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2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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3. |
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6. |
- van Rheenen, W, et al.
(författare)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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7. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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8. |
- Dupont, E., et al.
(författare)
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Overview of the dissemination of n_TOF experimental data and resonance parameters
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
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Konferensbidrag (refereegranskat)abstract
- The n_TOF neutron time-of-flight facility at CERN is used for nuclear data measurements. The n_TOF Collaboration works closely with the Nuclear Reaction Data Centres (NRDC) network to disseminate the experimental data through the international EXFOR library. In addition, the Collaboration helps integrate the results in the evaluated library projects. The present contribution describes the dissemination status of n_TOF results, their impact on evaluated libraries and ongoing efforts to provide n_TOF resonance parameters in ENDF-6 format for further use by evaluation projects.
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9. |
- Tagliente, G., et al.
(författare)
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The n_TOF facility at CERN
- 2024
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Ingår i: 16<sup>th</sup> Varenna Conference on Nuclear Reaction Mechanisms (NRM2023). - : EDP Sciences. - 9782759891245
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Konferensbidrag (refereegranskat)abstract
- The neutron Time-of-Flight facility (n_TOF) is an innovative facility operative since 2001 at CERN, with three experimental areas. In this paper the n_TOF facility will be described, together with the upgrade of the facility during the Long Shutdown 2 at CERN. The main features of the detectors used for capture fission cross section measurements will be presented with perspectives for the future measurements.
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10. |
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11. |
- Alcayne, V., et al.
(författare)
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A Segmented Total Energy Detector (sTED) optimized for (n,ϒ) cross-section measurements at n_TOF EAR2
- 2024
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Ingår i: Radiation Physics and Chemistry. - : Elsevier. - 0969-806X .- 1879-0895. ; 217
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Tidskriftsartikel (refereegranskat)abstract
- The neutron time-of-flight facility n_TOF at CERN is a spallation source dedicated to measurements of neutroninduced reaction cross-sections of interest in nuclear technologies, astrophysics, and other applications. Since 2014, Experimental ARea 2 (EAR2) is operational and delivers a neutron fluence of similar to 4 center dot 10(7) neutrons per nominal proton pulse, which is similar to 50 times higher than the one of Experimental ARea 1 (EAR1) of similar to 8 center dot 10(5) neutrons per pulse. The high neutron flux at EAR2 results in high counting rates in the detectors that challenged the previously existing capture detection systems. For this reason, a Segmented Total Energy Detector (sTED) has been developed to overcome the limitations in the detector's response, by reducing the active volume per module and by using a photo-multiplier (PMT) optimized for high counting rates. This paper presents the main characteristics of the sTED, including energy and time resolution, response to gamma-rays, and provides as well details of the use of the Pulse Height Weighting Technique (PHWT) with this detector. The sTED has been validated to perform neutron-capture cross-section measurements in EAR2 in the neutron energy range from thermal up to at least 400 keV. The detector has already been successfully used in several measurements at n_TOF EAR2.
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12. |
- Balibrea-Correa, J., et al.
(författare)
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First measurement of the 94Nb(n,γ) cross section at the CERN n_TOF facility
- 2023
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Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X. ; 279
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Tidskriftsartikel (refereegranskat)abstract
- One of the crucial ingredients for the improvement of stellar models is the accurate knowledge of neutron capture cross-sections for the different isotopes involved in the s-,r- and i- processes. These measurements can shed light on existing discrepancies between observed and predicted isotopic abundances and help to constrain the physical conditions where these reactions take place along different stages of stellar evolution.In the particular case of the radioactive 94Nb, the 94Nb(n,γ) cross-section could play a role in the determination of the s-process production of 94Mo in AGB stars, which presently cannot be reproduced by state-of-the-art stellar models. There are no previous 94Nb(n,γ) experimental data for the resolved and unresolved resonance regions mainly due to the difficulties in producing highquality samples and also due to limitations in conventional detection systems commonly used in time-of-flight experiments.Motivated by this situation, a first measurement of the 94Nb(n,γ) reaction was carried out at CERN n_TOF, thereby exploiting the high luminosity of the EAR2 area in combination with a new detection system of small-volume C6D6-detectors and a high quality 94Nb-sample. The latter was based on hyper-pure 93Nb material activated at the high-flux reactor of ILL-Grenoble. An innovative ring-configuration detection system in close geometry around the capture sample allowed us to significantly enhance the signal-to-background ratio. This set-up was supplemented with two conventional C6D6-detectors and a highresolution LaCl3(Ce)-detector, which will be employed for addressing reliably systematic effects and uncertainties.At the current status of the data analysis, 18 resonance in 94Nb+n have been observed for the first time in the neutron energy range from thermal up to 10 keV.
