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- Abdalla, H., et al.
(författare)
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Sensitivity of the Cherenkov Telescope Array for probing cosmology and fundamental physics with gamma-ray propagation
- 2021
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : Institute of Physics Publishing (IOPP). - 1475-7516. ; :2
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Tidskriftsartikel (refereegranskat)abstract
- The Cherenkov Telescope Array (CTA), the new-generation ground-based observatory for gamma-ray astronomy, provides unique capabilities to address significant open questions in astrophysics, cosmology, and fundamental physics. We study some of the salient areas of gamma-ray cosmology that can be explored as part of the Key Science Projects of CTA, through simulated observations of active galactic nuclei (AGN) and of their relativistic jets. Observations of AGN with CTA will enable a measurement of gamma-ray absorption on the extragalactic background light with a statistical uncertainty below 15% up to a redshift z = 2 and to constrain or detect gamma-ray halos up to intergalactic-magnetic-field strengths of at least 0.3 pG. Extragalactic observations with CTA also show promising potential to probe physics beyond the Standard Model. The best limits on Lorentz invariance violation from gamma-ray astronomy will be improved by a factor of at least two to three. CTA will also probe the parameter space in which axion-like particles could constitute a significant fraction, if not all, of dark matter. We conclude on the synergies between CTA and other upcoming facilities that will foster the growth of gamma-ray cosmology.
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| 2. |
- Archer, A, et al.
(författare)
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Fasting-induced FGF21 is repressed by LXR activation via recruitment of an HDAC3 corepressor complex in mice
- 2012
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Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 26:12, s. 1980-1990
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Tidskriftsartikel (refereegranskat)abstract
- The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα−/−, and LXRβ−/− mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα−/− and LXRβ−/− mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting.
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- Campanella, Gianluca, et al.
(författare)
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Epigenome-wide association study of adiposity and future risk of obesity-related diseases
- 2018
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Ingår i: International Journal of Obesity. - : Nature Publishing Group. - 0307-0565 .- 1476-5497. ; 42:12, s. 2022-2035
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.Methods: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waistheight ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.Results: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P=9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P=6.00×10−7), higher triglyceride levels (P=5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P=1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P<1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P<1.25×10−3), independently of obesity and established risk factors.Conclusion: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.
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- Hudson, D.S., et al.
(författare)
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Hospitalizations for immersion-related injuries in Alaska 1991-2000
- 2006
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Ingår i: Safety Science. - : Elsevier BV. - 0925-7535 .- 1879-1042. ; 44:6, s. 479-489
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This study analyzed factors associated with injuries to hospitalized victims of nonfatal immersion-related events in Alaska from 1991 through 2000. Data: Alaska Trauma Registry (ATR) records of victims of nonfatal immersion events requiring hospitalization were examined to identify factors associated with injury outcomes. Subjects were divided into two groups: the "immersion only" (IO) group had no additional injuries associated with their immersion-related events, while subjects in the "associated injury" (AI) group incurred additional trauma during injury events. Results: There were 176 ATR records of nonfatal immersion events. In 87 (49.5%) cases, hospitalizations were due to the effects of immersion only (IO group). In 89 (50.5%) cases, hospitalizations were due not only to the effects of immersion, but also due to additional injuries occurring immediately before or while immersion took place (AI group). The final logistic regression model revealed statistically significant relationships between age greater than 12 years, female gender, white ethnicity, and operation of water transport vehicles, and increased risk for associated injury outcomes (p < 0.05). Discussion: This study is the first of its kind to analyze factors associated with the most severe nonfatal immersion-related injuries in Alaska, and identifies target populations for future safety campaigns. © 2005 Elsevier Ltd. All rights reserved.
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| 15. |
- Frick, F, et al.
