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| 4. |
- Feroci, M., et al.
(author)
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The large observatory for x-ray timing
- 2014
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In: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 9780819496126
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Conference paper (peer-reviewed)abstract
- The Large Observatory For x-ray Timing (LOFT) was studied within ESA M3 Cosmic Vision framework and participated in the final downselection for a launch slot in 2022-2024. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument, LOFT will study the behaviour of matter under extreme conditions, such as the strong gravitational field in the innermost regions of accretion flows close to black holes and neutron stars, and the supranuclear densities in the interior of neutron stars. The science payload is based on a Large Area Detector (LAD, 10 m2 effective area, 2-30 keV, 240 eV spectral resolution, 1° collimated field of view) and a Wide Field Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g. GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the status of the mission at the end of its Phase A study.
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| 5. |
- Feroci, M., et al.
(author)
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LOFT - The large observatory for x-ray timing
- 2012
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In: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE - International Society for Optical Engineering. - 9780819491442 ; , s. 84432D-
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Conference paper (peer-reviewed)abstract
- The LOFT mission concept is one of four candidates selected by ESA for the M3 launch opportunity as Medium Size missions of the Cosmic Vision programme. The launch window is currently planned for between 2022 and 2024. LOFT is designed to exploit the diagnostics of rapid X-ray flux and spectral variability that directly probe the motion of matter down to distances very close to black holes and neutron stars, as well as the physical state of ultradense matter. These primary science goals will be addressed by a payload composed of a Large Area Detector (LAD) and a Wide Field Monitor (WFM). The LAD is a collimated (<1 degree field of view) experiment operating in the energy range 2-50 keV, with a 10 m2 peak effective area and an energy resolution of 260 eV at 6 keV. The WFM will operate in the same energy range as the LAD, enabling simultaneous monitoring of a few-steradian wide field of view, with an angular resolution of <5 arcmin. The LAD and WFM experiments will allow us to investigate variability from submillisecond QPO's to yearlong transient outbursts. In this paper we report the current status of the project.
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| 6. |
- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 7. |
- Feroci, M., et al.
(author)
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The Large Observatory for X-ray Timing (LOFT)
- 2012
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In: Experimental Astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 34:2, s. 415-444
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Journal article (peer-reviewed)abstract
- High-time-resolution X-ray observations of compact objects provide direct access to strong-field gravity, to the equation of state of ultradense matter and to black hole masses and spins. A 10 m(2)-class instrument in combination with good spectral resolution is required to exploit the relevant diagnostics and answer two of the fundamental questions of the European Space Agency (ESA) Cosmic Vision Theme "Matter under extreme conditions", namely: does matter orbiting close to the event horizon follow the predictions of general relativity? What is the equation of state of matter in neutron stars? The Large Observatory For X-ray Timing (LOFT), selected by ESA as one of the four Cosmic Vision M3 candidate missions to undergo an assessment phase, will revolutionise the study of collapsed objects in our galaxy and of the brightest supermassive black holes in active galactic nuclei. Thanks to an innovative design and the development of large-area monolithic silicon drift detectors, the Large Area Detector (LAD) on board LOFT will achieve an effective area of similar to 12 m(2) (more than an order of magnitude larger than any spaceborne predecessor) in the 2-30 keV range (up to 50 keV in expanded mode), yet still fits a conventional platform and small/medium-class launcher. With this large area and a spectral resolution of < 260 eV, LOFT will yield unprecedented information on strongly curved spacetimes and matter under extreme conditions of pressure and magnetic field strength.
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| 8. |
- Hermsen, W., et al.
(author)
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Synchronous X-ray and Radio Mode Switches: A Rapid Global Transformation of the Pulsar Magnetosphere
- 2013
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 339:6118, s. 436-439
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Journal article (peer-reviewed)abstract
- Pulsars emit from low-frequency radio waves up to high-energy gamma-rays, generated anywhere from the stellar surface out to the edge of the magnetosphere. Detecting correlated mode changes across the electromagnetic spectrum is therefore key to understanding the physical relationship among the emission sites. Through simultaneous observations, we detected synchronous switching in the radio and x-ray emission properties of PSR B0943+10. When the pulsar is in a sustained radio-"bright" mode, the x-rays show only an unpulsed, nonthermal component. Conversely, when the pulsar is in a radio-"quiet" mode, the x-ray luminosity more than doubles and a 100% pulsed thermal component is observed along with the nonthermal component. This indicates rapid, global changes to the conditions in the magnetosphere, which challenge all proposed pulsar emission theories.
