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- Ferreira, Mjv, et al.
(författare)
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Poster Session 3 : Tuesday 5 May 2015, 08
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 4. |
- Lange, Jonathan, et al.
(författare)
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Novel lithographic printing techniques enabling sustainable and high quality multi material manufacturing process for future space outposts
- 2021
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Ingår i: IAC 2021 Congress Proceedings, 72nd International Astronautical Congress (IAC), Dubai, United Arab Emirates. - : International Astronautical Federation (IAF).
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Konferensbidrag (refereegranskat)abstract
- Several challenges remain before the full potential of on-orbit manufacturing can be realized. There may be some limitations to the types of items that can be manufactured in space. Such limitations could be caused by a variety of factors, including the materials required for a particular structure, the size of the object to be manufactured, the time required to execute the architecture, the configuration of the object being manufactured, and the raw material needed to support the manufacturing process. The complementary challenge to the relevant fabrication processes is the possibility to achieve the required precision demanded by geometrically complex structures and the ability to be versatile in processing a broad material spectrum. In this context, novel lithographic 3D printing techniques will be an asset to pave the way towards overcoming these challenges. Currently, the European Space Agency (ESA) is investigating the implementation of such technology in the context of a lunar base. In particular, two different applications are being studied: • Lithography-Based Ceramic Manufacturing (LCM), where the ceramic powder is distributed in a photocurable monomer formulation in presence of a photoinitiator. Ceramic materials are extensively used in a vast number of technological processes as well as in space applications. They are usually considered as the material of choice for applications where other materials such as plastic and metal fail to deliver the required performance. The LCM process will also allow processing lunar regolith simulant adding value to the current material portfolio of this technique, as well as to the range of processes potentially applicable on the lunar or Martian surface. • Lithography-based Metal Manufacturing (LMM) for processing metallic powders. In contrast to the currently predominantly used powder bed fusion (direct metal laser melting) techniques, this process uses a paste/suspension as feedstock and hence, does not rely on the use of highly spherical gas atomized powders. This will enable the utilization of recycled powders from scrap metals that are available at Moon bases or of metallic alloys reduced from lunar regolith, thus providing higher flexibility in accepting raw material with poor quality and purity. The paper addresses the results from both activities in terms of printed parts quality (roughness, density, resolution and accuracy) as well as the implementation requirements for the whole process chain, including suitable pre- and post-processing steps, with the aim to achieve a zero-waste flow in a lunar environment.
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| 8. |
- Lovric, A, et al.
(författare)
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Single-cell sequencing deconvolutes cellular responses to exercise in human skeletal muscle
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 1121-
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal muscle adaptations to exercise have been associated with a range of health-related benefits, but cell type-specific adaptations within the muscle are incompletely understood. Here we use single-cell sequencing to determine the effects of exercise on cellular composition and cell type-specific processes in human skeletal muscle before and after intense exercise. Fifteen clusters originating from six different cell populations were identified. Most cell populations remained quantitatively stable after exercise, but a large transcriptional response was observed in mesenchymal, endothelial, and myogenic cells, suggesting that these cells are specifically involved in skeletal muscle remodeling. We found three subpopulations of myogenic cells characterized by different maturation stages based on the expression of markers such asPAX7,MYOD1,TNNI1, andTNNI2. Exercise accelerated the trajectory of myogenic progenitor cells towards maturation by increasing the transcriptional features of fast- and slow-twitch muscle fibers. The transcriptional regulation of these contractile elements upon differentiation was validated in vitro on primary myoblast cells. The cell type-specific adaptive mechanisms induced by exercise presented here contribute to the understanding of the skeletal muscle adaptations triggered by physical activity and may ultimately have implications for physiological and pathological processes affecting skeletal muscle, such as sarcopenia, cachexia, and glucose homeostasis.
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| 11. |
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| 12. |
- Peters, L., et al.
(författare)
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Correlation effects and orbital magnetism of Co clusters
- 2016
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Ingår i: PHYSICAL REVIEW B. - 2469-9950. ; 93:22
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Tidskriftsartikel (refereegranskat)abstract
- Recent experiments on isolated Co clusters have shown huge orbital magnetic moments in comparison with their bulk and surface counterparts. These clusters hence provide the unique possibility to study the evolution of the orbital magnetic moment with respect to the cluster size and how competing interactions contribute to the quenching of orbital magnetism. We investigate here different theoretical methods to calculate the spin and orbital moments of Co clusters, and assess the performances of the methods in comparison with experiments. It is shown that density-functional theory in conventional local density or generalized gradient approximations, or even with a hybrid functional, severely underestimates the orbital moment. As natural extensions/corrections, we considered the orbital polarization correction, the LDA+U approximation as well as the LDA+DMFT method. Our theory shows that of the considered methods, only the LDA+DMFT method provides orbital moments in agreement with experiment, thus emphasizing the importance of dynamic correlations effects for determining fundamental magnetic properties of magnets in the nanosize regime.
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| 18. |
- 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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| 19. |
- Kanellis, Dimitris C., et al.
(författare)
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The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:32
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Tidskriftsartikel (refereegranskat)abstract
- Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3's tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint-mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3's unexpected role in RiBi, with implications for cancer pathogenesis and treatment.
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| 20. |
- Mahmood, Sultan, et al.
(författare)
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RECOMBINATION RATE COEFFICIENTS OF BORON-LIKE Ne
- 2013
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 771:2, s. 78-
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Tidskriftsartikel (refereegranskat)abstract
- Recombination of Ne5+ was measured in a merged-beam type experiment at the heavy-ion storage ring CRYRING. In the collision energy range 0-110 eV resonances due to 2s(2)2p -> 2s2p(2) (Delta n=0) and 2s(2)2p -> 2s(2)3l (Delta n=1), core excitations were observed. The experimentally derived rate coefficients agree well with the calculations obtained using AUTOSTRUCTURE. At low energies, recombination is dominated by resonances belonging to the spin-forbidden 2s2p(2)(P-4(J))nl series. The energy-dependent rate coefficients were convoluted with a Maxwell-Boltzmann electron energy distribution to obtain plasma recombination rate coefficients. The data from the literature deviate from the measured results at low temperature.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Visnes, Torkild, et al.
(författare)
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Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 362:6416, s. 834-
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Tidskriftsartikel (refereegranskat)abstract
- The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-alpha-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kappa B and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
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