| 1. |
- Andersson, L-O, et al.
(författare)
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A new neutron beam facility
- 2004
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Ingår i: Proc. of the 9th European Particle Accelerator Conference.
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Konferensbidrag (refereegranskat)
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| 2. |
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| 3. |
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| 4. |
- Pomp, Stephan, et al.
(författare)
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The New Uppsala Neutron Beam Facility
- 2004
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Ingår i: Proc. Int. Conf. on Nuclear Data for Science and Technology.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Prokofiev, A, et al.
(författare)
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A New Neutron Facility for Single-Event Effect Testing
- 2004
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Ingår i: Proceedings of the 6th International Workshop on Radiation Effects on Semiconductor Devices for Space Application. ; , s. 160-162
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 6. |
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| 7. |
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| 8. |
- Prokofiev, A.V, et al.
(författare)
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A new neutron facility for single-event testing
- 2005
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Ingår i: IEEE International Reliability Physics Symposium (IRPS2005): San José, California, USA, April 17-21, 2005, (in press).
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Konferensbidrag (populärvet., debatt m.m.)
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| 9. |
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| 10. |
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| 11. |
- Björk, Glenn R, et al.
(författare)
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A primordial tRNA modification required for the evolution of life?
- 2001
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 20:1-2, s. 231-239
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of reading frame maintenance must have been an early event, and presumably preceded the emergence of the three domains Archaea, Bacteria and Eukarya. Features evolved early in reading frame maintenance may still exist in present-day organisms. We show that one such feature may be the modified nucleoside 1-methylguanosine (m(1)G37), which prevents frameshifting and is present adjacent to and 3' of the anticodon (position 37) in the same subset of tRNAs from all organisms, including that with the smallest sequenced genome (Mycoplasma genitalium), and organelles. We have identified the genes encoding the enzyme tRNA(m(1)G37)methyltransferase from all three domains. We also show that they are orthologues, and suggest that they originated from a primordial gene. Lack of m(1)G37 severely impairs the growth of a bacterium and a eukaryote to a similar degree. Yeast tRNA(m(1)G37)methyltransferase also synthesizes 1-methylinosine and participates in the formation of the Y-base (yW). Our results suggest that m(1)G37 existed in tRNA before the divergence of the three domains, and that a tRNA(m(1)G37)methyltrans ferase is part of the minimal set of gene products required for life.
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| 12. |
- Byström, Martin G., et al.
(författare)
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Optimal Disturbances in Three-dimensional Boundary-Layer Flows
- 2007
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Konferensbidrag (refereegranskat)abstract
- In the present paper, two di!erent approaches tocompute the optimal disturbances in the quasi three-dimensional flows are presented. One of the approachesis based on the Multiple Scales method and the otherone utilises the Parabolised Stability Equations.
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| 13. |
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| 14. |
- Esberg, Anders, et al.
(författare)
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Elevated levels of two tRNA species bypass the requirement for elongator complex in transcription and exocytosis.
- 2006
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 24:1, s. 139-148
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Tidskriftsartikel (refereegranskat)abstract
- The Saccharomyces cerevisiae Elongator complex consisting of the six Elp1-Elp6 proteins has been proposed to participate in three distinct cellular processes: transcriptional elongation, polarized exocytosis, and formation of modified wobble uridines in tRNA. Therefore it was important to clarify whether Elongator has three distinct functions or whether it regulates one key process that leads to multiple downstream effects. Here, we show that the phenotypes of Elongator-deficient cells linking the complex to transcription and exocytosis are suppressed by increased expression of two tRNA species. Elongator is required for formation of the mcm(5) group of the modified wobble nucleoside 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U) in these tRNAs. Hence, in cells with normal levels of these tRNAs, presence of mcm(5)s(2)U is crucial for posttranscriptional expression of gene products important in transcription and exocytosis. Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs.
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| 15. |
- Groenen, M. A., et al.
(författare)
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Analyses of pig genomes provide insight into porcine demography and evolution
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 491:7424, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
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| 16. |
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| 17. |
- Holmberg, M., et al.
