluated radiomitigative potential of necrostatin-1 after total body irradiation (TBI) and the contribution of necroptosis to cell death induced by radiation. Circulating TNFα levels were increased starting on d1 after TBI and associated with increased plasmalemma permeability in ileum of irradiated mice. Necrostatin-1 given iv. 48h after 9.5Gy TBI attenuated radiation-induced receptor interacting protein kinase 3 (RIPK3) serine phosphorylation in ileum and improved survival vs. vehicle. Utilizing apoptosis resistant cytochrome c(-/-) cells, we showed that radiation can induce necroptosis, which is attenuated by RNAi knock down of RIPK1 and RIPK3 or by treatment with necrostatin-1 or -1s whereas 1-methyl-L-tryptophan, an indoleamine-2,3-dioxygenase inhibitor, did not exhibit radiomitigative effect. This suggests that the beneficial effect of necrostatin-1 is likely through inhibition of RIPK1-mediated necroptotic pathway. Overall, our data indicate that necroptosis, a form of programmed necrosis, may play a significant role in cell death contributing to radiation disease and mortality. This study provides a proof of principle that necrostatin-1 and perhaps other RIPK1 inhibitors are promising therapeutic agents for radiomitigation after TBI. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Accelerated enamel mineralization in Dspp mutant mice

    PubMed Central

    Verdelis, Kostas; Szabo-Rogers, Heather L.; Xu, Yang; Chong, Rong; Kang, Ryan; Cusack, Brian J.; Jani, Priyam; Boskey, Adele L.; Qin, Chunlin; Beniash, Elia

    2016-01-01

    Dentin sialophosphoprotein (DSPP) is one of the major non-collagenous proteins present in dentin, cementum and alveolar bone; it is also transiently expressed by ameloblasts. In humans many mutations have been found in DSPP and are associated with two autosomal-dominant genetic diseases — dentinogenesis imperfecta II (DGI-II) and dentin dysplasia (DD). Both disorders result in the development of hypomineralized and mechanically compromised teeth. The erupted mature molars of Dspp–/– mice have a severe hypomineralized dentin phenotype. Since dentin and enamel formations are interdependent, we decided to investigate the process of enamel onset mineralization in young Dspp–/– animals. We focused our analysis on the constantly erupting mouse incisor, to capture all of the stages of odontogenesis in one tooth, and the unerupted first molars. Using high-resolution microCT, we revealed that the onset of enamel matrix deposition occurs closer to the cervical loop and both secretion and maturation of enamel are accelerated in Dspp–/– incisors compared to the Dspp+/– control. Importantly, these differences did not translate into major phenotypic differences in mature enamel in terms of the structural organization, mineral density or hardness. The only observable difference was the reduction in thickness of the outer enamel layer, while the total enamel thickness remained unchanged. We also observed a compromised dentin-enamel junction, leading to delamination between the dentin and enamel layers. The odontoblast processes were widened and lacked branching near the DEJ. Finally, for the first time we demonstrate expression of Dspp mRNA in secretory ameloblasts. In summary, our data show that DSPP is important for normal mineralization of both dentin and enamel. PMID:26780724

  13. Cytogenetic studies of mice chronically fed carcinogens

    SciTech Connect

    Director, A.E.; Ramsey, M.J.; Tucker, J.D.

