| 1. |
- Abelsson, J, et al.
(author)
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The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries.
- 2012
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In: Bone Marrow Transplantation. - : Nature Publishing Group. - 0268-3369 .- 1476-5365. ; 47:3, s. 380-386
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Journal article (peer-reviewed)abstract
- Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.
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| 2. |
- Abildgaard, Amanda B., et al.
(author)
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HSP70-binding motifs function as protein quality control degrons
- 2023
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 80:1
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Journal article (peer-reviewed)abstract
- Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.
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| 3. |
- Agardh, Emilie E., et al.
(author)
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Alcohol and type 2 diabetes : The role of socioeconomic, lifestyle and psychosocial factors
- 2019
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In: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 47:4, s. 408-416
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Journal article (peer-reviewed)abstract
- AIMS: We investigate (a) alcohol consumption in association with type 2 diabetes, taking heavy episodic drinking (HED), socioeconomic, health and lifestyle, and psychosocial factors into account, and (b) whether a seemingly protective effect of moderate alcohol consumption on type 2 diabetes persists when stratified by occupational position.METHODS: This population-based longitudinal cohort study comprises 16,223 Swedes aged 18-84 years who answered questionnaires about lifestyle, including alcohol consumption in 2002, and who were followed-up for self-reported or register-based diabetes in 2003-2011. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated in a multivariable-adjusted logistic regression model for all participants and stratified by high and low occupational position. We adjusted for HED, socioeconomic (occupational position, cohabiting status and unemployment), health and lifestyle (body mass index (BMI), blood pressure, smoking, physical inactivity, poor general health, anxiety/depression and psychosocial (low job control and poor social support) characteristics one by one, and the sets of these factors.RESULTS: Moderate consumption was inversely associated with type 2 diabetes after controlling for health and lifestyle (OR=0.47; 95% CI: 0.29-0.79) and psychosocial factors (OR=0.40; 95% CI: 0.22-0.79) when compared to non-drinkers. When adjusting for socioeconomic factors, there was still an inverse but non-significant association (OR=0.59; 95% CI: 0.35-1.00). In those with high occupational position, there was no significant association between moderate consumption and type 2 diabetes after adjusting for socioeconomic (OR=0.67; 95% CI: 0.3-1.52), health and lifestyle (OR=0.70; 95% CI: 0.32-1.5), and psychosocial factors (OR=0.75; 95% CI: 0.23-2.46). On the contrary, in those with low occupational position, ORs decreased from 0.55 (95% CI: 0.28-1.1) to 0.35 (95% CI: 0.15-0.82) when adjusting for psychosocial factors, a decrease that was solely due to low job control. HED did not influence any of these associations.CONCLUSIONS: Moderate alcohol consumption is associated with a lower risk of type 2 diabetes, after adjusting for HED, health and lifestyle, and psychosocial characteristics. The association was inverse but non-significant after adjusting for socioeconomic factors. When stratified by occupational position, there was an inverse association only in those with low occupational position and after adjusting for low job control.
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| 4. |
- Andreasson, Claes, et al.
(author)
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Direct Cloning of Isogenic Murine DNA in Yeast and Relevance of Isogenicity for Targeting in Embryonic Stem Cells
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9, s. e74207-
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Journal article (peer-reviewed)abstract
- Efficient gene targeting in embryonic stem cells requires that modifying DNA sequences are identical to those in the targeted chromosomal locus. Yet, there is a paucity of isogenic genomic clones for human cell lines and PCR amplification cannot be used in many mutation-sensitive applications. Here, we describe a novel method for the direct cloning of genomic DNA into a targeting vector, pRTVIR, using oligonucleotide-directed homologous recombination in yeast. We demonstrate the applicability of the method by constructing functional targeting vectors for mammalian genes Uhrf1 and Gfap. Whereas the isogenic targeting of the gene Uhrf1 showed a substantial increase in targeting efficiency compared to non-isogenic DNA in mouse E14 cells, E14-derived DNA performed better than the isogenic DNA in JM8 cells for both Uhrf1 and Gfap. Analysis of 70 C57BL/6-derived targeting vectors electroporated in JM8 and E14 cell lines in parallel showed a clear dependence on isogenicity for targeting, but for three genes isogenic DNA was found to be inhibitory. In summary, this study provides a straightforward methodological approach for the direct generation of isogenic gene targeting vectors.
