| 1. |
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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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| 4. |
- 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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| 5. |
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| 6. |
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| 7. |
- 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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| 8. |
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- 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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| 13. |
- 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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| 14. |
- 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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| 15. |
- 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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| 16. |
- 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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| 17. |
- 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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| 18. |
- 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
-
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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| 19. |
- 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.
-
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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| 20. |
- 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
-
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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| 21. |
- 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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| 22. |
- 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.
-
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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| 23. |
- Massimi, C., et al.
(författare)
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Neutron-induced cross section measurements
- 2023
-
Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X. ; 279
-
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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| 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.
-
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. |
- 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
-
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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| 26. |
- 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
-
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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| 27. |
- 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.
-
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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| 28. |
- 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
-
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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| 29. |
- 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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| 30. |
- 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
-
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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| 31. |
- 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
-
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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| 32. |
- 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
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
-
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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| 33. |
- Makitie, R. E., et al.
(författare)
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An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility
- 2021
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Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5 ' untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)-stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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- Ernberg, M, et al.
(författare)
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Examina och utbildning inom svensk odontologisk forskning
- 2003
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Ingår i: Tandläkartidn. ; 95:9, s. 54-59
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- En internationell utvärdering visade för några år sedan att Sverige riskerar att förlora sin position som världsledande nation inom odontologisk forskning. För att få en uppfattning om förändringarna inom forskarutbildningen och den postdoktorala meriteringen samlades data för 1990-2001 in från fakulteterna, Statistiska Centralbyrån samt Högskoleverket. Avsikten var att undersöka antalet forskarutbildade tandläkare, mångfalden bland doktoranderna och de som disputerat samt deras nuvarande anställningsform. Materialet jämfördes sedan med tidigare data. I medeltal avlade 25 personer per år doktorsexamen åren 1990-2001. Antalet har minskat under senare år. En majoritet av dem som avlade doktorsexamen hade odontologisk bakgrund. Relativt få har meriterat sig för en fortsatt akademisk karriär. 32 studerande påbörjade forskarutbildning åren 1991-2001. Andelen doktorander med annan akademisk grundexamen än odontologisk ökar. Sedan 1999 har forskningsvolymen minskat med motsvarande en hel fakultets forskningsvolym. Vi drar därför slutsatsen att kunskapsutvecklingen inom svensk odontologi riskerar att stagnera samt att fakulteternas behov av lärare till högre akademiska tjänster liksom folktandvårdens behov av handledare inom specialistutbildningen inte kommer att kunna tillgodoses i framtiden.
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- 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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- Lerner, M.S., et al.
(författare)
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A 100 GHZ map of 3C 446
- 1993
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Ingår i: Astronomy and Astrophysics. - Les Ulis : EDP Sciences. - 0004-6361 .- 1432-0746. ; 280:1, s. 117-120
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Tidskriftsartikel (refereegranskat)abstract
- The first map made from 100 GHz VLBI observations of the quasar/BL Lac object 3C446 is presented. This map represents a 25-fold increase in resolution compared to earlier maps. Our main conclusions are that the core of 3C 446 is still almost unresolved (less than or similar to 30 muas) at this frequency and that a jet extends several hundred microarcseconds at position angle almost-equal-to -142-degrees. A comparison is also made with observations at other size scales.
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- Baltanas, R., et al.
(författare)
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Pheromone-Induced Morphogenesis Improves Osmoadaptation Capacity by Activating the HOG MAPK Pathway
- 2013
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1937-9145 .- 1945-0877. ; 6:272
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Tidskriftsartikel (refereegranskat)abstract
- Environmental and internal conditions expose cells to a multiplicity of stimuli whose consequences are difficult to predict. We investigate the response to mating pheromone of yeast cells adapted to high osmolarity. Events downstream of pheromone binding involve two mitogen-activated protein kinase (MAPK) cascades: the pheromone response (PR) and the cell wall integrity (CWI) response. Although the PR MAPK pathway shares components with a third MAPK pathway, the high osmolarity (HOG) response, each one is normally only activated by its cognate stimulus, a phenomenon called insulation. We found that in cells adapted to high osmolarity, PR activated the HOG pathway in a pheromone- and osmolarity-dependent manner. Activation of HOG by the PR was not due to loss of insulation, but rather a response to a reduction in internal osmolarity, which resulted from an increase in glycerol release caused by the PR. By analyzing single-cell time courses, we found that stimulation of HOG occurred in discrete bursts that coincided with the "shmooing" morphogenetic process. Activation required the polarisome, the CWI MAPK Slt2, and the aquaglyceroporin Fps1. HOG activation resulted in high glycerol turnover, which improved adaptability to rapid changes in osmolarity. Our work shows how a differentiation signal can recruit a second, unrelated sensory pathway to fine-tune yeast response in a complex environment.
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| 49. |
- Bergman, Per, 1960, et al.
(författare)
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Emission from HCN and CH3OH in comets Onsala 20-m observations and radiative transfer modelling
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 660
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Tidskriftsartikel (refereegranskat)abstract
- Aims. The aim of this work is to characterise HCN and CH3OH emission from recent comets. Methods. We used the Onsala 20-m telescope to search for millimetre transitions of HCN towards a sample of 11 recent and mostly bright comets in the period from December 2016 to November 2019. Also, CH3OH was searched for in two comets. The HCN sample includes the interstellar comet 2I/Borisov. For the short-period comet 46P/Wirtanen, we were able to monitor the variation of HCN emission over a time-span of about one month. We performed radiative transfer modelling for the observed molecular emission by also including time-dependent effects due to the outgassing of molecules. Results. HCN was detected in six comets. Two of these are short-period comets and four are long-period. Six methanol transitions were detected in 46P/Wirtanen, enabling us to determine the gas kinetic temperature. From the observations, we determined the molecular production rates using time-dependent radiative transfer modelling. For five comets, we were able to determine that the HCN mixing ratios lie near 0.1% using contemporary water production rates, Q(H2O), taken from other studies. This HCN mixing ratio was also found to be typical in our monitoring observations of 46P/Wirtanen but here we notice deviations of up to 0.2% on a daily timescale which could indicate short-time changes in outgassing activity. From our radiative transfer modelling of cometary comae, we find that time-dependent effects on the HCN level populations are of the order of 5-15% when Q(H2O) is around 2 x 10(28) mol s(-1). The effects may be stronger for comets with lower Q(H2O). The exact details of the time-dependent effects depend on the amount of neutral and electron collisions, radiative pumping, and molecular parameters such as the spontaneous rate coefficient.
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| 50. |
- Bostrom, E. A., et al.
(författare)
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Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-alpha (TNF-alpha and interleukin-1 beta (IL-1 beta), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-kappa B pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.
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