    1997-10-01

    Over the past few years, we have carried out chronic feeding studies in C57BL/6 female mice. These experiments examined the effect of the chronic ingestion of a single chemical carcinogen on chromosomes. The carcinogens studied were PhIP,MeIQx, cyclophosphamide and urethane. These studies used traditional assays, such as SCEs and MN, as well as chromosome painting. In all four cases, the traditional assays showed an increase in the frequency of lesions, demonstrating that the chemicals, and/or their reactive metabolites, reached the target nuclei. This, however, seemed at odds with the data obtained from chromosome painting, which did not show an increasemore » in the frequency of stable chromosome aberrations. This discrepancy between traditional assays and chromosome painting may be due to the nature of the lesions that each assay identifies. The traditional assays tend to identify lesions on the chromatid level, where as chromosome painting identifies lesions on the chromosome level requires two or more DNA double strand breaks occurring proximally in both time and space. In other words, for exposure to a chemical carcinogen to induce an increase in chromosome aberrations as measured by chromosome painting, the chemical, or its metabolites, would have to cause a large number of double strand breaks. By applying this logic to the data obtained from the four chronic feeding studies, one can infer that the chronic ingestion of chemical carcinogens does not result in the frequent formation of double strand breaks and therefore, does not result in the frequent formation of double strand breaks and therefore, does not result in increased frequencies of stable chromosome aberrations. We must, therefore, look elsewhere for the mechanism(s) underlying carcinogenesis due to chronic exposure to chemical carcinogens.« less

  14. Metoprolol impairs resistance artery function in mice

    PubMed Central

    El Beheiry, Mostafa H.; Heximer, Scott P.; Voigtlaender-Bolz, Julia; Mazer, C. David; Connelly, Kim A.; Wilson, David F.; Beattie, W. Scott; Tsui, Albert K. Y.; Zhang, Hangjun; Golam, Kabir; Hu, Tina; Liu, Elaine; Lidington, Darcy; Bolz, Steffen-Sebastian

    2011-01-01

    Acute β-blockade with metoprolol has been associated with increased mortality by undefined mechanisms. Since metoprolol is a relatively high affinity blocker of β2-adrenoreceptors, we hypothesized that some of the increased mortality associated with its use may be due to its abrogation of β2-adrenoreceptor-mediated vasodilation of microvessels in different vascular beds. Cardiac output (CO; pressure volume loops), mean arterial pressure (MAP), relative cerebral blood flow (rCBF; laser Doppler), and microvascular brain tissue Po2 (G2 oxyphor) were measured in anesthetized mice before and after acute treatment with metoprolol (3 mg/kg iv). The vasodilatory dose responses to β-adrenergic agonists (isoproterenol and clenbuterol), and the myogenic response, were assessed in isolated mesenteric resistance arteries (MRAs; ∼200-μm diameter) and posterior cerebral arteries (PCAs ∼150-μm diameter). Data are presented as means ± SE with statistical significance applied at P < 0.05. Metoprolol treatment did not effect MAP but reduced heart rate and stroke volume, CO, rCBF, and brain microvascular Po2, while concurrently increasing systemic vascular resistance (P < 0.05 for all). In isolated MRAs, metoprolol did not affect basal artery tone or the myogenic response, but it did cause a dose-dependent impairment of isoproterenol- and clenbuterol-induced vasodilation. In isolated PCAs, metoprolol (50 μM) impaired maximal vasodilation in response to isoproterenol. These data support the hypothesis that acute administration of metoprolol can reduce tissue oxygen delivery by impairing the vasodilatory response to β2-adrenergic agonists. This mechanism may contribute to the observed increase in mortality associated with acute administration of metoprolol in perioperative patients. PMID:21799135

