| 1. |
- Aad, G., et al.
(author)
-
- 2010
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swepub:Mat__t
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| 2. |
- Aad, G., et al.
(author)
-
- 2010
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swepub:Mat__t
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| 3. |
- Aad, G., et al.
(author)
-
- 2010
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swepub:Mat__t
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| 4. |
- Aad, G., et al.
(author)
-
- 2012
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swepub:Mat__t (peer-reviewed)
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| 5. |
- Aad, G., et al.
(author)
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- 2013
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swepub:Mat__t (peer-reviewed)
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| 6. |
- Aad, G., et al.
(author)
-
- 2011
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swepub:Mat__t
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| 7. |
- Aad, G., et al.
(author)
-
- 2010
-
swepub:Mat__t
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| 8. |
- Aad, G., et al.
(author)
-
- 2012
-
swepub:Mat__t (peer-reviewed)
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Aad, G., et al.
(author)
-
- 2012
-
Journal article (peer-reviewed)
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| 13. |
- Aad, G., et al.
(author)
-
Studies of the performance of the ATLAS detector using cosmic-ray muons
- 2011
-
In: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 71:3
-
Journal article (peer-reviewed)abstract
- Muons from cosmic-ray interactions in the atmosphere provide a high-statistics source of particles that can be used to study the performance and calibration of the ATLAS detector. Cosmic-ray muons can penetrate to the cavern and deposit energy in all detector subsystems. Such events have played an important role in the commissioning of the detector since the start of the installation phase in 2005 and were particularly important for understanding the detector performance in the time prior to the arrival of the first LHC beams. Global cosmic-ray runs were undertaken in both 2008 and 2009 and these data have been used through to the early phases of collision data-taking as a tool for calibration, alignment and detector monitoring. These large datasets have also been used for detector performance studies, including investigations that rely on the combined performance of different subsystems. This paper presents the results of performance studies related to combined tracking, lepton identification and the reconstruction of jets and missing transverse energy. Results are compared to expectations based on a cosmic-ray event generator and a full simulation of the detector response.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Obers, Niels A., et al.
(author)
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Quantum gravity phenomenology at the dawn of the multi-messenger era—A review
- 2022
-
In: Progress in Particle and Nuclear Physics. - : Elsevier BV. - 0146-6410 .- 1873-2224. ; 125
-
Research review (peer-reviewed)abstract
- The exploration of the universe has recently entered a new era thanks to the multi-messenger paradigm, characterized by a continuous increase in the quantity and quality of experimental data that is obtained by the detection of the various cosmic messengers (photons, neutrinos, cosmic rays and gravitational waves) from numerous origins. They give us information about their sources in the universe and the properties of the intergalactic medium. Moreover, multi-messenger astronomy opens up the possibility to search for phenomenological signatures of quantum gravity. On the one hand, the most energetic events allow us to test our physical theories at energy regimes which are not directly accessible in accelerators; on the other hand, tiny effects in the propagation of very high energy particles could be amplified by cosmological distances. After decades of merely theoretical investigations, the possibility of obtaining phenomenological indications of Planck-scale effects is a revolutionary step in the quest for a quantum theory of gravity, but it requires cooperation between different communities of physicists (both theoretical and experimental). This review, prepared within the COST Action CA18108 “Quantum gravity phenomenology in the multi-messenger approach”, is aimed at promoting this cooperation by giving a state-of-the art account of the interdisciplinary expertise that is needed in the effective search of quantum gravity footprints in the production, propagation and detection of cosmic messengers.
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| 19. |
- White, H, et al.
(author)
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A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real time quantitative PCR.
- 2015
-
In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 29:2, s. 369-376
-
Journal article (peer-reviewed)abstract
- Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukemia, but there is substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/μL. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise the numbers of measured transcripts of e14a2 BCR-ABL1 and three control genes; ABL1, BCR and GUSB. The set of 6 plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (http://irmm.jrc.ec.europa.eu; CRM code ERM-AD623a-f).Leukemia accepted article preview online, 18 July 2014; doi:10.1038/leu.2014.217.
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| 20. |
- Jahnke, T., et al.