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13. |
- Domingo-Pardo, C., et al.
(författare)
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Advances and new ideas for neutron-capture astrophysics experiments at CERN n_TOF
- 2023
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Ingår i: European Physical Journal A. - : Springer. - 1434-6001 .- 1434-601X. ; 59:1
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Tidskriftsartikel (refereegranskat)abstract
- This article presents a few selected developments and future ideas related to the measurement of (n,γ) data of astrophysical interest at CERN n_TOF. The MC-aided analysis methodology for the use of low-efficiency radiation detectors in time-of-flight neutron-capture measurements is discussed, with particular emphasis on the systematic accuracy. Several recent instrumental advances are also presented, such as the development of total-energy detectors with γ-ray imaging capability for background suppression, and the development of an array of small-volume organic scintillators aimed at exploiting the high instantaneous neutron-flux of EAR2. Finally, astrophysics prospects related to the intermediate i neutron-capture process of nucleosynthesis are discussed in the context of the new NEAR activation area.
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14. |
- Domingo-Pardo, C., et al.
(författare)
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Compton imaging for enhanced sensitivity (n,gamma) cross section TOF experiments : Status and prospects
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
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Konferensbidrag (refereegranskat)abstract
- Radiative neutron-capture cross sections are of pivotal importance in many fields such as nucle-osynthesis studies or innovative reactor technologies. A large number of isotopes have been measured with high accuracy, but there are still a large number of relevant isotopes whose cross sections could not be experimentally determined yet, at least with sufficient accuracy and completeness, owing to limitations in detection techniques, sample production methods or in the facilities themselves. In the context of the HYMNS (High-sensitivitY Measurements of key stellar Nucleo-Synthesis reactions) project over the last six years we have developed a novel detection technique aimed at background suppression in radiative neutron-capture time-of-flight measurements. This new technique utilizes a complex detection set-up based on position-sensitive radiation-detectors deployed in a Compton-camera array configuration. The latter enables to implement gamma-ray imaging techniques, which help to disentangle true capture events arising from the sample under study and contaminant background events from the surroundings. A summary on the main developments is given in this contribution together with an update on recent experiments at CERN n_TOF and an outlook on future steps.
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15. |
- Domingo-Pardo, C., et al.
(författare)
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The neutron time-of-flight facility n_TOF at CERN Recent facility upgrades and detector developments
- 2023
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Ingår i: Journal of Physics, Conference Series. - : Institute of Physics (IOP). - 1742-6588 .- 1742-6596. ; 2586
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Tidskriftsartikel (refereegranskat)abstract
- Based on an idea by Carlo Rubbia, the n_TOF facility at CERN has been operating for over 20 years. It is a neutron spallation source, driven by the 20 GeV/c proton beam from the CERN PS accelerator. Neutrons in a very wide energy range (from GeV, down to sub-eV kinetic energy) are generated by a massive Lead spallation target feeding two experimental areas. EAR1, horizonal with respect to the proton beam direction is set at 185 meters from the spallation target. EAR2, on the vertical line from the spallation source, is placed at 20 m. Neutron energies for experiments are selected by the time-of-flight technique (hence the name n_TOF), while the long flight paths ensure a very good energy resolution. Over one hundred experiments have been performed by the n_TOF Collaboration at CERN, with applications ranging from nuclear astrophysics (synthesis of the heavy elements in stars, big bang nucleosynthesis, nuclear cosmo-chronology), to advanced nuclear technologies (nuclear data for applications, nuclear safety), as well as for basic nuclear science (reaction mechanisms, structure and decay of highly excited compound states). During the planned shutdown of the CERN accelerator complex between 2019 and 2021, the facility went through a substantial upgrade with a new target-moderator assembly, refurbishing of the neutron beam lines and experimental areas. An additional measuring and irradiation station (the NEAR Station) has been envisaged and its capabilities for performing material test studies and new physics opportunities are presently explored. An overview of the facility and of the activities performed at CERN is presented in this contribution, with a particular emphasis on the most relevant experiments for nuclear astrophysics.
