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- Conrad, Donald F., et al.
(författare)
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Origins and functional impact of copy number variation in the human genome
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 704-712
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Tidskriftsartikel (refereegranskat)abstract
- Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.
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- Harre, U, et al.
(författare)
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Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 6651-
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Tidskriftsartikel (refereegranskat)abstract
- Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss.
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- Kissel, T, et al.
(författare)
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Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation
- 2022
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:6, s. eabm1759-
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Tidskriftsartikel (refereegranskat)abstract
- The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hypermutation, and their presence is predictive for disease development. However, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease.
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- Kristan, Matej, et al.
(författare)
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The first visual object tracking segmentation VOTS2023 challenge results
- 2023
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Ingår i: 2023 IEEE/CVF International conference on computer vision workshops (ICCVW). - : Institute of Electrical and Electronics Engineers Inc.. - 9798350307443 - 9798350307450 ; , s. 1788-1810
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Konferensbidrag (refereegranskat)abstract
- The Visual Object Tracking Segmentation VOTS2023 challenge is the eleventh annual tracker benchmarking activity of the VOT initiative. This challenge is the first to merge short-term and long-term as well as single-target and multiple-target tracking with segmentation masks as the only target location specification. A new dataset was created; the ground truth has been withheld to prevent overfitting. New performance measures and evaluation protocols have been created along with a new toolkit and an evaluation server. Results of the presented 47 trackers indicate that modern tracking frameworks are well-suited to deal with convergence of short-term and long-term tracking and that multiple and single target tracking can be considered a single problem. A leaderboard, with participating trackers details, the source code, the datasets, and the evaluation kit are publicly available at the challenge website1
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