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| 5. |
- Andréasson, Claes
(author)
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Ligand-activated proteolysis in nutrient signaling
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Cells respond to changing nutrient availability and make adjustments in physiological processes. Central for making proper adjustments is the ability to execute appropriate changes in patterns of gene expression. The budding yeast Saccharomyces cerevisiae, responds to the presence of extracellular amino acids by up regulating systems that internalize these nutrients. Extracellular amino acids are sensed by the amino acid transporter-like receptor Ssy1p that is localized to the plasma membrane. Ssy1p generates a signal that is transmitted via a pathway minimally composed of the core components Ssy1p, Ptr3p, and Ssy5p (SPS). The SPS sensor pathway ultimately up regulates genes encoding amino acid transporters, also known as amino acid permeases. This thesis describes the elucidation of the mechanism connecting amino acid induced signals generated at the plasma membrane and gene regulation in the nucleus. A genetic selection for mutations that enable amino acid permease genes to be expressed even in the absence of a functional SPS sensor pathway identified the dominant ASI13-1 mutation. The ASI13-1 gene encodes a constitutively active form of the transcription factor Stp1p that lacks its regulatory N-terminal domain. Stp1p and its close homologue Stp2p are synthesized as latent cytoplasmic precursors. In response to extracellular amino acids, the SPS sensor induces the rapid endoproteolytic processing of Stp1p and Stp2p. The shorter forms of these transcription factors, lacking N-terminal inhibitory domains, are targeted to the nucleus, where they transactivate SPS-sensor target genes. Several genetic approaches have been applied to identify mutations that affect the SPS sensor pathway. A novel genetic selection specifically designed for rare mutations that affect the SPS-sensing pathway identified the F-box protein Grr1p as an obligatory factor required for Stp1p and Stp2p processing. Genetic analysis suggests that Grr1p has a role in signal transduction within the SPS sensor. The N-terminal domains of Stp1p and Stp2p contain two conserved motifs that are required for proper nuclear exclusion and proteolytic processing. These motifs function in parallel; mutations that abolish processing inhibit signaling, whereas mutations that interfere with cytoplasmic retention result in constitutive activation of SPS sensorregulated genes independently of processing. The N-terminal domain of Stp1p is functionally autonomous and transferable to other transcription factors, where its presence confers regulated nuclear exclusion and SPS sensor-induced proteolytic processing. Proteolytic processing of recombinant Stp1p in cell free lysates supports the notion of a SPS sensor activated protease. Analysis indicates that Ssy5p is a chymotrypsin-like serine protease that is activated via the SPS sensor pathway and is responsible for Stp1p and Stp2p processing. Mutations in the predicted catalytic triad of Ssy5p abolish Stp1p processing. A constitutive SSY5 mutant promotes processing of Stp1p even in the absence of amino acids or Ssy1p and Ptr3p. Finally, Stp1p is processed when heterologously coexpressed together with activated Ssy5p in Schizosaccharomyces pombe, an organism that lacks the SPS sensor pathway. Taken together, these results define a unique and streamline metabolic control pathway that directly routes nutrient signals initiated at the plasma membrane to transcriptional activation in the nucleus.
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| 6. |
- Andréasson, Claes, et al.
(author)
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Mitochondria orchestrate proteostatic and metabolic stress responses
- 2019
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In: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20:10
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Journal article (peer-reviewed)abstract
- The eukaryotic cell is morphologically and functionally organized as an interconnected network of organelles that responds to stress and aging. Organelles communicate via dedicated signal transduction pathways and the transfer of information in form of metabolites and energy levels. Recent data suggest that the communication between organellar proteostasis systems is a cornerstone of cellular stress responses in eukaryotic cells. Here, we discuss the integration of proteostasis and energy fluxes in the regulation of cellular stress and aging. We emphasize the molecular architecture of the regulatory transcriptional pathways that both sense and control metabolism and proteostasis. A special focus is placed on mechanistic insights gained from the model organism budding yeast in signaling from mitochondria to the nucleus and how this shapes cellular fitness.
