| 1. |
- Barré, Benjamin P., et al.
(författare)
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Intragenic repeat expansion in the cell wall protein gene HPF1 controls yeast chronological aging
- 2020
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 30:5, s. 697-710
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Tidskriftsartikel (refereegranskat)abstract
- Aging varies among individuals due to both genetics and environment, but the underlying molecular mechanisms remain largely unknown. Using a highly recombined Saccharomyces cerevisiae population, we found 30 distinct quantitative trait loci (QTLs) that control chronological life span (CLS) in calorie-rich and calorie-restricted environments and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes FLO11 and HPF1. We found that massive expansion of intragenic tandem repeats within the N-terminal domain of HPF1 was sufficient to cause pronounced life span shortening. Life span impairment by HPF1 was buffered by rapamycin but not by calorie restriction. The HPF1 repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast-evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity.
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| 2. |
- D'Angiolo, M., et al.
(författare)
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A yeast living ancestor reveals the origin of genomic introgressions
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587, s. 420-425
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Tidskriftsartikel (refereegranskat)abstract
- A yeast clonal descendant of an ancient hybridization event is identified and sheds light on the early evolution of the Saccharomyces cerevisiae Alpechin lineage and its abundant Saccharomyces paradoxus introgressions. Genome introgressions drive evolution across the animal(1), plant(2) and fungal(3) kingdoms. Introgressions initiate from archaic admixtures followed by repeated backcrossing to one parental species. However, how introgressions arise in reproductively isolated species, such as yeast(4), has remained unclear. Here we identify a clonal descendant of the ancestral yeast hybrid that founded the extant Saccharomyces cerevisiae Alpechin lineage(5), which carries abundant Saccharomyces paradoxus introgressions. We show that this clonal descendant, hereafter defined as a 'living ancestor', retained the ancestral genome structure of the first-generation hybrid with contiguous S. cerevisiae and S. paradoxus subgenomes. The ancestral first-generation hybrid underwent catastrophic genomic instability through more than a hundred mitotic recombination events, mainly manifesting as homozygous genome blocks generated by loss of heterozygosity. These homozygous sequence blocks rescue hybrid fertility by restoring meiotic recombination and are the direct origins of the introgressions present in the Alpechin lineage. We suggest a plausible route for introgression evolution through the reconstruction of extinct stages and propose that genome instability allows hybrids to overcome reproductive isolation and enables introgressions to emerge.
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| 3. |
- De Chiara, Matteo, et al.
(författare)
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Domestication reprogrammed the budding yeast life cycle
- 2022
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Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X .- 2397-334X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Domestication of plants and animals is the foundation for feeding the world human population but can profoundly alter the biology of the domesticated species. Here we investigated the effect of domestication on one of our prime model organisms, the yeast Saccharomyces cerevisiae, at a species-wide level. We tracked the capacity for sexual and asexual reproduction and the chronological life span across a global collection of 1,011 genome-sequenced yeast isolates and found a remarkable dichotomy between domesticated and wild strains. Domestication had systematically enhanced fermentative and reduced respiratory asexual growth, altered the tolerance to many stresses and abolished or impaired the sexual life cycle. The chronological life span remained largely unaffected by domestication and was instead dictated by clade-specific evolution. We traced the genetic origins of the yeast domestication syndrome using genome-wide association analysis and genetic engineering and disclosed causative effects of aneuploidy, gene presence/absence variations, copy number variations and single-nucleotide polymorphisms. Overall, we propose domestication to be the most dramatic event in budding yeast evolution, raising questions about how much domestication has distorted our understanding of the natural biology of this key model species.
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| 4. |
- Fredén Jansson, Karl-Johan, 1988, et al.
(författare)
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Bone Conduction Stimulated VEMP Using the B250 Transducer
- 2021
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Ingår i: Medical Devices: Evidence and Research. - 1179-1470. ; 14, s. 225-237
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Bone conduction (BC) stimulation is rarely used for clinical testing of vestibular evoked myogenic potentials (VEMPs) due to the limitations of conventional stimulation alternatives. The aim of this study is to compare VEMP using the new B250 transducer with the Minishaker and air conduction (AC) stimulation. Methods: Thirty normal subjects between 20 and 37 years old and equal gender distribution were recruited, 15 for ocular VEMP and 15 for cervical VEMP. Four stimulation conditions were compared: B250 on the mastoid (FM); Minishaker and B250 on the forehead (FZ); and AC stimulation using an insert earphone. Results: It was found that B250 at FM required a statistically significant lower hearing level than with AC stimulation, in average 41 dB and 35 dB lower for ocular VEMP and cervical VEMP, respectively, but gave longer n10 (1.1 ms) and n23 (1.6 ms). No statistical difference was found between B250 at FM and Minishaker at FZ. Conclusion: VEMP stimulated with B250 at FM gave similar response as the Minishaker at FZ and for a much lower hearing level than AC stimulation using insert earphones.
