| 1. |
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| 2. |
- Akaberi, Dario, et al.
(författare)
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Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors
- 2021
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Ingår i: Antiviral Research. - : Elsevier. - 0166-3542 .- 1872-9096. ; 190
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Tidskriftsartikel (refereegranskat)abstract
- Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC50 = 0.92 mu M in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC50 = 0.25 mu M. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.
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| 3. |
- Alekseenko, Alisa, et al.
(författare)
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Direct detection of SARS-CoV-2 using non-commercial RT-LAMP reagents on heat-inactivated samples
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- RT-LAMP detection of SARS-CoV-2 has been shown to be a valuable approach to scale up COVID-19 diagnostics and thus contribute to limiting the spread of the disease. Here we present the optimization of highly cost-effective in-house produced enzymes, and we benchmark their performance against commercial alternatives. We explore the compatibility between multiple DNA polymerases with high strand-displacement activity and thermostable reverse transcriptases required for RT-LAMP. We optimize reaction conditions and demonstrate their applicability using both synthetic RNA and clinical patient samples. Finally, we validate the optimized RT-LAMP assay for the detection of SARS-CoV-2 in unextracted heat-inactivated nasopharyngeal samples from 184 patients. We anticipate that optimized and affordable reagents for RT-LAMP will facilitate the expansion of SARS-CoV-2 testing globally, especially in sites and settings where the need for large scale testing cannot be met by commercial alternatives.
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| 4. |
- Bárcenas-Walls, José Ramón, et al.
(författare)
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Nano-CUT&Tag for multimodal chromatin profiling at single-cell resolution
- 2024
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Ingår i: Nature Protocols. - 1754-2189 .- 1750-2799. ; 19:3, s. 791-830
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Tidskriftsartikel (refereegranskat)abstract
- The ability to comprehensively analyze the chromatin state with single-cell resolution is crucial for understanding gene regulatory principles in heterogenous tissues or during development. Recently, we developed a nanobody-based single-cell CUT&Tag (nano-CT) protocol to simultaneously profile three epigenetic modalities-two histone marks and open chromatin state-from the same single cell. Nano-CT implements a new set of secondary nanobody-Tn5 fusion proteins to direct barcoded tagmentation by Tn5 transposase to genomic targets labeled by primary antibodies raised in different species. Such nanobody-Tn5 fusion proteins are currently not commercially available, and their in-house production and purification can be completed in 3-4 d by following our detailed protocol. The single-cell indexing in nano-CT is performed on a commercially available platform, making it widely accessible to the community. In comparison to other multimodal methods, nano-CT stands out in data complexity, low sample requirements and the flexibility to choose two of the three modalities. In addition, nano-CT works efficiently with fresh brain samples, generating multimodal epigenomic profiles for thousands of brain cells at single-cell resolution. The nano-CT protocol can be completed in just 3 d by users with basic skills in standard molecular biology and bioinformatics, although previous experience with single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) is beneficial for more in-depth data analysis. As a multimodal assay, nano-CT holds immense potential to reveal interactions of various chromatin modalities, to explore epigenetic heterogeneity and to increase our understanding of the role and interplay that chromatin dynamics has in cellular development. This protocol involves profiling gene regulatory dynamics in complex tissues at the single-cell level. This is achieved by generating two nanobody-Tn5 fusion proteins to recognize primary antibodies against widespread histone modifications.The nanobody-Tn5 fusions are combined with ATAC-seq to simultaneously profile three epigenetic modalities from the same single cell, thousands of cells at the same time. A bioinformatic pipeline, Nanoscope, for seamless analysis of nano-CT datasets is also described. Mapping of chromatin states at single-cell resolution is still challenging. This protocol describes nano-CT, a novel method to simultaneously characterize up to three epigenetic modalities at single-cell resolution.
