| 1. |
- Akansel, Serkan, et al.
(författare)
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Enhanced Gilbert damping in Re-doped FeCo films : Combined experimental and theoretical study
- 2019
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Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 99:17
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Tidskriftsartikel (refereegranskat)abstract
- The effects of rhenium doping in the range 0-10 at.% on the static and dynamic magnetic properties of Fe65Co35 thin films have been studied experimentally as well as with first-principles electronic structure calculations focusing on the change of the saturation magnetization (M-s) and the Gilbert damping parameter (alpha). Both experimental and theoretical results show that M-s decreases with increasing Re-doping level, while at the same time alpha increases. The experimental low temperature saturation magnetic induction exhibits a 29% decrease, from 2.31 to 1.64 T, in the investigated doping concentration range, which is more than predicted by the theoretical calculations. The room temperature value of the damping parameter obtained from ferromagnetic resonance measurements, correcting for extrinsic contributions to the damping, is for the undoped sample 2.1 x 10(-3), which is close to the theoretically calculated Gilbert damping parameter. With 10 at.% Re doping, the damping parameter increases to 7.8 x 10(-3), which is in good agreement with the theoretical value of 7.3 x 10(-3). The increase in damping parameter with Re doping is explained by the increase in the density of states at the Fermi level, mostly contributed by the spin-up channel of Re. Moreover, both experimental and theoretical values for the damping parameter weakly decrease with decreasing temperature.
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| 2. |
- Akansel, Serkan, et al.
(författare)
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Enhanched Gilbert Damping in Re doped FeCo Films : A combined experimental and theoretical study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The effects of rhenium doping in the range 0 – 10 at% on the static and dynamic magnetic properties of Fe65Co35 thin films have been studied experimentally as well as with first principles electronic structure calculations focussing on the change of the saturation magnetization (Ms ) and the Gilbert damping parameter (α ). Both experimental and theoretical results show that Ms decreases with increasing Re doping level, while at the same time α increases. The experimental low temperature saturation magnetic induction exhibits a 29% decrease, from 2.31T to 1.64T, in the investigated doping concentration range, which is more than predicted by the theoretical calculations. The room temperature value of the damping parameter obtained from ferromagnetic resonance measurements, correcting for extrinsic contributions to the damping, is for the undoped sample 2.7X103, which is close to the Gilbert damping parameter extracted from the theoretical calculations. The room temperature experimental value for the damping parameter increases to 9X103 when doping with 10 at% Re; the corresponding increase of the Gilbert damping parameter obtained from theoretical calculations is 7.3X103. Both experimental and theoretical values for the damping parameter weakly decrease with decreasing temperature.
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| 3. |
- Amato, Alberto, et al.
(författare)
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Grazer-induced transcriptomic and metabolomic response of the chain-forming diatom Skeletonema marinoi
- 2018
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Ingår i: ISME Journal. - : Springer Science and Business Media LLC. - 1751-7362 .- 1751-7370. ; 12, s. 1594-1604
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Tidskriftsartikel (refereegranskat)abstract
- Diatoms and copepods are main actors in marine food webs. The prey-predator interactions between them affect bloom dynamics, shape marine ecosystems and impact the energy transfer to higher trophic levels. Recently it has been demonstrated that the presence of grazers may affect the diatom prey beyond the direct effect of grazing. Here, we investigated the response of the chain-forming centric diatom Skeletonema marinoi to grazer cues, including changes in morphology, gene expression and metabolic profile. S. marinoi cells were incubated with Calanus finmarchicus or with Centropages typicus and in both cases responded by reducing the chain length, whereas changes in gene expression indicated an activation of stress response, changes in the lipid and nitrogen metabolism, in cell cycle regulation and in frustule formation. Transcripts linked to G protein-coupled receptors and to nitric oxide synthesis were differentially expressed suggesting involvement of these signalling transduction pathways in the response. Downregulation of a lipoxygenase in the transcriptomic data and of its products in the metabolomic data also indicate an involvement of oxylipins. Our data contribute to a better understanding of the gene function in diatoms, providing information on the nature of genes implicated in the interaction with grazers, a crucial process in marine ecosystems.
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| 4. |
- Basu, Swaraj, et al.
