| 1. |
- Ma, L, et al.
(författare)
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SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth
- 2014
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 5, s. e1483-
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Tidskriftsartikel (refereegranskat)abstract
- Sirtuins are NAD+ dependent deacetylases and/or ADP-ribosyl transferases active on histone and non-histone substrates. The first sirtuin was discovered as a transcriptional repressor of the mating-type-loci (Silent Information Regulator sir2) in the budding yeast, where it was shown to extend yeast lifespan. Seven mammalian sirtuins (SIRT1-7) have been now identified with distinct subcellular localization, enzymatic activities and substrates. These enzymes regulate cellular processes such as metabolism, cell survival, differentiation, DNA repair and they are implicated in the pathogenesis of solid tumors and leukemias. The purpose of the present study was to investigate the role of sirtuin expression, activity and inhibition in the survival of pediatric sarcoma cell lines.We have analyzed the expression of SIRT1 and SIRT2 in a series of pediatric sarcoma tumor cell lines and normal cells, and we have evaluated the activity of the sirtuin inhibitor and p53 activator tenovin-6 (Tv6) in synovial sarcoma and rhabdomyosarcoma cell lines. We show that SIRT1 is overexpressed in synovial sarcoma biopsies and cell lines in comparison with normal mesenchymal cells. Tv6 induced apoptosis as well as impaired autophagy flux. Using siRNA to knock down SIRT1 and SIRT2, we show that the expression of both proteins is crucial for the survival of rhabdomyosarcoma cells and that the loss of SIRT1 expression results in a decreased LC3II expression. Our results show that SIRT1 and SIRT2 expressions are crucial for the survival of synovial sarcomas and rhabdomyosarcomas, and demonstrate that the pharmacological inhibition of sirtuins impairs the autophagy process and induces tumor cell death.
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| 2. |
- Oberstedt, Andreas, et al.
(författare)
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Improved values for the characteristics of prompt-fission gamma-ray spectra from the reaction U-235(n(th), f)
- 2013
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Ingår i: Physical Review C. Nuclear Physics. - : American Physical Society. - 0556-2813 .- 1089-490X .- 2469-9985 .- 2469-9993. ; 87:5, s. 051602-
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we present results from measurements of prompt gamma rays from the thermal neutron induced fission of U-235. Photons were measured in coincidence with fission fragments with cerium-doped LaCl3 and LaBr3 as well as CeBr3 scintillation detectors, which offer an intriguing combination of excellent timing resolution and good resolving power. The spectra measured with all employed detectors are in excellent agreement with respect to their shapes. Characteristic parameters were extracted for a gamma-energy range from 0.1 to 6.0 MeV and the results obtained with several detectors were averaged. From that, the average emission yield of prompt-fission gamma rays was determined to be (nu) over bar (gamma) = (8.19 +/- 0.11) per fission, the average energy per photon to be epsilon(gamma) = (0.85 +/- 0.02) MeV, and the total energy to be E-gamma,E-tot = (6.92 +/- 0.09) MeV. The uncertainties are much lower than the 7.5% requested for the modeling of advanced nuclear reactor cores. Estimating the influence of gamma rays with energies between 6 and 10 MeV on the values determined in this work revealed a negligible deviation of the order of the found uncertainties.
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| 3. |
- Oberstedt, S., et al.
(författare)
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Correlation measurements of fission-fragment properties
- 2010
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Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X.
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Konferensbidrag (refereegranskat)abstract
- For the development of future nuclear fission applications and for a responsible handling of nuclear waste the a-priori assessment of the fission-fragments' heat production and toxicity is a fundamental necessity. The success of an indispensable modelling of the fission process strongly depends on a good understanding of the particular mechanism of scission, the mass fragmentation and partition of excitation energy. Experimental observables are fission-fragment properties like mass- and energy-distributions, and the prompt neutron as well as γ-ray multiplicities and emission spectra. The latter quantities should preferably be known as a function of fragment mass and excitation energy. Those data are highly demanded as published by the OECD-NEA in its high priority data request list. With the construction of the double (v, E) spectrometer VERDI we aim at measuring pre- and post-neutron masses directly and simultaneously to avoid prompt neutron corrections. From the simultaneous measurement of pre- and post-neutron fission-fragment data the prompt neutron multiplicity may then be inferred fully correlated with fragment mass yield and total kinetic energy. Using an ultra-fast fission event trigger spectral prompt fission γ-ray measurements may be performed. For that purpose recently developed lanthanum-halide detectors, with excellent timing characteristics, were coupled to the VERDI spectrometer allowing for a very good discrimination of fission γ-rays and prompt neutrons due to their different time-of-flight.
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| 4. |
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| 5. |
- Gurung, Iman S., et al.
(författare)
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Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia
- 2011
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Ingår i: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 92:1, s. 29-38
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β(-/-) hearts potentially associated with increased arrhythmic risk in metabolic diseases.METHODS AND RESULTS: Microarray analysis in mouse PGC1β(-/-) hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β(-/-) mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β(-/-) hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β(-/-) ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca(2+) transients, whose amplitude and frequency were increased by isoprenaline, and Ca(2+) currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K(+) currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca(2+)-calmodulin dependent protein kinase II expression.CONCLUSION: PGC1β(-/-) hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca(2+) homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.
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| 6. |
- Oberstedt, S., et al.
(författare)
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High-precision prompt-gamma-ray spectral data from the reaction Pu-241(n(th), f)
- 2014
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993. ; 90:2, s. Art. no. 024618-
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we present results from the first high-precision prompt-gamma-ray spectral measurements from the reaction Pu-241(n(th), f). Apart from one recent experiment, no data are reported in the literature for this fissioning system, which motivated a new dedicated experiment. We have measured prompt-fission gamma rays with three cerium-doped LaBr3 (two 5.08 cm x 5.08 cm and one 7.62 cm x 7.62 cm) and one CeBr3 (5.08 cm x 5.08 cm) scintillation detectors, which all exhibit excellent timing and good energy resolution. The average gamma-ray multiplicity was determined to be (nu) over bar (gamma) = (8.21 +/- 0.09) per fission, the average energy to be epsilon(gamma) = (0.78 +/- 0.01) MeV, and the total energy to be E-gamma,E-tot = (6.41 +/- 0.06) MeV as the weighted average from all detectors. Since the results from all detectors are in excellent agreement, and the total released gamma energy is modestly higher than the one in the present evaluated nuclear data files, we suspect that the underestimation of the prompt-gamma heating in nuclear reactors is due to fast-neutron-induced fission on U-238 or rather from fission induced by gamma rays from neutron capture in the construction material.
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