(författare)
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Treatment outcome 6-10 years after diagnosis of hyperthyroidism in 2916 patients : a longitudinal evaluation of a swedish incidence cohort
- 2018
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Ingår i: Thyroid. - : Mary Ann Liebert. - 1050-7256 .- 1557-9077. ; :S1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Treatment of Graves’ disease (GD) and toxic nodular goiter (TNG) has the objectives to cure hyperthyroidism, prevent recurrent disease and preserve thyroid function. Treatment efficacies and long-termout comes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery varies in the literature. We report outcome of treatment, cure rate and risk factors for relapse for GD and TNG in an unselected cohort. A prospective incidence-cohort of de novo diagnosed GD and TNG patients (n = 2916) from 2003-05, were invited to a follow-up 6 - 10 years after diagnosis. Questionnaires were sent to 2430 patients regarding treatments, cure rate, recurrence, quality of life, demographic data, comorbidities and life-style factors. Patients were treated according to clinical routine with ATD, RAI or surgery. Of those included, 1186 (83.3%) had GD and 237 (16.7%) had TNG. In GD patients, 351 (45.3%), 264 (81.5%), and 52 (96.3%) were cured by ATD, RAI or surgery respectively as first line treatment. Of those, 77.0%, 15.4% and 3.8% respectively were without levothyr-oxine supplementation at follow-up at 8 – 0.9 years. Including all treatment modalities, 851 (71.8%) of GD patients were cured within one treatment period. At follow-up, 278 (23%) of GD patients had been operated. In TNG patients, RAI cured 88.6% and surgery 92.9%, whereof 52/154 (33.8%) and 3/15 (20%) had no levothyroxine supplementation post RAI and surgery, respectively.The proportion that did not feel fully recovered at follow-up was 25.3% of GD and 18.1% of the TNG patients. Overall, treatment of hyperthyroidism results in preserved thyroid function only in 35.3% and 44.7% of GD and TNG cases, respectively. As many as 23.4% of the GD patients end up with surgery although only 4.6% choose it from the beginning. Our treatment tradition cures 71.8% of GD patients and 78.1% of TNG patients within one treatment period. The high number of patients who do not feel recovered 6 -10 years after hyperthyroidism in GD and TNG is are minder of the chronic nature of hyperthyroidism.
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| 18. |
- Huang, Bo, et al.
(författare)
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An early step in wobble uridine tRNA modification requires the Elongator complex
- 2005
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Ingår i: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 11:4, s. 424-436
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Tidskriftsartikel (refereegranskat)abstract
- Elongator has been reported to be a histone acetyltransferase complex involved in elongation of RNA polymerase II transcription. In Saccharomyces cerevisiae, mutations in any of the six Elongator protein subunit (ELP1–ELP6) genes or the three killer toxin insensitivity (KTI11–KTI13) genes cause similar pleiotropic phenotypes. By analyzing modified nucleosides in individual tRNA species, we show that the ELP1–ELP6 and KTI11–KTI13 genes are all required for an early step in synthesis of 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) groups present on uridines at the wobble position in tRNA. Transfer RNA immunoprecipitation experiments showed that the Elp1 and Elp3 proteins specifically coprecipitate a tRNA susceptible to formation of an mcm5 side chain, indicating a direct role of Elongator in tRNA modification. The presence of mcm5U, ncm5U, or derivatives thereof at the wobble position is required for accurate and efficient translation, suggesting that the phenotypes of elp1–elp6 and kti11–kti13 mutants could be caused by a translational defect. Accordingly, a deletion of any ELP1–ELP6 or KTI11–KTI13 gene prevents an ochre suppressor tRNA that normally contains mcm5U from reading ochre stop codons.
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| 19. |
- Johansson, Marcus J O, et al.