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| 5. |
- Fredén Jansson, Karl-Johan, 1988, et al.
(författare)
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Electroacoustic evaluation of the bone conduction transducer B250 for vestibular and hearing diagnostics in comparison with Radioear B71 and B81
- 2024
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Ingår i: International Journal of Audiology. - 1499-2027 .- 1708-8186. ; In Press
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The objective is to evaluate the electroacoustic performance of the B250 transducer and to compare it with the two most widely used audiometric transducers B71 and B81. Design: The electroacoustic performance was evaluated in terms of sensitivity level, distortion, maximum hearing level and electrical impedance. Study sample: Six B250 prototype transducers were evaluated and compared with published data of B71 and B81 together with complementary measurements of maximum hearing level at 125 Hz and phase of electrical impedance. Differences in reference equivalent threshold vibratory force levels were estimated by comparing hearing threshold measurements of 60 healthy ears using B81 and B250. Results: B250 has approximately 27 dB higher sensitivity levels than both B71 and B81 at 250 Hz and can generate higher maximum hearing level at low frequencies: 11.8 to 35.8 dB (125–1000 Hz) higher than B71, and 1.4 to 18.6 dB (125–750 Hz) higher than B81. The maximum average difference in reference threshold force levels was 13.5 ± 8.7 dB higher for B250 at 250 Hz compared to B81. Conclusions: B250 can produce higher output force with less distortion than B71 and B81, especially at 125 and 250 Hz, which could possibly improve low frequency investigations of the audio-vestibular system.
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| 6. |
- Fredén Jansson, Karl-Johan, 1988, et al.
(författare)
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Electroacoustic evaluation of the bone conduction transducer B250 for vestibular and hearing diagnostics in comparison with Radioear B71 and B81
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF AUDIOLOGY. - 1499-2027 .- 1708-8186.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveThe objective is to evaluate the electroacoustic performance of the B250 transducer and to compare it with the two most widely used audiometric transducers B71 and B81.DesignThe electroacoustic performance was evaluated in terms of sensitivity level, distortion, maximum hearing level and electrical impedance.Study sampleSix B250 prototype transducers were evaluated and compared with published data of B71 and B81 together with complementary measurements of maximum hearing level at 125 Hz and phase of electrical impedance. Differences in reference equivalent threshold vibratory force levels were estimated by comparing hearing threshold measurements of 60 healthy ears using B81 and B250.ResultsB250 has approximately 27 dB higher sensitivity levels than both B71 and B81 at 250 Hz and can generate higher maximum hearing level at low frequencies: 11.8 to 35.8 dB (125-1000 Hz) higher than B71, and 1.4 to 18.6 dB (125-750 Hz) higher than B81. The maximum average difference in reference threshold force levels was 13.5 +/- 8.7 dB higher for B250 at 250 Hz compared to B81.ConclusionsB250 can produce higher output force with less distortion than B71 and B81, especially at 125 and 250 Hz, which could possibly improve low frequency investigations of the audio-vestibular system.
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| 7. |
- Håkansson, Bo, 1953, et al.
(författare)
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The bone conduction implant - a review and 1-year follow-up
- 2019
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Ingår i: International Journal of Audiology. - : Informa UK Limited. - 1499-2027 .- 1708-8186. ; 58:12, s. 945-955
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The objective of this study is to evaluate its safety and effectiveness of the bone conduction implant (BCI) having an implanted transducer and to review similar bone conduction devices. Design: This is a consecutive prospective case series study where the patients were evaluated after 1, 3, 6 and 12 months. Outcome measures were focussed on intraoperative and postoperative safety, the effectiveness of the device in terms of audiological performance and patient's experience. Study sample: Sixteen patients with average age of 40.2 (range 18-74) years have been included. Thirteen patients were operated in Gothenburg and three in Stockholm. Results: It was found that the procedure for installing the BCI is safe and the transmission condition was stable over the follow-up time. No serious adverse events or severe adverse device effects occurred. The hearing sensitivity, speech in noise and the self-assessment as compared with the unaided condition improved significantly with the BCI. These patients also performed similar or better than with a conventional bone conduction reference device on a softband. Conclusions: In summary, it was found that the BCI can provide a safe and effective hearing rehabilitation alternative for patients with mild-to-moderate conductive or mixed hearing impairments.