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| 10. |
- Hilson, P., et al.
(author)
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Versatile gene-specific sequence tags for Arabidopsis functional genomics : Trancript profiling and reverse genetics applications
- 2004
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In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 14:10B, s. 2176-2189
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Journal article (peer-reviewed)abstract
- Microarray transcript profiling and RNA interference are two new technologies crucial for large-scale gene function studies in multicellular eukaryotes. Both rely on sequence-specific hybridization between complementary nucleic acid strands, inciting us to create a collection of gene-specific sequence tags (GSTs) representing at least 21,500 Arabidopsis genes and which are compatible with both approaches. The GSTs were carefully selected to ensure that each of them shared no significant similarity with any other region in the Arabidopsis genome. They were synthesized by PCR amplification from genomic DNA. Spotted microarrays fabricated from the GSTs show good dynamic range, specificity, and sensitivity in transcript profiling experiments. The GSTs have also been transferred to bacterial plasmid vectors via recombinational cloning protocols. These cloned GSTs constitute the ideal starting point for a variety of functional approaches, including reverse genetics. We have subcloned GSTs on a large scale into vectors designed for gene silencing in plant cells. We show that in planta expression of GST hairpin RNA results in the expected phenotypes in silenced Arabidopsis lines. These versatile GST resources provide novel and powerful tools for functional genomics.
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| 11. |
- Went, M, et al.
(author)
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Author Correction: Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 213-
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Journal article (peer-reviewed)abstract
- The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
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| 12. |
- Dankiewicz, Josef, et al.
(author)
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Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial - Rationale and design
- 2019
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 217, s. 23-31
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Journal article (peer-reviewed)abstract
- Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. Discussion: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest. © 2019
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| 13. |
- Greiner, J., et al.
(author)
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GRIPS - Gamma-Ray Imaging, Polarimetry and Spectroscopy
- 2012
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In: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 34:2, s. 551-582
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Journal article (peer-reviewed)abstract
- We propose to perform a continuously scanning all-sky survey from 200 keV to 80 MeV achieving a sensitivity which is better by a factor of 40 or more compared to the previous missions in this energy range (COMPTEL, INTEGRAL; see Fig. 1). These gamma-ray observations will be complemented by observations in the soft X-ray and (near-)infrared region with the corresponding telescopes placed on a separate satellite. The Gamma-Ray Imaging, Polarimetry and Spectroscopy ("GRIPS") mission with its three instruments Gamma-Ray Monitor (GRM), X-Ray Monitor (XRM) and InfraRed Telescope (IRT) addresses fundamental questions in ESA's Cosmic Vision plan. Among the major themes of the strategic plan, GRIPS has its focus on the evolving, violent Universe, exploring a unique energy window. We propose to investigate γ-ray bursts and blazars, the mechanisms behind supernova explosions, nucleosynthesis and spallation, the enigmatic origin of positrons in our Galaxy, and the nature of radiation processes and particle acceleration in extreme cosmic sources including pulsars and magnetars. The natural energy scale for these non-thermal processes is of the order of MeV. Although they can be partially and indirectly studied using other methods, only the proposed GRIPS measurements will provide direct access to their primary photons. GRIPS will be a driver for the study of transient sources in the era of neutrino and gravitational wave observatories such as IceCUBE and LISA, establishing a new type of diagnostics in relativistic and nuclear astrophysics. This will support extrapolations to investigate star formation, galaxy evolution, and black hole formation at high redshifts.
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| 15. |
- Benavente, ED, et al.
(author)
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Female gene networks are expressed in myofibroblast-like smooth muscle cells in vulnerable atherosclerotic plaques
- 2023
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In: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- Women presenting with coronary artery disease (CAD) more often present with fibrous atherosclerotic plaques, which are currently understudied. Phenotypically modulated smooth muscle cells (SMCs) contribute to atherosclerosis in women. How these phenotypically modulated SMCs shape female versus male plaques is unknown. Here, we show sex-stratified gene regulatory networks (GRNs) from human carotid atherosclerotic tissue. Prioritization of these networks identified two main SMC GRNs in late-stage atherosclerosis. Single-cell RNA-sequencing mapped these GRNs to two SMC phenotypes: a phenotypically modulated myofibroblast-like SMC network and a contractile SMC network. The myofibroblast-like GRN was mostly expressed in plaques that were vulnerable in females. Finally, mice orthologs of the female myofibroblast-like genes showed retained expression in advanced plaques from female mice but were downregulated in male mice during atherosclerosis progression. Female atherosclerosis is driven by GRNs that promote a fibrous vulnerable plaque rich in myofibroblast-like SMCs.
