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- 2019
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Tidskriftsartikel (refereegranskat)
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| 16. |
- Adjuik, Martin A., et al.
(författare)
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The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data
- 2015
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
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| 17. |
- Dahal, Prabin, et al.
(författare)
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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
- 2019
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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| 18. |
- Jeske, Jan Torsten, 1983-
(författare)
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Microbial adaptations and controlling mechanisms of surface-associated microhabitat heterogeneity in aquatic systems
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Habitat heterogeneity is a driving factor for speciation and ecosystem functioning and is well studied in macro-ecology. Yet our understanding of microbial adaptations, and governing processes is incomplete. The here presented thesis aims at giving us a better understanding of patterns in micro-heterogeneity, and microbial adaptations to such heterogeneity with particular focus on surface-dominated, aquatic habitats. The most prominent microbial adaptation to surface associated mode of life is biofilm formation. Biofilms rely heavily on type IV pili. These pili systems are well studied in Bacteria, but largely unknown in Archaea. Therefore, the first part of this thesis focuses on resolving genetic and structural feature of the type IV like aap-pilus of the thermo-acidophilic Sulfolobus acidocaldarius. We found the aap-pilus to be indispensible for biofilm formation, and to be unparalleled in variability of its quaternary structure and cross regulation with other filaments. The second part of this thesis investigates particle colonization in the water column, focusing on diatoms as a model system, allowing an in situ assessment of different stages of particle colonization, and potential particle-specificity of the associated bacterial community. Opposing reports from marine systems, we did not observe diatom-specificity in the associated bacterial community. Instead we found bacterial community subsets, one likely originating from sediment resuspension, and the other being controlled by biofilm-forming populations (e.g. Flexibacter), able to attach to newly formed particle surfaces and subsequently facilitate secondary colonization by other bacteria. Finally, the habitat heterogeneity in top-layers of lake sediments were investigated in experimental microcosms. Cell-specific oxygen consumption rates were determined, to assess microbial activity across different scales. Individual activity rates differed strongly across all investigated scales, likely due to spatially heterogeneous distribution of nutrients with differing quality. Vice versa, the influence of microbial activity on micro-habitat-heterogeneity was investigated. We correlated sediment redox-state with bacterial community composition and populations. Our results indicate that habitat heterogeneity is generally beneficial for microorganism, and greater heterogeneity results in greater bacterial diversity. However, this heterogeneity-diversity relationship is limited and microorganisms actively stabilize their immediate redox environment to a preferred, community-specific, stable state, if cell abundances exceed a minimum threshold.
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| 19. |
- Marshall, Ian P. G., et al.
(författare)
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The novel bacterial phylum Calditrichaeota is diverse, widespread and abundant in marine sediments and has the capacity to degrade detrital proteins
- 2017
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Ingår i: Environmental Microbiology Reports. - : Wiley. - 1758-2229. ; 9:4, s. 397-403
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Tidskriftsartikel (refereegranskat)abstract
- Calditrichaeota is a recently recognized bacterial phylum with three cultured representatives, isolated from hydrothermal vents. Here we expand the phylogeny and ecology of this novel phylum with metagenome-derived and single-cell genomes from six uncultivated bacteria previously not recognized as members of Calditrichaeota. Using 16S rRNA gene sequences from these genomes, we then identified 322 16S rRNA gene sequences from cultivation-independent studies that can now be classified as Calditrichaeota for the first time. This dataset was used to re-analyse a collection of 16S rRNA gene amplicon datasets from marine sediments showing that the Calditrichaeota are globally distributed in the seabed at high abundance, making up to 6.7% of the total bacterial community. This wide distribution and high abundance of Calditrichaeota in cold marine sediment has gone unrecognized until now. All Calditrichaeota genomes show indications of a chemoorganoheterotrophic metabolism with the potential to degrade detrital proteins through the use of extracellular peptidases. Most of the genomes contain genes encoding proteins that confer O-2 tolerance, consistent with the relatively high abundance of Calditrichaeota in surficial bioturbated part of the seabed and, together with the genes encoding extracellular peptidases, suggestive of a general ecophysiological niche for this newly recognized phylum in marine sediment.