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| 8. |
- Johansson, Nina, 1983, et al.
(författare)
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Comparative sequence analysis and mutagenesis of Ethylene Forming Enzyme (EFE) 2-oxoglutarate/Fe(II)-dependent dioxygenase homologs
- 2014
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Ingår i: BMC Biochemistry. - : Springer Science and Business Media LLC. - 1471-2091. ; 15:1, s. Art. no. 22-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ethylene is one of the most used chemical monomers derived from non-renewable sources and we are investigating the possibility of producing it in yeast via the ethylene forming enzyme (EFE) from Pseudomonas syringae. To enable engineering strategies to improve the enzyme, it is necessary to identify the regions and amino acid residues involved in ethylene formation.Results: We identified the open reading frame for the EFE homolog in Penicillium digitatum and also showed its capability of mediating ethylene production in yeast. The sequence of the EFE homologs from P. digitatum and P. syringae was compared to that of the non-functional EFE-homolog from Penicillium chrysogenum and ten amino acids were found to correlate with ethylene production. Several of these amino acid residues were found to be important for ethylene production via point mutations in P. syringae EFE. The EFE homolog from P. chrysogenum was engineered at 10 amino acid residues to mimic the P. syringae EFE, but this did not confer ethylene producing capability. Furthermore, we predicted the structure of EFE by homology to known structures of 2-oxoglutarate/Fe(II) dependent dioxygenases. Three of the amino acids correlating with ethylene production are located in the predicted 2 oxoglutarate binding domain. A protein domain specific for the EFE class was shown to be essential for activity. Based on the structure and alanine substitutions, it is likely that amino acids (H189, D191 and H268) are responsible for binding the Fe(II) ligand.Conclusion: We provide further insight into the structure and function of the ethylene forming (EFE) - subclass of 2-oxoglutarate/Fe(II) dependent dioxygenases. We conclude that residues in addition to the 10 identified positions implicated in ethylene production by sequence comparison, are important for determining ethylene formation. We also demonstrate the use of an alternative EFE gene. The data from this study will provide the basis for directed protein engineering to enhance the ethylene production capability and properties of EFE.
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| 9. |
- Johansson, Nina, 1983, et al.
(författare)
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Ethylene production in relation to nitrogen metabolism in Saccharomyces cerevisiae
- 2014
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Ingår i: FEMS Yeast Research. - : Oxford University Press (OUP). - 1567-1356 .- 1567-1364. ; 14:7, s. 1110-1118
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that ethylene production in Saccharomyces cerevisiae expressing the ethylene-forming enzyme (EFE) from Pseudomonas syringae is strongly influenced by variations in the mode of cultivation as well as the choice of nitrogen source. Here, we have studied the influence of nitrogen metabolism on the production of ethylene further. Using ammonium, glutamate, glutamate/arginine, and arginine as nitrogen sources, it was found that glutamate (with or without arginine) correlates with a high ethylene production, most likely linked to an observed increase in 2-oxoglutarate levels. Arginine as a sole nitrogen source caused a reduced ethylene production. A reduction of arginine levels, accomplished using an arginine auxotrophic ARG4-deletion strain in the presence of limiting amounts of arginine or through CAR1 overexpression, did however not correlate with an increased ethylene production. As expected, arginine was necessary for ethylene production as ethylene production in the ARG4-deletion strain ceased at the time when arginine was depleted. In conclusion, our data suggest that high levels of 2-oxoglutarate and a limited amount of arginine are required for successful ethylene production in yeast.
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| 10. |
- Johansson, Nina, 1983, et al.