(författare)
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Dual function of the tRNA(m(5)U54)methyltransferase in tRNA maturation
- 2002
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Ingår i: RNA. - 1355-8382 .- 1469-9001. ; 8:3, s. 324-335
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Tidskriftsartikel (refereegranskat)abstract
- A 5-methyluridine (m(5)U) residue at position 54 is a conserved feature of bacterial and eukaryotic tRNAs. The methylation of U54 is catalyzed by the tRNA(m5U54)methyltransferase, which in Saccharomyces cerevisiae is encoded by the nonessential TRM2 gene. In this study, we identified four different strains with mutant forms of tRNA(Ser)CGA. The absence of the TRM2 gene in these strains decreased the stability of tRNA(Ser)CGA and induced lethality. Two alleles of TRM2 encoding catalytically inactive tRNA(m5U54)methyltransferases were able to stabilize tRNA(Ser)CGA in one of the mutants, revealing a role for the Trm2 protein per se in tRNA maturation. Other tRNA modification enzymes interacting with tRNA(Ser)CGA in the maturation process, such as Pus4p, Trm1 p, and Trm3p were essential or important for growth of the tRNA(Ser)CGA mutants. Moreover, Lhp1p, a protein binding RNA polymerase III transcripts, was required to stabilize the mutant tRNAs. Based on our results, we suggest that tRNA modification enzymes might have a role in tRNA maturation not necessarily linked to their known catalytic activity.
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| 20. |
- Johansson, Marcus J O, et al.
(författare)
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Elongator-a tRNA modifying complex that promotes efficient translational decoding
- 2018
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1861:4, s. 401-408
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Tidskriftsartikel (refereegranskat)abstract
- Naturally occurring modifications of the nucleosides in the anticodon region of tRNAs influence their translational decoding properties. Uridines present at the wobble position in eukaryotic cytoplasmic tRNAs often contain a 5-carbamoylmethyl (ncm5) or 5-methoxycarbonylmethyl (mcm5) side-chain and sometimes also a 2-thio or 2'-O-methyl group. The first step in the formation of the ncm5 and mcm5 side-chains requires the conserved six-subunit Elongator complex. Although Elongator has been implicated in several different cellular processes, accumulating evidence suggests that its primary, and possibly only, cellular function is to promote modification of tRNAs. In this review, we discuss the biosynthesis and function of modified wobble uridines in eukaryotic cytoplasmic tRNAs, focusing on the in vivo role of Elongator-dependent modifications in Saccharomyces cerevisiae.
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| 21. |
- Johansson, Marcus J O, et al.
(författare)
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Eukaryotic wobble uridine modifications promote a functionally redundant decoding system.
- 2008
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 28:10, s. 3301-3312
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Tidskriftsartikel (refereegranskat)abstract
- The translational decoding properties of tRNAs are modulated by naturally occurring modifications of their nucleosides. Uridines located at the wobble position (nucleoside 34 [U34]) in eukaryotic cytoplasmic tRNAs often harbor a 5-methoxycarbonylmethyl (mcm(5)) or a 5-carbamoylmethyl (ncm(5)) side chain and sometimes an additional 2-thio (s2) or 2'-O-methyl group. Although a variety of models explaining the role of these modifications have been put forth, their in vivo functions have not been defined. In this study, we utilized recently characterized modification-deficient Saccharomyces cerevisiae cells to test the wobble rules in vivo. We show that mcm5 and ncm5 side chains promote decoding of G-ending codons and that concurrent mcm5 and s2 groups improve reading of both A- and G-ending codons. Moreover, the observation that the mcm5U34- and some ncm5U34-containing tRNAs efficiently read G-ending codons challenges the notion that eukaryotes do not use U-G wobbling.
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| 22. |
- Johansson, Marcus J O, et al.
(författare)
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The Saccharomyces cerevisiae TAN1 gene is required for N4-acetylcytidine formation in tRNA.
- 2004
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Ingår i: RNA. - 1355-8382. ; 10:4, s. 712-9
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Tidskriftsartikel (refereegranskat)abstract
- The biogenesis of transfer RNA is a process that requires many different factors. In this study, we describe a genetic screen aimed to identify gene products participating in this process. By screening for mutations lethal in combination with a sup61-T47:2C allele, coding for a mutant form of, the nonessential TAN1 gene was identified. We show that the TAN1 gene product is required for formation of the modified nucleoside N(4)-acetylcytidine (ac(4)C) in tRNA. In Saccharomyces cerevisiae, ac(4)C is present at position 12 in tRNAs specific for leucine and serine as well as in 18S ribosomal RNA. Analysis of RNA isolated from a tan1-null mutant revealed that ac(4)C was absent in tRNA, but not rRNA. Although no tRNA acetyltransferase activity by a GST-Tan1 fusion protein was detected, a gel-shift assay revealed that Tan1p binds tRNA, suggesting a direct role in synthesis of ac(4)C(12). The absence of the TAN1 gene in the sup61-T47:2C mutant caused a decreased level of mature, indicating that ac(4)C(12) and/or Tan1p is important for tRNA stability.