(author)
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Inner-Shell-Ionization-Induced Femtosecond Structural Dynamics of Water Molecules Imaged at an X-Ray Free-Electron Laser
- 2021
-
In: Physical Review X. - : American Physical Society. - 2160-3308. ; 11:4
-
Journal article (peer-reviewed)abstract
- The ultrafast structural dynamics of water following inner-shell ionization is a crucial issue in high-energy radiation chemistry. We have exposed isolated water molecules to a short x-ray pulse from a free-electron laser and detected momenta of all produced ions in coincidence. By combining experimental results and theoretical modeling, we can image dissociation dynamics of individual molecules in unprecedented detail. We reveal significant molecular structural dynamics in H2O2+, such as asymmetric deformation and bond-angle opening, leading to two-body or three-body fragmentation on a timescale of a few femtoseconds. We thus reconstruct several snapshots of structural dynamics at different time intervals, which highlight dynamical patterns that are relevant as initiating steps of subsequent radiation-damage processes.
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| 21. |
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| 22. |
- Pfeifer, H., et al.
(author)
-
Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph plus ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1
- 2019
-
In: Leukemia. - : NATURE PUBLISHING GROUP. - 0887-6924 .- 1476-5551. ; 33:8, s. 1910-1922
-
Journal article (peer-reviewed)abstract
- Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10(-3) and 36/67 (53%) and 53/67 (79%) at 10(-4)BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.
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| 23. |
- Berrah, N., et al.
(author)
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Femtosecond-resolved observation of the fragmentation of buckminsterfullerene following X-ray multiphoton ionization
- 2019
-
In: Nature Physics. - : Springer Science and Business Media LLC. - 1745-2473 .- 1745-2481. ; 15, s. 1279-1283
-
Journal article (peer-reviewed)abstract
- X-ray free-electron lasers have, over the past decade, opened up the possibility of understanding the ultrafast response of matter to intense X-ray pulses. In earlier research on atoms and small molecules, new aspects of this response were uncovered, such as rapid sequences of inner-shell photoionization and Auger ionization. Here, we studied a larger molecule, buckminsterfullerene (C60), exposed to 640eV X-rays, and examined the role of chemical effects, such as chemical bonds and charge transfer, on the fragmentation following multiple ionization of the molecule. To provide time resolution, we performed femtosecond-resolved X-ray pump/X-ray probe measurements, which were accompanied by advanced simulations. The simulations and experiment reveal that despite substantial ionization induced by the ultrashort (20fs) X-ray pump pulse, the fragmentation of C60 is considerably delayed. This work uncovers the persistence of the molecular structure of C60, which hinders fragmentation over a timescale of hundreds of femtoseconds. Furthermore, we demonstrate that a substantial fraction of the ejected fragments are neutral carbon atoms. These findings provide insights into X-ray free-electron laser-induced radiation damage in large molecules, including biomolecules.
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| 24. |
- Guillemin, R., et al.
(author)
-
Isotope effects in dynamics of water isotopologues induced by core ionization at an x-ray free-electron laser
- 2023
-
In: STRUCTURAL DYNAMICS-US. - 2329-7778. ; 10:5
-
Journal article (peer-reviewed)abstract
- Dynamical response of water exposed to x-rays is of utmost importance in a wealth of science areas. We exposed isolated water isotopologues to short x-ray pulses from a free-electron laser and detected momenta of all produced ions in coincidence. By combining experimental results and theoretical modeling, we identify significant structural dynamics with characteristic isotope effects in H2O2+, D2O2+, and HDO2+, such as asymmetric bond elongation and bond-angle opening, leading to two-body or three-body fragmentation on a timescale of a few femtoseconds. A method to disentangle the sequences of events taking place upon the consecutive absorption of two x-ray photons is described. The obtained deep look into structural properties and dynamics of dissociating water isotopologues provides essential insights into the underlying mechanisms.
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| 25. |
- Adamczewski-Musch, J., et al.
(author)
-
Production and electromagnetic decay of hyperons : a feasibility study with HADES as a phase-0 experiment at FAIR
- 2021
-
In: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
-
Journal article (peer-reviewed)abstract
- A feasibility study has been performed in order to investigate the performance of the HADES detector to measure the electromagnetic decays of the hyperon resonances Sigma(1385)(0), Lambda(1405) and Lambda(1520) as well as the production of double strange baryon systems Xi(-) and Lambda Lambda in p + p reactions at a beam kinetic energy of 4.5GeV. The existing HADES detector will be upgraded by a new Forward Detector, which extends the detector acceptance into a range of polar angles that plays a crucial role for these investigations. The analysis of each channel is preceded by a consideration of the production cross-sections. Afterwards the expected signal count rates using a target consisting of either liquid hydrogen or polyethylene are summarized.