  15. Minimally Invasive Transverse Aortic Constriction in Mice.

    PubMed

    Zaw, Aung Moe; Williams, Connor M; Law, Helen K W; Chow, Billy Kwok Chong

    2017-03-14

    Minimally invasive transverse aortic constriction (MTAC) is a more desirable method for the constriction of the transverse aorta in mice than standard open-chest transverse aortic constriction (TAC). Although transverse aortic constriction is a highly functional method for the induction of high pressure in the left ventricle, it is a more difficult and lengthy procedure due to its use of artificial ventilation with tracheal intubation. TAC is oftentimes also less survivable, as the newer method, MTAC, neither requires the cutting of the ribs and intercostal muscles nor tracheal intubation with a ventilation setup. In MTAC, as opposed to a thoracotomy to access to the chest cavity, the aortic arch is reached through a midline incision in the anterior neck. The thyroid is pulled back to reveal the sternal notch. The sternum is subsequently cut down to the second rib level, and the aortic arch is reached simply by separating the connective tissues and thymus. From there, a suture can be wrapped around the arch and tied with a spacer, and then the sternal cut and skin can be closed. MTAC is a much faster and less invasive way to induce left ventricular hypertension and enables the possibility for high-throughput studies. The success of the constriction can be verified using high-frequency trans-thoracic echocardiography, particularly color Doppler and pulsed-wave Doppler, to determine the flow velocities of the aortic arch and left and right carotid arteries, the dimension of the blood vessels, and the left ventricular function and morphology. A successful constriction will also trigger significant histopathological changes, such as cardiac muscle cell hypertrophy with interstitial and perivascular fibrosis. Here, the procedure of MTAC is described, demonstrating how the resulting flow changes in the carotid arteries can be examined with echocardiography, gross morphology, and histopathological changes in the heart.

  16. Manipulating a "cocaine engram" in mice.

    PubMed

    Hsiang, Hwa-Lin Liz; Epp, Jonathan R; van den Oever, Michel C; Yan, Chen; Rashid, Asim J; Insel, Nathan; Ye, Li; Niibori, Yosuke; Deisseroth, Karl; Frankland, Paul W; Josselyn, Sheena A

    2014-10-15

    Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the "cocaine memory trace" or "cocaine engram"). We found that a small population of neurons (∼10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine-conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsáki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. Copyright © 2014 the authors 0270-6474/14/3414115-13$15.00/0.

  17. A comprehensive glycome profiling of Huntington's disease transgenic mice.

    PubMed

    Gizaw, Solomon T; Koda, Toshiaki; Amano, Maho; Kamimura, Keiko; Ohashi, Tetsu; Hinou, Hiroshi; Nishimura, Shin-Ichiro

    2015-09-01

    Huntington's disease (HD) is an autosomal, dominantly inherited and progressive neurodegenerative disease, nosologically classified as the presence of intranuclear inclusion bodies and the loss of GABA-containing neurons in the neostriatum and subsequently in the cerebellar cortex. Abnormal processing of neuronal proteins can result in the misfolding of proteins and altered post-translational modification of newly synthesized proteins. Total glycomics, namely, N-glycomics, O-glycomics, and glycosphingolipidomics (GSL-omics) of HD transgenic mice would be a hallmark for central nervous system disorders in order to discover disease specific biomarkers. Glycoblotting method, a high throughput glycomic protocol, and matrix-assisted laser desorption ionization-time of flight/mass spectrometry (MALDI-TOF/MS) were used to study the total glycome expression levels in the brain tissue (3 mice of each sex) and sera (5 mice of each sex) of HD transgenic and control mice. All experiments were performed twice and differences in the expression levels of major glycoforms were compared between HD transgenic and control mice. We estimated the structure and expression levels of 87 and 58N-glycans in brain tissue and sera, respectively, of HD transgenic and control mice. The present results clearly indicated that the brain glycome and their expression levels are significantly gender specific when compared with those of other tissues and serum. Core-fucosylated and bisecting-GlcNAc types of N-glycans were found in increased levels in the brain tissue HD transgenic mice. Accordingly, core-fucosylated and sialic acid (particularly N-glycolylneuraminic acid, NeuGc) for biantennary type glycans were found in increased amounts in the sera of HD transgenic mice compared to that of control mice. Core 3 type O-glycans were found in increased levels in male and in decreased levels in both the striatum and cortexes of female HD transgenic mice. Furthermore, serum levels of core 1 type O

  18. Electrophysiology and metabolism of caveolin-3 overexpressing mice

    PubMed Central

    Schilling, Jan M.; Horikawa, Yousuke T.; Zemljic-Harpf, Alice E.; Vincent, Kevin P.; Tyan, Leonid; Yu, Judith K.; McCulloch, Andrew D.; Balijepalli, Ravi C.; Patel, Hemal H.; Roth, David M.