(författare)
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Expression of NADH-oxidases enhances ethylene productivity in Saccharomyces cerevisiae expressing the bacterial EFE
- 2017
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Ingår i: Biotechnology and Bioprocess Engineering. - : Springer Science and Business Media LLC. - 1226-8372 .- 1976-3816. ; 22:2, s. 195-199
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Tidskriftsartikel (refereegranskat)abstract
- Ethylene is a major petrochemical for which biotechnological production methods are an attractive alternative. Here we use a system based on a bacterial ethylene forming enzyme (EFE) expressed in Saccharomyces cerevisiae. Metabolic modelling performed in a previous study identified re-oxidation of NADH as a factor limiting ethylene production in S. cerevisiae. In line with this, we here found that strains with multicopy plasmid expression of the heterologous oxidases nox and Aox1 led to significantly increased specific ethylene productivity, up 12 and 36%, respectively, compared to the control strain with empty plasmid. However the productivity and yield was only improved in the AOX expressing strain compared to that of the control strain. Both oxidase expressing strains also exhibited increased respiration rates compared to the reference strain, with specific oxygen consumption rates being roughly doubled in both strains. The AOX strain furthermore exhibited a significant increase in the EFE substrate 2-oxoglutarate formation compared to the reference strain, linking an improvement in ethylene production to both increased respiratory capacity and increased substrate availability, thereby corroborating our previous finding.
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| 11. |
- Li, Jing, et al.
(författare)
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Shared Molecular Targets Confer Resistance over Short and Long Evolutionary Timescales
- 2019
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Ingår i: Molecular Biology and Evolution. - : Oxford University Press (OUP). - 1537-1719 .- 0737-4038. ; 36:4, s. 691-708
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Tidskriftsartikel (refereegranskat)abstract
- Pre-existing and de novo genetic variants can both drive adaptation to environmental changes, but their relative contributions and interplay remain poorly understood. Here we investigated the evolutionary dynamics in drug-treated yeast populations with different levels of pre-existing variation by experimental evolution coupled with time-resolved sequencing and phenotyping. We found a doubling of pre-existing variation alone boosts the adaptation by 64.1% and 51.5% in hydroxyurea and rapamycin, respectively. The causative pre-existing and de novo variants were selected on shared targets: RNR4 in hydroxyurea and TOR1, TOR2 in rapamycin. Interestingly, the pre-existing and de novo TOR variants map to different functional domains and act via distinct mechanisms. The pre-existing TOR variants from two domesticated strains exhibited opposite rapamycin resistance effects, reflecting lineage-specific functional divergence. This study provides a dynamic view on how pre-existing and de novo variants interactively drive adaptation and deepens our understanding of clonally evolving populations.
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| 12. |
- Mozzachiodi, S., et al.
(författare)
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Aborting meiosis allows recombination in sterile diploid yeast hybrids
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Hybrids are often considered evolutionary dead ends because they do not generate viable offspring. Here, the authors show that sterile yeast hybrids generate genetic diversity through meiotic-like recombination by aborting meiosis and return to asexual growth. Hybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility. Genome analyses of 275 clones reveal that RTG promotes recombination and generates extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination is reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially arises in regions with low local heterozygosity and near meiotic recombination hotspots. The loss-of-heterozygosity has a profound impact on sexual and asexual fitness, and enables genetic mapping of phenotypic differences in sterile lineages where linkage analysis would fail. We propose that RTG gives sterile yeast hybrids access to a natural route for genome recombination and adaptation.
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| 13. |
- Mozzachiodi, Simone, et al.
(författare)
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Aborting meiosis overcomes hybrid sterility
- 2020
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hybrids between species or diverged lineages contain fundamentally novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explored to what extent and how an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 yeast diploid backgrounds with different genomic structures and levels of sterility. Genome analyses of 284 clones revealed that RTG promoted recombination and generated extensive regions of loss-ofheterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination was reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially occurred in regions with local sequence homology and in meiotic recombination hotspots. The loss-of-heterozygosity had a profound impact on sexual and asexual fitness, and enabled genetic mapping of phenotypic differences in sterile lineages where linkage or association analyses failed. We propose that RTG gives sterile hybrids access to a natural route for genome recombination and adaptation.
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| 14. |
- Peri, Kameshwara Venkata Ramana, 1990, et al.