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| 5. |
- Blissing, Annica
(författare)
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Thiopurine S-methyltransferase - characterization of variants and ligand binding
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thiopurine S-methyltransferase (TPMT) belongs to the Class I S-adenosylmethionine-dependent methyltransferase (SAM-MT) super family of structurally related proteins. Common to the members of this large protein family is the catalysis of methylation reactions using S-adenosylmethionine (SAM) as a methyl group donor, although SAM-MTs act on a wide range of different substrates and carry out numerous biologically important functions. While the natural function of TPMT is unknown, this enzyme is involved in the metabolism of thiopurines, a class of pharmaceutical substances administered in treatment of immune-related disorders. Specifically, methylation by TPMT inactivates thiopurines and their metabolic intermediates, which reduces the efficacy of clinical treatment and increases the risk of adverse side effects. To further complicate matters, TPMT is a polymorphic enzyme with over 40 naturally occurring variants known to date, most of which exhibit lowered methylation activity towards thiopurines. Consequently, there are individual variations in TPMTmediated thiopurine inactivation, and the administered dose has to be adjusted prior to clinical treatment to avoid harmful side effects.Although the clinical relevance of TPMT is well established, few studies have investigated the molecular causes of the reduced methylation activity of variant proteins. In this thesis, the results of biophysical characterization of two variant proteins, TPMT*6 (Y180F) and TPMT*8 (R215H), are presented. While the properties of TPMT*8 were indistinguishable from those of the wild-type protein, TPMT*6 was found to be somewhat destabilized. Interestingly, the TPMT*6 amino acid substitution did not affect the functionality or folding pattern of the variant protein. Therefore, the decreased in vivo functionality reported for TPMT*6 is probably caused by increased proteolytic degradation in response to the reduced stability of this protein variant, rather than loss of function.Also presented herein are novel methodological approaches for studies of TPMT and its variants. Firstly, the advantages of using 8-anilinonaphthalene-1-sulfonic acid (ANS) to probe TPMT tertiary structure and active site integrity are presented. ANS binds exclusively to the native state of TPMT with high affinity (KD ~ 0.2 μm) and a 1:1 ratio. The stability of TPMT was dramatically increased by binding of ANS, which was shown to co-localize with the structurally similar adenine moiety of the cofactor SAM. Secondly, an enzyme activity assay based on isothermal titration calorimetry (ITC) is presented. Using this approach, the kinetics of 6-MP and 6-TG methylation by TPMT has been characterized.
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| 6. |
- Carlstedt, Thomas, et al.
(författare)
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Cortical activity and hand function restoration in a patient after spinal cord surgery
- 2009
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Ingår i: NATURE REVIEWS NEUROLOGY. - : Springer Science and Business Media LLC. - 1759-4758 .- 1759-4766. ; 5:10, s. 571-574
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Tidskriftsartikel (refereegranskat)abstract
- Background. Following a motorcycle accident, a 9-year-old boy experienced a complete right-sided ( dominant) arm and hand paralysis with total sensory loss, Horner syndrome and severe constant pain. This study assessed the long-term outcome of spinal cord surgery undertaken on the patient, focusing on the restored hand function and related cortical activity. The study follows on from previous reports on the same patient. Investigations. Clinical functional and electrophysiological examinations. Functional MRI of cortical activity. Diagnosis. Complete brachial plexus (C5-T1) avulsion from the spinal cord. Management. Spinal cord surgery to restore motor trajectories.
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| 7. |
- Diaz de Grenu, Borja, et al.
(författare)
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Fluorescent Discrimination between Traces of Chemical Warfare Agents and Their Mimics
- 2014
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 136:11, s. 4125-4128
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Tidskriftsartikel (refereegranskat)abstract
- An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the in-the-field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds.
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| 8. |
- Egeblad, Louise, et al.
(författare)
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Structural and functional studies of the human phosphoribosyltransferase domain containing protein 1
- 2010
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 277:23, s. 4920-30
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Tidskriftsartikel (refereegranskat)abstract
- Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 2.4.2.8) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency (k(cat)/K(m)) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway.
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| 9. |
- Ekblad, Torun, et al.
