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  • 1
    Publication Date: 2012-08-16
    Description: Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function, yet they do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 wk (postweaning) and 6 wk (young adult) of age had markedly less adipose tissue than non-CF mice. Food intake was markedly lower in 3-wk-old CF mice but normalized by 6 wk of age. Both 3- and 6-wk-old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF mice. Hepatic de novo lipogenesis (DNL), determined by 2 H incorporation, was reduced in CF mice. At 3 wk, F508del mice had significantly decreased DNL of palmitate and stearate, by 83% and 80%, respectively. By 6 wk, DNL rates in non-CF mice remained unchanged compared with 3-wk-old mice, while DNL rates of F508del mice were still reduced, by 33% and 40%, respectively. Adipose tissue fatty acid (FA) profiles were comparable in CF and non-CF mice, indicating that adipose differences are quantitative, not qualitative. A correspondingly lower content of 2 H-labeled FA was found in CF adipose tissue, consistent with reduced deposition of newly made hepatic triglycerides and/or decreased adipose tissue lipogenesis. Hepatic transcriptome analysis revealed lower mRNA expression from several genes involved in FA biosynthesis, suggesting downregulation of this pathway as a mechanism for the reduced lipogenesis. These novel data provide a model for altered lipid metabolism in CF, independent of malabsorption, and may partly explain the inability of pancreatic enzyme replacement therapy to completely restore normal body mass to CF patients.
    Print ISSN: 0193-1857
    Electronic ISSN: 1522-1547
    Topics: Medicine
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  • 2
    Publication Date: 2013-05-16
    Description: Many common, important diseases are either caused or exacerbated by hyperactivation (e.g., cancer) or inactivation (e.g., heart failure) of the cell division cycle. A better understanding of the cell cycle is critical for interpreting numerous types of physiological changes in cells. Moreover, new insights into how to control it will facilitate new therapeutics for a variety of diseases and new avenues in regenerative medicine. The progression of cells through the four main phases of their division cycle [G 0 /G 1 , S (DNA synthesis), G 2 , and M (mitosis)] is a highly conserved process orchestrated by several pathways (e.g., transcription, phosphorylation, nuclear import/export, and protein ubiquitination) that coordinate a core cell cycle pathway. This core pathway can also receive inputs that are cell type and cell niche dependent. "Broken cell" methods (e.g., use of labeled nucleotide analogs) to assess for cell cycle activity have revealed important insights regarding the cell cycle but lack the ability to assess living cells in real time (longitudinal studies) and with single-cell resolution. Moreover, such methods often require cell synchronization, which can perturb the pathway under study. Live cell cycle sensors can be used at single-cell resolution in living cells, intact tissue, and whole animals. Use of these more recently available sensors has the potential to reveal physiologically relevant insights regarding the normal and perturbed cell division cycle.
    Print ISSN: 0363-6143
    Electronic ISSN: 1522-1563
    Topics: Medicine
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  • 3
    Publication Date: 2013-07-31
    Description: Nature Geoscience 6, 632 (2013). doi:10.1038/ngeo1855 Authors: M. E. Pritchard, J. A. Jay, F. Aron, S. T. Henderson & L. E. Lara Large earthquakes provoke unrest in volcanic areas hundreds of kilometres away from their epicentre. For example, earthquakes can induce ground deformation, thermal anomalies, additional earthquakes, hydrological changes or eruptions in volcanic regions. Two earthquakes in the Chilean subduction zone, in 1906 and 1960, triggered eruptions in the Andean southern volcanic zone within one year, yet no significant eruptions in the past three years are clearly associated with the 2010 Mw 8.8 Maule, Chile earthquake. We use satellite Interferometric Synthetic Aperture Radar (InSAR) and night-time thermal infrared data to analyse subtle changes in ground deformation and thermal activity at volcanoes in the southern volcanic zone since 2010. We document unprecedented subsidence of up to 15 cm in five volcanic areas within weeks of the earthquake, but no detectable thermal changes. We suggest that the deformation is related to coseismic release of fluids from hydrothermal systems documented at three of the five subsiding regions. The depth and shape of these hydrothermal reservoirs can also be constrained by our deformation data, implying that coseismic volcano subsidence could be used to prospect for geothermal resources. Similar subsidence observed at Japanese volcanoes following the 2011 Tohoku earthquake suggests this phenomenon is widespread.