(författare)
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A Catalogue of Putative cis-Regulatory Interactions Between Long Non-coding RNAs and Proximal Coding Genes Based on Correlative Analysis Across Diverse Human Tumors
- 2018
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Ingår i: G3-Genes Genomes Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 8:6, s. 2019-2025
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Tidskriftsartikel (refereegranskat)abstract
- Antisense transcripts and other long non-coding RNAs are pervasive in mammalian cells, and some of these molecules have been proposed to regulate proximal protein-coding genes in cis. For example, non-coding transcription can contribute to inactivation of tumor suppressor genes in cancer, and antisense transcripts have been implicated in the epigenetic inactivation of imprinted genes. However, our knowledge is still limited and more such regulatory interactions likely await discovery. Here, we make use of available gene expression data from a large compendium of human tumors to generate hypotheses regarding non-coding-to-coding cis-regulatory relationships with emphasis on negative associations, as these are less likely to arise for reasons other than cis-regulation. We document a large number of possible regulatory interactions, including 193 coding/non-coding pairs that show expression patterns compatible with negative cis-regulation. Importantly, by this approach we capture several known cases, and many of the involved coding genes have known roles in cancer. Our study provides a large catalog of putative non-coding/coding cis-regulatory pairs that may serve as a basis for further experimental validation and characterization.
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| 5. |
- Basu, Swaraj, et al.
(författare)
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Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing
- 2020
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:12
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Tidskriftsartikel (refereegranskat)abstract
- Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy. Author summary Deletions in the mitochondrial genome cause a wide variety of rare disorders, but are also linked to more common conditions such as neurodegeneration, diabetes type 2, and the normal ageing process. There is also a growing awareness that mtDNA duplications, which are also relevant for human disease, may be more common than previously thought. Despite their clinical importance, our current knowledge about the abundance, characteristics and diversity of mtDNA deletions and duplications is fragmented, and based to large extent on a limited view provided by traditional low-throughput analyses. Here, we describe a bioinformatics method, MitoSAlt, that can accurately map and classify mtDNA deletions and duplications using high-throughput sequencing. Application of this methodology to mouse models of mitochondrial deficiencies revealed a large number of duplications, suggesting that these may previously have been underestimated.
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| 6. |
- Credendino, S. C., et al.
(författare)
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A ceRNA Circuitry Involving the Long Noncoding RNA Klhl14-AS, Pax8, and Bcl2 Drives Thyroid Carcinogenesis
- 2019
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Ingår i: Cancer Research. - 0008-5472. ; 79:22, s. 5746-5757
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Tidskriftsartikel (refereegranskat)abstract
- Klhl14-AS is a long noncoding RNA expressed since early specification of thyroid bud and is the most enriched gene in the mouse thyroid primordium at E10.5. Here, we studied its involvement in thyroid carcinogenesis by analyzing its expression in cancer tissues and different models of neoplastic transformation. Compared with normal thyroid tissue and cells, Klhl14-AS was significantly downregulated in human thyroid carcinoma tissue specimens, particularly the anaplastic histotype, thyroid cancer cell lines, and rodent models of thyroid cancer. Downregulating the expression of Klhl14-AS in normal thyroid cells decreased the expression of thyroid differentiation markers and cell death and increased cell viability. These effects were mediated by the binding of Klhl14-AS to two miRNAs, Mir182-5p and Mir20a-5p, which silenced Pax8 and Bcl2, both essential players of thyroid differentiation. MIR182-5p and MIR20a-5p were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on Pax8 and Bcl2 were rescued by Klhl14-AS overexpression, confirming Klhl14-AS as a ceRNA for both Pax8 and Bcl2. This work connects deregulation of differentiation with increased proliferation and survival in thyroid neoplastic cells and highlights a novel ceRNA circuitry involving key regulators of thyroid physiology. Significance: This study describes a new ceRNA with potential tumor suppression activity and helps us better understand the regulatory mechanisms during thyroid differentiation and carcinogenesis.
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| 7. |
- Credendino, S. C., et al.
(författare)
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Tissue- and Cell Type-Specific Expression of the Long Noncoding RNA Klhl14-AS in Mouse
- 2017
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Ingår i: International Journal of Genomics. - : Hindawi Limited. - 2314-436X .- 2314-4378.