(författare)
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Regulation of lactose and galactose growth: Insights from a unique metabolic gene cluster in Candida intermedia
- 2023
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Lactose assimilation is a relatively rare trait in yeasts, and Kluyveromyces yeast species have long served as model organisms for studying lactose metabolism. Meanwhile, the metabolic strategies of most other lactose-assimilating yeasts remain unknown. In this work, we have elucidated the genetic determinants of the superior lactose-growing yeast Candida intermedia. Through genomic and transcriptomic analyses and deletion mutant phenotyping, we identified three interdependent gene clusters responsible for the metabolism of lactose and its hydrolysis product galactose: the conserved LAC cluster (LAC12, LAC4) for lactose uptake and hydrolysis, the conserved GAL cluster (GAL1, GAL7, GAL10) for galactose catabolism, and a unique “GALLAC” cluster. This novel GALLAC cluster, which has evolved through gene duplication and divergence, proved indispensable for C. intermedia’s growth on lactose and galactose. The cluster contains the transcriptional activator gene LAC9, second copies of GAL1 and GAL10 and the XYL1 gene encoding an aldose reductase involved in carbon overflow metabolism. Notably, the regulatory network in C. intermedia, governed by Lac9 and Gal1 from the GALLAC cluster, differs significantly from the (ga)lactose regulons in Saccharomyces cerevisiae, Kluyveromyces lactis and Candida albicans. Moreover, although lactose and galactose metabolism are closely linked in C. intermedia, our results also point to important regulatory differences. This study paves the way to a better understanding of lactose and galactose metabolism in C. intermedia and provides new evolutionary insights into yeast metabolic pathways and regulatory networks. In extension, the results will facilitate future development and use of C. intermedia as a cell-factory for conversion of lactose-rich whey into value-added products.
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| 15. |
- Peri, Kameshwara Venkata Ramana, 1990, et al.
(författare)
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Understanding gene cluster interactions enables cell factory application of non-conventional yeast Candida intermedia
- 2023
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Lactose-rich cheese whey is an abundant industrial side stream that can be converted into value-added products using lactose-assimilating yeasts. Whereas the dairy yeasts Kluyveromyces lactis and marxianus have been well studied in terms of their lactose-metabolising traits, most other lactose-assimilating yeast species have not yet been characterized at a genomic and molecular level. The aim of this project was to elucidate the genetic determinants behind the lactose metabolism in one such yeast, Candida intermedia, and thereafter demonstrate the yeast’s potential as a cell factory for production of metabolites from cheese whey. Through comparative growth assays, we found that C. intermedia is one of the top ten among 36 tested lactose-growing ascomycetous yeast, ranked on growth rates in lactose containing media. Transcriptomic analysis revealed that in addition to the well conserved LAC and GAL metabolic gene clusters for (ga)lactose metabolism, C. intermedia also contains a third gene cluster that we refer to as the GALLAC cluster, which is unique to this yeast and essential for its (ga)lactose metabolism. Through targeted genome editing we have confirmed and assigned physiological functions to individual genes in the three clusters and revealed close cluster interdependence. Using the acquired knowledge, we have managed to engineer a C. intermedia that overproduces the sugar alcohol galactitol from lactose. Subsequent strain improvement led to an increased productivity and a >95% galactitol yield from the galactose moiety of lactose. Our work sheds light on gene clusters dynamics and lactose metabolism in C. intermedia. We envision that C. intermedia can be used as a new model organism for deciphering evolutionary aspects of lactose metabolism in ascomycetous yeast as well as a cell factory for production of added-value chemicals using lactose-rich industrial side streams as raw material.
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| 16. |
- Persson, Ann-Charlotte, 1970, et al.
(författare)
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A novel method for objective in-situ measurement of audibility in bone conduction hearing devices - a pilot study using a skin drive BCD
- 2023
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Ingår i: International Journal of Audiology. - : Informa UK Limited. - 1499-2027 .- 1708-8186. ; 62:4, s. 357-361
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Tidskriftsartikel (refereegranskat)abstract
- Objective Objective measurement of audibility (verification) using bone conduction devices (BCDs) has long remained an elusive problem for BCDs. For air conduction hearing aids there are well-defined and often used objective methods, and the aim of this study is to develop an objective method for BCDs. Design In a novel setup for audibility measurements of bone-anchored hearing aid (BAHA) attached via a soft band, we used a skin microphone (SM) on the forehead measuring in-situ sound field thresholds, maximum power output (MPO) and international speech test signal (ISTS) responses. Study sample Five normal-hearing persons. Result Using the electrical output of SM it was possible to objectively measure the audibility of a skin drive BCD, presented as an eSPL-o-gram showing thresholds, MPO and ISTS response. Normalised eSPL-o-gram was verified against corresponding FL-o-grams (corresponding force levels from skull simulator and artificial mastoid (AM)). Conclusion The proposed method with the SM can be used for objective measurements of the audibility of any BCDs based on thresholds, MPO and speech response allowing for direct comparisons of hearing and BCD output on the same graph using an eSPL-o-gram. After normalisation to hearing thresholds, the audibility can be assessed without the need for complicated calibration procedures.
