| 1. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 27. |
- Baird, Denis A., et al.
(författare)
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Identification of Novel Loci Associated With Hip Shape : A Meta-Analysis of Genomewide Association Studies.
- 2019
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Ingår i: Journal of Bone and Mineral Research. - : Wiley-Blackwell. - 0884-0431 .- 1523-4681. ; 34:2, s. 241-251
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
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| 28. |
- Bergemalm, Daniel, 1977-, et al.
(författare)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 29. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 30. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 31. |
- Friebel, Daniel, et al.
(författare)
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In situ x-ray probing reveals the importance of surface platinum oxide formation in fuel cell catalysis
- 2011
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 13:1, s. 262-266
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Tidskriftsartikel (refereegranskat)abstract
- In situ X-ray absorption spectroscopy (XAS) at the Pt L3 edge is a useful probe for Pt–O interactions at polymer electrolyte membrane fuel cell (PEMFC) cathodes. We show that XAS using the high energy resolution fluorescence detection (HERFD) mode, applied to a well-defined monolayer Pt/Rh(111) sample where the bulk penetrating hard X-rays probe only surface Pt atoms, provides a unique sensitivity to structure and chemical bonding at the Pt-electrolyte interface. Ab initio multiple-scattering calculations using the FEFF code and complementary extended X-ray absorption fine structure (EXAFS) results indicate that the commonly observed large increase of the white-line at high electrochemical potentials on PEMFC cathodes originates from platinum oxide formation, whereas previously proposed chemisorbed oxygen-containing species merely give rise to subtle spectral changes.
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| 32. |
- Mariedahl, Daniel, et al.
(författare)
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X-ray Scattering and O-O Pair-Distribution Functions of Amorphous Ices
- 2018
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 122:30, s. 7616-7624
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Tidskriftsartikel (refereegranskat)abstract
- The structure factor and oxygen-oxygen pair distribution functions of amorphous ices at liquid nitrogen temperature (T = 77 K) have been derived from wide-angle X-ray scattering (WAXS) up to interatomic distances of r = 23 angstrom, where local structure differences between the amorphous ices can be seen for the entire range. The distances to the first coordination shell for low-, high-, and very-high-density amorphous ice (LDA, HDA, VHDA) were determined to be 2.75, 2.78, and 2.80 angstrom, respectively, with high accuracy due to measurements up to a large momentum transfer of 23 angstrom(-1). Similarities in pair-distribution functions between LDA and supercooled water at 254.1 K, HDA and liquid water at 365.9 K, and VHDA and high-pressure liquid water were found up to around 8 angstrom, but beyond that at longer distances, the similarities were lost. In addition, the structure of the high-density amorphous ices was compared to high-pressure crystalline ices IV, IX, and XII, and conclusions were drawn about the local ordering.
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| 33. |
- Niklison-Chirou, Maria Victoria, et al.
(författare)
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TAp73 is a marker of glutamine addiction in medulloblastoma
- 2017
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Ingår i: Genes & Development. - : COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. - 0890-9369 .- 1549-5477. ; 31:17, s. 1738-1753
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.
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| 34. |
- Perakis, Fivos, et al.
(författare)
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Diffusive dynamics during the high-to-low density transition in amorphous ice
- 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. ; 114:31, s. 8193-8198
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Tidskriftsartikel (refereegranskat)abstract
- Water exists in high- and low-density amorphous ice forms (HDA and LDA), which could correspond to the glassy states of high(HDL) and low-density liquid (LDL) in the metastable part of the phase diagram. However, the nature of both the glass transition and the high-to-low-density transition are debated and new experimental evidence is needed. Here we combine wide-angle X-ray scattering (WAXS) with X-ray photon-correlation spectroscopy (XPCS) in the small-angle X-ray scattering (SAXS) geometry to probe both the structural and dynamical properties during the high-to-low-density transition in amorphous ice at 1 bar. By analyzing the structure factor and the radial distribution function, the coexistence of two structurally distinct domains is observed at T = 125 K. XPCS probes the dynamics in momentum space, which in the SAXS geometry reflects structural relaxation on the nanometer length scale. The dynamics of HDA are characterized by a slow component with a large time constant, arising from viscoelastic relaxation and stress release from nanometer-sized heterogeneities. Above 110 K a faster, strongly temperature-dependent component appears, with momentum transfer dependence pointing toward nanoscale diffusion. This dynamical component slows down after transition into the low-density form at 130 K, but remains diffusive. The diffusive character of both the high- and low-density forms is discussed among different interpretations and the results are most consistent with the hypothesis of a liquid-liquid transition in the ultraviscous regime.