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| 23. |
- Johansson, Marcus J O, et al.
(författare)
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Transfer RNA modifications and modifying enzymes in Saccharomyces cerevisiae.
- 2005
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Ingår i: Fine-Tuning of RNA Functions by Modification and Editing.. - Berlin, Heidelberg : Springer Berlin/Heidelberg. - 9783540244950 - 9783540314547 ; , s. 87-120
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Bokkapitel (refereegranskat)abstract
- Transfer RNAs are adaptor molecules, which decode mRNA into protein and, thereby, play a central role in gene expression. During the maturation of a primary tRNA transcript, specific subsets of the four normal nucleosides adenosine, cytidine, guanosine, and uridine are modified. The formation of a modified nucleoside can require more than one gene product and may involve several enzymatic steps. In the last few years, the identification of gene products required for formation of modified nucleosides in tRNA has dramatically increased. In this review, proteins involved in modification of cytoplasmic tRNAs in Saccharomyces cerevisiae are described, emphasizing phenotypic characteristics of modification deficient strains and genetic approaches used to determine the in vivo role of modified nucleosides/modifying enzymes.
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| 24. |
- Lu, Jian, et al.
(författare)
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The Kluyveromyces lactis γ-toxin targets tRNA anticodons.
- 2005
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Ingår i: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 11:11, s. 1648-1654
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Tidskriftsartikel (refereegranskat)abstract
- Kluyveromyces lactis killer strains secrete a heterotrimeric toxin (zymocin), which causes an irreversible growth arrest of sensitive yeast cells. Despite many efforts, the target(s) of the cytotoxic gamma-subunit of zymocin has remained elusive. Here we show that three tRNA species tRNA(Glu)(mcm(5)s(2)UUC), tRNA(Lys)(mcm(5)s(2)UUU), and tRNA(Gln)(mcm(5)s(2)UUG) are the targets of gamma-toxin. The toxin inhibits growth by cleaving these tRNAs at the 3' side of the modified wobble nucleoside 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U). Transfer RNA lacking a part of or the entire mcm(5) group is inefficiently cleaved by gamma-toxin, explaining the gamma-toxin resistance of the modification-deficient trm9, elp1-elp6, and kti11-kti13 mutants. The K. lactis gamma-toxin is the first eukaryotic toxin shown to target tRNA.
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| 25. |
- Nordlund, Monica E, et al.
(författare)
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Identification of the TRM2 gene encoding the tRNA(m5U54)methyltransferase of Saccharomyces cerevisiae.
- 2000
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Ingår i: RNA. - 1355-8382 .- 1469-9001. ; 6:6, s. 844-60
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Tidskriftsartikel (refereegranskat)abstract
- The presence of 5-methyluridine (m5U) at position 54 is a ubiquitous feature of most bacterial and eukaryotic elongator tRNAs. In this study, we have identified and characterized the TRM2 gene that encodes the tRNA(m5U54)methyltransferase, responsible for the formation of this modified nucleoside in Saccharomyces cerevisiae. Transfer RNA isolated from TRM2-disrupted yeast strains does not contain the m5U54 nucleoside. Moreover, a glutathione S-transferase (GST) tagged recombinant, Trm2p, expressed in Escherichia coli displayed tRNA(m5U54)methyltransferase activity using as substrate tRNA isolated from a trm2 mutant strain, but not tRNA isolated from a TRM2 wild-type strain. In contrast to what is found for the tRNA(m5U54)methyltransferase encoding gene trmA+ in E. coli, the TRM2 gene is not essential for cell viability and a deletion strain shows no obvious phenotype. Surprisingly, we found that the TRM2 gene was previously identified as the RNC1/NUD1 gene, believed to encode the yNucR endo-exonuclease. The expression and activity of the yNucR endo-exonuclease is dependent on the RAD52 gene, and does not respond to increased gene dosage of the RNC1/NUD1 gene. In contrast, we find that the expression of a trm2-LacZ fusion and the activity of the tRNA(m5U54)methyltransferase is not regulated by the RAD52 gene and does respond on increased gene dosage of the TRM2 (RNC1/NUD1) gene. Furthermore, there was no nuclease activity associated with a GST-Trm2 recombinant protein. The purified yNucR endo-exonuclease has been reported to have an NH2-D-E-K-N-L motif, which is not found in the Trm2p. Therefore, we suggest that the yNucR endo-exonuclease is encoded by a gene other than TRM2.