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| 20. |
- Marzocchi, Ugo, et al.
(författare)
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Transient bottom water oxygenation creates a niche for cable bacteria in long‐term anoxic sediments of the Eastern Gotland Basin
- 2018
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Ingår i: Environmental Microbiology. - : Wiley. - 1462-2912 .- 1462-2920. ; 20:8, s. 3031-3041
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Tidskriftsartikel (refereegranskat)abstract
- Cable bacteria have been reported in sediments from marine and freshwater locations, but the environmental factors that regulate their growth in natural settings are not well understood. Most prominently, the physiological limit of cable bacteria in terms of oxygen availability remains poorly constrained. In this study, we investigated the presence, activity and diversity of cable bacteria in relation to a natural gradient in bottom water oxygenation in a depth transect of the Eastern Gotland Basin (Baltic Sea). Cable bacteria were identified by FISH at the oxic and transiently oxic sites, but not at the permanently anoxic site. Three species of the candidate genus Electrothrix, i.e. marina, aarhusiensis and communis were found coexisting within one site. The highest filament density (33 m cm−2) was associated with a 6.3 mm wide zone depleted in both oxygen and free sulphide, and the presence of an electric field resulting from the electrogenic sulphur oxidizing metabolism of cable bacteria. However, the measured filament densities and metabolic activities remained low overall, suggesting a limited impact of cable bacteria at the basin level. The observed bottom water oxygen levels (< 5 μM) are the lowest so far reported for cable bacteria, thus expanding their known environmental distribution.
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| 21. |
- Schreiber, Lars, et al.
(författare)
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Description of Endozoicomonas ascidiicola sp nov., isolated from Scandinavian ascidians
- 2016
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Ingår i: Systematic and Applied Microbiology. - : Elsevier BV. - 0723-2020 .- 1618-0984. ; 39:5, s. 313-318
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Tidskriftsartikel (refereegranskat)abstract
- Two gram-negative, facultative anaerobic, chemoorganoheterotrophic, motile and rod-shaped bacteria, strains AVMARTO5(T) and KASP37, were isolated from ascidians (Tunicata, Ascidiaceae) of the genus Ascidiella collected at Gullmarsfjord, Sweden. The strains are the first cultured representatives of an ascidian-specific lineage within the genus Endozoicomonas (Gammaproteobacteria, Oceanospirillales, Hahellaceae). Both strains feature three distinct 16S rRNA gene paralogs, with identities of 98.9-99.1% (AVMARTO5(T)) and 97.7-98.8% (KASP37) between paralogs. The strains are closely related to Endozoicomonas atrinae and Endozoicomonas elysicola, with which they share 97.3-98.0% 16S rRNA gene sequence identity. Digital DNA-DNA hybridization, average nucleotide identity, and tetra-nucleotide correlation analysis indicate that both strains belong to a single species distinct from their closest relatives. Both strains feature similar DNA G + C contents of 46.70 mol%(AVMARTO5T) and 44.64 mol%(KASP37).The fatty acid patterns of AVMARTO5(T) and KASP37 are most similar to those of Endozoicomonas euniceicola and Endozoicomonas gorgoniicola. Based on the polyphasic approach, we propose the species Endozoicomonas ascidiicola sp. nov. to accommodate the newly isolated strains. E. ascidiicola sp. nov. is represented by the type strain AVMARTO5(T) (=DSM 100913(T) = LMG 29095(T)) and strain KASP37 (=DSM 100914= LMG 29096).
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| 22. |
- Simon, Matthias, et al.
(författare)
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TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas.
- 2015
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 17:1, s. 45-52
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Tidskriftsartikel (refereegranskat)abstract
- Activating somatic mutations in the promoter region of the telomerase reverse transcriptase gene (TERT) have been detected in several cancers. In this study we investigated the TERT promoter mutations and their impact on patient survival in World Health Organization grade IV glioblastoma multiforme (GBM).
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| 23. |
- Starnawski, Piotr, et al.