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Tidskriftsartikel (refereegranskat)abstract
- lncRNAs are acquiring increasing relevance as regulators in a wide spectrum of biological processes. The extreme heterogeneity in the mechanisms of action of these molecules, however, makes them very difficult to study, especially regarding their molecular function. A novel lncRNA has been recently identified as the most enriched transcript in mouse developing thyroid. Due to its genomic localization antisense to the protein-encoding Klhl14 gene, we named it Klhl14-AS. In this paper, we highlight that mouse Klhl14-AS produces at least five splicing variants, some of which have not been previously described. Klhl14-AS is expressed with a peculiar pattern, characterized by diverse relative abundance of its isoforms in different mouse tissues. We examine the whole expression level of Klhl14-AS in a panel of adult mouse tissues, showing that it is expressed in the thyroid, lung, kidney, testis, ovary, brain, and spleen, although at different levels. In situ hybridization analysis reveals that, in the context of each organ, Klhl14-AS shows a cell type-specific expression. Interestingly, databases report a similar expression profile for human Klhl14-AS. Our observations suggest that this lncRNA could play cell type-specific roles in several organs and pave the way for functional characterization of this gene in appropriate biological contexts.
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| 8. |
- Gupta, Rahul, et al.
(författare)
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Engineering of spin mixing conductance at Ru/FeCo/Ru interfaces : Effect of Re doping
- 2020
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - : AMER PHYSICAL SOC. - 1098-0121 .- 1550-235X. ; 101:2
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Tidskriftsartikel (refereegranskat)abstract
- We have deposited polycrystalline Re-doped (Fe65Co35)(100-x)Rex (0 ≤ x ≤ 12.6 at. %) thin films grown under identical conditions and sandwiched between thin layers of Ru in order to study the phenomenon of spin pumping as a function of Re concentration. In-plane and out-of-plane ferromagnetic resonance spectroscopy results show an enhancement of the Gilbert damping with an increase in Re doping. We find 98% enhancement in the real part of effective spin mixing conductance [Re(g↑↓eff)] with Re doping. Conversely, the Re(g↑↓eff) does not change with Re doping in Fe65Co35 thin films which are seeded and capped with Cu layers. The enhancement in Re(g↑↓eff) of Re-doped Fe65Co35 thin films sandwiched between thin layers of Ru is linked to the Re doping-induced change of the interface electronic structure in the nonmagnetic Ru layer. The saturation magnetization decreases 35% with increasing Re doping up to 12.6 at. %. This study opens a direction of tuning the spin mixing conductance in magnetic heterostructures by doping of the ferromagnetic layer, which is essential for the realization of energyefficient operation of spintronic devices.
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| 9. |
- Mendoza, Patricia, et al.
(författare)
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DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as an Alk target in the Drosophila visceral mesoderm
- 2021
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 148:23
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Tidskriftsartikel (refereegranskat)abstract
- Development of the Drosophila visceral muscle depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signaling, which specifies founder cells (FCs) in the circular visceral mesoderm (VM). Although Alk activation by its ligand Jelly Belly (Jeb) is well characterized, few target molecules have been identified. Here, we used targeted DamID (TaDa) to identify Alk targets in embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differentially expressed genes, including the Snail/Scratch family transcription factor Kahuli (Kah). We confirmed Kah mRNA and protein expression in the VM, and identified midgut constriction defects in Kah mutants similar to those of pointed (pnt). ChIP and RNA-Seq data analysis defined a Kah target-binding site similar to that of Snail, and identified a set of common target genes putatively regulated by Kah and Pnt during midgut constriction. Taken together, we report a rich dataset of Alk-responsive loci in the embryonic VM and functionally characterize the role of Kah in the regulation of embryonic midgut morphogenesis.
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| 10. |
- Morud, Julia, 1984, et al.
(författare)
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Deorphanization of novel biogenic amine-gated ion channels identifies a new serotonin receptor for learning
- 2021
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Ingår i: Current biology : CB. - : Elsevier BV. - 1879-0445 .- 0960-9822. ; 31:19, s. 4282-4292
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Tidskriftsartikel (refereegranskat)abstract
- Pentameric ligand-gated ion channels (LGICs) play conserved, critical roles in both excitatory and inhibitory synaptic transmission and can be activated by diverse neurochemical ligands. We have performed a characterization of orphan channels from the nematode C.elegans, identifying five new monoamine-gated LGICs with diverse functional properties and expression postsynaptic to aminergic neurons. These include polymodal anion channels activated by both dopamine and tyramine, which may mediate inhibitory transmission by both molecules invivo. Intriguingly, we also find that a novel serotonin-gated cation channel, LGC-50, is essential for aversive olfactory learning of pathogenic bacteria, a process known to depend on serotonergic neurotransmission. Remarkably, the redistribution of LGC-50 to neuronal processes is modulated by olfactory conditioning, and lgc-50 point mutations that cause misregulation of receptor membrane expression interfere with olfactory learning. Thus, the intracellular trafficking and localization of these receptors at synapses may represent a molecular cornerstone of the learning mechanism.