    Print ISSN: 1752-0894
    Electronic ISSN: 1752-0908
    Topics: Geosciences
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  • 4
    Publication Date: 2013-11-22
    Description: A growing number of studies provide evidence that female plumage coloration is indicative of individual quality and can influence male mate choice. In blue tits ( Cyanistes caeruleus ), both sexes exhibit bright ultraviolet (UV)-reflectant crown feathers, which have previously been shown to be attractive to the opposite sex. In males, there is evidence that UV reflectance of the crown feathers is an honest signal of quality in this species, but it is unclear whether this is the case for females. To address this, the UV signal (an index of relative UV reflectance specific to the visual sensitivities of the blue tit) of mothers was measured during brood rearing for 3 years (2008–2010) and related to indices of reproductive success, that is, lay date, clutch size, and number of chicks fledged and maternal state, that is, body condition and baseline corticosterone (CORT). Maternal UV signal was unrelated to clutch size but was positively correlated with number of chicks fledged in 3 years. Maternal UV signal was also negatively correlated with lay date, but this was not consistent across years. In addition, maternal UV signal was negatively correlated with baseline CORT in all years but was not predictive of body condition. Taken together, these results provide evidence that female plumage coloration is indicative of female quality and may serve as a signal for mate choice. Further, it provides novel evidence that maternal baseline CORT is associated with UV plumage signal in free-living birds and may be an important mechanistic link between an individual’s ornamentation, state, and reproductive performance.
    Print ISSN: 1045-2249
    Electronic ISSN: 1465-7279
    Topics: Biology
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  • 5
    Publication Date: 2014-01-09
    Description: Background Endogenous hormones and growth factors that increase mammographic breast density could increase ovarian cancer risk. We examined whether high breast density is associated with ovarian cancer risk. Methods We conducted a cohort study of 724603 women aged 40 to 79 years with 2506732 mammograms participating in the Breast Cancer Surveillance Consortium from 1995 to 2009. Incident epithelial ovarian cancer was diagnosed in 1373 women. We used partly conditional Cox regression to estimate the association between breast density and 5-year risk of incident epithelial ovarian cancer overall and stratified by 10-year age group. All statistical tests were two-sided. Results Compared with women with scattered fibroglandular densities, women with heterogeneously dense and extremely dense breast tissue had 20% and 18% increased 5-year risk of incident epithelial ovarian cancer (hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 1.06 to 1.36; HR = 1.18, 95% CI = 0.93 to 1.50, respectively; P trend = .01). Among women aged 50 to 59 years, we observed a trend in elevated risk associated with increased breast density ( P trend = .02); women with heterogeneously and extremely dense breast tissue had 30% (HR = 1.30; 95% CI = 1.03 to 1.64) and 65% (HR = 1.65; 95% CI = 1.12 to 2.44) increased risk, respectively, compared with women with scattered fibroglandular densities. The pattern was similar but not statistically significant at age 40 to 49 years. There were no consistent patterns of breast density and ovarian cancer risk at age 60 to 79 years. Conclusions Dense breast tissue was associated with a modest increase in 5-year ovarian cancer risk in women aged 50 to 59 years but was not associated with ovarian cancer at ages 40 to 49 or 60 to 79 years.