(författare)
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Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol
- 2018
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Ingår i: SLAS Discovery. - : Sage Publications. - 2472-5560 .- 2472-5552. ; 23:4, s. 353-362
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Tidskriftsartikel (refereegranskat)abstract
- Macrodomains recognize intracellular adenosine diphosphate (ADP)-ribosylation resulting in either removal of the modification or a protein interaction event. Research into compounds that modulate macrodomain functions could make important contributions. We investigated the interactions of all seven individual macrodomains of the human poly(ADP-ribose) polymerase (PARP) family members PARP9, PARP14, and PARP15 with five mono-ADP-ribosylated (automodified) ADP-ribosyltransferase domains using an AlphaScreen assay. Several mono-ADP-ribosylation-dependent interactions were identified, and they were found to be in the micromolar affinity range using surface plasmon resonance (SPR). We then focused on the interaction between PARP14 macrodomain-2 and the mono-ADP-ribosylated PARP10 catalytic domain, and probed a similar to 1500-compound diverse library for inhibitors of this interaction using AlphaScreen. Initial hit compounds were verified by concentration-response experiments using AlphaScreen and SPR, and they were tested against PARP14 macrodomain-2 and -3. Two initial hit compounds and one chemical analog each were further characterized using SPR and microscale thermophoresis. In conclusion, our results reveal novel macrodomain interactions and establish protocols for identification of inhibitors of such interactions.
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| 10. |
- Fahlström, Markus, et al.
(författare)
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Aortastentgraft ingen kontraindikation för undersökning med MR : Men undersökningskvaliteten kan påverkas, visar litteraturstudie
- 2014
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 111:27-28, s. 1184-1187
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Tidskriftsartikel (refereegranskat)abstract
- Endovascular implantation of stent grafts is currently considered the preferred treatment for many aortic pathologies. In Sweden, approximately 900 patients are treated with an aortic stent graft. Stent grafts consists of a metal stent which is manufactured in stainless steel or nitinol covered by a prosthetic graft material. The possibility to perform successful magnetic resonance imaging (MRI) of a patient depends on the metal composition of and the localisation of the stent graft. This article presents the most common types of stent grafts and how they affect patients’ possibility to undergo an MRI examination successfully.
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| 11. |
- Herman, Maria Dolores, et al.
(författare)
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Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim
- 2008
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 582:25-26, s. 3590-3594
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Tidskriftsartikel (refereegranskat)abstract
- Evasion of apoptosis is recognized as a characteristic of malignant growth. Anti-apoptotic B-cell lymphoma-2 (Bcl-2) family members have therefore emerged as potential therapeutic targets due to their critical role in proliferating cancer cells. Here, we present the crystal structure of Bfl-1, the last anti-apoptotic Bcl-2 family member to be structurally characterized, in complex with a peptide corresponding to the BH3 region of the pro-apoptotic protein Bim. The structure reveals distinct features at the peptide-binding site, likely to define the binding specificity for pro-apoptotic proteins. Superposition of the Bfl-1:Bim complex with that of Mcl-1:Bim reveals a significant local plasticity of hydrophobic interactions contributed by the Bim peptide, likely to be the basis for the multi specificity of Bim for anti-apoptotic proteins.
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| 12. |
- Herman, Maria Dolores, et al.
(författare)
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Structures of BIR domains from human NAIP and cIAP2
- 2009
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Ingår i: Acta Crystallographica. Section F. - 1744-3091 .- 1744-3091. ; 65, s. 1091-1096
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Tidskriftsartikel (refereegranskat)abstract
- The inhibitor of apoptosis (IAP) family of proteins contains key modulators of apoptosis and inflammation that interact with caspases through baculovirus IAP-repeat (BIR) domains. Overexpression of IAP proteins frequently occurs in cancer cells, thus counteracting the activated apoptotic program. The IAP proteins have therefore emerged as promising targets for cancer therapy. In this work, X-ray crystallography was used to determine the first structures of BIR domains from human NAIP and cIAP2. Both structures harbour an N-terminal tetrapeptide in the conserved peptide-binding groove. The structures reveal that these two proteins bind the tetrapeptides in a similar mode as do other BIR domains. Detailed interactions are described for the P1'-P4' side chains of the peptide, providing a structural basis for peptide-specific recognition. An arginine side chain in the P3' position reveals favourable interactions with its hydrophobic moiety in the binding pocket, while hydrophobic residues in the P2' and P4' pockets make similar interactions to those seen in other BIR domain-peptide complexes. The structures also reveal how a serine in the P1' position is accommodated in the binding pockets of NAIP and cIAP2. In addition to shedding light on the specificity determinants of these two proteins, the structures should now also provide a framework for future structure-based work targeting these proteins.
