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| 2. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 4. |
- Yates, James A. Fellows, et al.
(författare)
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The evolution and changing ecology of the African hominid oral microbiome
- 2021
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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 (PNAS). - 0027-8424 .- 1091-6490. ; 118:20
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Tidskriftsartikel (refereegranskat)abstract
- The oral microbiome plays key roles in human biology, health, and disease, but little is known about the global diversity, variation, or evolution of this microbial community. To better understand the evolution and changing ecology of the human oral microbiome, we analyzed 124 dental biofilm metagenomes from humans, including Neanderthals and Late Pleistocene to present-day modern humans, chimpanzees, and gorillas, as well as New World howler monkeys for comparison. We find that a core microbiome of primarily biofilm structural taxa has been maintained throughout African hominid evolution, and these microbial groups are also shared with howler monkeys, suggesting that they have been important oral members since before the catarrhine-platyrrhine split ca. 40 Mya. However, community structure and individual microbial phylogenies do not closely reflect host relationships, and the dental biofilms of Homo and chimpanzees are distinguished by major taxonomic and functional differences. Reconstructing oral metagenomes from up to 100 thousand years ago, we show that the microbial profiles of both Neanderthals and modern humans are highly similar, sharing functional adaptations in nutrient metabolism. These include an apparent Homo-specific acquisition of salivary amylase-binding capability by oral streptococci, suggesting microbial coadaptation with host diet. We additionally find evidence of shared genetic diversity in the oral bacteria of Neanderthal and Upper Paleolithic modern humans that is not observed in later modern human populations. Differences in the oral microbiomes of African hominids provide insights into human evolution, the ancestral state of the human microbiome, and a temporal framework for understanding microbial health and disease.
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| 6. |
- Chakraborti, Sayan, et al.
(författare)
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A MISSING-LINK IN THE SUPERNOVA-GRB CONNECTION : THE CASE OF SN 2012ap
- 2015
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 805:2
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray bursts (GRBs) are characterized by ultra-relativistic outflows, while supernovae are generally characterized by non-relativistic ejecta. GRB afterglows decelerate rapidly, usually within days, because their low-mass ejecta rapidly sweep up a comparatively larger mass of circumstellar material. However, supernovae with heavy ejecta can be in nearly free expansion for centuries. Supernovae were thought to have non-relativistic outflows except for a few relativistic ones accompanied by GRBs. This clear division was blurred by SN 2009bb, the first supernova with a relativistic outflow without an observed GRB. However, the ejecta from SN 2009bb was baryon loaded and in nearly free expansion for a year, unlike GRBs. We report the first supernova discovered without a GRB but with rapidly decelerating mildly relativistic ejecta, SN 2012ap. We discovered a bright and rapidly evolving radio counterpart driven by the circumstellar interaction of the relativistic ejecta. However, we did not find any coincident GRB with an isotropic fluence of more than one-sixth of the fluence from GRB 980425. This shows for the first time that central engines in SNe Ic, even without an observed GRB, can produce both relativistic and rapidly decelerating outflows like GRBs.
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| 8. |
- Margutti, R., et al.
(författare)
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INVERSE COMPTON X-RAY EMISSION FROM SUPERNOVAE WITH COMPACT PROGENITORS : APPLICATION TO SN2011fe
- 2012
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 751:2, s. 134-
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Tidskriftsartikel (refereegranskat)abstract
- We present a generalized analytic formalism for the inverse Compton X-ray emission from hydrogen-poor supernovae and apply this framework to SN 2011fe using Swift X-Ray Telescope (XRT), UVOT, and Chandra observations. We characterize the optical properties of SN 2011fe in the Swift bands and find them to be broadly consistent with a normal SN Ia, however, no X-ray source is detected by either XRT or Chandra. We constrain the progenitor system mass-loss rate (M) over dot < 2 x 10(-9) M-circle dot yr(-1) (3 sigma c.l.) for wind velocity v(w) = 100 km s(-1). Our result rules out symbiotic binary progenitors for SN 2011fe and argues against Roche lobe overflowing subgiants and main-sequence secondary stars if greater than or similar to 1% of the transferred mass is lost at the Lagrangian points. Regardless of the density profile, the X-ray non-detections are suggestive of a clean environment (n(CSM) < 150 cm(-3)) for 2 x 10(15) less than or similar to R less than or similar to 5 x 10(16) cm around the progenitor site. This is either consistent with the bulk of material being confined within the binary system or with a significant delay between mass loss and supernova explosion. We furthermore combine X-ray and radio limits from Chomiuk et al. to constrain the post-shock energy density in magnetic fields. Finally, we searched for the shock breakout pulse using gamma-ray observations from the Interplanetary Network and find no compelling evidence for a supernova-associated burst. Based on the compact radius of the progenitor star we estimate that the shock breakout pulse was likely not detectable by current satellites.
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| 9. |
- Moraitou, Markella, et al.
(författare)
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Ecology, Not Host Phylogeny, Shapes the Oral Microbiome in Closely Related Species
- 2022
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Ingår i: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 39:12
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Tidskriftsartikel (refereegranskat)abstract
- Host-associated microbiomes are essential for a multitude of biological processes. Placed at the contact zone between external and internal environments, the little-studied oral microbiome has important roles in host physiology and health. Here, we investigate the roles of host evolutionary relationships and ecology in shaping the oral microbiome in three closely related gorilla subspecies (mountain, Grauer's, and western lowland gorillas) using shotgun metagenomics of 46 museum-preserved dental calculus samples. We find that the oral microbiomes of mountain gorillas are functionally and taxonomically distinct from the other two subspecies, despite close evolutionary relationships and geographic proximity with Grauer's gorillas. Grauer's gorillas show intermediate bacterial taxonomic and functional, and dietary profiles. Altitudinal differences in gorilla subspecies ranges appear to explain these patterns, suggesting a close connection between dental calculus microbiomes and the environment, likely mediated through diet. This is further supported by the presence of gorilla subspecies-specific phyllosphere/rhizosphere taxa in the oral microbiome. Mountain gorillas show a high abundance of nitrate-reducing oral taxa, which may promote adaptation to a high-altitude lifestyle by modulating blood pressure. Our results suggest that ecology, rather than evolutionary relationships and geographic distribution, shape the oral microbiome in these closely related species.
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