| 1. |
- Amati, L., et al.
(författare)
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The THESEUS space mission concept : science case, design and expected performances
- 2018
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Ingår i: Advances in Space Research. - : ELSEVIER SCI LTD. - 0273-1177 .- 1879-1948. ; 62:1, s. 191-244
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Tidskriftsartikel (refereegranskat)abstract
- THESEUS is a space mission concept aimed at exploiting Gamma-Ray Bursts for investigating the early Universe and at providing a substantial advancement of multi-messenger and time-domain astrophysics. These goals will be achieved through a unique combination of instruments allowing GRB and X-ray transient detection over a broad field of view (more than 1 sr) with 0.5-1 arcmin localization, an energy band extending from several MeV down to 0.3 keV and high sensitivity to transient sources in the soft X-ray domain, as well as on-board prompt (few minutes) follow-up with a 0.7 m class IR telescope with both imaging and spectroscopic capabilities. THESEUS will be perfectly suited for addressing the main open issues in cosmology such as, e.g., star formation rate and metallicity evolution of the inter-stellar and intra-galactic medium up to redshift similar to 10, signatures of Pop III stars, sources and physics of re-ionization, and the faint end of the galaxy luminosity function. In addition, it will provide unprecedented capability to monitor the X-ray variable sky, thus detecting, localizing, and identifying the electromagnetic counterparts to sources of gravitational radiation, which may be routinely detected in the late '20s/early '30s by next generation facilities like aLIGO/ aVirgo, eLISA, KAGRA, and Einstein Telescope. THESEUS will also provide powerful synergies with the next generation of multi-wavelength observatories (e.g., LSST, ELT, SKA, CTA, ATHENA).
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| 2. |
- Nijkamp, P., et al.
(författare)
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Towards a regional science academy : A manifesto
- 2016
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Ingår i: Region. - : European Regional Science Association. - 2409-5370. ; 3:1, s. R1-R16
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Tidskriftsartikel (refereegranskat)abstract
- This Manifesto provides a joint proposal to create a Regional Science Academy as a think-tank support platform for a strategic development of the spatial sciences. The Regional Science Academy is a strategic spatial knowledge catalyst: it acts as a global intellectual powerhouse for new knowledge network initiatives and scholarly views on regions and cities as vital centrepieces of interconnected spatial systems. This contribution highlights its role and presents various activity plans.
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| 3. |
- Dey, Lankeswar, et al.
(författare)
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Authenticating the Presence of a Relativistic Massive Black Hole Binary in OJ 287 Using Its General Relativity Centenary Flare : Improved Orbital Parameters
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 866:1
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Tidskriftsartikel (refereegranskat)abstract
- Results from regular monitoring of relativistic compact binaries like PSR 1913+16 are consistent with the dominant (quadrupole) order emission of gravitational waves (GWs). We show that observations associated with the binary black hole (BBH) central engine of blazar OJ 287 demand the inclusion of gravitational radiation reaction effects beyond the quadrupolar order. It turns out that even the effects of certain hereditary contributions to GW emission are required to predict impact flare timings of OJ 287. We develop an approach that incorporates this effect into the BBH model for OJ 287. This allows us to demonstrate an excellent agreement between the observed impact flare timings and those predicted from ten orbital cycles of the BBH central engine model. The deduced rate of orbital period decay is nine orders of magnitude higher than the observed rate in PSR 1913+16, demonstrating again the relativistic nature of OJ 287's central engine. Finally, we argue that precise timing of the predicted 2019 impact flare should allow a test of the celebrated black hole no-hair theorem at the 10% level.
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| 4. |
- Caballero-Garcia, M. D., et al.
(författare)
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Activity from the Be/X-ray binary system V0332+53 during its intermediate-luminosity outburst in 2008
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 589
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We present a study of the Be/X-ray binary system V 0332+53 with the main goal of characterizing its behaviour mainly during the intermediate-luminosity X-ray event in 2008. In addition, we aim to contribute to the understanding of the behaviour of the donor companion by including optical data from our dedicated campaign starting in 2006. Methods. V 0332+53 was observed by RXTE and Swift during the decay of the intermediate-luminosity X-ray outburst of 2008, and with Suzaku before the rising of the third normal outburst of the 2010 series. In addition, we present recent data from the Spanish ground-based astronomical observatories of El Teide (Tenerife), Roque de los Muchachos (La Palma), and Sierra Nevada (Granada), and since 2006 from the Turkish TUBITAK National Observatory (Antalya). We have performed temporal analyses to investigate the transient behaviour of this system during several outbursts. Results. Our optical study revealed that continuous mass ejection episodes from the Be star have been taking place since 2006 and another is currently ongoing. The broad-band 1-60 keV X-ray spectrum of the neutron star during the decay of the 2008 outburst was well fitted with standard phenomenological models that were enhanced by an absorption feature of unknown origin at about 10 keV and a narrow iron K-alpha fluorescence line at 6.4 keV. For the first time in V 0332+ 53 we tentatively see an increase in the cyclotron line energy with increasing flux (although further and more sensitive observations are needed to confirm this). The fast aperiodic variability shows a quasi-periodic oscillation (QPO) at 227 +/- 9 mHz only during the lowest luminosities, which might indicate that the inner regions surrounding the magnetosphere are more visible during the lowest flux states.
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| 5. |
- Paulus, A, et al.
(författare)
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Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells
- 2016
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Ingår i: Blood cancer journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 6:11, s. e492-
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Tidskriftsartikel (refereegranskat)abstract
- The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.
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| 6. |
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| 7. |
- Puschmann, Andreas, et al.
(författare)
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Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
- 2017
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 140:1, s. 98-117
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Tidskriftsartikel (refereegranskat)abstract
- SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.
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| 8. |
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| 9. |
- Springer, W, et al.
(författare)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Konferensbidrag (refereegranskat)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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