(författare)
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Microbial community assembly and evolution in subseafloor sediment
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:11, s. 2940-2945
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial and archaeal communities inhabiting the subsurface seabed live under strong energy limitation and have growth rates that are orders of magnitude slower than laboratory-grown cultures. It is not understood how subsurface microbial communities are assembled and whether populations undergo adaptive evolution or accumulate mutations as a result of impaired DNA repair under such energy-limited conditions. Here we use amplicon sequencing to explore changes of microbial communities during burial and isolation from the surface to the >5,000-y-old subsurface of marine sediment and identify a small core set of mostly uncultured bacteria and archaea that is present throughout the sediment column. These persisting populations constitute a small fraction of the entire community at the surface but become predominant in the subsurface. We followed patterns of genome diversity with depth in four dominant lineages of the persisting populations by mapping metagenomic sequence reads onto single-cell genomes. Nucleotide sequence diversity was uniformly low and did not change with age and depth of the sediment. Likewise, there was no detectable change inmutation rates and efficacy of selection. Our results indicate that subsurface microbial communities predominantly assemble by selective survival of taxa able to persist under extreme energy limitation.
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| 24. |
- Zaremba-Niedzwiedzka, Katarzyna, et al.
(författare)
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Asgard archaea illuminate the origin of eukaryotic cellular complexity
- 2017
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 541:7637, s. 353-
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Tidskriftsartikel (refereegranskat)abstract
- The origin and cellular complexity of eukaryotes represent a major enigma in biology. Current data support scenarios in which an archaeal host cell and an alphaproteobacterial (mitochondrial) endosymbiont merged together, resulting in the first eukaryotic cell. The host cell is related to Lokiarchaeota, an archaeal phylum with many eukaryotic features. The emergence of the structural complexity that characterizes eukaryotic cells remains unclear. Here we describe the 'Asgard' superphylum, a group of uncultivated archaea that, as well as Lokiarchaeota, includes Thor-, Odin- and Heimdallarchaeota. Asgard archaea affiliate with eukaryotes in phylogenomic analyses, and their genomes are enriched for proteins formerly considered specific to eukaryotes. Notably, thorarchaeal genomes encode several homologues of eukaryotic membrane-trafficking machinery components, including Sec23/24 and TRAPP domains. Furthermore, we identify thorarchaeal proteins with similar features to eukaryotic coat proteins involved in vesicle biogenesis. Our results expand the known repertoire of 'eukaryote-specific' proteins in Archaea, indicating that the archaeal host cell already contained many key components that govern eukaryotic cellular complexity.
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| 25. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813 .- 1089-490X. ; 92:3
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Tidskriftsartikel (refereegranskat)
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| 26. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813 .- 1089-490X. ; 92:3
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Tidskriftsartikel (refereegranskat)
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| 27. |
- Aad, G., et al.
(författare)
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- 2015
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Tidskriftsartikel (refereegranskat)
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| 28. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368 .- 1550-7998. ; 91:11, s. 112011-
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Tidskriftsartikel (refereegranskat)
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| 29. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 115:9
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Tidskriftsartikel (refereegranskat)
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| 30. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Journal of High Energy Physics. - : Springer-Verlag New York. - 1029-8479 .- 1126-6708. ; :9
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Tidskriftsartikel (refereegranskat)
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| 31. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368 .- 1550-7998. ; 92:1
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Tidskriftsartikel (refereegranskat)
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| 32. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review Letters. - : American Physical Society. - 1079-7114 .- 0031-9007. ; 114:22
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Tidskriftsartikel (refereegranskat)
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| 33. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Journal of High Energy Physics. - 1029-8479 .- 1126-6708. ; :8
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Tidskriftsartikel (refereegranskat)
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| 34. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368 .- 1550-7998. ; 92:9
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Tidskriftsartikel (refereegranskat)
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| 35. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 115:13
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Tidskriftsartikel (refereegranskat)
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| 36. |
- Aad, G., et al.
(författare)
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- 2015
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Tidskriftsartikel (refereegranskat)
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| 37. |
- Aad, G., et al.
(författare)
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- 2015
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Tidskriftsartikel (refereegranskat)
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| 38. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 115:3
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Tidskriftsartikel (refereegranskat)
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