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| 13. |
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| 14. |
- Johansson, Tomas, et al.
(författare)
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A cluster of genes encoding major isozymes of lignin peroxidase and manganese peroxidase from the white-rot fungus Trametes versicolor
- 1996
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Ingår i: Gene. - : Elsevier BV. - 1879-0038 .- 0378-1119. ; 170:1, s. 31-38
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Tidskriftsartikel (refereegranskat)abstract
- A gene cluster from the white-rot basidiomycete Trametes (Coriolus) versicolor (Tv) PRL 572 containing three structural genes, LPGIII, LPGIV and MPGI, was characterized. The genes are arranged in the same transcriptional direction, within a 10-kb region, and found to encode quantitatively dominant isozymes of lignin peroxidase (LP) and manganese peroxidase (MP). The second gene in sequence, LPGIV, predicts a 346-amino-acid (aa) mature polypeptide (36.9 kDa, pI 4.31) which is identical with the partial aa sequence information available on the LP12 isozyme (43.1 kDa, pI 3.27). The first gene, LPGIII, encodes a 341-aa polypeptide (36.1 kDa, pI 3.93) which has not been identified at the protein level. However, the similarity to LPGIV would suggest that the predicted product is an LP-type enzyme. LPGIII andLPGIV are homologous to the tandemly arranged genes LPGII and LPGI, respectively, recently described by Jonsson and Nyman [Biochim. Biophys. Acta 1218 (1994) 408-412]. The homologous genes, LPGIII/LPGII and LPGIV/LPGI, are 99% and 96% identical in sequence, respectively, and are predicted to encode identical polypeptides, since base substitutions in the predicted exons are all synonymous. The third gene, MPGI, is different in intron-exon organization and predicted to be disrupted by five rather than six introns, as are the LP genes. The deduced polypeptide, 339 aa in size (35.9 kDa, pI 4.07), is identical with the partial aa sequence information available for isozyme MP2 (44.5 kDa, pI 3.09). The MPGI- and LPGIV-encoded polypeptides are 70% identical in sequence which suggests that MP and LP from Tv may be regarded as members of the same family within the plant peroxidase superfamily. Most importantly, this study identifies a gene encoding the MP2 isozyme, and further shows that genes encoding MP and LP can be closely linked on the chromosome and may be coordinately transcribed.
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| 15. |
- Johansson, Tomas, et al.
(författare)
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Differential regulation of mnp2, a new manganese peroxidase-encoding gene from the ligninolytic fungus Trametes versicolor PRL 572
- 2002
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Ingår i: Applied and Environmental Microbiology. - 0099-2240. ; 68:4, s. 2077-2080
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Tidskriftsartikel (refereegranskat)abstract
- A peroxidase-encoding gene, mnp2, and its corresponding cDNA were characterized from the white-rot basidiomycete Trametes versicolor PRL 572. We used quantitative reverse transcriptase-mediated PCR to identify mnp2 transcripts in nutrient-limited stationary cultures. Although mnp2 lacks upstream metal response elements (MREs), addition of MnSO4 to cultures increased mnp2 transcript levels 250-fold. In contrast, transcript levels of an MRE-containing gene of T. versicolor, mnp1, increased only eightfold under the same conditions. Thus, the manganese peroxidase genes in T. versicolor are differentially regulated, and upstream MREs are not necessarily involved. Our results support the hypothesis that fungal and plant peroxidases arose through an ancient duplication and folding of two structural domains, since we found the mnp1 and mnp2 polypeptides to have internal homology.
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| 16. |
- Johansson, Tomas, et al.
(författare)
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The gene from the white-rot fungus Trametes versicolor encoding the lignin peroxidase isozyme LP7*1
- 1995
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Ingår i: Biochimica et Biophysica Acta, Gene Structure and Expression. - 0167-4781. ; 1263:1, s. 71-74
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Tidskriftsartikel (refereegranskat)abstract
- The structural gene LPGVI (1463 bp including 6 introns), characterized from the white-rot basidiomycete Trametes versicolor (PRL 572), encodes a 342-residue mature polypeptide of 36.7 kDa, preceded by a 26-residue signal/propeptide. LPGVI is identified as the gene encoding the 43 kDa lignin peroxidase isozyme LP7 as based on the partial amino acid sequence information available. The polypeptide deduced shares 72–74% identity in sequence with other lignin peroxidases and 70% with a manganese (II) peroxidase from T. versicolor.