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16. |
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17. |
- Lerendegui-Marco, J., et al.
(författare)
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New detection systems for an enhanced sensitivity in key stellar (n,γ) measurements
- 2023
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Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X. ; 279
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Tidskriftsartikel (refereegranskat)abstract
- Neutron capture cross-section measurements are fundamental in the study of astrophysical phenomena, such as the slow neutron capture (s-) process of nucleosynthesis operating in red-giant and massive stars. However, neutron capture measurements via the time-of-flight (TOF) technique on key s-process nuclei are often challenging. Difficulties arise from the limited mass (∼mg) available and the high sample-related background in the case of the unstable s-process branching points. Measurements on neutron magic nuclei, that act as s-process bottlenecks, are affected by low (n,γ) cross sections and a dominant neutron scattering background. Overcoming these experimental challenges requires the combination of facilities with high instantaneous flux, such as n_TOFEAR2, with detection systems with an enhanced detection sensitivity and high counting rate capabilities. This contribution reviews some of the latest detector developments in detection systems for (n,γ) measurements at n_TOF, such as i-TED, an innovative detection system which exploits the Compton imaging technique to reduce the dominant neutron scattering background and s-TED, a highly segmented total energy detector intended for high flux facilities. The discussion will be illustrated with results of the first measurement of key the s-process branching-point reaction 79Se(n,γ).
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18. |
- Lerendegui-Marco, J., et al.
(författare)
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New perspectives for neutron capture measurements in the upgraded CERN-n_TOF Facility
- 2023
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Ingår i: 15th International Conference on Nuclear Data for Science and Technology, ND2022. - : EDP Sciences.
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Konferensbidrag (refereegranskat)abstract
- The n_TOF facility has just undergone in 2021 a major upgrade with the installation of its third generation spallation target that has been designed to optimize the performance of the two n_TOF time-of-flight lines. This contribution describes the key features and limitations for capture measurements in the two beam lines prior to the target upgrade and presents first results of (n,gamma) measurements carried out as part of the commissioning of the upgraded facility. In particular, the energy resolution, a key factor for both increasing the signal-to background ratio and obtaining accurate resonance parameters, has been clearly improved for the 20 m long vertical beam-line with the new target design while keeping the remarkably high resolution of the long beamline n_TOF-EAR1. The improvements in the n_TOF neutron beam-lines need to be accompanied by improvements in the instrumentation. A review is given on recent detector R&D projects aimed at tackling the existing challenges and further improving the capabilities of this facility.
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19. |
- Massimi, C., et al.
(författare)
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Neutron-induced cross section measurements
- 2023
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Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X. ; 279
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-induced cross sections represent the main nuclear input to models of stellar and Big-Bang nucleosynthesis. While (n,γ) reactions are relevant for the formation of elements heavier than iron, (n,p) and (n,α) reactions can play an important role in specific cases. The time-of-flight method is routinely used at n_TOF to experimentally determine the cross section data. In addition, recent upgrades of the facility will allow the use of activation techniques as well, possibly opening the way to a systematic study of neutron interaction with radioactive isotopes. In the last 20 years n_TOF has provided a large amount of experimental data for Nuclear Astrophysics. Our plan is to carry on challenging measurements and produce nuclear data in the next decades as well.
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20. |
- Mastromarco, M., et al.