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| 26. |
- Potapenko, Ivan O., et al.
(författare)
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Donor Endothelial Cell Count Does Not Correlate With Descemet Stripping Automated Endothelial Keratoplasty Transplant Survival After 2 Years of Follow-up
- 2017
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Ingår i: Cornea. - : Lippincott Williams & Wilkins. - 0277-3740 .- 1536-4798. ; 36:6, s. 649-654
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To analyze the influence of low endothelial cell density (ECD) of donor cornea tissue, donor age, and sex on the transplant survival rate after Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: Graft ECD, age, and sex of donors used for DSAEK (n = 1789) during 7 years (2007-2014) in 4 Scandinavian hospitals were assessed for potential association with transplant survival at 2 years of follow-up using a Cox regression model correcting for confounding factors. The data were obtained from The Swedish Cornea Transplant Registry. Results: Transplant failure occurred in 196 patients, with 69 early failures during the first 3 postoperative months, and 127 late secondary failures. Twenty-five of the late secondary failures were due to rejection. Reversible rejections occurred in 67 patients. There was no significant impact of donor age [hazard ratio (HR) 1.0, 95% confidence interval (CI), 0.99-1.02, P = 0.32] or endothelial cell count (HR 1.00, 95% CI, 0.99-1.01, P = 0.3) on the survival rate of DSAEK transplants at 2 years of follow-up. The use of donor grafts with low ECD (, 2300 cells/mm(2)) did not influence the survival rate (HR 1.3, 95% CI, 0.76-2.35, P = 0.31). Male donor sex was associated with lower 2-year graft survival (HR 1.5, 95% CI, 1.042.28, P = 0.03), but not with rejection events (P = 0.26). Conclusions: Based on data from The Swedish Cornea Transplant Registry, low donor ECD was not detrimental to graft survival, whereas donor sex seemed to influence the outcome at the end of the 2-year follow-up.
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| 27. |
- Prokofiev, A. V, et al.
(författare)
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A new neutron beam facility at TSL
- 2006
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Ingår i: International workshop on Fast Neutron Detectors and Applications,Cape Town, South Africa, April 3-6. ; , s. 016-
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Konferensbidrag (refereegranskat)
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| 28. |
- Prokofiev, A.V, et al.
(författare)
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A New Neutron Beam Facility at TSL
- 2007
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Ingår i: Tenth Symposium on Neutron Dosimetry,Uppsala, Sweden, June 12-16, 2006 (accepted)..
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Konferensbidrag (refereegranskat)
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| 29. |
- Prokofiev, A.V, et al.
(författare)
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A new neutron facility for SEE testing
- 2005
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Ingår i: 8th European Conference on Radiation and its Effects on Components and systems, 2005, (in press).
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Konferensbidrag (refereegranskat)
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| 30. |
- Prokofiev, Alexander V., et al.
(författare)
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The TSL neutron beam facility
- 2007
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Ingår i: Radiation Protection Dosimetry. - : Oxford University Press (OUP). - 0144-8420 .- 1742-3406. ; 126:1-4, s. 18-22
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Tidskriftsartikel (refereegranskat)abstract
- A new quasi-monoenergetic neutron beam facility has been constructed at The Svedberg Laboratory (TSL) in Uppsala, Sweden. Key features include a neutron energy range of 11-175 MeV, high fluxes, user flux control, flexible neutron field size and shape, and spacious and easily accessible user area. The first results of the beam characterisation measurements are reported.
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| 31. |
- Sj?lin, G., et al.