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| 26. |
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| 27. |
- Mazza, T., et al.
(author)
-
Mapping Resonance Structures in Transient Core-Ionized Atoms
- 2020
-
In: Physical Review X. - 2160-3308. ; 10:4
-
Journal article (peer-reviewed)abstract
- The nature of transient electronic states created by photoabsorption critically determines the dynamics of the subsequently evolving system. Here, we investigate K-shell photoionized atomic neon by absorbing a second photon within the Auger-decay lifetime of 2.4 fs using the European XFEL, a unique high-repetition-rate, wavelength-tunable x-ray free-electron laser. By high-resolution electron spectroscopy, we map out the transient Rydberg resonances unraveling the details of the subsequent decay of the hollow atom. So far, ultra-short-lived electronic transients, which are often inaccessible by experiments, were mainly inferred from theory but are now addressed by nonlinear x-ray absorption. The successful characterization of these resonances with femtosecond lifetimes provides the basis for a novel class of site-specific, nonlinear, and time-resolved studies with strong impact for a wide range of topics in physics and chemistry.
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| 28. |
- Micke, Patrick, et al.
(author)
-
The Heidelberg compact electron beam ion traps
- 2018
-
In: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 89:6
-
Journal article (peer-reviewed)abstract
- Electron beam ion traps (EBITs) are ideal tools for both production and study of highly charged ions (HCIs). In order to reduce their construction, maintenance, and operation costs, we have developed a novel, compact, room-temperature design, the Heidelberg Compact EBIT (HC-EBIT). Four already commissioned devices operate at the strongest fields (up to 0.86 T) reported for such EBITs using permanent magnets, run electron beam currents up to 80 mA, and energies up to 10 keV. They demonstrate HCI production, trapping, and extraction of pulsed Ar16+ bunches and continuous 100 pA ion beams of highly charged Xe up to charge state 29+, already with a 4 mA, 2 keV electron beam. Moreover, HC-EBITs offer large solid-angle ports and thus high photon count rates, e.g., in x-ray spectroscopy of dielectronic recombination in HCIs up to Fe24+, achieving an electron-energy resolving power of E/ΔE > 1500 at 5 keV. Besides traditional on-axis electron guns, we have also implemented a novel off-axis gun for laser, synchrotron, and free-electron laser applications, offering clear optical access along the trap axis. We report on its first operation at a synchrotron radiation facility demonstrating the resonant photoexcitation of highly charged oxygen.
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| 29. |
- Okhuijsen-Pfeifer, C, et al.
(author)
-
Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
- 2022
-
In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1, s. 145-
-
Journal article (peer-reviewed)abstract
- Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.
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| 30. |
- Tobias, Deirdre K, et al.
(author)
-
Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
-
In: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
-
Research review (peer-reviewed)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 31. |
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| 32. |
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| 33. |
- Ilchen, M., et al.
(author)
-
X-ray spectroscopy on ultrafast-decaying core-excited atomic ions
- 2020
-
In: Charge-exchange. - : IOP Publishing. - 1742-6588. ; 1412
-
Conference paper (peer-reviewed)abstract
- Results from the first soft X-ray user experiment at the European XFEL on nonlinear photon-matter interaction will be presented. Angle-resolved electron time-of-flight spectroscopy employed at the AQS (Atomic- like Quantum Systems) endstation of the SQS (Small Quantum Systems) instrument reveals insight into the character of resonances in highly transient, core ionized neon ions, i.e. Ne:+ 1s12s22p6 → Ne+&∗ 1s02s22p6np, together with their respective relaxation dynamics. Enabled by the unique properties of the European XFEL, novel perspectives on efficient nonlinear spectroscopy will be discussed.
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| 34. |
- Augustin, S., et al.
(author)
-
Signatures of autoionization in the angular electron distribution in two-photon double ionization of Ar
- 2018
-
In: Physical Review A. - 2469-9926. ; 98:3
-
Journal article (peer-reviewed)abstract
- A kinematically complete experiment on two-photon double ionization of Ar by free-electron laser radiation with a photon energy of 27.93 eV was performed. The electron energy spectra show that double ionization is dominated by the sequential process. Comparison of the electron angular distributions to our data for single ionization and to theory confirms that even in the sequential process the electrons from both ionization steps are correlated with each other through polarization of the intermediate Ar+ state. Furthermore, a very important role of autoionization in both ionization steps is found.