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| 17. |
- Johnson, Tomas, 1979, et al.
(författare)
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A Multi-Scale Simulation Method for the Prediction of Edge Wicking in Multi-Ply Paperboard
- 2015
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Ingår i: Nordic Pulp and Paper Research Journal. - 2000-0669 .- 0283-2631. ; 30:4, s. 640-650
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Tidskriftsartikel (refereegranskat)abstract
- When liquid packaging board is made aseptic in the filling machine the unsealed edges of the board are exposed to a mixture of water and hydrogen peroxide. A high level of liquid penetration may lead to aesthetic as well as functional defects. To be able to make a priori predictions of the edge wicking properties of a certain paperboard material is therefore of great interest to the paper industry as well as to packaging manufacturers. In this paper an extended multi-scale model of edge wicking in multi-ply paperboard is presented. The geometric and physical properties of the paperboard are modeled on the micro-scale, and include fillers and fines. The absolute air permeabilities and pore size distributions are validated with experimental and tomographic values. On the macro-scale random porosity and sizing distributions, time and sizing dependent contact angles, and inter-ply dependence are modeled. Arbitrary shapes of the paperboard are handled through an unstructured 3D surface mesh. Stationary and transient edge wicking simulations are validated against experiments with excellent agreement. The simulations show that the diffusive menisci between the liquid and air phases together with the two-ply model is necessary to achieve good agreement with the transient edge wicking experiments.
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| 18. |
- Jungholm, Oscar, et al.
(författare)
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Novel druggable space in human KRAS G13D discovered using structural bioinformatics and a P-loop targeting monoclonal antibody
- 2024
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Ingår i: SCIENTIFIC REPORTS. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- KRAS belongs to a family of small GTPases that act as binary switches upstream of several signalling cascades, controlling proliferation and survival of cells. Mutations in KRAS drive oncogenesis, especially in pancreatic, lung, and colorectal cancers (CRC). Although historic attempts at targeting mutant KRAS with small molecule inhibitors have proven challenging, there are recent successes with the G12C, and G12D mutations. However, clinically important RAS mutations such as G12V, G13D, Q61L, and A146T, remain elusive drug targets, and insights to their structural landscape is of critical importance to develop novel, and effective therapeutic concepts. We present a fully open, P-loop exposing conformer of KRAS G13D by X-ray crystallography at 1.4-2.4 & Aring; resolution in Mg2+-free phosphate and malonate buffers. The G13D conformer has the switch-I region displaced in an upright position leaving the catalytic core fully exposed. To prove that this state is druggable, we developed a P-loop-targeting monoclonal antibody (mAb). The mAb displayed high-affinity binding to G13D and was shown using high resolution fluorescence microscopy to be spontaneously taken up by G13D-mutated HCT 116 cells (human CRC derived) by macropinocytosis. The mAb inhibited KRAS signalling in phosphoproteomic and genomic studies. Taken together, the data propose novel druggable space of G13D that is reachable in the cellular context. It is our hope that these findings will stimulate attempts to drug this fully open state G13D conformer using mAbs or other modalities.
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| 19. |
- Kaldmae, Margit, et al.
(författare)
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Gas-Phase Collisions with Trimethylamine-N-Oxide Enable Activation-Controlled Protein Ion Charge Reduction
- 2019
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Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 30:8, s. 1385-1388
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Tidskriftsartikel (refereegranskat)abstract
- Modulating protein ion charge is a useful tool for the study of protein folding and interactions by electrospray ionization mass spectrometry. Here, we investigate activation-dependent charge reduction of protein ions with the chemical chaperone trimethylamine-N-oxide (TMAO). Based on experiments carried out on proteins ranging from 4.5 to 35kDa, we find that when combined with collisional activation, TMAO removes approximately 60% of the charges acquired under native conditions. Ion mobility measurements furthermore show that TMAO-mediated charge reduction produces the same end charge state and arrival time distributions for native-like and denatured protein ions. Our results suggest that gas-phase collisions between the protein ions and TMAO result in proton transfer, in line with previous findings for dimethyl- and trimethylamine. By adjusting the energy of the collisions experienced by the ions, it is possible to control the degree of charge reduction, making TMAO a highly dynamic charge reducer that opens new avenues for manipulating protein charge states in ESI-MS and for investigating the relationship between protein charge and conformation.