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| 11. |
- Musacchia, F., et al.
(författare)
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VarGenius executes cohort-level DNA-seq variant calling and annotation and allows to manage the resulting data through a PostgreSQL database
- 2018
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Ingår i: Bmc Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTargeted resequencing has become the most used and cost-effective approach for identifying causative mutations of Mendelian diseases both for diagnostics and research purposes. Due to very rapid technological progress, NGS laboratories are expanding their capabilities to address the increasing number of analyses. Several open source tools are available to build a generic variant calling pipeline, but a tool able to simultaneously execute multiple analyses, organize, and categorize the samples is still missing.ResultsHere we describe VarGenius, a Linux based command line software able to execute customizable pipelines for the analysis of multiple targeted resequencing data using parallel computing. VarGenius provides a database to store the output of the analysis (calling quality statistics, variant annotations, internal allelic variant frequencies) and sample information (personal data, genotypes, phenotypes). VarGenius can also perform the joint analysis of hundreds of samples with a single command, drastically reducing the time for the configuration and execution of the analysis.VarGenius executes the standard pipeline of the Genome Analysis Tool-Kit (GATK) best practices (GBP) for germinal variant calling, annotates the variants using Annovar, and generates a user-friendly output displaying the results through a web page.VarGenius has been tested on a parallel computing cluster with 52 machines with 120GB of RAM each. Under this configuration, a 50M whole exome sequencing (WES) analysis for a family was executed in about 7h (trio or quartet); a joint analysis of 30 WES in about 24h and the parallel analysis of 34 single samples from a 1M panel in about 2h.ConclusionsWe developed VarGenius, a master tool that faces the increasing demand of heterogeneous NGS analyses and allows maximum flexibility for downstream analyses. It paves the way to a different kind of analysis, centered on cohorts rather than on singleton. Patient and variant information are stored into the database and any output file can be accessed programmatically. VarGenius can be used for routine analyses by biomedical researchers with basic Linux skills providing additional flexibility for computational biologists to develop their own algorithms for the comparison and analysis of data.The software is freely available at: https://github.com/frankMusacchia/VarGenius
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| 12. |
- Nicholls, Thomas J., et al.
(författare)
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Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA
- 2018
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 69:1
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Tidskriftsartikel (refereegranskat)abstract
- How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network. The importance of this process is highlighted in a patient with mitochondrial disease caused by biallelic pathogenic variants in TOP3A, characterized by muscle-restricted mtDNA deletions and chronic progressive external ophthalmoplegia (CPEO) plus syndrome. Our work establishes Top3α as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery. Nicholls et al. identify a role for topoisomerase 3α in the separation of mtDNA following replication. Loss of Top3α activity impairs mtDNA segregation and, consequently, segregation of the mtDNA nucleoid within the mitochondrial network. Mutations in TOP3A cause human mitochondrial disease associated with mtDNA deletions and impaired mtDNA separation. © 2017 Elsevier Inc.
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| 13. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Deep sequencing of mitochondrial DNA and characterization of a novel POLG mutation in a patient with arPEO.
- 2020
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Ingår i: Neurology. Genetics. - 2376-7839. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- To determine the pathogenicity of a novel POLG mutation in a man with late-onset autosomal recessive progressive external ophthalmoplegia using clinical, molecular, and biochemical analyses.A multipronged approach with detailed neurologic examinations, muscle biopsy analyses, molecular genetic studies, and in vitro biochemical characterization.The patient had slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze. Muscle biopsy showed slight variability in muscle fiber size, scattered ragged red fibers, and partial cytochrome c oxidase deficiency. Biallelic mutations were identified in the POLG gene encoding the catalytic A subunit of POLγ. One allele carried a novel mutation in the exonuclease domain (c.590T>C; p.F197S), and the other had a previously characterized null mutation in the polymerase domain (c.2740A>C; p.T914P). Biochemical characterization revealed that the novel F197S mutant protein had reduced exonuclease and DNA polymerase activities and confirmed that T914P was inactive. By deep sequencing of mitochondrial DNA (mtDNA) extracted from muscle, multiple large-scale rearrangements were mapped and quantified.The patient's phenotype was caused by biallelic POLG mutations, resulting in one inactive POLγA protein (T914P) and one with decreased polymerase and exonuclease activity (F197S). The reduction in polymerase activity explains the presence of multiple pathogenic large-scale deletions in the patient's mtDNA.
