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  • 1
    In: Immunity, Elsevier BV, Vol. 10, No. 5 ( 1999-05), p. 503-513
    Type of Medium: Online Resource
    ISSN: 1074-7613
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1999
    detail.hit.zdb_id: 2001966-X
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  • 2
    Online Resource
    Online Resource
    American Physiological Society ; 2023
    In:  Physiology Vol. 38, No. S1 ( 2023-05)
    In: Physiology, American Physiological Society, Vol. 38, No. S1 ( 2023-05)
    Abstract: Bmal1 is a core component of the molecular clock which is responsible for generating circadian rhythms in many physiological parameters, including blood pressure (BP). Sodium intake can affect circadian rhythms, as high salt consumption can increase BP and alter the expression of the molecular clock. However, the effect of low salt consumption on the circadian rhythm of BP and hormones crucial to sodium homeostasis has not been extensively studied. Using a whole-body Bmal1-knockout (KO) rat, we wanted to determine the contribution of the molecular clock to circadian BP rhythms during low salt diet (LSD, 0.0049%).We hypothesized that Bmal1-KO rats on a LSD would have lower mean BP and higher aldosterone levels in comparison to littermate controls on LSD. Male and female Bmal1-KO rats and littermate controls (WT) had telemeters implanted in the abdominal aorta at 8-10 weeks old. After a 10-day surgical recovery period, BP was continuously recorded while rats were maintained on ad libitum normal salt diet (0.49% NaCl, NSD) for 1 week. Rats were placed in metabolic cages and 12-hour urine samples collected at ZT0 and ZT12 for two days. Next, rats were placed on LSD for one week while maintaining BP measurements. This was again followed by two day, 12-hour urine collections. BP was averaged hourly and analyzed for circadian rhythmicity (cosinor). The MESOR for mean arterial pressure was significantly higher in WT (n=10, 4/10 male) and KO groups (n=8, 4/8 male) on NSD (WT: 108±2 mmHg; KO: 104±2 mmHg) compared to LSD (WT: 104±2 mmHg; KO: 102±2 mmHg; p 〈 0.05 for diet, 2-way ANOVA). BP amplitude was significantly higher in WT rats (NSD: 7.6±0.6 mmHg; LSD: 6.9±0.7 mmHg) compared to KO rats (NSD: 5.2±0.4 mmHg; LSD: 5.3±0.9 mmHg) (p 〈 0.05 for genotype). BP acrophase was similar between groups on both diets. Urinary aldosterone excretion (ELISA) was similar between WT and KO rats on NSD (Daytime: WT 26±5 pg/12hrs, KO 16±1 pg/12hrs; Nighttime: WT 48±8 pg/12hrs, KO 46±4 pg/12hrs) and on LSD (Daytime: WT 95±38 pg/12hrs, KO 109±44 pg/12hrs; Nighttime: WT 174±63 pg/12hrs, KO 155±47 pg/12hrs), with statistically significant overall effects of diet and time of day (p 〈 0.05, 3-way ANOVA). Together, these data support a role for Bmal1 in control of BP amplitude in rats on NSD and LSD. This does not appear to involve changes in aldosterone since urinary excretion followed predicted patterns by time of day and salt diet, but were not impacted by loss of Bmal1 in ad libitum fed rats. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
    Type of Medium: Online Resource
    ISSN: 1548-9213 , 1548-9221
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 3115360-4
    detail.hit.zdb_id: 2005759-3
    SSG: 12
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  • 3
    In: The European Physical Journal A, Springer Science and Business Media LLC, Vol. 55, No. 10 ( 2019-10)
    Type of Medium: Online Resource
    ISSN: 1434-6001 , 1434-601X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 1413603-X
    detail.hit.zdb_id: 1459066-9
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  • 4
    Online Resource
    Online Resource
    American Physiological Society ; 2023
    In:  Physiology Vol. 38, No. S1 ( 2023-05)
    In: Physiology, American Physiological Society, Vol. 38, No. S1 ( 2023-05)
