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- Bestas, Burcu, et al.
(författare)
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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:9, s. 4067-4081
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Tidskriftsartikel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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- Matsubara, N., et al.
(författare)
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Neutron powder diffraction study of NaMn2O4 and Li0.92Mn2O4: Insights on spin-charge-orbital ordering
- 2020
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Ingår i: Physical Review Research. - 2643-1564. ; 2:4
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Tidskriftsartikel (refereegranskat)abstract
- High-pressure synthesized quasi-one-dimensional NaMn2O4 and Li0.92Mn2O4 are both antiferromagnetic insulators. Here their atomic and magnetic structures are investigated using neutron powder diffraction. The present crystal structural analyses of NaMn2O4 reveal that a Mn3+/Mn4+ charge-ordering state exists even at low temperature (down to 1.5 K). It is evident that one of the Mn sites shows a strongly distorted Mn3+ octahedron due to the Jahn-Teller effect. Above T-N = 35 K, a two-dimensional short-range correlation is observed, as indicated by asymmetric diffuse scattering. Below T-N, two antiferromagnetic transitions are observed: (i) a commensurate long-range Mn3+ spin ordering below T-N1 = 35 K and (ii) an incommensurate Mn4+ spin ordering below T-N2 = 11 K. Surprisingly, the two antiferromagnetic orders are found to be independent of each other. The commensurate magnetic structure (k(C) = 0.5, 0.5, 0.5) follows the magnetic anisotropy of the local easy axes of Mn3+, while the incommensurate Mn4+ one shows a spin-density-wave or a cycloidal order with k(IC) = (0, 0, 0.216). For Li0.92Mn2O4, on the other hand, the absence of a long-range spin-ordered state is confirmed down to 1.5 K.
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- Minderjahn, J, et al.
(författare)
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Postmitotic differentiation of human monocytes requires cohesin-structured chromatin
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4301-
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Tidskriftsartikel (refereegranskat)abstract
- Cohesin is a major structural component of mammalian genomes and is required to maintain loop structures. While acute depletion in short-term culture models suggests a limited importance of cohesin for steady-state transcriptional circuits, long-term studies are hampered by essential functions of cohesin during replication. Here, we study genome architecture in a postmitotic differentiation setting, the differentiation of human blood monocytes (MO). We profile and compare epigenetic, transcriptome and 3D conformation landscapes during MO differentiation (either into dendritic cells or macrophages) across the genome and detect numerous architectural changes, ranging from higher level compartments down to chromatin loops. Changes in loop structures correlate with cohesin-binding, as well as epigenetic and transcriptional changes during differentiation. Functional studies show that the siRNA-mediated depletion of cohesin (and to a lesser extent also CTCF) markedly disturbs loop structures and dysregulates genes and enhancers that are primarily regulated during normal MO differentiation. In addition, gene activation programs in cohesin-depleted MO-derived macrophages are disturbed. Our findings implicate an essential function of cohesin in controlling long-term, differentiation- and activation-associated gene expression programs.
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