(författare)
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Measurement of the Gd-160(n, gamma) cross section at n_TOF and its medical implications
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
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Konferensbidrag (refereegranskat)abstract
- Neutron-capture reactions on gadolinium isotopes play an important role in several fields of physics, in particular in nuclear Astrophysics for the understanding of the nucleosynthesis of heavy elements (beyond iron) in stars via the s- and r-processes [1] and in nuclear technology. Another important application of gadolinium is linked to the production of terbium, that offers a set of clinically interesting isotopes for theranostics, characterized by complementary physical decay characteristics. In particular, the low -energy beta(-) emitter terbium-161 is very similar to lutetium-177 in terms of half-life (6.89 d), beta(-) - energy and chemical properties. Being a significant emitter of conversion/Auger electrons, greater therapeutic effect can therefore be expected in comparison to Lu-177 [2, 3]. For this reason, in the last decade, the study of the neutron capture reaction Gd-160(n,,gamma)(161) Gd and the subsequent beta(-) - decay in terbium-161 is getting particular attention. As the nuclear data on the Gd-160 neutron capture reaction are quite scarce and inconsistent, a new measurement of the capture cross section of Gd-160 at the CERN neutron Time -Of-Flight facilty was performed in order to provide high resolution, high -accuracy data on this important reaction, in the energy range from thermal to hundreds of keV. In this contribution, the preliminary results of the n_TOF measurement are presented.
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21. |
- Patronis, N., et al.
(författare)
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Status report of the n_TOF facility after the 2nd CERN long shutdown period
- 2023
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Ingår i: EPJ TECHNIQUES AND INSTRUMENTATION. - : Springer Nature. - 2195-7045. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- During the second long shutdown period of the CERN accelerator complex (LS2, 2019-2021), several upgrade activities took place at the n_TOF facility. The most important have been the replacement of the spallation target with a next generation nitrogen-cooled lead target. Additionally, a new experimental area, at a very short distance from the target assembly (the NEAR Station) was established. In this paper, the core commissioning actions of the new installations are described. The improvement in the n_TOF infrastructure was accompanied by several detector development projects. All these upgrade actions are discussed, focusing mostly on the future perspectives of the n_TOF facility. Furthermore, some indicative current and future measurements are briefly reported.
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22. |
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23. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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24. |
- Mucciola, R., et al.
(författare)
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Neutron capture and total cross-section measurements on Mo-94'95'96 at n_TOF and GELINA
- 2023
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Ingår i: 15th International Conference on Nuclear Data for Science and Technology, ND2022. - : EDP Sciences.
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Konferensbidrag (refereegranskat)abstract
- Capture and total cross section measurements for 94'95'96 MO have been performed at the neutron time -of-flight facilities, n_TOF at CERN and GELINA at JRC-Geel. The measurements were performed using isotopically enriched samples with an enrichment above 95% for each of the (94'95'96)M0 isotopes. The capture measurements were performed at n_TOF using C6D6 detectors and a new sTED detector. The transmission measurements were performed at a 10 m station of GELINA using a Li-6 glass neutron detector. Preliminary results of these measurements are presented.
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25. |
- Alcayne, V., et al.
(författare)
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A segmented total energy detector (sTED) for (n, gamma) cross section measurements at n_TOF EAR2
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
-
Konferensbidrag (refereegranskat)abstract
- The neutron time-of-flight facility n_TOF is characterised by its high instantaneous neutron intensity, high resolution and broad neutron energy spectra, specially conceived for neutron-induced reaction cross section measurements. Two Time-Of-Flight (TOR) experimental areas are available at the facility: experimental area 1 (EAR1), located at the end of the 185 m horizontal flight path from the spallation target, and experimental area 2 (EAR2), placed at 20 m from the target in the vertical direction. The neutron fluence in EAR2 is similar to 300 times more intense than in EARL in the relevant time-of-flight window. EAR2 was designed to carry out challenging cross-section measurements with low mass samples (approximately 1 mg), reactions with small cross-sections or/and highly radioactive samples. The high instantaneous fluence of EAR2 results in high counting rates that challenge the existing capture systems. Therefore, the sTED detector has been designed to mitigate these effects. In 2021, a dedicated campaign was done validating the performance of the detector up to at least 300 keV neutron energy. After this campaign, the detector has been used to perform various capture cross section measurements at n_TOF EAR2.
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26. |
- Garcia-Infantes, F., et al.
(författare)
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First high resolution measurement of neutron capture resonances in Yb-176 at the n_TOF CERN facility.