    2017-01-01

    Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: 1) ECG telemetry recordings at baseline and during pharmacological interventions, 2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and 3) baseline metabolism in Cav-3 OE and transgene negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. Expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, and heat generation, feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection. PMID:27023865

  19. Deletion of alpha-synuclein decreases impulsivity in mice.

    PubMed

    Peña-Oliver, Y; Buchman, V L; Dalley, J W; Robbins, T W; Schumann, G; Ripley, T L; King, S L; Stephens, D N

    2012-03-01

    The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  20. Chimeric elk/mouse prion proteins in transgenic mice.

    PubMed

    Tamgüney, Gültekin; Giles, Kurt; Oehler, Abby; Johnson, Natrina L; DeArmond, Stephen J; Prusiner, Stanley B

    2013-02-01

    Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.

  1. Interstrain Differences in CO2-Induced Pulmonary Hemorrhage in Mice.

    PubMed

    Fisher, Suhrim; Burgess, Winona L; Hines, Kenneth D; Mason, Gary L; Owiny, James R

    2016-11-01

    Carbon dioxide is the most commonly used gas for euthanasia of rodents. The current AVMA Guidelines recommend slowly filling the container with CO2 (SF) and now indicate that the practice of placing conscious animals in containers prefilled with CO2 (PF) is unacceptable. An investigator noted pulmonary hemorrhage (PH) in BALB/c mice euthanized by SF that was not observed after PF. Here we evaluated whether the air-displacement rate (SF compared with PF) influenced the development of PH or nasal hemorrhage (NH) in 2 commonly used mouse strains. In addition, we investigated the prevalence of PH and NH in mice euthanized by isoflurane overdose (IO). Male and female (age groups, 6 wk and 6 mo) BALB/c and C57BL/6 mice were euthanized by SF or PF. In addition, 6-mo-old BALB/c male mice were euthanized by IO. Lung, nasal turbinates, brain, and reproductive organs were collected for gross and histologic evaluation and scored for degree of hemorrhage (score, 0 to 3). Severity of hemorrhage did not differ according to mouse age or sex. PH in BALB/c mice was more severe after SF than PF, and SF and PF induced more severe PH in BALB/c than in C57BL/6 mice. PH in 6-mo-old male BALB/c mice was more severe after SF than IO. Neither SF, PF, nor IO influenced the prevalence of NH in any group. This study demonstrates that the method of euthanasia may need to be altered depending on the mouse strain used.

  2. The Role of Serotonin in Ventricular Repolarization in Pregnant Mice

    PubMed Central

    Park, Hyelim; Mun, Dasom; Lee, Seung-Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui-Nam; Lee, Moon-Hyoung

    2018-01-01

    Purpose The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. Materials and Methods We measured current amplitudes and the expression levels of voltage-gated K+ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a−/−-NP). Results During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a−/−-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Conclusion Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. PMID:29436197

  3. The Role of Serotonin in Ventricular Repolarization in Pregnant Mice.

    PubMed

    Cui, Shanyu; Park, Hyewon; Park, Hyelim; Mun, Dasom; Lee, Seung Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui Nam; Lee, Moon Hyoung; Joung, Boyoung

    2018-03-01

    The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP). During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. © Copyright: Yonsei University College of Medicine 2018

  4. Transmammary infection in BALB/c mice with chronic toxocariasis.

    PubMed

    de Souza Aguiar, Patricia; Furtado, Raquel Dutra; de Avila, Luciana Farias da Costa; de Lima Telmo, Paula; Martins, Lourdes Helena Rodrigues; Berne, Maria Elisabeth Aires; da Silva, Pedro Eduardo Almeida; Scaini, Carlos James