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| 7. |
- Andréasson, Claes, et al.
(author)
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The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp11
- 2010
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:16, s. 12445-53
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Journal article (peer-reviewed)abstract
- Grp170 and Hsp110 proteins constitute two evolutionary distinct branches of the Hsp70 family that share the ability to function as nucleotide exchange factors (NEFs) for canonical Hsp70s. Although the NEF mechanism of the cytoplasmic Hsp110s is well understood, little is known regarding the mechanism used by Grp170s in the endoplasmic reticulum. In this study, we compare the yeast Grp170 Lhs1 with the yeast Hsp110 Sse1. We find that residues important for Sse1 NEF activity are conserved in Lhs1 and that mutations in these residues in Lhs1 compromise NEF activity. As previously reported for Sse1, Lhs1 requires ATP to trigger nucleotide exchange in its cognate Hsp70 partner Kar2. Using site-specific cross-linking, we show that the nucleotide-binding domain (NBD) of Lhs1 interacts with the NBD of Kar2 face to face, and that Lhs1 contacts the side of the Kar2 NBD via its protruding C-terminal alpha-helical domain. To directly address the mechanism of nucleotide exchange, we have compared the hydrogen-exchange characteristics of a yeast Hsp70 NBD (Ssa1) in complex with either Sse1 or Lhs1. We find that Lhs1 and Sse1 induce very similar changes in the conformational dynamics in the Hsp70. Thus, our findings demonstrate that despite some differences between Hsp110 and Grp170 proteins, they use a similar mechanism to trigger nucleotide exchange.
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| 8. |
- Andreasson, Jens, 1978, et al.
(author)
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”Den missförstådda traditionsprincipen”
- 2020
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In: Dagens Juridik. ; :2020-10-06
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Journal article (pop. science, debate, etc.)abstract
- I dagarna har en av landets största dagstidningar på sin ledarsida krävt traditionsprincipens avskaffande. Ledaraspekten av krönikan kan sammanfattas i att det är olyckligt att okända juridiska principer påverkar vår tillvaro och vår exportindustri! Den åsikten påminner om åsikterna bakom lagförslaget SOU 2015:18 Lösöreköp och registerpant.
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| 9. |
- Andreasson, Jens, 1978, et al.
(author)
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Efficient priority rules under default: the case of traditio versus contract principle
- 2021
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In: European Journal of Law and Economics. - : Springer Science and Business Media LLC. - 0929-1261 .- 1572-9990. ; 51:1, s. 97-128
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Journal article (peer-reviewed)abstract
- We investigate the economic consequences of the traditio and the contract principle-differing in how they determine the priority rights for an item sold but not delivered. Our results suggest that the two principles are equivalent in terms of the net utilities enjoyed by involved actors. For example, a lower price paid for a forward transaction under a traditio principle can be compensated by better credit terms, implying there is no competitive advantage for either the seller or buyer under any principle. We demonstrate how market prices, incorrectly used, may misleadingly favour a contract principle, and discuss how fraudulent behaviour better supports a traditio regime. We also contribute to the legal discussion on priority regimes of undelivered items basing our discussion on bankruptcy priority laws instead of distribution of ownership.
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| 10. |
- Andreasson, Jens, 1978, et al.
(author)
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Prioritet för köpare - en fråga om tradition eller princip?
- 2015
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In: Svensk Juristtidning. - 0039-6591. ; :9, s. 709-748
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Journal article (other academic/artistic)abstract
- Lösöreköpskommittén har i SOU 2015:18 föreslagit bl.a. att traditionsprincipen bör avskaffas. I denna artikel presenteras några resultat av en enkel argumentationsanalys avseende kommitténs argumentation. Analysen indikerar att kommittén haft en normativ ambition snarare än en utredande. Resultaten är därför relevanta för dem som är intresserade av den reella frågan om prioritet för köpare. Möjligen är artikeln också relevant som ett generellt exempel på en kritisk analys av argumentationen i en offentlig utredning.
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