(författare)
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The Long-Term Outcome of Treatment for Graves' Hyperthyroidism
- 2019
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 29:11, s. 1545-1557
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Tidskriftsartikel (refereegranskat)abstract
- Background: The treatment efficacy of antithyroid drug (ATD) therapy, radioactive iodine (I-131), or surgery for Graves' hyperthyroidism is well described. However, there are a few reports on the long-term total outcome of each treatment modality regarding how many require levothyroxine supplementation, the need of thyroid ablation, or the individual patient's estimation of their recovery. Methods: We conducted a pragmatic trial to determine the effectiveness and adverse outcome in a patient cohort newly diagnosed with Graves' hyperthyroidism between 2003 and 2005 (n = 2430). The patients were invited to participate in a longitudinal study spanning 8 +/- 0.9 years (mean +/- standard deviation) after diagnosis. We were able to follow 1186 (60%) patients who had been treated with ATD, I-131, or surgery. We determined the mode of treatment, remission rate, recurrence, quality of life, demographic data, comorbidities, and lifestyle factors through questionnaires and a review of the individual's medical history records. Results: At follow-up, the remission rate after first-line treatment choice with ATD was 45.3% (351/774), with I-131 therapy 81.5% (324/264), and with surgery 96.3% (52/54). Among those patients who had a second course of ATD, 29.4% achieved remission (vs. the 45.3% after the first course of ATD). The total number of patients who had undergone ablative treatment was 64.3% (763/1186), of whom 23% (278/1186) had received surgery, 43% (505/1186) had received I-131 therapy, including 2% (20/1186) who had received both surgery and I-131. Patients who received ATD as first-line treatment and possibly additional ATD had 49.7% risk (385/774) of having undergone ablative treatment at follow-up. Levothyroxine replacement was needed in 23% (81/351) of the initially ATD treated in remission, in 77.3% (204/264) of the I-131 treated, and in 96.2% (50/52) of the surgically treated patients. Taken together after 6-10 years, and all treatment considered, normal thyroid hormone status without thyroxine supplementation was only achieved in 35.7% (423/1186) of all patients and in only 40.3% of those initially treated with ATD. The proportion of patients that did not feel fully recovered at follow-up was 25.3%. Conclusion: A patient selecting ATD therapy as the initial approach in the treatment of Graves' hyperthyroidism should be informed that they have only a 50.3% chance of ultimately avoiding ablative treatment and only a 40% chance of eventually being euthyroid without thyroid medication. Surprisingly, 1 in 4 patients did not feel fully recovered after 6-10 years. The treatment for Graves' hyperthyroidism, thus, has unexpected long-term consequences for many patients.
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| 32. |
- Sjölin, Gabriel, 1979-, et al.
(författare)
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Long term outcome after toxic nodular goitre
- 2022
-
Ingår i: Thyroid Research. - : Springer Science and Business Media LLC. - 1756-6614. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose of treating toxic nodular goitre (TNG) is to reverse hyperthyroidism, prevent recurrent disease, relieve symptoms and preserve thyroid function. Treatment efficacies and long-term outcomes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery vary in the literature. Symptoms often persist for a long time following euthyroidism, and previous studies have demonstrated long-term cognitive and quality of life (QoL) impairments. We report the outcome of treatment, rate of cure (euthyroidism and hypothyroidism), and QoL in an unselected TNG cohort. Methods: TNG patients (n = 638) de novo diagnosed between 2003-2005 were invited to engage in a 6-10-year follow-up study. 237 patients responded to questionnaires about therapies, demographics, comorbidities, and quality of life (ThyPRO). Patients received ATD, RAI, or surgery according clinical guidelines. Results: The fraction of patients cured with one RAI treatment was 89%, and 93% in patients treated with surgery. The rate of levothyroxine supplementation for RAI and surgery, at the end of the study period, was 58% respectively 64%. Approximately 5% of the patients needed three or more RAI treatments to be cured. The patients had worse thyroid-related QoL scores, in a broad spectrum, than the general population. Conclusion: One advantage of treating TNG with RAI over surgery might be lost due to the seemingly similar incidence of hypothyroidism. The need for up to five treatments is rarely described and indicates that the treatment of TNG can be more complex than expected. This circumstance and the long-term QoL impairments are reminders of the chronic nature of hyperthyroidism from TNG.
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| 33. |
- Sjölin, Gabriel, 1979-, et al.
