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- Lundtoft, Christian, et al.
(författare)
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Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD–CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.Author summaryGenetic association studies have been very successful in identifying disease-associated single nucleotide polymorphisms (SNPs), but it has been challenging to define the molecular mechanisms underlying these associations. As interferons (IFNs) have a central role in the immune system, we hypothesized that some of the SNPs associated to immune-mediated diseases would affect the IFN system. By combining genetic data with characterization of interferon receptor levels and their responses on the protein level in immune cells from 303 genotyped healthy individuals, we show that two SNPs tagging the HLA class I alleles A*02/A*68 and B*44 are associated with a decreased response to type I IFN stimulation in B cells and T cells. Notably, both HLA-A*02 and HLA-B*44 confer protection from developing multiple sclerosis (MS), which is a chronic inflammatory neurologic disease. In addition to suggesting a pathogenic role of enhanced type I interferon signalling in B cells and T cells in MS, our data emphasize the fact that genetic associations in the HLA locus can affect functions not directly associated to antigen presentation, which conceptually may be important for other diseases genetically associated to the HLA locus.
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| 2. |
- Nygren, Ingrid, et al.
(författare)
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Fyrisåns avrinningsområde 2019 : Vattenkvalitet 2017-2019
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- NäringsämnenDe lägsta halterna av fosfor uppmättes under den senaste treårsperioden i Jumkilsån och Fyrisåns Vattholmastation medan de övriga stationerna legat betydligt högre, framförallt det två senaste åren. Även kvävehalterna är lägst i Jumkilsån och vid Vattholma men där är skillnaden inte lika stor mellan stationer utom vid Vindbron där kvävehalten är betydligt högre än vid någon annan station. Kvalitetsklassning avseende näringsämnen visade på måttlig status vid alla stationer utom vid Jumkilsån Kallön där den var hög och Fyrisån vid Vattholma där den var god.Syrgasförhållanden De flesta stationerna visar goda syreförhållanden i vattnet under hela året. Undantaget är stationen vid Vattholma där syrgashalten tidigare under vissa år legat mycket lågt under delar av året, framförallt vintertid. På senare år har detta blivit mycket bättre utom under en period vintern 2017-2018.Surhet/försurning Fyrisåns avrinningsområde har generellt bra motståndskraft mot försurning. Stationen i Jumkilsån vid Kallön avviker med en låg buffertförmåga, mätt som alkalinitet. Detta kan förklaras av att stationen ligger långt upp i avrinningsområdet och avvattnar ett område som domineras av skog.Metaller Metallhalterna har i de flesta fall sjunkit vid de stationer där mätningar gjorts under perioden även om variationen mellan åren stundtals är stor. De högsta metallhalterna finner man i Sävjaån medan Fyrisån vid Vindbron och Flottsund oftast visar lägre halter.Kiselalger.Bedömning av vattenkvaliteten avseende kiselalger visade hög ekologisk status vid två stationer, nämligen Vattholma N. Bron och Jumkilsån Kallön. Stationen vid Flottsund uppvisade god status och de övriga måttlig status. Kiselalgsindexet ACID indikerade att alla stationer har alkaliska eller nära neutrala förhållanden.BottenfaunaBottenfaunaprov togs vid stationerna Fyrisån Vattholma, Vendelån Lena kyrka, Jumkilsån Kallön samt Fyrisån Klastorp. Bedömning av bottenfaunans ekologiska status grundas på tre olika index: ASPT, DJ och MISA. ASPT och DJ, som indikerar näringspåverkan, visade båda hög status vid alla stationer. Surhetsindexet MISA gav statusen Nära neutralt vid alla stationer utom Jumkilsån Kallön där statusen var Måttligt surt.
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| 3. |
- Visnes, Torkild, et al.
(författare)
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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
- 2020
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:21, s. 12234-12251
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Tidskriftsartikel (refereegranskat)abstract
- Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.
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| 4. |
- Zhang, Si Min, et al.
(författare)
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Development of a chemical probe against NUDT15
- 2020
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 16:10, s. 1120-1128
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Tidskriftsartikel (refereegranskat)abstract
- The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.
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