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| 35. |
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| 36. |
- Sellberg, Jonas A., et al.
(författare)
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X-ray emission spectroscopy of bulk liquid water in no-man's land
- 2015
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 142:4
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Tidskriftsartikel (refereegranskat)abstract
- The structure of bulk liquid water was recently probed by x-ray scattering below the temperature limit of homogeneous nucleation (T-H) of similar to 232 K [J. A. Sellberg et al., Nature 510, 381-384 (2014)]. Here, we utilize a similar approach to study the structure of bulk liquid water below T-H using oxygen K-edge x-ray emission spectroscopy (XES). Based on previous XES experiments [T. Tokushima et al., Chem. Phys. Lett. 460, 387-400 (2008)] at higher temperatures, we expected the ratio of the 1b(1)' and 1b(1) peaks associated with the lone-pair orbital in water to change strongly upon deep supercooling as the coordination of the hydrogen (H-) bonds becomes tetrahedral. In contrast, we observed only minor changes in the lone-pair spectral region, challenging an interpretation in terms of two interconverting species. A number of alternative hypotheses to explain the results are put forward and discussed. Although the spectra can be explained by various contributions from these hypotheses, we here emphasize the interpretation that the line shape of each component changes dramatically when approaching lower temperatures, where, in particular, the peak assigned to the proposed disordered component would become more symmetrical as vibrational interference becomes more important.
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| 37. |
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| 38. |
- Öberg, Henrik, et al.
(författare)
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Stability of Pt-Modified Cu(111) in the Presence of Oxygen and Its Implication on the Overall Electronic Structure
- 2013
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 117:32, s. 16371-16380
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Tidskriftsartikel (refereegranskat)abstract
- The electronic structure and stability of Cu(111)-hosted Pt overlayers with and without the presence of atomic oxygen have been studied by means of core-level spectroscopy and density functional theory (DFT). Because of lattice mismatch, Pt(111) overlayers grown on Cu(111) are compressively strained, and hard X-ray photoelectron spectroscopy together with Pt L-3-edge X-ray absorption spectroscopy (XAS) reveals a pronounced downshift of the Pt d-band owing to the increased overlap of the d-orbitals, an effect also reproduced theoretically. Exposure to oxygen severely alters the surface composition; the O-Cu binding energy largely exceeds that of O-Pt, and DFT calculations predict surface segregation of Cu atoms. Comparing the adsorbate electronic structure for O on unstrained Pt(111) with that of O on Pt-modified Cu(111) using O K-edge XAS and X-ray emission spectroscopy salient differences are observed and calculations show that Cu-segregation to the topmost layer is required to reproduce the measured spectra. It is proposed that O is binding in a hollow site constituted by at least two Cu atoms and that up to 75% of the Pt atoms migrate below the surface.
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| 39. |
- Aad, G., et al.
(författare)
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- 2014
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Tidskriftsartikel (refereegranskat)
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| 40. |
- Aad, G., et al.
(författare)
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- 2014
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813 .- 1089-490X. ; 90:4
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Tidskriftsartikel (refereegranskat)
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| 41. |
- Aad, G., et al.
(författare)
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- 2014
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Ingår i: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 74:8
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Tidskriftsartikel (refereegranskat)
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| 42. |
- Aad, G., et al.
(författare)
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- 2015
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Tidskriftsartikel (refereegranskat)
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| 43. |
- Aad, G., et al.
(författare)
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- 2014
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Tidskriftsartikel (refereegranskat)
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| 44. |
- Aad, G., et al.
(författare)
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- 2014
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Ingår i: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 74:6
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Tidskriftsartikel (refereegranskat)
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| 45. |
- Aad, G., et al.
(författare)
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- 2014
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Ingår i: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 74:10
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Tidskriftsartikel (refereegranskat)
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| 46. |
- Aad, G., et al.
(författare)
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- 2014
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Tidskriftsartikel (refereegranskat)
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| 47. |
- Aad, G., et al.
(författare)
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- 2014
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Tidskriftsartikel (refereegranskat)
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| 48. |
- Aad, G., et al.
(författare)
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- 2014
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Tidskriftsartikel (refereegranskat)
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| 49. |
- Aad, G., et al.
(författare)
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- 2014
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813 .- 1089-490X. ; 90:2
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Tidskriftsartikel (refereegranskat)
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| 50. |
- Aad, G., et al.
(författare)
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- 2014
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Tidskriftsartikel (refereegranskat)
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