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| 20. |
- Liu, Haoyu, et al.
(författare)
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Dietary Fiber in Bilberry Ameliorates Pre-Obesity Events in Rats by Regulating Lipid Depot, Cecal Short-Chain Fatty Acid Formation and Microbiota Composition
- 2019
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is linked to non-alcoholic fatty liver disease and risk factors associated to metabolic syndrome. Bilberry (Vaccinium myrtillus) that contains easily fermentable fiber may strengthen the intestinal barrier function, attenuate inflammation and modulate gut microbiota composition, thereby prevent obesity development. In the current study, liver lipid metabolism, fat depot, cecal and serum short-chain fatty acids (SCFAs) and gut microbiome were evaluated in rats fed bilberries in a high-fat (HFD + BB) or low-fat (LFD + BB) setting for 8 weeks and compared with diets containing equal amount of fiber resistant to fermentation (cellulose, HFD and LFD). HFD fed rats did not obtain an obese phenotype but underwent pre-obesity events including increased liver index, lipid accumulation and increased serum cholesterol levels. This was linked to shifts of cecal bacterial community and reduction of major SCFAs. Bilberry inclusion improved liver metabolism and serum lipid levels. Bilberry inclusion under either LFD or HFD, maintained microbiota homeostasis, stimulated interscapular-brown adipose tissue depot associated with increased mRNA expression of uncoupling protein-1; enhanced SCFAs in the cecum and circulation; and promoted butyric acid and butyrate-producing bacteria. These findings suggest that bilberry may serve as a preventative dietary measure to optimize microbiome and associated lipid metabolism during or prior to HFD.
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| 21. |
- Liu, Haoyu, et al.
(författare)
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High-Fat Diet Enriched with Bilberry Modifies Colonic Mucus Dynamics and Restores Marked Alterations of Gut Microbiome in Rats
- 2019
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Ingår i: Molecular Nutrition & Food Research. - : WILEY. - 1613-4125 .- 1613-4133. ; 63:20
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Tidskriftsartikel (refereegranskat)abstract
- Scope Emerging evidence suggests that high-fat diet (HFD) is associated with gut microbiome dysbiosis and related disorders. Bilberry is a prebiotic food component with known health benefits. Herein, the dynamics of the colonic mucus layer and microbiome during HFD and bilberry supplementation are addressed. Methods and results The effects on colonic mucus thickness in vivo and gut microbiota composition (Illumina sequencing, quantitative real-time PCR) are investigated in young rats fed a low-fat diet or HFD with or without bilberries for 8 weeks (n = 8). HFD induced significant local colonic effects, despite no observed weight gain or systemic inflammation, as HFD causes epithelial upregulation of inducible nitric oxide synthase, which is counteracted by bilberry. The firmly adherent mucus layer becomes thicker and the mRNA levels of Muc2 and Tff3 are increased by HFD with or without bilberry. In parallel, HFD reduced the colonic abundance of mucolytic bacterial species Akkermansia muciniphila and Bacteroides spp. Finally, bilberry prevents HFD-induced microbiota dysbiosis, including expansion of pathobionts, for example, Enterobacteriaceae. Conclusion HFD expand firmly adherent mucus thickness and reduce mucus-foraging bacteria populations in the colon prior to obesity. Enriching HFD with bilberry protects against intestinal inflammation and marked microbiota encroachment.
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| 22. |
- Magnusdottir, Audur, et al.