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| 35. |
- Ertel, D., et al.
(author)
-
Ultrastable, high-repetition-rate attosecond beamline for time-resolved XUV-IR coincidence spectroscopy
- 2023
-
In: Review of Scientific Instruments. - 0034-6748. ; 94:7
-
Journal article (peer-reviewed)abstract
- The implementation of attosecond photoelectron-photoion coincidence spectroscopy for the investigation of atomic and molecular dynamics calls for a high-repetition-rate driving source combined with experimental setups characterized by excellent stability for data acquisition over time intervals ranging from a few hours up to a few days. This requirement is crucial for the investigation of processes characterized by low cross sections and for the characterization of fully differential photoelectron(s) and photoion(s) angular and energy distributions. We demonstrate that the implementation of industrial-grade lasers, combined with a careful design of the delay line implemented in the pump-probe setup, allows one to reach ultrastable experimental conditions leading to an error in the estimation of the time delays of only 12 as over an acquisition time of 6.5 h. This result opens up new possibilities for the investigation of attosecond dynamics in simple quantum systems.
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| 36. |
- Gnad, T., et al.
(author)
-
Adenosine activates brown adipose tissue and recruits beige adipocytes via A(2A) receptors
- 2014
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 516:7531
-
Journal article (peer-reviewed)abstract
- Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies(1-5). Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of beta-adrenergic receptors(1-5). Because BAT therapies based on cold exposureor beta-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat(6-8). However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A(2A) receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A(2A) receptors in mice causes adecrease in BAT-dependent thermogenesis, whereas treatment with A(2A) agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A(2A) receptors or injection of lentiviral vectors expressing the A(2A) receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A(2A) agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A(2A) signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
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| 37. |
- Klepac, K., et al.
(author)
-
The G(q) signalling pathway inhibits brown and beige adipose tissue
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the G(q) family, and inhibition of G(q) signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of G(q) signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of G(q) signalling in brown adipocytes. Expression of a constitutively active G(q) protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of G(q) in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that G(q) signalling regulates brown/beige adipocytes and inhibition of G(q) signalling may be a novel therapeutic approach to combat obesity.
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| 38. |
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| 39. |
- Li, Shunyi, et al.
(author)
-
Intrinsic energy band alignment of functional oxides
- 2014
-
In: Physica Status Solidi - Rapid Research Letetrs. - : Wiley. - 1862-6254 .- 1862-6270. ; 8:6, s. 571-576
-
Journal article (peer-reviewed)abstract
- The energy band alignment at interfaces between different materials is a key factor, which determines the function of electronic devices. While the energy band alignment of conventional semiconductors is quite well understood, systematic experimental studies on oxides are still missing. This work presents an extensive study on the intrinsic energy band alignment of a wide range of functional oxides using photoelectron spectroscopy with in-situ sample preparation. The studied materials have particular technological importance in diverse fields as solar cells, piezotronics, multiferroics, photoelectrochemistry and oxide electronics. Particular efforts have been made to verify the validity of transitivity, in order to confirm the intrinsic nature of the obtained band alignment and to understand the underlying principles. Valence band offsets up to 1.6 eV are observed. The large variation of valence band maximum energy can be explained by the different orbital contributions to the density of states in the valence band. The framework provided by this work enables the general understanding and prediction of energy band alignment at oxide interfaces, and furthermore the tailoring of energy level matching for charge transfer in functional oxides. (C) 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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| 40. |
- Li, Yi, et al.
(author)
-
In situ pneumococcal vaccine production and delivery through a hybrid biological-biomaterial vector
- 2016
-
In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 2:7
-
Journal article (peer-reviewed)abstract
- The type and potency of an immune response provoked during vaccination will determine ultimate success in disease prevention. The basis for this response will be the design and implementation of antigen presentation to the immune system. Whereas direct antigen administration will elicit some form of immunological response, a more sophisticated approach would couple the antigen of interest to a vector capable of broad delivery formats and designed for heightened response. New antigens associated with pneumococcal disease virulence were used to test the delivery and adjuvant capabilities of a hybrid biological-biomaterial vector consisting of a bacterial core electrostatically coated with a cationic polymer. The hybrid design provides (i) passive and active targeting of antigen-presenting cells, (ii) natural and multicomponent adjuvant properties, (iii) dual intracellular delivery mechanisms, and (iv) a simple formulation mechanism. In addition, the hybrid format enables device-specific, or in situ, antigen production and consolidation via localization within the bacterial component of the vector. This capability eliminates the need for dedicated antigen production and purification before vaccination efforts while leveraging the aforementioned features of the overall delivery device. We present the first disease-specific utilization of the vector toward pneumococcal disease highlighted by improved immune responses and protective capabilities when tested against traditional vaccine formulations and a range of clinically relevant Streptococcus pneumoniae strains. More broadly, the results point to similar levels of success with other diseases that would benefit from the production, delivery, and efficacy capabilities offered by the hybrid vector.