    2015-04-01

    Human toxocariasis is a neglected public health problem. Infection of humans generally results from the accidental ingestion of embryonated Toxocara canis eggs, but it is important to broaden knowledge about other forms of transmission. This study aimed to demonstrate the prevalence of transmammary transmission in mice with chronic toxocariasis. BALB/c mice in groups 1 (G1) and 3 (G3) were inoculated with 1200 T. canis eggs 60days before mating, whereas those of group 2 (G2) were not infected. After delivery, the G1 neonates were transferred to G2 females to be nursed, and vice versa. Thus, the mice generated by G2 females and breastfed by G1 females could be infected only during lactation. In the G3 group, offspring were not exchanged. The search for T. canis larvae in the bodies of the lactating females and their offspring was performed after weaning and at 60days old, respectively. The frequency of transmammary infection in the mice generated by G2 uninfected females and breastfed by G1 infected females was 19.8%, which was similar to that observed (19.6%) in the mice bred and fed by G3 females. The frequency of infection in the mice generated by G1 females and breastfed by G2 females was only 4.2%, which was lower than that of G1 (p=0.0064) and G3 (p=0.0062) groups. Transmammary infection by mice with chronic toxocariasis was found to be more prevalent than congenital infection. Copyright © 2014. Published by Elsevier Ireland Ltd.

  5. Targeted Deletion of Kynurenine 3-Monooxygenase in Mice

    PubMed Central

    Giorgini, Flaviano; Huang, Shao-Yi; Sathyasaikumar, Korrapati V.; Notarangelo, Francesca M.; Thomas, Marian A. R.; Tararina, Margarita; Wu, Hui-Qiu; Schwarcz, Robert; Muchowski, Paul J.

    2013-01-01

    Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo−/− mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo−/− mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo−/− mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD+, did not differ between Kmo−/− and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo−/− mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo−/− mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease. PMID:24189070

  6. Characteristics of Vibration that Alter Cardiovascular Parameters in Mice

    PubMed Central

    Li, Yao; Rabey, Karyne N; Schmitt, Daniel; Norton, John N; Reynolds, Randall P

    2015-01-01

    We hypothesized that short-term exposure of mice to vibration within a frequency range thought to be near the resonant frequency range of mouse tissue and at an acceleration of 0 to 1 m/s2 would alter heart rate (HR) and mean arterial pressure (MAP). We used radiotelemetry to evaluate the cardiovascular response to vibration in C57BL/6 and CD1 male mice exposed to vertical vibration of various frequencies and accelerations. MAP was consistently increased above baseline values at an acceleration near 1 m/s2 and a frequency of 90 Hz in both strains, and HR was increased also in C57BL/6 mice. In addition, MAP increased at 80 Hz in individual mice of both strains. When both strains were analyzed together, mean MAP and HR were increased at 90 Hz at 1 m/s2, and HR was increased at 80 Hz at 1 m/s2. No consistent change in MAP or HR occurred when mice were exposed to frequencies below 80 Hz or above 90 Hz. The increase in MAP and HR occurred only when the mice had conscious awareness of the vibration, given that these changes did not occur when anesthetized mice were exposed to vibration. Tested vibration acceleration levels lower than 0.75 m/s2 did not increase MAP or HR at 80 or 90 Hz, suggesting that a relatively high level of vibration is necessary to increase these parameters. These data are important to establish the harmful frequencies and accelerations of environmental vibration that should be minimized or avoided in mouse facilities. PMID:26224436