(författare)
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The structure of the PP2A regulatory subunit B56gamma : The remaining piece of the PP2A jigsaw puzzle
- 2009
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 74:1, s. 212-221
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Tidskriftsartikel (refereegranskat)abstract
- The PP2A serine/threonine phosphatase regulates a plethora of cellular processes. In the cell the predominant form of the enzyme is a heterotrimer, formed by a core dimer composed of a catalytic and a scaffolding subunit, which assemble together with one of a range of different regulatory B subunits. Here, we present the first structure of a free non-complexed B subunit, B56. Comparison with the recent structures of a heterotrimeric complex and the core dimer reveals several significant conformational changes in the interface region between the B56 and the core dimer. These allow for an assembly scheme of the PP2A holoenzyme to be put forth where B56 first complexes with the scaffolding subunit and subsequently binds to the catalytic subunit and this induces the formation of a binding site for the invariant C-terminus of the catalytic subunit that locks in the complex as a last step of assembly.
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| 23. |
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| 24. |
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| 25. |
- Welin, Martin, et al.
(författare)
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Structural studies of tri-functional human GART
- 2010
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 38:20, s. 7308-19
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Tidskriftsartikel (refereegranskat)abstract
- Human purine de novo synthesis pathway contains several multi-functional enzymes, one of which, tri-functional GART, contains three enzymatic activities in a single polypeptide chain. We have solved structures of two domains bearing separate catalytic functions: glycinamide ribonucleotide synthetase and aminoimidazole ribonucleotide synthetase. Structures are compared with those of homologous enzymes from prokaryotes and analyzed in terms of the catalytic mechanism. We also report small angle X-ray scattering models for the full-length protein. These models are consistent with the enzyme forming a dimer through the middle domain. The protein has an approximate seesaw geometry where terminal enzyme units display high mobility owing to flexible linker segments. This resilient seesaw shape may facilitate internal substrate/product transfer or forwarding to other enzymes in the pathway.
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| 26. |
- Åström Paulsson, Sofia, 1979-, et al.
(författare)
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Procurement and implementation processes for Occupational Health Services in Sweden
- 2024
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer. - 1432-1246.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study investigates how contracts with OHS-providers in Sweden are established and implemented to explore i) the procurement process ii) contractual terms and conditions and iii) processes for implementing and evaluating the services provided.Methods: Review and analysis of 17 OHS contracts using both quantitative and qualitative approaches. Follow-up interviews were conducted with Human Resource managers, management, health and safety representatives and OHS professionals.Results: Contracts with OHS providers were mainly drawn up by HR departments. First-line managers or health and safety representatives were not involved. The contracts were not integrated with the companies’ occupational health and safety management. The organisations lacked knowledge on when or why to use services from their OHS provider, which promoted reactive rather than preventive interventions. Terms and conditions of contracts were found to be quite irrelevant to what services that were actually utilised.Conclusions: Important factors in creating conditions for a more preventive and group-oriented use of OHS expertise could be 1) the inclusion of first-line managers and health and safety representatives in needs analysis and implementation processes, 2) the definition of relevant, achievable and measurable goals regarding the collaboration and 3) the arrangement of regularly meetings with the OHS-provider.
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| 27. |
- Åström-Paulsson, Sofia, et al.
(författare)
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Procurement and implementation processes for Occupational Health Services in Sweden
- 2020
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Ingår i: Work. - : IOS PRESS. - 1051-9815 .- 1875-9270. ; 65:3, s. 607-615
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Employers are required to get expert advice whenever needed to ensure a safe work environment. Providers of Occupational Health Services (OHS) could be such experts, but their services are usually used to provide health-related support to individuals, not preventive Occupational Health and Safety Management (OHSM) or other group-focused interventions. OBJECTIVE: To investigate how contracts with OHS providers in Sweden are established and implemented. METHODS: Written OHS contracts were reviewed, and follow-up interviews were conducted with Human Resource (HR) managers, management, safety representatives, and OHS professionals in seven organizations. RESULTS: Generally, the HR departments drew up the contracts with the OHS providers. The contracts were not integrated with the companies' occupational health and safety management. Managers lacked knowledge on how to utilize services offered by their OHS provider. Terms and conditions of contracts were found to be inconsistent with services actually utilized. CONCLUSIONS: The procurement and implementation process promotes reactive rather than preventive interventions. Employers should include managers and safety representatives in procurement- and implementation processes and define relevant and measurable goals regarding the collaboration.
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