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| 2. |
- Lambert, J-C, et al.
(författare)
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Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
- 2013
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 18:4, s. 461-470
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Tidskriftsartikel (refereegranskat)abstract
- Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 x 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A beta plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma A beta 42/A beta 40 ratio (best signal, P=5.4 x 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
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| 4. |
- Onuţ-Brännström, Ioana, et al.
(författare)
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A Mitosome With Distinct Metabolism in the Uncultured Protist Parasite Paramikrocytos canceri (Rhizaria, Ascetosporea)
- 2023
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Ingår i: Genome Biology and Evolution. - : Oxford University Press. - 1759-6653. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Ascetosporea are endoparasites of marine invertebrates that include economically important pathogens of aquaculture species. Owing to their often-minuscule cell sizes, strict intracellular lifestyle, lack of cultured representatives and minimal availability of molecular data, these unicellular parasites remain poorly studied. Here, we sequenced and assembled the genome and transcriptome of Paramikrocytos canceri, an endoparasite isolated from the European edible crab Cancer pagurus. Using bioinformatic predictions, we show that P. canceri likely possesses a mitochondrion-related organelle (MRO) with highly reduced metabolism, resembling the mitosomes of other parasites but with key differences. Like other mitosomes, this MRO is predicted to have reduced metabolic capacity and lack an organellar genome and function in iron–sulfur cluster (ISC) pathway-mediated Fe–S cluster biosynthesis. However, the MRO in P. canceri is uniquely predicted to produce ATP via a partial glycolytic pathway and synthesize phospholipids de novo through the CDP-DAG pathway. Heterologous gene expression confirmed that proteins from the ISC and CDP-DAG pathways retain mitochondrial targeting sequences that are recognized by yeast mitochondria. This represents a unique combination of metabolic pathways in an MRO, including the first reported case of a mitosome-like organelle able to synthesize phospholipids de novo. Some of these phospholipids, such as phosphatidylserine, are vital in other protist endoparasites that invade their host through apoptotic mimicry.
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| 5. |
- Jokipii-Lukkari, Soile, et al.
(författare)
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Dual targeted poplar ferredoxin NADP+ oxidoreductase interacts with hemoglobin 1
- 2016
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Ingår i: Plant Science. - : Elsevier BV. - 0168-9452. ; 247, s. 138-149
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Tidskriftsartikel (refereegranskat)abstract
- Previous reports have connected non-symbiotic and truncated hemoglobins (Hbs) to metabolism of nitric oxide (NO), an important signalling molecule involved in wood formation. We have studied the capability of poplar (Populus tremula × tremuloides) Hbs PttHb1 and PttTrHb proteins alone or with a flavin-protein reductase to relieve NO cytotoxicity in living cells. Complementation tests in a Hb-deficient, NO-sensitive yeast (Saccharomyces cerevisiae) δyhb1 mutant showed that neither PttHb1 nor PttTrHb alone protected cells against NO. To study the ability of Hbs to interact with a reductase, ferredoxin NADP+ oxidoreductase PtthFNR was characterized by sequencing and proteomics. To date, by far the greatest number of the known dual-targeted plant proteins are directed to chloroplasts and mitochondria. We discovered a novel variant of hFNR that lacks the plastid presequence and resides in cytosol. The coexpression of PttHb1 and PtthFNR partially restored NO resistance of the yeast δyhb1 mutant, whereas PttTrHb coexpressed with PtthFNR failed to rescue growth. YFP fusion proteins confirmed the interaction between PttHb1 and PtthFNR in plant cells. The structural modelling results indicate that PttHb1 and PtthFNR are able to interact as NO dioxygenase. This is the first report on dual targeting of central plant enzyme FNR to plastids and cytosol.
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| 6. |
- Zarsky, Vojtech, et al.
(författare)
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Contrasting outcomes of genome reduction in mikrocytids and microsporidians
- 2023
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Ingår i: BMC Biology. - : BioMed Central (BMC). - 1741-7007. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intracellular symbionts often undergo genome reduction, losing both coding and non-coding DNA in a process that ultimately produces small, gene-dense genomes with few genes. Among eukaryotes, an extreme example is found in microsporidians, which are anaerobic, obligate intracellular parasites related to fungi that have the smallest nuclear genomes known (except for the relic nucleomorphs of some secondary plastids). Mikrocytids are superficially similar to microsporidians: they are also small, reduced, obligate parasites; however, as they belong to a very different branch of the tree of eukaryotes, the rhizarians, such similarities must have evolved in parallel. Since little genomic data are available from mikrocytids, we assembled a draft genome of the type species, Mikrocytos mackini, and compared the genomic architecture and content of microsporidians and mikrocytids to identify common characteristics of reduction and possible convergent evolution.Results: At the coarsest level, the genome of M. mackini does not exhibit signs of extreme genome reduction; at 49.7 Mbp with 14,372 genes, the assembly is much larger and gene-rich than those of microsporidians. However, much of the genomic sequence and most (8075) of the protein-coding genes code for transposons, and may not contribute much of functional relevance to the parasite. Indeed, the energy and carbon metabolism of M. mackini share several similarities with those of microsporidians. Overall, the predicted proteome involved in cellular functions is quite reduced and gene sequences are extremely divergent. Microsporidians and mikrocytids also share highly reduced spliceosomes that have retained a strikingly similar subset of proteins despite having reduced independently. In contrast, the spliceosomal introns in mikrocytids are very different from those of microsporidians in that they are numerous, conserved in sequence, and constrained to an exceptionally narrow size range (all 16 or 17 nucleotides long) at the shortest extreme of known intron lengths.Conclusions: Nuclear genome reduction has taken place many times and has proceeded along different routes in different lineages. Mikrocytids show a mix of similarities and differences with other extreme cases, including uncoupling the actual size of a genome with its functional reduction.