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| 16. |
- Lilja, Gisela, et al.
(author)
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Anxiety and depression among out-of-hospital cardiac arrest survivors.
- 2015
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In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 97, s. 68-75
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Journal article (peer-reviewed)abstract
- Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA-survivors.
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| 17. |
- Mooij, Wolf M., et al.
(author)
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Modeling water quality in the Anthropocene : directions for the next-generation aquatic ecosystem models
- 2019
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In: Current Opinion in Environmental Sustainability. - : Elsevier BV. - 1877-3435 .- 1877-3443. ; 36, s. 85-95
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Research review (peer-reviewed)abstract
- Everything changes and nothing stands still (Heraclitus). Here we review three major improvements to freshwater aquatic ecosystem models - and ecological models in general - as water quality scenario analysis tools towards a sustainable future. To tackle the rapid and deeply connected dynamics characteristic of the Anthropocene, we argue for the inclusion of eco-evolutionary, novel ecosystem and social-ecological dynamics. These dynamics arise from adaptive responses in organisms and ecosystems to global environmental change and act at different integration levels and different time scales. We provide reasons and means to incorporate each improvement into aquatic ecosystem models. Throughout this study we refer to Lake Victoria as a microcosm of the evolving novel social-ecological systems of the Anthropocene. The Lake Victoria case clearly shows how interlinked eco-evolutionary, novel ecosystem and social-ecological dynamics are, and demonstrates the need for transdisciplinary research approaches towards global sustainability.
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| 19. |
- Düring, J., et al.
(author)
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Lactate, lactate clearance and outcome after cardiac arrest : A post-hoc analysis of the TTM-Trial
- 2018
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 62:10, s. 1436-1442
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Journal article (peer-reviewed)abstract
- Background: Admission lactate and lactate clearance are implemented for risk stratification in sepsis and trauma. In out-of-hospital cardiac arrest, results regarding outcome and lactate are conflicting. Methods: This is a post-hoc analysis of the Target Temperature Management trial in which 950 unconscious patents after out-of-hospital cardiac arrest were randomized to a temperature intervention of 33°C or 36°C. Serial lactate samples during the first 36 hours were collected. Admission lactate, 12-hour lactate, and the clearance of lactate within 12 hours after admission were analyzed and the association with 30-day mortality assessed. Results: Samples from 877 patients were analyzed. In univariate logistic regression analysis, the odds ratio for death by day 30 for each mmol/L was 1.12 (1.08-1.16) for admission lactate, P <.01, 1.21 (1.12-1.31) for 12-hour lactate, P <.01, and 1.003 (1.00-1.01) for each percentage point increase in 12-hour lactate clearance, P =.03. Only admission lactate and 12-hour lactate levels remained significant after adjusting for known predictors of outcome. The area under the receiver operating characteristic curve was 0.65 (0.61-0.69), P <.001, 0.61 (0.57-0.65), P <.001, and 0.53 (0.49-0.57), P =.15 for admission lactate, 12-hour lactate, and 12-hour lactate clearance, respectively. Conclusions: Admission lactate and 12-hour lactate values were independently associated with 30-day mortality after out-of-hospital cardiac arrest while 12-hour lactate clearance was not. The clinical value of lactate as the sole predictor of outcome after out-of-hospital cardiac arrest is, however, limited.
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| 20. |
- Kranenburg, LJC, et al.