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
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Konferensbidrag (refereegranskat)abstract
- Several international agencies recommend the study of new routes and new facilities for producing radioisotopes with application to nuclear medicine. Lu-177 is a versatile radioisotope used for therapy and diagnosis (theranostics) of cancer with good success in neuroendocrine tumours that is being studied to be applied to a wider range of tumours. Lu-177 is produced in few nuclear reactors mainly by the neutron capture on Lu-176. However, it could be produced at high -intensity accelerator-based neutron facilities. The energy of the neutrons in accelerator-based neutron facilities is higher than in thermal reactors. Thus, experimental data on the Yb-176(n,(sic)) cross-section in the eV and keV region are mandatory to calculate accurately the production of Yb-177, which beta decays to 177Lu. At present, there are not experimental data available from thermal to 3 keV of the Yb-176(n,(sic)) cross-section. In addition, there is no data in the resolved resonance region (RRR). This contribution shows the first results of the Yb-176 capture measurement performed at the n_TOF facility at CERN.
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27. |
- Pavon-Rodriguez, J. A., et al.
(författare)
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Characterisation of the n_TOF 20 m beam line at CERN with the new spallation target
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
-
Konferensbidrag (refereegranskat)abstract
- The n_TOF facility hosts CERN's pulsed neutron source, comprising two beam lines of different flight paths and one activation station. It is based on a proton beam delivered by the PS accelerator impinging on a lead spallation target. During Long Shutdown 2 (LS2) at CERN (2019-2021), a major upgrade of the spallation target was carried out in order to optimize the performances of the neutron beam. Therefore, the characteristics of n_TOF two experimental areas were investigated in detail. In this work, the focus is on the second experimental area (EAR2), located 20 m above the spallation target. Preliminary results of the neutron energy distribution and beam line energy resolution are presented, compared to previous experimental campaigns and Monte Carlo simulations with the FLUKA code. Moreover, preliminary results of the spatial beam profile measurements are shown.
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28. |
- Stamati, M. E., et al.
(författare)
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The n_TOF NEAR Station Commissioning and first physics case
- 2023
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Ingår i: 15TH INTERNATIONAL CONFERENCE ON NUCLEAR DATA FOR SCIENCE AND TECHNOLOGY, ND2022. - : EDP Sciences.
-
Konferensbidrag (refereegranskat)abstract
- The NEAR Station is a new experimental area developed at the n_TOF Facility at CERN. The activation station of NEAR underwent a characterization of the beam following the installation of the new n_TOF Spallation Target. The commissioning of the neutron beam comprises a set of simulations made with the FLUKA code and experimental verification. The experimental determination of the neutron spectrum was made using activation techniques with three separate set-ups. Two set-ups were based on the Multi-foil Activation technique (MAM-1 and MAM-2), and the third set-up relied on the process of neutron moderation and activation of a single material (ANTILoPE). The three set-ups are presented. Also the present plans and future perspectives of the activation station of NEAR are discussed.
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34. |
- Manigart, S., et al.
(författare)
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The syndication of venture capital investments in Europe: evidence from five European countries
- 2002
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Ingår i: Frontiers of Entrepreneurship Research: Proceedings of the Twenty-Second Annual Entrepreneurship Research Conference. - 0910897239
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Konferensbidrag (refereegranskat)abstract
- Financial theory, resource-based theory and deal flow generation are used to explain synd ication practices among venture capitalists in Belgium, France, The Netherlands, Sweden and the UK. Similar motives drive syndication in the five countries: the desire to share risk and increase portfolio diversification is more important than the desire to access additional intangible resources or deal flow. When resource-based motives are more important, however, the propensity to syndicate increases. Syndication practices are more important in young venture capital (VC) firms and in VC firms with more portfolio companies.
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35. |
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36. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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37. |
- Brommage, Robert, et al.
(författare)
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NOTUM inhibition increases endocortical bone formation and bone strength
- 2019
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Ingår i: Bone Research. - : Springer Science and Business Media LLC. - 2095-4700 .- 2095-6231. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum(-/-) mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.
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38. |
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39. |
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40. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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41. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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42. |
- Zheng, J., et al.
(författare)
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Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures
- 2019
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 34:10, s. 1824-1836
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Tidskriftsartikel (refereegranskat)abstract
- In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (beta = 0.20, p = 4.6 x 10(-49)) and GALNT1 (beta = 0.11 per G allele, p = 4.4 x 10(-11)). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (beta = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (beta = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (beta = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. (c) 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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43. |
- Belibasakis, G N, et al.
