| 1. |
- Mansouri, Larry, et al.
(författare)
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Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 128:23, s. 2666-2670
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Tidskriftsartikel (refereegranskat)abstract
- We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
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| 2. |
- Settele, Josef, et al.
(författare)
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Rice ecosystem services in South-east Asia
- 2018
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Ingår i: Paddy and Water Environment. - : Springer. - 1611-2490 .- 1611-2504. ; 16:2, s. 211-224
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 4. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 5. |
- Andréasson, Claes, et al.
(författare)
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Mitochondria orchestrate proteostatic and metabolic stress responses
- 2019
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20:10
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Tidskriftsartikel (refereegranskat)abstract
- The eukaryotic cell is morphologically and functionally organized as an interconnected network of organelles that responds to stress and aging. Organelles communicate via dedicated signal transduction pathways and the transfer of information in form of metabolites and energy levels. Recent data suggest that the communication between organellar proteostasis systems is a cornerstone of cellular stress responses in eukaryotic cells. Here, we discuss the integration of proteostasis and energy fluxes in the regulation of cellular stress and aging. We emphasize the molecular architecture of the regulatory transcriptional pathways that both sense and control metabolism and proteostasis. A special focus is placed on mechanistic insights gained from the model organism budding yeast in signaling from mitochondria to the nucleus and how this shapes cellular fitness.
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| 6. |
- Bareth, Bettina, et al.
(författare)
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Oms1 associates with cytochrome c oxidase assembly intermediates to stabilize newly synthesized Cox1
- 2016
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Ingår i: Molecular Biology of the Cell. - 1059-1524 .- 1939-4586. ; 27:10, s. 1570-1580
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial cytochrome c oxidase assembles in the inner membrane from subunits of dual genetic origin. The assembly process of the enzyme is initiated by membrane insertion of the mitochondria-encoded Cox1 subunit. During complex maturation, transient assembly intermediates, consisting of structural subunits and specialized chaperone-like assembly factors, are formed. In addition, cofactors such as heme and copper have to be inserted into the nascent complex. To regulate the assembly process, the availability of Cox1 is under control of a regulatory feedback cycle in which translation of COX1 mRNA is stalled when assembly intermediates of Cox1 accumulate through inactivation of the translational activator Mss51. Here we isolate a cytochrome c oxidase assembly intermediate in preparatory scale from coa1 Delta. mutant cells, using Mss51 as bait. We demonstrate that at this stage of assembly, the complex has not yet incorporated the heme a cofactors. Using quantitative mass spectrometry, we define the protein composition of the assembly intermediate and unexpectedly identify the putative methyltransferase Oms1 as a constituent. Our analyses show that Oms1 participates in cytochrome c oxidase assembly by stabilizing newly synthesized Cox1.
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| 7. |
- Besnard, E, et al.
(författare)
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The mTOR Complex Controls HIV Latency
- 2016
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Ingår i: Cell host & microbe. - : Elsevier BV. - 1934-6069 .- 1931-3128. ; 20:6, s. 785-797
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Tidskriftsartikel (refereegranskat)
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| 8. |
- Björck, Markus L., et al.
(författare)
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Reaction of S-cerevisiae mitochondria with ligands : Kinetics of CO and O-2 binding to flavohemoglobin and cytochrome c oxidase
- 2017
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1858:2, s. 182-188
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Tidskriftsartikel (refereegranskat)abstract
- Kinetic methods used to investigate electron and proton transfer within cytochrome c oxidase (CytcO) are often based on the use of light to dissociate small ligands, such as CO, thereby initiating the reaction. Studies of intact mitochondria using these methods require identification of proteins that may bind CO and determination of the ligand-binding kinetics. In the present study we have investigated the kinetics of CO-ligand binding to S. cerevisiae mitochondria and cellular extracts. The data indicate that CO binds to two proteins, CytcO and a (yeast) flavohemoglobin (yHb). The latter has been shown previously to reside in both the cell cytosol and the mitochondrial matrix. Here, we found that yHb resides also in the intermembrane space and binds CO in its reduced state. As observed previously, we found that the yHb population in the mitochondrial matrix binds CO, but only after removal of the inner membrane. The mitochondrial yHb (in both the intermembrane space and the matrix) recombines with CO with T congruent to 270 ms, which is significantly slower than observed with the cytosolic yHb (main component T congruent to 1.3 ms). The data indicate that the yHb populations in the different cell compartments differ in structure.