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| 17. |
- Persson, Ann-Charlotte, 1970, et al.
(författare)
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Objective verification of audibility in bone conduction devices
- 2024
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Ingår i: International Journal of Audiology. - 1499-2027 .- 1708-8186.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To objectively measure audibility in patients wearing bone conduction devices (BCDs) with a new approach using a skin microphone at the patient’s forehead. Design: The skin microphone was attached by a softband and shielded by an earmuff. This set-up was confirmed not to be influenced by neither noise floor nor sound bypassing the BCD. Sound field warble tones were used for measuring aided hearing thresholds and maximum power output (MPO) whereas an international speech test signal (ISTS) was presented at different speech levels. Study sample: 29 patients were tested (two were bilateral), 19 used percutaneous, eight used active transcutaneous and two used passive transcutaneous devices. Results: The skin microphone responses at ISTS levels, hearing threshold and MPO, could be obtained in all patients. Two patients with poor audibility are highlighted in this article as examples. After adjusting the gain of the BCD, they were retested with the skin microphone (for verification) and with speech-in-noise tests (for validation). Both tests confirmed an improved audibility after the adjustments. Conclusion: In summary, the proposed measurement of audibility of speech using a skin microphone is a promising method that can be used in a clinical setting for all types of BCDs.
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| 18. |
- Persson, Ann-Charlotte, 1970, et al.
(författare)
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Three-Year Follow-Up with the Bone Conduction Implant
- 2020
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Ingår i: Audiology and Neuro-Otology. - : S. Karger AG. - 1421-9700 .- 1420-3030. ; 25:5, s. 263-275
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Tidskriftsartikel (refereegranskat)abstract
- Background: The bone conduction implant (BCI) is an active transcutaneous bone conduction device where the transducer has direct contact to the bone, and the skin is intact. Sixteen patients have been implanted with the BCI with a planned follow-up of 5 years. This study reports on hearing, quality of life, and objective measures up to 36 months of follow-up in 10 patients. Method: Repeated measures were performed at fitting and after 1, 3, 6, 12, and 36 months including sound field warble tone thresholds, speech recognition thresholds in quiet, speech recognition score in noise, and speech-to-noise thresholds for 50% correct words with adaptive noise. Three quality of life questionnaires were used to capture the benefit from the intervention, appreciation from different listening situations, and the ability to interact with other people when using the BCI. The results were compared to the unaided situation and a Ponto Pro Power on a soft band. The implant functionality was measured by nasal sound pressure, and the retention force from the audio processor against the skin was measured using a specially designed audio processor and a force gauge. Results: Audiometry and quality of life questionnaires using the BCI or the Ponto Pro Power on a soft band were significantly improved compared to the unaided situation and the results were statistically supported. There was generally no significant difference between the two devices. The nasal sound pressure remained stable over the study period and the force on the skin from the audio processor was 0.71 ± 0.22 N (mean ± 1 SD). Conclusion: The BCI improves the hearing ability for tones and speech perception in quiet and in noise for the indicated patients. The results are stable over a 3-year period, and the patients subjectively report a beneficial experience from using the BCI. The transducer performance and contact to the bone is unchanged over time, and the skin area under the audio processor remains without complications during the 3-year follow-up.
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| 19. |
- Persson, Karl, 1988, et al.
(författare)
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Adaptation of the yeast gene knockout collection is near-perfectly predicted by fitness and diminishing return epistasis.