(author)
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Global Application of the Assessment of Communication Skills of Paediatric Endocrinology Fellows in the Management of Differences in Sex Development Using the ESPE E-Learning.Org Portal
- 2017
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In: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 88:2, s. 127-139
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Information sharing in chronic conditions such as disorders of/differences in sex development (DSD) is essential for a comprehensive understanding by parents and patients. We report on a qualitative analysis of communication skills of fellows undergoing training in paediatric endocrinology. Guidelines are created for the assessment of communication between health professionals and individuals with DSD and their parents. <b><i>Methods:</i></b> Paediatric endocrinology fellows worldwide were invited to study two interactive online cases (www.espe-elearning.org) and to describe a best practice communication with (i) the parents of a newborn with congenital adrenal hyperplasia and (ii) a young woman with 46,XY gonadal dysgenesis. The replies were analysed regarding completeness, quality, and evidence of empathy. Guidelines for structured assessment of responses were developed by 22 senior paediatric endocrinologists worldwide who assessed 10 selected replies. Consensus of assessors was established and the evaluation guidelines were created. <b><i>Results:</i></b> The replies of the fellows showed considerable variation in completeness, quality of wording, and evidence of empathy. Many relevant aspects of competent clinical communication were not mentioned; 15% (case 1) and 17% (case 2) of the replies were considered poor/insufficient. There was also marked variation between 17 senior experts in the application of the guidelines to assess communication skills. The guidelines were then adjusted to a 3-level assessment with empathy as a separate key item to better reflect the qualitative differences in the replies and for simplicity of use by evaluators. <b><i>Conclusions:</i></b> E-learning can play an important role in assessing communication skills. A practical tool is provided to assess how information is shared with patients with DSD and their families and should be refined by all stakeholders, notably interdisciplinary health professionals and patient representatives.
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| 21. |
- Kuiper, Jan J., et al.
(author)
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Exploring desirable nature futures for Nationaal Park Hollandse Duinen
- 2022
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In: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 18:1, s. 329-347
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Journal article (peer-reviewed)abstract
- Achieving global sustainability goals requires most people and societies to fundamentally revisit their relationship with nature. New approaches are called for to guide change processes towards sustainable futures that embrace the plurality of people’s desired relationships with nature. This paper presents a novel approach to exploring desirable futures for nature and people that was developed through an application in Nationaal Park Hollandse Duinen in the Netherlands. This new national park is developed bottom-up by a diverse group of actors reshaping their interactions with each other and with nature. Our approach, co-designed with key stakeholders of the national park, engages with a new pluralistic framework for human-nature relationships presented by the IPBES task force on scenarios and models to catalyze the development of nature-centered scenarios. We integrated this Nature Futures Framework with the Three Horizons Framework in a participatory workshop process designed to bring people’s diverse relationships with nature to the fore, and jointly envision desirable futures and the pathways to get there. We present a methodology to analyze and compare the visions and assess their potential contribution to the SDGs. We summarize the results of the application in Nationaal Park Hollandse Duinen and reflect on lessons learned. The approach successfully engaged participants in joint exploration of desirable futures for the national park based on their plural perspectives on human-nature relationships. We see much potential for its applications to support change processes in various social-ecological contexts toward more sustainable futures for nature and people.
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| 22. |
- Padovani, M., et al.
(author)
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Adaptable radiative transfer innovations for submillimetre telescopes (ARTIST) Dust polarisation module (DustPol)
- 2012
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 543, s. Article Number: A16 -
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Journal article (peer-reviewed)abstract
- We present a new publicly available tool (DustPol) aimed to model the polarised thermal dust emission. The module DustPol, which is publicly available, is part of the ARTIST (Adaptable Radiative Transfer Innovations for Submillimetre Telescopes) package, which also offers tools for modelling the polarisation of line emission together with a model library and a Python-based user interface. DustPol can easily manage analytical as well as pre-gridded models to generate synthetic maps of the Stokes I, Q, and U parameters. These maps are stored in FITS format which is straightforwardly read by the data reduction software used, e. g., by the Atacama Large Millimeter Array (ALMA). This turns DustPol into a powerful engine for the prediction of the expected polarisation features of a source observed with ALMA or the Planck satellite as well as for the interpretation of existing submillimetre observations obtained with other telescopes. DustPol allows the parameterisation of the maximum degree of polarisation and we find that, in a prestellar core, if there is depolarisation, this effect should happen at densities of 10(6) cm(-3) or larger. We compare a model generated by DustPol with the observational polarisation data of the low-mass Class 0 object NGC 1333 IRAS 4A, finding that the total and the polarised emission are consistent.
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| 23. |
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| 25. |
- Went, Molly, et al.
(author)
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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
- 2018
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In: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:1
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Journal article (peer-reviewed)abstract
- The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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