(författare)
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Treatment of patients with Graves' disease in Sweden compared to international surveys of an 'index patient'
- 2021
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Ingår i: Endocrinology, Diabetes & Metabolism. - : Wiley. - 2398-9238. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The treatment strategies for a 42-year-old female index patient with moderate Graves' disease (GD) vary according to several international surveys. The important question whether surveys of treatment preferences in theoretical patient cases also match how real patients are treated has not yet been addressed. Materials and Methods From a Swedish cohort of 1186 GD patients (TT-12 cohort), 27 women were identified using the same criteria as from the index patient surveys from the European and American Thyroid Associations. This 'index patient cohort' was age 40-45, otherwise healthy female, with two children and uncomplicated GD. The applied first-line treatment of the patients in the index cohort, together with its variations, was compared with the treatment preferences according to international surveys. A comparison with the TT-12 cohort was also performed. Results In the 'Index cohort', 77.8% were treated with antithyroid drugs (ATD), and 22.2% were treated with radioiodine (I-131). This preference for ATD is in line with most countries/regions, with the exception of USA and the Middle East/North Africa, where I-131 was preferred. The distribution of treatment in the TT-12 cohort did not significantly differ from the index cohort. ATD was the preferred treatment in male and young (age 19-22) patients, as was RAI in old (age 69-73) patients. The age-related, but not the gender-related, cases differed significantly from the entire TT-12 cohort. Conclusion The treatment choice in an index patient in Sweden seems in line with European practice, where ATD is the preferred first choice. This differs compared to US and North African survey intentions, where I-131 is more often used. Age more than gender influences the treatment choice of GD patients. This is, to our best knowledge, the first time an index patient from 'real life' has been presented and compared to treatment preferences of international thyroid association surveys.
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| 34. |
- Xu, Fu, 1988-
(författare)
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Factors modulating tRNA biogenesis and function in Saccharomyces cerevisiae
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Transfer RNA (tRNA) genes are transcribed by RNA polymerase III as precursors that undergo multiple processing steps to form mature tRNAs. These steps include processing of the 5’ leader and 3’ trailer sequences, addition of a 3’ CCA tail, removal of introns, and formation of modified nucleosides. The mature tRNAs carry amino acids to the ribosome where proteins are synthesized. The aim of this thesis is to identify and characterize factors that influence tRNA biogenesis and function in Saccharomyces cerevisiae.Nonsense suppressor tRNAs are encoded by mutated tRNA genes and able to read stop codons. The SUP4 gene encodes such a suppressor tRNA that base-pairs with UAA stop codons. By screening for mutations that impair the nonsense suppression of the SUP4-encoded tRNA, we identified a loss-of-function mutation in the YPK9 gene. Inactivation of Ypk9p causes a reduction in the readthrough of UAA stop codon. We found that phenotypes of ypk9Δ cells including decreased UAA readthrough and sensitivity to Mn2+ are counteracted by increasing the cellular levels of putrescine, one type of polyamine. Importantly, cells lacking Ypk9p show reduced levels of putrescine. Our results suggest that the YPK9 gene product influences the cellular levels of putrescine, which plays a role in maintaining the fidelity of translation termination.The Elongator complex, consisting of Elp1p-Elp6p six proteins, catalyzes the formation of U34 modifications in the anticodon region of 11 tRNA species. Elongator mutants display pleiotropic phenotypes that are caused by decreased tRNA functionality. We found that the genetic background, largely due to a polymorphism at the SSD1 locus, influences the pleiotropic phenotypes of Elongator mutants.In a genetic screen for factors that are essential for the survival of cells encoding a destabilized tRNASerCGA, several gene products were identified. We demonstrate that mutations in these genes result in reduced levels of the destabilized tRNASerCGA, suggesting a role for these gene products in tRNASerCGA biosynthesis.
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| 35. |
- Xu, Fu, et al.