  7. Agmatine blocks ethanol-induced locomotor hyperactivity in male mice.

    PubMed

    Ozden, Onder; Kayir, Hakan; Ozturk, Yusuf; Uzbay, Tayfun

    2011-05-20

    Ethanol-induced locomotor activity is associated to rewarding effects of ethanol and ethanol dependence. Agmatine is a novel endogenous ligand at α2-adrenoceptors, imidazoline and N-methyl-d-aspartate (NMDA) receptors, as well as a nitric oxide synthase (NOS) inhibitor. There is no evidence presented for the relationship between the acute locomotor stimulating effect of ethanol and agmatine. Thus, the present study investigated the effects of agmatine on acute ethanol-induced locomotor hyperactivity in mice. Adult male Swiss-Webster mice (26-36g) were used as subjects. Locomotor activity of the mice was recorded for 30min immediately following intraperitoneal administration of ethanol (0.5, 1 and 2g/kg) or saline (n=8 for each group). Agmatine (5, 10 and 20mg/kg) or saline was administered intraperitoneally to another four individual groups (n=8 for each group) of the mice 20min before the ethanol injection. In these groups, locomotor activity was also recorded immediately following ethanol (0.5g/kg) injection for 30min. Ethanol (0.5g/kg) produced some significant increases in locomotor activity of the mice. Agmatine (5-20mg/kg) significantly blocked the ethanol (0.5g/kg)-induced locomotor hyperactivity. These doses of agmatine did not affect the locomotor activity in naive mice when they were administered alone. Our results suggest that agmatine has an important role in ethanol-induced locomotor hyperactivity in mice. There may be a relationship between the addictive psychostimulant effects of the ethanol and central agmatinergic system. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Kcne3 deletion initiates extracardiac arrhythmogenesis in mice

    PubMed Central

    Hu, Zhaoyang; Crump, Shawn M.; Anand, Marie; Kant, Ritu; Levi, Roberto; Abbott, Geoffrey W.

    2014-01-01

    Mutations in the human KCNE3 potassium channel ancillary subunit gene are associated with life-threatening ventricular arrhythmias. Most genes underlying inherited cardiac arrhythmias, including KCNE3, are not exclusively expressed in the heart, suggesting potentially complex disease etiologies. Here we investigated mechanisms of KCNE3-linked arrhythmogenesis in Kcne3−/− mice using real-time qPCR, echo- and electrocardiography, ventricular myocyte patch-clamp, coronary artery ligation/reperfusion, blood analysis, cardiac synaptosome exocytosis, microarray and pathway analysis, and multitissue histology. Kcne3 transcript was undetectable in adult mouse atria, ventricles, and adrenal glands, but Kcne3−/− mice exhibited 2.3-fold elevated serum aldosterone (P=0.003) and differentially expressed gene networks consistent with an adrenal-targeted autoimmune response. Furthermore, 8/8 Kcne3−/− mice vs. 0/8 Kcne3+/+ mice exhibited an activated-lymphocyte adrenal infiltration (P=0.0002). Kcne3 deletion also caused aldosterone-dependent ventricular repolarization delay (19.6% mean QTc prolongation in females; P<0.05) and aldosterone-dependent predisposition to postischemia arrhythmogenesis. Thus, 5/11 Kcne3−/− mice vs. 0/10 Kcne3+/+ mice exhibited sustained ventricular tachycardia during reperfusion (P<0.05). Kcne3 deletion is therefore arrhythmogenic by a novel mechanism in which secondary hyperaldosteronism, associated with an adrenal-specific lymphocyte infiltration, impairs ventricular repolarization. The findings highlight the importance of considering extracardiac pathogenesis when investigating arrhythmogenic mechanisms, even in inherited, monogenic channelopathies.—Hu, Z., Crump, S. M., Anand, M., Kant, R., Levi, R., Abbott, G. W. Kcne3 deletion initiates extracardiac arrhythmogenesis in mice. PMID:24225147

  9. Mitochondrial gene polymorphisms that protect mice from colitis.

    PubMed

    Bär, Florian; Bochmann, Wiebke; Widok, Andrea; von Medem, Kilian; Pagel, Rene; Hirose, Misa; Yu, Xinhua; Kalies, Kathrin; König, Peter; Böhm, Ruwen; Herdegen, Thomas; Reinicke, Anna T; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh; Sina, Christian