(författare)
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Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin.
- 2005
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 30:2, s. 56-63
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Tidskriftsartikel (refereegranskat)abstract
- Actinobacillus actinomycetemcomitans is implicated in the pathogenesis of localized aggressive periodontitis, and has the capacity to express a cytolethal distending toxin (Cdt). Gingival fibroblasts (GF) are resident cells of the periodontium, which can express several osteolytic cytokines. The aims of this study were a) to investigate the role of Cdt in A. actinomycetemcomitans-induced expression of osteolytic cytokines and their cognate receptors in GF and b) to determine if the previously demonstrated induction of receptor activator of NFkappaB ligand (RANKL) by A. actinomycetemcomitans is mediated by these pro-inflammatory cytokines or by prostaglandin E(2) (PGE(2)). A. actinomycetemcomitans clearly induced interleukin (IL)-6, IL-1beta, and to a minimal extent, tumor necrosis factor (TNF)-alpha mRNA expression. At the protein level, IL-6 but not IL-1beta or TNF-alpha expression was stimulated. The mRNA expression of the different receptor subtypes recognizing IL-6, IL-1beta and TNF-alpha was not affected. A cdt-knockout strain of A. actinomycetemcomitans had similar effects on cytokine and cytokine receptor mRNA expression, compared to its parental wild-type strain. Purified Cdt stimulated IL-6, but not IL-1beta or TNF-alpha protein biosynthesis. Antibodies neutralizing IL-6, IL-1 or TNF-alpha, and the PGE(2) synthesis inhibitor indomethacin, did not affect A. actinomycetemcomitans-induced RANKL expression. In conclusion, a) A. actinomycetemcomitans induces IL-6 production in GF by a mechanism largely independent of its Cdt and b) A. actinomycetemcomitans-induced RANKL expression in GF occurs independently of IL-1, IL-6, TNF-alpha, or PGE(2).
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44. |
- Belibasakis, G N, et al.
(författare)
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The cytolethal distending toxin induces receptor activator of NF-kappaB ligand expression in human gingival fibroblasts and periodontal ligament cells.
- 2005
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Ingår i: Infection and immunity. - 0019-9567 .- 1098-5522. ; 73:1, s. 342-51
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Tidskriftsartikel (refereegranskat)abstract
- Actinobacillus actinomycetemcomitans is associated with localized aggressive periodontitis, a disease characterized by rapid loss of the alveolar bone surrounding the teeth. Receptor activator of NF-kappaB Ligand (RANKL) and osteoprotegerin (OPG) are two molecules that regulate osteoclast formation and bone resorption. RANKL induces osteoclast differentiation and activation, whereas OPG blocks this process by acting as a decoy receptor for RANKL. The purpose of this study was to investigate the effect of A. actinomycetemcomitans on the expression of RANKL and OPG in human gingival fibroblasts and periodontal ligament cells. RANKL mRNA expression was induced in both cell types challenged by A. actinomycetemcomitans extract, whereas OPG mRNA expression remained unaffected. Cell surface RANKL protein was also induced by A. actinomycetemcomitans, whereas there was no change in OPG protein secretion. A cytolethal distending toxin (Cdt) gene-knockout strain of A. actinomycetemcomitans did not induce RANKL expression, in contrast to its wild-type strain. Purified Cdt from Haemophilus ducreyi alone, or in combination with extract from the A. actinomycetemcomitans cdt mutant strain, induced RANKL expression. Pretreatment of A. actinomycetemcomitans wild-type extract with Cdt antiserum abolished RANKL expression. In conclusion, A. actinomycetemcomitans induces RANKL expression in periodontal connective tissue cells. Cdt is crucial for this induction and may therefore be involved in the pathological bone resorption during the process of localized aggressive periodontitis.
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45. |
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46. |
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47. |
- Cepeda, D., et al.
(författare)
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CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
- 2013
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 5:7, s. 999-1018
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Tidskriftsartikel (refereegranskat)abstract
- SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
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48. |
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49. |
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50. |
- Figueroa, Jonine D., et al.
(författare)
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Genome-wide association study identifies multiple loci associated with bladder cancer risk
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:5, s. 1387-1398
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Tidskriftsartikel (refereegranskat)abstract
- andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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