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- Naukkarinen, J., et al.
(author)
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Characterising metabolically healthy obesity in weight-discordant monozygotic twins
- 2014
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In: Diabetologia. - New York, USA : Springer. - 0012-186X .- 1432-0428. ; 57:1, s. 167-176
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this ‘metabolically healthy obesity’ (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon.Methods: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥3 kg/m2), aged 22.8–35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT.Results: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics.Conclusions/interpretation: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.
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- Richter, U, et al.
(author)
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RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis
- 2018
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3966-
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Journal article (peer-reviewed)abstract
- Post-transcriptional RNA modifications play a critical role in the pathogenesis of human mitochondrial disorders, but the mechanisms by which specific modifications affect mitochondrial protein synthesis remain poorly understood. Here we used a quantitative RNA sequencing approach to investigate, at nucleotide resolution, the stoichiometry and methyl modifications of the entire mitochondrial tRNA pool, and establish the relevance to human disease. We discovered that a N1-methyladenosine (m1A) modification is missing at position 58 in the mitochondrial tRNALys of patients with the mitochondrial DNA mutation m.8344 A > G associated with MERRF (myoclonus epilepsy, ragged-red fibers). By restoring the modification on the mitochondrial tRNALys, we demonstrated the importance of the m1A58 to translation elongation and the stability of selected nascent chains. Our data indicates regulation of post-transcriptional modifications on mitochondrial tRNAs is finely tuned for the control of mitochondrial gene expression. Collectively, our findings provide novel insight into the regulation of mitochondrial tRNAs and reveal greater complexity to the molecular pathogenesis of MERRF.
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- Tatlisumak, Turgut, et al.
(author)
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Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population
- 2016
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 263:2, s. 257-262
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Journal article (peer-reviewed)abstract
- Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middle-aged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (a parts per thousand currency sign165 cm for males; a parts per thousand currency sign155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A > G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A > G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.
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- Draxler, K., et al.
(author)
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International comparison of current transformer calibration systems up to 10 kA at 50 Hz frequency
- 2016
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In: 2016 Conference on Precision Electromagnetic Measurements (CPEM 2016). - 9781467391344
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Conference paper (peer-reviewed)abstract
- Current transformers (CTs) are precision devices that scale high currents down to values that can be easily handled by measurement equipment. To support CT applications in revenue metering, a comparison on AC current transformer calibration systems was performed among 15 European national metrology institutes using a precision CT as the travelling device. The first comparison results for the transformation ratios (4, 5, 6, 8, 10) kA/5 A of the travelling CT at nominal burden of 5 VA and 15 VA indicate good agreement between the participating laboratories. The main differences are found for phase displacement, at least partly caused by the instability of the traveling standard.
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- Suomalainen, A, et al.
(author)
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Quantification of tRNA3243(Leu) point mutation of mitochondrial DNA in MELAS patients and its effects on mitochondrial transcription
- 1993
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 2:5, s. 525-534
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Journal article (peer-reviewed)abstract
- The MELAS syndrome is a mitochondrial encephalomyopathy associated with a point mutation at nucleotide 3243 of mitochondrial DNA (mtDNA). The same mutation has also been found in patients with maternally inherited diabetes mellitus. The mutation occurs within a sequence needed for termination of mitochondrial transcription downstream of the ribosomal RNA (rRNA) genes, thus possibly reducing rRNA synthesis in relation to more distal transcripts. This study presents a family in which maternally transmitted diabetes and MELAS syndrome overlap, and a suggestive correlation between the amount of mutant mtDNA and clinical symptoms is observed. Mutant mtDNA was quantified in several tissues of a newborn infant and the highest amount of mutant mtDNA was found in the placenta, which is promising for the development of genetic counselling in MELAS. The consequences of the MELAS mutation were further studied in cultured clonal myoblasts. We found that the myoblasts with 93% of mutant mtDNA terminate the mitochondrial transcription, resulting in a steady-state amount of 16S rRNA 45 times as high as the more distal transcripts. However, myoblasts with a deletion of mtDNA not involving the transcription termination site had 120 times as much 16S rRNA as the distal transcripts. In both the MELAS myoblasts and in those with a deletion of mtDNA the amount of 16S rRNA increased as the mutant mtDNA increased, suggesting that the production of ribosomal RNAs is a response to the translational defect caused by the mutation. We present evidence here that the MELAS mutation causes a defect in transcription termination, thus leading to no absolute deficiency of ribosomal RNAs, but to a reduced capacity to compensate the defective translation.
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| 16. |
- Draxler, K., et al.
(author)
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Results of an International Comparison of Instrument Current Transformers up to 10 kA at 50 Hz Frequency
- 2018
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In: CPEM 2018 - Conference on Precision Electromagnetic Measurements. - 9781538609736
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Conference paper (peer-reviewed)abstract
- Traceability of the current ratio is crucial for the measurement of electrical energy in revenue metering. A comparison of the AC current ratio was therefore performed within EURAMET in the time period 2012-2016, using a precision CT as the traveling device. The Czech Metrology Institute (CMI) as coordinator processed the measurement results of the 15 European participating laboratories. The comparison of the results for transformer ratios of (4, 5, 6, 8, 10) kA 5 A at 15 VA burden and (4 and 10) kA 5 A ratios at 5 VA burden indicates good agreement between the participating laboratories. The main differences are found for phase displacement, at least in part due to instability of the traveling standard. .
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| 17. |
- Euro, L., et al.
(author)
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Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation
- 2015
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 5:FEB
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Journal article (peer-reviewed)abstract
- The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.
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- Hallstrom, J., et al.
(author)
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Performance of a modular wideband 1000 kV HVDC reference divider
- 2014
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In: CPEM Digest (Conference on Precision Electromagnetic Measurements). - 9781479952052 ; , s. 782-783
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Conference paper (peer-reviewed)abstract
- This paper describes the performance of a wideband HVDC reference divider. The divider concept is a shielded modular divider and it is intended for traceable calibration of HVDC measuring systems up to 1000 kV in customers' laboratories. The first priority in the design was the accuracy of HVDC measurements. In addition, the divider was designed to have wide bandwidth, both to enable measurement of ripple voltages and to prevent damage during possible flashovers. © 2014 IEEE.
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- Lehtonen, J. M., et al.
(author)
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Diagnostic value of serum biomarkersFGF21andGDF15compared to muscle sample in mitochondrial disease
- 2021
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In: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 44:2, s. 469-480
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Journal article (peer-reviewed)abstract
- The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial etiology as an underlying cause of a muscle manifesting disease. Normal biomarker values do not, however, rule out a mitochondrial disorder, especially if the disease does not manifest in muscle. We suggest that FGF21 and GDF15 together should be first-line diagnostic investigations in mitochondrial disease complementing muscle biopsy.
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