    2013-11-01

    Dysregulated energy homeostasis in the intestinal mucosa frequently is observed in patients with ulcerative colitis (UC). Intestinal tissues from these patients have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex, so mitochondrial dysfunction could contribute to the pathogenesis of UC. However, little is known about the mechanisms by which OXPHOS activity could be altered. We used conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex. Colitis was induced in C57BL/6J wild-type (B6.B6) and 3 strains of conplastic mice (B6.NZB, B6.NOD, and B6.AKR) by administration of dextran sodium sulfate or rectal application of trinitrobenzene sulfonate. Colon tissues were collected and analyzed by histopathology, immunohistochemical analysis, and immunoblot analysis; we also measured mucosal levels of adenosine triphosphate (ATP) and reactive oxygen species, OXPHOS complex activity, and epithelial cell proliferation and apoptosis. We identified mice with increased mucosal OXPHOS complex activities and levels of ATP. These mice developed less-severe colitis after administration of dextran sodium sulfate or trinitrobenzene sulfonate than mice with lower mucosal levels of ATP. Colon tissues from these mice also had increased enterocyte proliferation and transcription factor nuclear factor-κB activity, which have been shown to protect the mucosal barrier-defects in these processes have been associated with inflammatory bowel disease. Variants in mitochondrial DNA that increase mucosal levels of ATP protect mice from colitis. Increasing mitochondrial ATP synthesis in intestinal epithelial cells could be a therapeutic approach for UC. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Dendritic Cells Promote Pancreatic Viability in Mice with Acute Pancreatitis

    PubMed Central

    Bedrosian, Andrea S.; Nguyen, Andrew H.; Hackman, Michael; Connolly, Michael K.; Malhotra, Ashim; Ibrahim, Junaid; Cieza-Rubio, Napoleon E.; Henning, Justin R.; Barilla, Rocky; Rehman, Adeel; Pachter, H. Leon; Medina-Zea, Marco V.; Cohen, Steven M.; Frey, Alan B.; Acehan, Devrim; Miller, George

    2011-01-01

    Background & Aims Acute pancreatitis increases morbidity and mortality from organ necrosis by mechanisms that are incompletely understood. Dendritic cells (DCs) can promote or suppress inflammation, depending on their subtype and context. We investigated the roles of DC in development of acute pancreatitis. Methods Acute pancreatitis was induced in CD11c.DTR mice using caerulein or L-arginine; DCs were depleted by administration of diphtheria toxin. Survival was analyzed using Kaplan-Meier analysis. Results Numbers of MHC II+CD11c+DC increased 100-fold in pancreas of mice with acute pancreatitis, to account for nearly 15% of intra-pancreatic leukocytes. Intra-pancreatic DC acquired an immune phenotype in mice with acute pancreatitis; they expressed higher levels of MHC II and CD86 and increased production of interleukin-6, membrane cofactor protein (MCP)-1, and tumor necrosis factor (TNF)-α. However, rather than inducing an organ-destructive inflammatory process, DC were required for pancreatic viability; the exocrine pancreas died in mice that were depleted of DC and challenged with caerulein or L-arginine. All mice with pancreatitis that were depleted of DC died from acinar cell death within 4 days. Depletion of DC from mice with pancreatitis resulted in neutrophil infiltration and increased levels of systemic markers of inflammation. However, the organ necrosis associated with depletion of DC did not require infiltrating neutrophils, activation of NF-κB, or signaling by mitogen-activated protein kinase or TNF-α. Conclusions DC are required for pancreatic viability in mice with acute pancreatitis and might protect organs against cell stress. PMID:21801698

  11. Increased anxiety-related behaviour in Hint1 knockout mice.

    PubMed

    Varadarajulu, Jeeva; Lebar, Maria; Krishnamoorthy, Gurumoorthy; Habelt, Sonja; Lu, Jia; Bernard Weinstein, I; Li, Haiyang; Holsboer, Florian; Turck, Christoph W; Touma, Chadi

