| 1. |
- Hathazi, D., et al.
(författare)
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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
- 2020
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Ingår i: Embo Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 39:23
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Tidskriftsartikel (refereegranskat)abstract
- Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only similar to 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
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| 2. |
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| 3. |
- Menger, K. E., et al.
(författare)
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Two type I topoisomerases maintain DNA topology in human mitochondria
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 50:19, s. 11154-11174
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Tidskriftsartikel (refereegranskat)abstract
- Genetic processes require the activity of multiple topoisomerases, essential enzymes that remove topological tension and intermolecular linkages in DNA. We have investigated the subcellular localisation and activity of the six human topoisomerases with a view to understanding the topological maintenance of human mitochondrial DNA. Our results indicate that mitochondria contain two topoisomerases, TOP1MT and TOP3A. Using molecular, genomic and biochemical methods we find that both proteins contribute to mtDNA replication, in addition to the decatenation role of TOP3A, and that TOP1MT is stimulated by mtSSB. Loss of TOP3A or TOP1MT also dysregulates mitochondrial gene expression, and both proteins promote transcription elongation in vitro. We find no evidence for TOP2 localisation to mitochondria, and TOP2B knockout does not affect mtDNA maintenance or expression. Our results suggest a division of labour between TOP3A and TOP1MT in mtDNA topology control that is required for the proper maintenance and expression of human mtDNA.
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| 4. |
- Nuntiyakul, W., et al.
(författare)
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Direct Determination of a Bare Neutron Counter Yield Function
- 2020
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 125:4
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Tidskriftsartikel (refereegranskat)abstract
- Ground-based neutron counters are a standard tool for detecting atmospheric showers from GeV range primary cosmic rays of either solar or galactic origin. Bare neutron counters, a type of lead-free neutron monitor, function much like standard neutron monitors but have different yield functions primarily because they are more sensitive to neutrons of lower energy. When operated together with standard monitors, the different yield functions allow estimates to be made of the energy spectrum of galactic or solar particles. In 2010 a new array of 12 bare neutron detectors was installed at the South Pole to operate together with the neutron monitor there. Prior to installation, two of the detectors were operated on a ship that traveled from Sweden to Antarctica and back from November 2009 to April 2010. The purpose of this latitude survey was to use Earth's magnetic field as a spectrometer, blocking cosmic rays below the local cutoff rigidity (momentum per unit charge), from which we determined the response function versus rigidity of these bare counters. By comparing that measured response function to direct measurements of the cosmic ray spectrum taken by the PAMELA spacecraft, we were able to make a direct determination of the yield function for these detectors.
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| 5. |
- Nuntiyakul, W., et al.
(författare)
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Direct Determination of a Bare Neutron Counter Yield Function
- 2022
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Ingår i: 37th International Cosmic Ray Conference, ICRC2021. - Trieste, Italy : Proceedings of Science.
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Konferensbidrag (refereegranskat)abstract
- Ground based neutron counters are a standard tool for detecting atmospheric showers from GeV-range primary cosmic rays of either solar or galactic origin. Bare neutron counters, a type of lead-free neutron monitor, function much like standard neutron monitors but have different yield functions primarily because they are more sensitive to neutrons of lower energy. When operated together with standard monitors the different yield functions allow estimates to be made of the energy spectrum of galactic or solar particles. In 2010 a new array of twelve bare neutron detectors was installed at the South Pole to operate together with the neutron monitor there. Prior to installation, two of the detectors were operated on a ship that traveled from Sweden to Antarctica and back from November 2009 to April 2010. The purpose of this latitude survey was to use Earth's magnetic field as a spectrometer, blocking cosmic rays below the local cutoff rigidity (momentum per unit charge), from which we determined the response function vs. rigidity of these bare counters. By comparing that measured response function to direct measurements of the cosmic ray spectrum taken by the PAMELA spacecraft, we were able to make a direct determination of the yield function for these detectors.
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| 6. |
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| 7. |
- Pluta, J, et al.
(författare)
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Identification of 22 susceptibility loci associated with testicular germ cell tumors
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 4487-
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Tidskriftsartikel (refereegranskat)abstract
- Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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