(författare)
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Identification of factors that promote biogenesis of tRNACGASer
- 2018
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Ingår i: RNA Biology. - : Taylor & Francis. - 1547-6286 .- 1555-8584. ; 15:10, s. 1286-1294
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Tidskriftsartikel (refereegranskat)abstract
- A wide variety of factors are required for the conversion of pre-tRNA molecules into the mature tRNAs that function in translation. To identify factors influencing tRNA biogenesis, we previously performed a screen for strains carrying mutations that induce lethality when combined with a sup61-T47:2C allele, encoding a mutant form of tRNACGASer. Analyzes of two complementation groups led to the identification of Tan1 as a protein involved in formation of the modified nucleoside N4-acetylcytidine (ac4C) in tRNA and Bud13 as a factor controlling the levels of ac4C by promoting TAN1 pre-mRNA splicing. Here, we describe the remaining complementation groups and show that they include strains with mutations in genes for known tRNA biogenesis factors that modify (DUS2, MOD5 and TRM1), transport (LOS1), or aminoacylate (SES1) tRNACGASer. Other strains carried mutations in genes for factors involved in rRNA/mRNA synthesis (RPA49, RRN3 and MOT1) or magnesium uptake (ALR1). We show that mutations in not only DUS2, LOS1 and SES1 but also in RPA49, RRN3 and MOT1 cause a reduction in the levels of the altered tRNACGASer. These results indicate that Rpa49, Rrn3 and Mot1 directly or indirectly influence tRNACGASer biogenesis.
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| 36. |
- Xu, Fu, et al.
(författare)
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SSD1 modifies phenotypes of Elongator mutants
- 2020
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Ingår i: Current Genetics. - : Springer-Verlag New York. - 0172-8083 .- 1432-0983. ; 66, s. 481-485
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Forskningsöversikt (refereegranskat)abstract
- The translational decoding properties of tRNAs are influenced by post-transcriptional modification of nucleosides in their anticodon region. The Elongator complex promotes the first step in the formation of 5-methoxycarbonylmethyl (mcm(5)), 5-methoxycarbonylhydroxymethyl (mchm(5)), and 5-carbamoylmethyl (ncm(5)) groups on wobble uridine residues in eukaryotic cytosolic tRNAs. Elongator mutants in yeast, worms, plants, mice, and humans not only show a tRNA modification defect, but also a diverse range of additional phenotypes. Even though the phenotypes are almost certainly caused by the reduced functionality of the hypomodified tRNAs in translation, the basis for specific phenotypes is not well understood. Here, we discuss the recent finding that the phenotypes of Saccharomyces cerevisiae Elongator mutants are modulated by the genetic background. This background-effect is largely due to the allelic variation at the SSD1 locus, which encodes an mRNA-binding protein involved in post-transcriptional regulation of gene expression. A nonsense ssd1 allele is found in several wild-type laboratory strains and the presence of this allele aggravates the stress-induced phenotypes of Elongator mutants. Moreover, other phenotypes, such as the histone acetylation and telomeric gene silencing defects, are dependent on the mutant ssd1 allele. Thus, SSD1 is a genetic modifier of the phenotypes of Elongator-deficient yeast cells.
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| 37. |
- Xu, Fu, et al.
(författare)
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SSD1 suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications
- 2019
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Ingår i: PLOS Genetics. - San Francisco : Public Library of Science. - 1553-7390 .- 1553-7404. ; 15:8
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Tidskriftsartikel (refereegranskat)abstract
- The Elongator complex promotes formation of 5-methoxycarbonylmethyl (mcm5 ) and 5-carbamoylmethyl (ncm5 ) side-chains on uridines at the wobble position of cytosolic eukaryotic tRNAs. In all eukaryotic organisms tested to date, the inactivation of Elongator not only leads to the lack of mcm5 /ncm5 groups in tRNAs, but also a wide variety of additional phenotypes. Although the phenotypes are most likely caused by a translational defect induced by reduced functionality of the hypomodified tRNAs, the mechanism(s) underlying individual phenotypes are poorly understood. In this study, we show that the genetic background modulates the phenotypes induced by the lack of mcm5 /ncm5 groups in Saccharomyces cerevisiae. We show that the stress-induced growth defects of Elongator mutants are stronger in the W303 than in the closely related S288C genetic background and that the phenotypic differences are caused by the known polymorphism at the locus for the mRNA binding protein Ssd1. Moreover, the mutant ssd1 allele found in W303 cells is required for the reported histone H3 acetylation and telomeric gene silencing defects of Elongator mutants. The difference at the SSD1 locus also partially explains why the simultaneous lack of mcm5 and 2- thio groups at wobble uridines is lethal in the W303 but not in the S288C background. Collectively, our results demonstrate that the SSD1 locus modulates phenotypes induced by the lack of Elongator-dependent tRNA modifications.
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