- 2022
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Ingår i: G3 (Bethesda, Md.). - : Oxford University Press (OUP). - 2160-1836. ; 12:11
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Tidskriftsartikel (refereegranskat)abstract
- Adaptive evolution of clonally dividing cells and microbes is the ultimate cause of cancer and infectious diseases. The possibility of constraining the adaptation of cell populations, by inhibiting proteins enhancing the evolvability, has therefore attracted interest. However, our current understanding of how genes influence adaptation kinetics is limited, partly because accurately measuring adaptation for many cell populations is challenging. We used a high-throughput adaptive laboratory evolution platform to track the adaptation of >18,000 cell populations corresponding to single-gene deletion strains in the haploid yeast deletion collection. We report that the preadaptation fitness of gene knockouts near-perfectly (R2= 0.91) predicts their adaptation to arsenic, leaving at the most a marginal role for dedicated evolvability gene functions. We tracked the adaptation of another >23,000 gene knockout populations to a diverse range of selection pressures and generalized the almost perfect (R2=0.72-0.98) capacity of preadaptation fitness to predict adaptation. We also reconstructed mutations in FPS1, ASK10, and ARR3, which together account for almost all arsenic adaptation in wild-type cells, in gene deletions covering a broad fitness range and show that the predictability of arsenic adaptation can be understood as a by global epistasis, where excluding arsenic is more beneficial to arsenic unfit cells. The paucity of genes with a meaningful evolvability effect on adaptation diminishes the prospects of developing adjuvant drugs aiming to slow antimicrobial and chemotherapy resistance.
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| 20. |
- Persson, Karl, 1988
(författare)
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The Genetics of Adaptation and Evolvability in Yeast
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Evolution is the hereditary change in life forms that has shaped the divergence of all organisms that inhabit planet Earth. I used the yeast Saccharomyces cerevisiae to study how adaptive evolution increases the fitness and changes the properties of experimental and natural yeast populations. In Paper I, I screened for evolvability genes that control how fast S. cerevisiae adapts using experimental evolution and highthroughput growth phenotyping. I investigated the rate of adaptation of nearly all viable single gene deletion strains. I found that the dynamics of adaptation was decided by diminishing returns epistasis, i.e. the decreasing effect size of beneficial mutations in fitter backgrounds, with almost no impact of specific evolvability genes. In Paper II, my co-workers and I found that S. cerevisiae adaptation to high mitochondrial superoxide production paraquat was extraordinarily swift. We revealed a novel regulatory mechanism whereby this adaptation was achieved: a genetically controlled reduction in the copy numbers of mitochondrial ETC genes through induction of mitochondrial DNA deletions. Intact mitochondrial genomes were rapidly restored after release from short-term stress, while the mitochondrial genome deletions become irreversible during long-term exposure to high mitochondrial superoxide production. In Paper III, my co-workers and I evolved S. cerevisiae populations with different levels of pre-existing genetic variation under exposure to anticancer drugs. We found that a higher amount of pre-existing variation speeded up adaptation and that selection on pre-existing and new variation acted on the same proteins, albeit on different aspects of the functions of these proteins. In Paper IV, my co-workers and I studied how DNA introgressions from the wild yeast Saccharomyces paradoxus have appeared in its sister species S. cerevisiae, despite the reproductive isolation of these two species. We show that this can be explained by the hybrid going through a genome destabilization event that leads to scattered islands of homozygosity. These in turn provide sufficient base-pairing for meiosis to proceed, and thereby allow two reproductively isolated species to generate offspring, and in the process, also serve as origins of the S. paradoxus introgressions into S. cerevisiae. Finally, in Paper V, my co-workers and I studied how the domestication of S. cerevisiae affected its phenotypes, particularly its life cycle. We compared key properties of the life cycle across nearly 1000 wild and domesticated yeast isolates. We found that domestication recently had profoundly altered the life cycle of S. cerevisiae, raising questions on how suitable domesticated yeast isolates are as models. Together, these works shed light on the molecular mechanisms whereby one of our key model organism adapts, and have adapted, to changes in the environment and what the consequences of this adaptation are.
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| 21. |
- Reinfeldt, Sabine, 1978, et al.
(författare)
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Long-term follow-up and review of the Bone Conduction Implant
- 2022
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Ingår i: Hearing Research. - : Elsevier BV. - 0378-5955 .- 1878-5891. ; 421
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Tidskriftsartikel (refereegranskat)abstract
- Active transcutaneous bone conduction devices are a type of bone conduction device developed to keep the skin intact and provide direct bone conduction stimulation. The Bone Conduction Implant (BCI) is such a device and has been implanted in 16 patients. The objective of this paper is to give a broad overview of the BCI development to the final results of 13 patients at 5-year follow-up. Follow-up of these patients included audiological performance investigations, questionnaires, as well as safety evaluation and objective functionality testing of the device. Among those audiological measure-ments were sound field warble tone thresholds, speech recognition threshold (SRT), speech recognition score (SRS) and signal to noise ratio threshold (SNR-threshold).The accumulated implant time for all 16 patients was 113 years in February 2022. During this time, no serious adverse events have occurred. The functional improvement for the 13 patients reported in this paper was on average 29.5 dB (average over 0.5, 1, 2 and 4 kHz), while the corresponding effective gain was-12.4 dB. The SRT improvement was 24.5 dB and the SRS improvement was 38.1%, while the aided SNR-threshold was on average -6.4 dB.It was found that the BCI can give effective and safe hearing rehabilitation for patients with conduc-tive and mild-to-moderate mixed hearing loss. (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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| 22. |
- Stenberg, Simon, et al.