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- Galloway, Aaron W. E., et al.
(författare)
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Diet-specific biomarkers show that high-quality phytoplankton fuels herbivorous zooplankton in large boreal lakes
- 2014
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Ingår i: Freshwater Biology. - : Wiley. - 0046-5070 .- 1365-2427. ; 59:9, s. 1902-1915
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Tidskriftsartikel (refereegranskat)abstract
- 1. The zooplankton is a key link in the transfer of energy from primary producers up through aquatic food webs. Previous efforts to quantify the importance of basal resources to aquatic consumers have used stable isotopes (SI) and simple ternary models, including only 'bulk' phytoplankton, bacteria or terrestrial particulate organic matter (t-POM). 2. We used a novel Bayesian mixing model based on fatty acids (FA) to quantify the dietary assimilation of seven basal resources, including five phytoplankton groups, pelagic bacteria and t-POM, to Cladocera in large boreal lakes in Finland. To account for trophic enrichment of FA from the diet to consumers, we parameterised the model with a resource library, from many feeding trials, consisting of Daphnia magna fed 22 diverse basal taxa. 3. The results of the feeding trials show that the distinctive FA profiles of algal groups are transferred to consumers. Moreover, the large number of FA variables (n = 22) used in the model avoids the limitations of underdetermined mixing problems, common to SI modelling, in cases when the number of resources outnumbers the tracer variables. 4. We show that cladocerans were generally supported by phytoplankton (86-94%), with little use of t-POM (1-9%) and bacteria (1-3%). Cladocerans used primarily high-quality phytoplankton (cryptophytes, diatoms and dinoflagellates) in both summer (51 +/- 22%) and autumn (79 +/- 12%), and the relative importance of medium-quality resources (cyanobacteria, chlorophytes and chrysophytes) declined from 37 +/- 23% in the summer to 8 +/- 2% in the autumn. 5. High-quality resources, rich in essential biochemical compounds, are critical in fuelling food webs in large lakes, even those with high concentrations of allochthonous organic matter.
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| 8. |
- Strandberg, U., et al.
(författare)
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Inferring phytoplankton community composition with a fatty acid mixing model
- 2015
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Ingår i: Ecosphere. - 2150-8925 .- 2150-8925. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The taxon specificity of fatty acid composition in algal classes suggests that fatty acids could be used as chemotaxonomic markers for phytoplankton composition. The applicability of phospholipid-derived fatty acids as chemotaxonomic markers for phytoplankton composition was evaluated by using a Bayesian fatty acid-based mixing model. Fatty acid profiles from monocultures of chlorophytes, cyanobacteria, diatoms, euglenoids, dinoflagellates, raphidophyte, cryptophytes and chrysophytes were used as a reference library to infer phytoplankton community composition in five moderately humic, large boreal lakes in three different seasons ( spring, summer and fall). The phytoplankton community composition was also estimated from microscopic counts. Both methods identified diatoms and cryptophytes as the major phytoplankton groups in the study lakes throughout the sampling period, together accounting for 54-63% of the phytoplankton. In addition, both methods revealed that the proportion of chlorophytes and cyanobacteria was lowest in the spring and increased towards the summer and fall, while dinoflagellates peaked in the spring. The proportion of euglenoids and raphidophytes was less than 8% of the phytoplankton biomass throughout the sampling period. The model estimated significantly lower proportions of chrysophytes in the seston than indicated by microscopic analyses. This is probably because the reference library for chrysophytes included too few taxa. Our results show that a fatty acid-based mixing model approach is a promising tool for estimating the phytoplankton community composition, while also providing information on the nutritional quality of the seston for consumers. Both the quantity and the quality of seston as a food source for zooplankton were high in the spring; total phytoplankton biomass was; similar to 56 mu g C L-1, and the physiologically important polyunsaturated fatty acids 20:5n-3 and 22:6n-3 comprised; similar to 22% of fatty acids.
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| 9. |
- Sridhar, Shruthi, et al.
(författare)
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Crystallographic binding studies of rat peroxisomal multifunctional enzyme type 1 with 3-ketodecanoyl-CoA : capturing active and inactive states of its hydratase and dehydrogenase catalytic sites
- 2020
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Ingår i: Acta Crystallographica Section D. - : International Union of Crystallography (IUCr). - 2059-7983. ; 76:12, s. 1256-1269
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Tidskriftsartikel (refereegranskat)abstract
- The peroxisomal multifunctional enzyme type 1 (MFE1) catalyzes two successive reactions in the beta-oxidation cycle: the 2E-enoyl-CoA hydratase (ECH) and NAD(+)-dependent 3S-hydroxyacyl-CoA dehydrogenase (HAD) reactions. MFE1 is a monomeric enzyme that has five domains. The N-terminal part (domains A and B) adopts the crotonase fold and the C-terminal part (domains C, D and E) adopts the HAD fold. A new crystal form of MFE1 has captured a conformation in which both active sites are noncompetent. This structure, at 1.7 angstrom resolution, shows the importance of the interactions between Phe272 in domain B (the linker helix; helix H10 of the crotonase fold) and the beginning of loop 2 (of the crotonase fold) in stabilizing the competent ECH active-site geometry. In addition, protein crystallographic binding studies using optimized crystal-treatment protocols have captured a structure with both the 3-ketodecanoyl-CoA product and NAD(+) bound in the HAD active site, showing the interactions between 3-ketodecanoyl-CoA and residues of the C, D and E domains. Structural comparisons show the importance of domain movements, in particular of the C domain with respect to the D/E domains and of the A domain with respect to the HAD part. These comparisons suggest that the N-terminal part of the linker helix, which interacts tightly with domains A and E, functions as a hinge region for movement of the A domain with respect to the HAD part.
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