    2011-07-07

    Several reports have implicated a role for the histidine triad nucleotide-binding protein-1 (Hint1) in psychiatric disorders. We have studied the emotional behaviour of male Hint1 knockout (Hint1 KO) mice in a battery of tests and performed biochemical analyses on brain tissue. The behavioural analysis revealed that Hint1 KO mice exhibit an increased emotionality phenotype compared to wildtype (WT) mice, while no significant differences in locomotion or general exploratory activity were noted. In the elevated plus-maze (EPM) test, the Hint1 KO animals entered the open arms of the apparatus less often than WT littermates. Similarly, in the dark-light box test, Hint1 KO mice spent less time in the lit compartment and the number of entries were reduced, which further confirmed an increased anxiety-related behaviour. Moreover, the Hint1 KO animals showed significantly more struggling and less floating behaviour in the forced swim test (FST), indicating an increased emotional arousal in aversive situations. Hint1 is known as a protein kinase C (PKC) interacting protein. Western blot analysis showed that PKCγ expression was elevated in Hint1 KO compared to WT mice. Interestingly, PKCγ mRNA levels of the two groups did not show a significant difference, implying a post-transcriptional PKCγ regulation. In addition, PKC enzymatic activity was increased in Hint1 KO compared to WT mice. In summary, our results indicate a role for Hint1 and PKCγ in modulating anxiety-related and stress-coping behaviour in mice. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Autism-related behavioral abnormalities in synapsin knockout mice.

    PubMed

    Greco, Barbara; Managò, Francesca; Tucci, Valter; Kao, Hung-Teh; Valtorta, Flavia; Benfenati, Fabio

    2013-08-15

    Several synaptic genes predisposing to autism-spectrum disorder (ASD) have been identified. Nonsense and missense mutations in the SYN1 gene encoding for Synapsin I have been identified in families segregating for idiopathic epilepsy and ASD and genetic mapping analyses have identified variations in the SYN2 gene as significantly contributing to epilepsy predisposition. Synapsins (Syn I/II/III) are a multigene family of synaptic vesicle-associated phosphoproteins playing multiple roles in synaptic development, transmission and plasticity. Lack of SynI and/or SynII triggers a strong epileptic phenotype in mice associated with mild cognitive impairments that are also present in the non-epileptic SynIII(-/-) mice. SynII(-/-) and SynIII(-/-) mice also display schizophrenia-like traits, suggesting that Syns could be involved in the regulation of social behavior. Here, we studied social interaction and novelty, social recognition and social dominance, social transmission of food preference and social memory in groups of male SynI(-/-), SynII(-/-) and SynIII(-/-) mice before and after the appearance of the epileptic phenotype and compared their performances with control mice. We found that deletion of Syn isoforms widely impairs social behaviors and repetitive behaviors, resulting in ASD-related phenotypes. SynI or SynIII deletion altered social behavior, whereas SynII deletion extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment and increased self-grooming. Social impairments of SynI(-/-) and SynII(-/-) mice were evident also before the onset of seizures. The results demonstrate an involvement of Syns in generation of the behavioral traits of ASD and identify Syn knockout mice as a useful experimental model of ASD and epilepsy. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Curcumin Alleviates the Functional Gastrointestinal Disorders of Mice In Vivo.

    PubMed

    Yu, Jing; Xu, Wen-Hua; Sun, Wei; Sun, Yi; Guo, Zhi-Li; Yu, Xiao-Ling

    2017-12-01

    Curcumin is a natural polyphenol extracted from the turmeric rhizome, which has a wide range of biological activities, but until now the effects of curcumin on the gastrointestinal peristalsis have not been fully understood. In vivo study, we observed the effects of curcumin on gastric emptying and intestinal propulsion rates of mice in normal state and in delayed state by atropine (ATR) or nitric oxide precursor L-arginine (L-Arg). An in vitro study explored the direct effects of curcumin on the intestinal contractility, but were studied through measuring spontaneous contraction of isolated jejunum of mice. Our results showed that intragastric administration of curcumin (200 mg/kg/day) for 10-20 days significantly improved gastric emptying and intestinal propulsion rates of mice delayed by ATR. Moreover, intragastric administration of curcumin (200 mg/kg/day) for 15 days also significantly improved mice gastric emptying and intestinal propulsion rates delayed by L-Arg. There was no significant effect on normal gastrointestinal propulsion of mice after intragastric administration of curcumin (200 mg/kg/day) for 1-20