    Electronic ISSN: 1460-2105
    Topics: Medicine
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  • 6
    Publication Date: 2014-03-19
    Description: Two modes of germ cell formation are known in animals. Specification through maternally inherited germ plasm occurs in many well-characterized model organisms, but most animals lack germ plasm by morphological and functional criteria. The only known alternative mechanism is induction, experimentally described only in mice, which specify germ cells through...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 7
    Publication Date: 2012-08-10
    Description: Molecular regulation of HIV transcription is a multifaceted process dictated in part by the abundance of cellular transcription factors that induce or repress HIV promoter activity. β-Catenin partners with members of the T cell factor (TCF)/LEF transcription factors to regulate gene expression. The interaction between β-catenin and TCF-4 is linked to inhibition of HIV replication in multiple cell types, including lymphocytes and astrocytes. Here, we evaluated the molecular mechanism by which β-catenin/TCF-4 repress HIV replication. We identified for the first time multiple TCF-4 binding sites at –336, –143, +66, and +186 relative to the transcription initiation site on the HIV long terminal repeat (LTR). Two of the sites (–143 and +66) were present in approximately 1/3 of 500 HIV-1 isolates examined. Although all four sites could bind to TCF-4, the strongest association occurred at –143. Deletion and/or mutation of –143, in conjunction with β-catenin or TCF-4 knockdown in cells stably expressing an LTR reporter construct, enhanced basal HIV promoter activity by 5-fold but had no effect on Tat-mediated transactivation of the HIV LTR. We also found that TCF-4, β-catenin, and the nuclear matrix binding protein SMAR1 tether at the –143-nucleotide (nt) site on the HIV LTR to inhibit HIV promoter activity. Collectively, these data indicate that TCF-4 and β-catenin at –143 associate with SMAR1, which likely pulls the HIV DNA segment into the nuclear matrix and away from transcriptional machinery, leading to repression of basal HIV LTR transcription. These studies point to novel avenues for regulation of HIV replication by manipulation of β-catenin signaling within cells.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 8
    Publication Date: 2014-06-20
    Description: The design of the ITER Electron Cyclotron Heating and Current Drive (EC H&CD) system has evolved in the last years both in goals and functionalities by considering an expanded range of applications. A large effort has been devoted to a better integration of the equatorial and the upper launchers, both from the point of view of the performance and of the design impact on the engineering constraints. However, from the analysis of the ECCD performance in two references H-mode scenarios at burn (the inductive H-mode and the advanced non-inductive scenario), it was clear that the EC power deposition was not optimal for steady-state applications in the plasma region around mid radius. An optimization study of the equatorial launcher is presented here aiming at removing this limitation of the EC system capabilities. Changing the steering of the equatorial launcher from toroidal to poloidal ensures EC power deposition out to the normalized toroidal radius ρ ≈ 0.6, and nearly doubles the EC driven current around mid radius, without significant performance degradation in the core plasma region. In addition to the improved performance, the proposed design change is able to relax some engineering design constraints on both launchers.
    Print ISSN: 1070-664X
    Electronic ISSN: 1089-7674
    Topics: Physics
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  • 9
    Publication Date: 2012-07-25
    Description: Aims This double-blind, randomized, parallel, placebo-controlled investigation evaluated the effects of cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD). Methods and results The primary endpoint was change in serum potassium over time. Exploratory endpoints included: weight, physician and patient assessment of exertional dyspnoea, effect on N-terminal pro brain natriuretic peptide (NT-proBNP) levels, New York Heart Association (NYHA) classification, 6 min walk test (6MWT), and quality of life by Kansas City Cardiomyopathy Questionnaire (KCCQ). Serum potassium was similar in CLP ( n =59) and placebo ( n =52) groups throughout the 8-week study. Weight loss was greater in the CLP than in the placebo group at Weeks 1 ( P =0.014) and 2 ( P =0.004), and this trend continued until the end of the study. After 8 weeks, by physician assessment, the percentage of patients experiencing marked or disabling dyspnoea tended to be lower in the CLP than in the placebo group (7.3% vs. 23.9%, P =0.128). Fewer patients in the CLP than in the placebo group had NT-proBNP levels 〉1000 pg/mL at Week 4 ( P =0.039) and Week 8 ( P =0.065). The proportion of patients improving by at least one NYHA functional class over the study was higher in the CLP than in the placebo group (48.8% vs. 17.4%; P =0.002). Effects on 6MWT at Week 8 (p =0.072) and quality of life (overall KCCQ score) at Week 4 ( p =0.005) and 8 ( P =0.062) all favoured the CLP cohort. Four treatment-unrelated deaths occurred in the CLP group and none in the placebo group ( P =0.056). Conclusion In advanced, symptomatic HF with CKD, CLP is associated with beneficial clinical effects without significant serum potassium changes. Trial registration: NCT01265524.
    Print ISSN: 1388-9842
    Electronic ISSN: 1879-0844
    Topics: Medicine
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