(författare)
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Interaction between growth hormone and insulin in the regulation of lipoprotein metabolism in the rat
- 2002
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 283:5, s. E1023-E1031
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Tidskriftsartikel (refereegranskat)abstract
- The importance of insulin for the in vivo effects of growth hormone (GH) on lipid and lipoprotein metabolism was investigated by examining the effects of GH treatment of hypophysectomized (Hx) female rats with and without concomitant insulin treatment. Hypophysectomy-induced changes of HDL, apolipoprotein (apo)E, LDL, and apoB levels were normalized by GH treatment but not affected by insulin treatment. The hepatic triglyceride secretion rate was lower in Hx rats than in normal rats and increased by GH treatment. This effect of GH was blunted by insulin treatment. The triglyceride content in the liver changed in parallel with the changes in triglyceride secretion rate, indicating that the effect of the hormones on triglyceride secretion was dependent on changed availability of triglycerides for VLDL assembly. GH and insulin independently increased editing of apoB mRNA, but the effects were not additive. The expression of fatty-acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and sterol regulatory element-binding protein-1c (SREBP-1c) was increased by GH treatment. Insulin and GH had no additive effects on these genes; instead, insulin blunted the effect of GH on SREBP-1c mRNA. In contrast to the liver, adipose tissue expression of SREBP-1c, FAS, or SCD-1 mRNA was not influenced by GH. In conclusion, the increased hepatic expression of lipogenic enzymes after GH treatment may be explained by increased expression of SREBP-1c. Insulin does not mediate the effects of GH but inhibits the stimulatory effect of GH on hepatic SREBP-1c expression and triglyceride secretion rate.
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| 18. |
- Gardmo, C, et al.
(författare)
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In vivo transfection of rat liver discloses binding sites conveying GH-dependent and female-specific gene expression
- 2006
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Ingår i: Journal of molecular endocrinology. - : Bioscientifica. - 0952-5041 .- 1479-6813. ; 37:3, s. 433-441
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Tidskriftsartikel (refereegranskat)abstract
- The sexually dimorphic mode of GH secretion leads to a sex-differentiated expression of many hepatic target genes. Expression of the a1bg gene in rat liver is specifically induced by the female pattern of GH secretion. In this study, we have used the a1bg promoter in in vivo transfection experiments to investigate molecular mechanisms of GH-mediated female-specific hepatic gene regulation. Rat liver transfection was achieved by rapid tail vein injection of large volumes of plasmid solution. Expression of reporter constructs showed that the 160 bp proximal part of the a1bg promoter contained elements directing sex-specific expression. In vitro footprinting analysis and electromobility shift assays identified binding of hepatic nuclear factor 6 (HNF6), signal transducer and activator of transcriptions (Stat5) and nuclear factor 1 (NF1) in liver nuclear extracts to the 160 bp proximal promoter. Transfection of mutated and/or deletion constructs showed that HNF6 and NF1 binding markedly enhanced expression in female livers, whereas Stat5 reduces the sex difference by enhancing expression more strongly in male than in female rat liver. Based on our present results, we propose that adjacent binding sites for NF1 and HNF6 constitute a gene regulatory unit of importance for transducing the female-specific effect of GH in rat liver.
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| 23. |
- Kotokorpi, P, et al.
(författare)
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Activation of the glucocorticoid receptor or liver X receptors interferes with growth hormone-induced akr1b7 gene expression in rat hepatocytes
- 2004
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 145:12, s. 5704-5713
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Tidskriftsartikel (refereegranskat)abstract
- The akr1b7 gene encodes an aldo-keto reductase involved in detoxification of isocaproaldehyde, the product from side chain cleavage of cholesterol, and of 4-hydroxynonenal (4-HNE) formed by lipid peroxidation and cleavage. Here we show that the expression of akr1b7 mRNA in rat liver is sexually differentiated, expressed in females but not in males, and regulated by the sexually dimorphic secretion pattern of GH. A GH dose-dependent induction of akr1b7 was demonstrated in cultured primary rat hepatocytes, which was sensitive to cycloheximide. Activation of the glucocorticoid receptor (GR) or liver X receptors (LXR) by dexamethasone (Dex) and T1317, respectively, attenuated the GH-induced expression of akr1b7 and CYP2C12, the prototypical rat hepatic gene dependent on the female-characteristic secretion pattern of GH. In contrast, neither Dex nor T1317 had any repressive effect on the GH induction of IGF-I mRNA. A common mechanism for LXR- and GR-mediated repressive actions on gene transcription is inhibition of nuclear factor (NF)-κB; however, EMSAs and pharmacological interference with NF-κB signaling provided no evidence for the involvement of NF-κB in the repressive action of Dex and T1317 on GH-induced akr1b7 expression.
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