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| 9. |
- Dawitz, Hannah, 1991-
(författare)
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Mechanistic Insights in the Biogenesis and Function of the Respiratory Chain
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondria fulfill a plethora of functions, including harboring metabolic pathways and converting energy stored in metabolites into ATP, the common energy source of the cell. This last function is performed by the oxidative phosphorylation system, consisting of the respiratory chain and the ATP synthase. Electrons are channeled through the complexes of the respiratory chain, while protons are translocated across the inner mitochondrial membrane. This process establishes an electrochemical gradient, which is used by the ATP synthase to generate ATP. The subunits of two of the respiratory chain complexes, the bc1 complex and the cytochrome c oxidase, are encoded by two genetic origins, the nuclear and the mitochondrial genome. Therefore, the assembly of these complexes needs to be coordinated and highly regulated.Several proteins are involved in the biogenesis of the bc1 complex. Amongst these proteins, the Cbp3-Cbp6 complex was shown to regulate translation and assembly of the bc1 complex subunit cytochrome b. In this work, we established a homology model of yeast Cbp3. Using a site-specific crosslink approach, we identified binding sites of Cbp3 to its obligate binding partner Cbp6 and its client, cytochrome b, enabling a deeper insight in the molecular mechanisms of bc1 complex biogenesis. The bc1 complex and the cytochrome c oxidase form macromolecular structures, called supercomplexes. The detailed assembly mechanisms and functions of these structures remain to be solved. Two proteins, Rcf1 and Rcf2, were identified associating with supercomplexes in the yeast Saccharomyces cerevisiae. Our studies demonstrate that, while Rcf1 has a minor effect on supercomplex assembly, its main function is to modulate cytochrome c oxidase activity. We show that cytochrome c oxidase is present in three structurally different populations. Rcf1 is needed to maintain the dominant population in a functionally active state. In absence of Rcf1, the abundance of a population with an altered active site is increased. We propose that Rcf1 is needed, especially under a high work load of the respiratory chain, to maintain the function of cytochrome c oxidase.This thesis aims to unravel molecular mechanisms of proteins involved in biogenesis and functionality of respiratory chain complexes to enable a deeper understanding. Dysfunctional respiratory chain complexes lead to severe disease, emphasizing the importance of this work.
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| 10. |
- Espada, D., et al.
(författare)
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Disentangling the Circumnuclear Environs of Centaurus A. III. An Inner Molecular Ring, Nuclear Shocks, and the CO to Warm H-2 Interface
- 2017
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 843:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the distribution and kinematics of the molecular gas in the circumnuclear disk (CND; 400 pc ×200 pc) of Centaurus A with resolutions of ∼5 pc (0.″3) and shed light onto the mechanism feeding the active galactic nucleus (AGN) using CO(3-2), HCO + (4-3), HCN(4-3), and CO(6-5) observations obtained with ALMA. Multiple filaments or streamers of tens to a hundred parsec scale exist within the CND, which form a ring-like structure with an unprojected diameter of 9″ ×6″ (162 pc ×108 pc) and a position angle P.A. ≃ 155°. Inside the nuclear ring, there are two leading and straight filamentary structures with lengths of about 30-60 pc at P.A. ≃ 120° on opposite sides of the AGN, with a rotational symmetry of 180° and steeper position-velocity diagrams, which are interpreted as nuclear shocks due to non-circular motions. Along the filaments, and unlike other nearby AGNs, several dense molecular clumps present low HCN/HCO + (4-3) ratios (≲0.5). The filaments abruptly end in the probed transitions at r ≃ 20 pc from the AGN, but previous near-IR H 2 (J = 1-0)S(1) maps show that they continue in an even warmer gas phase (T ∼ 1000 K), winding up in the form of nuclear spirals, and forming an inner ring structure with another set of symmetric filaments along the N-S direction and within r ≃ 10 pc. The molecular gas is governed primarily by non-circular motions, being the successive shock fronts at different scales where loss of angular momentum occurs, a mechanism that may feed efficiently powerful radio galaxies down to parsec scales.
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