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- Robbe, P, et al.
(författare)
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Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:11, s. 1675-
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Tidskriftsartikel (refereegranskat)abstract
- The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia.
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- Rauschmeier, R, et al.
(författare)
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Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis
- 2021
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:2
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Tidskriftsartikel (refereegranskat)abstract
- The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.
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- Avula, Ramana R., et al.
(författare)
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Adversarial Inference Control in Cyber-Physical Systems : A Bayesian Approach With Application to Smart Meters
- 2024
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Ingår i: IEEE Access. - : Institute of Electrical and Electronics Engineers Inc.. - 2169-3536. ; 12, s. 24933-24948
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Tidskriftsartikel (refereegranskat)abstract
- With the emergence of cyber-physical systems (CPSs) in utility systems like electricity, water, and gas networks, data collection has become more prevalent. While data collection in these systems has numerous advantages, it also raises concerns about privacy as it can potentially reveal sensitive information about users. To address this issue, we propose a Bayesian approach to control the adversarial inference and mitigate the physical-layer privacy problem in CPSs. Specifically, we develop a control strategy for the worst-case scenario where an adversary has perfect knowledge of the user’s control strategy. For finite state-space problems, we derive the fixed-point Bellman’s equation for an optimal stationary strategy and discuss a few practical approaches to solve it using optimization-based control design. Addressing the computational complexity, we propose a reinforcement learning approach based on the Actor-Critic architecture. To also support smart meter privacy research, we present a publicly accessible ’Co-LivEn’ dataset with comprehensive electrical measurements of appliances in a co-living household. Using this dataset, we benchmark the proposed reinforcement learning approach. The results demonstrate its effectiveness in reducing privacy leakage. Our work provides valuable insights and practical solutions for managing adversarial inference in cyber-physical systems, with a particular focus on enhancing privacy in smart meter applications.
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- Chang, J., et al.
(författare)
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Electronic structure near the 1/8-anomaly in La-based cuprates
- 2008
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Ingår i: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- We report an angle-resolved photoemission study of the electronic structure of the pseudogap state in La1.48Nd0.4Sr0.12CuO4 (T-c < 7 K). Two opposite dispersing Fermi arcs are the main result of this study. Several scenarios that can explain this observation are discussed.
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- Heshmati, Y, et al.
(författare)
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The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 11202-
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Tidskriftsartikel (refereegranskat)abstract
- Nucleosome assembly proteins (NAPs) are histone chaperones with an important role in chromatin structure and epigenetic regulation of gene expression. We find that high gene expression levels of mouse Nap1l3 are restricted to haematopoietic stem cells (HSCs) in mice. Importantly, with shRNA or CRISPR-Cas9 mediated loss of function of mouse Nap1l3 and with overexpression of the gene, the number of colony-forming cells and myeloid progenitor cells in vitro are reduced. This manifests as a striking decrease in the number of HSCs, which reduces their reconstituting activities in vivo. Downregulation of human NAP1L3 in umbilical cord blood (UCB) HSCs impairs the maintenance and proliferation of HSCs both in vitro and in vivo. NAP1L3 downregulation in UCB HSCs causes an arrest in the G0 phase of cell cycle progression and induces gene expression signatures that significantly correlate with downregulation of gene sets involved in cell cycle regulation, including E2F and MYC target genes. Moreover, we demonstrate that HOXA3 and HOXA5 genes are markedly upregulated when NAP1L3 is suppressed in UCB HSCs. Taken together, our findings establish an important role for NAP1L3 in HSC homeostasis and haematopoietic differentiation.
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- Jouhilahti, EM, et al.
(författare)
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The human PRD-like homeobox gene LEUTX has a central role in embryo genome activation
- 2016
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 143:19, s. 3459-3469
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Tidskriftsartikel (refereegranskat)abstract
- Leucine twenty homeobox gene (LEUTX) is a PAIRED (PRD)-like homeobox gene that is expressed nearly exclusively in human preimplantation embryos. We previously identified a novel transcription start site for the predicted human LEUTX gene based on the transcriptional analysis of human preimplantation embryos. The novel variant encodes a protein with a complete homeodomain. Here we provide a detailed description of the molecular cloning of the complete homeodomain-containing LEUTX. Using a human embryonic stem cell overexpression model we show that the complete homeodomain isoform is functional and sufficient to activate the transcription of a large fraction of the genes found upregulated in human embryo genome activation, whereas the previously predicted partial homeodomain isoform is largely inactive. Another PRD-like transcription factor, DPRX, appears as a powerful repressor of transcription. We propose a two-stage model of human EGA in which LEUTX acts as a transcriptional activator at 4-cell stage, and DPRX as a balancing repressor at 8-cell stage. We conclude that LEUTX is a candidate regulator of human embryo genome activation.
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- Madissoon, E, et al.
(författare)
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Characterization and target genes of nine human PRD-like homeobox domain genes expressed exclusively in early embryos
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 28995-
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Tidskriftsartikel (refereegranskat)abstract
- PAIRED (PRD)-like homeobox genes belong to a class of predicted transcription factor genes. Several of these PRD-like homeobox genes have been predicted in silico from genomic sequence but until recently had no evidence of transcript expression. We found recently that nine PRD-like homeobox genes, ARGFX, CPHX1, CPHX2, DPRX, DUXA, DUXB, NOBOX, TPRX1 and TPRX2, were expressed in human preimplantation embryos. In the current study we characterized these PRD-like homeobox genes in depth and studied their functions as transcription factors. We cloned multiple transcript variants from human embryos and showed that the expression of these genes is specific to embryos and pluripotent stem cells. Overexpression of the genes in human embryonic stem cells confirmed their roles as transcription factors as either activators (CPHX1, CPHX2, ARGFX) or repressors (DPRX, DUXA, TPRX2) with distinct targets that could be explained by the amino acid sequence in homeodomain. Some PRD-like homeodomain transcription factors had high concordance of target genes and showed enrichment for both developmentally important gene sets and a 36 bp DNA recognition motif implicated in Embryo Genome Activation (EGA). Our data implicate a role for these previously uncharacterized PRD-like homeodomain proteins in the regulation of human embryo genome activation and preimplantation embryo development.
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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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