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| 14. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing
- 2021
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 31:3
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Tidskriftsartikel (refereegranskat)abstract
- Muscle pathology in inclusion body myositis (IBM) typically includes inflammatory cell infiltration, muscle fibers with rimmed vacuoles and cytochrome c oxidase (COX)-deficient fibers. Previous studies have revealed clonal expansion of large mitochondrial DNA (mtDNA) deletions in the COX-deficient muscle fibers. Technical limitations have prevented complete investigations of the mtDNA deletions and other mtDNA variants. Detailed characterization by deep sequencing of mtDNA in muscle samples from 21 IBM patients and 10 age-matched controls was performed after whole genome sequencing with a mean depth of mtDNA coverage of 46,000x. Multiple large mtDNA deletions and duplications were identified in all IBM and control muscle samples. In general, the IBM muscles demonstrated a larger number of deletions and duplications with a mean heteroplasmy level of 10% (range 1%-35%) compared to controls (1%, range 0.2%-3%). There was also a small increase in the number of somatic single nucleotide variants in IBM muscle. More than 200 rearrangements were recurrent in at least two or more IBM muscles while 26 were found in both IBM and control muscles. The deletions and duplications, with a high recurrence rate, were mainly observed in three mtDNA regions, m.534-4429, m.6330-13993, and m.8636-16072, where some were flanked by repetitive sequences. The mtDNA copy number in IBM muscle was reduced to 42% of controls. Immunohistochemical and western blot analyses of IBM muscle revealed combined complex I and complex IV deficiency affecting the COX-deficient fibers. In conclusion, deep sequencing and quantitation of mtDNA variants revealed that IBM muscles had markedly increased levels of large deletions and duplications, and there were also indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to age-matched controls. The distribution and type of variants were similar in IBM muscle and controls indicating an accelerated aging process in IBM muscle, possibly associated with chronic inflammation.
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| 15. |
- Persson, Örjan, 1974, et al.
(författare)
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Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.
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| 16. |
- Petrosino, Giuseppe, et al.
(författare)
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Identification of LINE retrotransposons and long non-coding RNAs expressed in the octopus brain
- 2022
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Ingår i: BMC Biology. - : BMC. - 1741-7007. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Transposable elements (TEs) widely contribute to the evolution of genomes allowing genomic innovations, generating germinal and somatic heterogeneity, and giving birth to long non-coding RNAs (lncRNAs). These features have been associated to the evolution, functioning, and complexity of the nervous system at such a level that somatic retrotransposition of long interspersed element (LINE) L1 has been proposed to be associated to human cognition. Among invertebrates, octopuses are fascinating animals whose nervous system reaches a high level of complexity achieving sophisticated cognitive abilities. The sequencing of the genome of the Octopus bimaculoides revealed a striking expansion of TEs which were proposed to have contributed to the evolution of its complex nervous system. We recently found a similar expansion also in the genome of Octopus vulgaris. However, a specific search for the existence and the transcription of full-length transpositionally competent TEs has not been performed in this genus. Results Here, we report the identification of LINE elements competent for retrotransposition in Octopus vulgaris and Octopus bimaculoides and show evidence suggesting that they might be transcribed and determine germline and somatic polymorphisms especially in the brain. Transcription and translation measured for one of these elements resulted in specific signals in neurons belonging to areas associated with behavioral plasticity. We also report the transcription of thousands of lncRNAs and the pervasive inclusion of TE fragments in the transcriptomes of both Octopus species, further testifying the crucial activity of TEs in the evolution of the octopus genomes. Conclusions The neural transcriptome of the octopus shows the transcription of thousands of putative lncRNAs and of a full-length LINE element belonging to the RTE class. We speculate that a convergent evolutionary process involving retrotransposons activity in the brain has been important for the evolution of sophisticated cognitive abilities in this genus.
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| 17. |
- Van den Eynden, Jimmy, 1977, et al.
(författare)
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Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution
- 2016
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 27:12
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Tidskriftsartikel (refereegranskat)abstract
- Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies.
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