    Abstract: The circadian clock regulates Na+ transport with a necessary diurnal variation for optimal health. The clock gene, Bmal1, is known to regulate mitochondrial O 2 consumption, but whether or how this occurs in the kidney has not been established. An estimated 95% of O 2 consumption in the kidney is linked to sodium transport. We developed and used a novel Bmal1 knockout rat on a Sprague Dawley background. Male Bmal1 -/- rats do not have the typical night-day difference in Na + excretion, while female rats maintain this pattern. We recently observed that ADP-dependent O 2 consumption in permeabilized kidney tissue was significantly higher in both sexes of Bmal1 -/- rats but only during the active/dark period. We also observed a significant increase in cytochrome c oxidase activity in Bmal1 -/- rats during the dark vs. light period (164 ± 40 vs. 306 ± 40 pmol/s·mg; p=0.0031, t-test). Since these effects were observed in both male and female rats, these changes in mitochondrial activity cannot explain the difference in diurnal sodium excretion. Since mitochondrial morphology can impact oxidative phosphorylation and energy availability, we hypothesized that Bmal1 regulates mitochondrial morphology in the kidney. Male and female global Bmal1 +/+ and Bmal1 -/- rats at 12-14 weeks of age were maintained in regular 12:12 LD cycles. Outer renal medullary tissue was dissected and prepared for mRNA expression and transmission electron microscopy (EM). For EM, tissues were obtained at light (ZT2-4) or dark (ZT14-16) periods to correspond with the minimum and maximum whole-body energy consumption and peak and trough Bmal1 protein expression. Digital droplet PCR mRNA expression was conducted from tissue collected at 4hr intervals over 24hrs. EM images appear to show an elongation of mitochondrial morphology in females but not male Bmal1 -/- during the active time of day. Mitofusion1 (Mfn1) and fission 1 (Fis1) are genes that regulate mitochondrial structural dynamics. Mfn1 and Fis1 mRNA expression over 24hrs showed a significant interaction between genotype and time of day in male rats (p=0.004 and p=0.020, respectively, 2way ANOVA). In contrast, there were no significant differences in overall Mfn1 or Fis1 expression between female Bmal1 +/+ and Bmal1 -/- rats. Our findings demonstrate that Bmal1 is crucial in maintaining mitochondrial respiration coupling and ATP generation in the kidney. Furthermore, we suggest that female Bmal1 -/- rats can better compensate for impaired respiration by mitochondrial morphological changes when the molecular clock is dysfunctional. We further propose that the rhythmicity of Na + excretion in females, but not male, Bmal1 -/- rats is due to adjustments in mitochondrial morphology. T32 HL007457, P01HL136267, AHA 908953 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
    Type of Medium: Online Resource
    ISSN: 1548-9213 , 1548-9221
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 3115360-4
    detail.hit.zdb_id: 2005759-3
    SSG: 12
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  • 5
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 12 ( 2002-06-11), p. 8173-8178
    Abstract: In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form γ-H2AX) in megabase chromatin domains flanking sites of DNA damage. To investigate the role of H2AX in mammalian cells, we generated H2AX-deficient (H2AX Δ / Δ ) mouse embryonic stem (ES) cells. H2AX Δ / Δ ES cells are viable. However, they are highly sensitive to ionizing radiation (IR) and exhibit elevated levels of spontaneous and IR-induced genomic instability. Notably, H2AX is not required for NHEJ per se because H2AX Δ / Δ ES cells support normal levels and fidelity of V(D)J recombination in transient assays and also support lymphocyte development in vivo . However, H2AX Δ / Δ ES cells exhibit altered IR-induced BRCA1 focus formation. Our findings indicate that H2AX function is essential for mammalian DNA repair and genomic stability.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 19 ( 2006-05-09), p. 7378-7383
    Abstract: Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene ( Ptc ), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2 , a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc -family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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