(författare)
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Control of mitochondrial superoxide production includes programmed mtDNA deletion and restoration
- 2020
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Deletion of mitochondrial DNA in eukaryotes is mainly attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that the regulatory circuitry underlying this editing critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. Our results may therefore be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.One-Sentence SummaryGenetically controlled editing of mitochondrial DNA is an integral part of the yeast’s defenses against oxidative damage.
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| 23. |
- Stenberg, Simon, et al.
(författare)
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Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation
- 2022
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Ingår i: eLife. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.
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| 24. |
- Stenberg, Simon, et al.
(författare)
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Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation.
- 2022
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Ingår i: eLife. - 2050-084X. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.
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| 25. |
- Westerberg, Sonja, et al.
(författare)
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Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells
- 2018
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Ingår i: Journal of Virology. - : AMER SOC MICROBIOLOGY. - 0022-538X .- 1098-5514. ; 92:7
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Tidskriftsartikel (refereegranskat)abstract
- Human adenovirus 41 (HAdV-41) causes acute gastroenteritis in young children. The main characteristics of HAdV-41 infection are diarrhea and vomiting. Nevertheless, the precise mechanism of HAdV-41-induced diarrhea is unknown, as a suitable small-animal model has not been described. In this study, we used the human midgut carcinoid cell line GOT1 to investigate the effect of HAdV-41 infection and the individual HAdV-41 capsid proteins on serotonin release by enterochromaffin cells and on enteric glia cell (EGC) activation. We first determined that HAdV-41 could infect the enterochromaffin cells. Immunofluorescence staining revealed that the cells expressed HAdV-41-specific coxsackievirus and adenovirus receptor (CAR); flow cytometry analysis supported these findings. HAdV-41 infection of the enterochromaffin cells induced serotonin secretion dose dependently. In contrast, control infection with HAdV-5 did not induce serotonin secretion in the cells. Confocal microscopy studies of enterochromaffin cells infected with HAdV-41 revealed decreased serotonin immunofluorescence compared to that in uninfected cells. Incubation of the enterochromaffin cells with purified HAdV-41 short fiber knob and hexon proteins increased the serotonin levels in the harvested cell supernatant significantly. HAdV-41 infection could also activate EGCs, as shown in the significantly altered expression of glia fibrillary acidic protein (GFAP) in EGCs incubated with HAdV-41. The EGCs were also activated by serotonin alone, as shown in the significantly increased GFAP staining intensity. Likewise, EGCs were activated by the cell supernatant of HAdV-41-infected enterochromaffin cells.
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| 26. |
- Yue, J. X., et al.
(författare)
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Contrasting evolutionary genome dynamics between domesticated and wild yeasts
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:6
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Tidskriftsartikel (refereegranskat)abstract
- Structural rearrangements have long been recognized as an important source of genetic variation, with implications in phenotypic diversity and disease, yet their detailed evolutionary dynamics remain elusive. Here we use long-read sequencing to generate end-to-end genome assemblies for 12 strains representing major subpopulations of the partially domesticated yeast Saccharomyces cerevisiae and its wild relative Saccharomyces paradoxus. These population-level high-quality genomes with comprehensive annotation enable precise definition of chromosomal boundaries between cores and subtelomeres and a high-resolution view of evolutionary genome dynamics. In chromosomal cores, S. paradoxus shows faster accumulation of balanced rearrangements (inversions, reciprocal translocations and transpositions), whereas S. cerevisiae accumulates unbalanced rearrangements (novel insertions, deletions and duplications) more rapidly. In subtelomeres, both species show extensive interchromosomal reshuffling, with a higher tempo in S. cerevisiae. Such striking contrasts between wild and domesticated yeasts are likely to reflect the influence of human activities on structural genome evolution.
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