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| 41. |
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| 42. |
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| 43. |
- Meeths, M, et al.
(author)
-
Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
- 2011
-
In: Blood. - Washington : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:22, s. 5783-5793
-
Journal article (peer-reviewed)abstract
- Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
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| 44. |
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| 45. |
- Nistér, M, et al.
(author)
-
The Swedish Biobank for Childhood Tumors
- 2014
-
In: 7th research meeting in Network for NeuroBlastoma and CNS-tumor research in children, Hässelby, Stockholm, November 10-11, 2014..
-
Conference paper (peer-reviewed)
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| 46. |
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| 47. |
- Siaw, Joachim T., et al.
(author)
-
Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice
- 2016
-
In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:20, s. 29011-29022
-
Journal article (peer-reviewed)abstract
- Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. ALK mutations are reported in about 5-7% of neuroblastoma cases but the ALK-positive percentage increases significantly in the relapsed patient population. Crizotinib, the first clinically approved ALK inhibitor for the treatment of ALK-positive lung cancer has had less dramatic responses in neuroblastoma. Here we investigate the efficacy of a second-generation ALK inhibitor, brigatinib, in a neuroblastoma setting. Employing neuroblastoma cell lines, mouse xenograft and Drosophila melanogaster model systems expressing different constitutively active ALK variants, we show clear and efficient inhibition of ALK activity by brigatinib. Similar abrogation of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. These results suggest that brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma that should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.
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| 48. |
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| 49. |
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- Wiedensohler, A., et al.
(author)
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Mobility particle size spectrometers: harmonization of technical standards and data structure to facilitate high quality long-term observations of atmospheric particle number size distributions
- 2012
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In: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 5:3, s. 657-685
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Journal article (peer-reviewed)abstract
- Mobility particle size spectrometers often referred to as DMPS (Differential Mobility Particle Sizers) or SMPS (Scanning Mobility Particle Sizers) have found a wide range of applications in atmospheric aerosol research. However, comparability of measurements conducted world-wide is hampered by lack of generally accepted technical standards and guidelines with respect to the instrumental set-up, measurement mode, data evaluation as well as quality control. Technical standards were developed for a minimum requirement of mobility size spectrometry to perform long-term atmospheric aerosol measurements. Technical recommendations include continuous monitoring of flow rates, temperature, pressure, and relative humidity for the sheath and sample air in the differential mobility analyzer. We compared commercial and custom-made inversion routines to calculate the particle number size distributions from the measured electrical mobility distribution. All inversion routines are comparable within few per cent uncertainty for a given set of raw data. Furthermore, this work summarizes the results from several instrument intercomparison workshops conducted within the European infrastructure project EUSAAR (European Supersites for Atmospheric Aerosol Research) and ACTRIS (Aerosols, Clouds, and Trace gases Research InfraStructure Network) to determine present uncertainties especially of custom-built mobility particle size spectrometers. Under controlled laboratory conditions, the particle number size distributions from 20 to 200 nm determined by mobility particle size spectrometers of different design are within an uncertainty range of around +/- 10% after correcting internal particle losses, while below and above this size range the discrepancies increased. For particles larger than 200 nm, the uncertainty range increased to 30%, which could not be explained. The network reference mobility spectrometers with identical design agreed within +/- 4% in the peak particle number concentration when all settings were done carefully. The consistency of these reference instruments to the total particle number concentration was demonstrated to be less than 5%. Additionally, a new data structure for particle number size distributions was introduced to store and disseminate the data at EMEP (European Monitoring and Evaluation Program). This structure contains three levels: raw data, processed data, and final particle size distributions. Importantly, we recommend reporting raw measurements including all relevant instrument parameters as well as a complete documentation on all data transformation and correction steps. These technical and data structure standards aim to enhance the quality of long-term size distribution measurements, their comparability between different networks and sites, and their transparency and traceability back to raw data.
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