| 11. |
- Bertolotto, Corine, et al.
(författare)
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A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 480:7375, s. 94-98
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Tidskriftsartikel (refereegranskat)abstract
- So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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| 12. |
- Galaup, Ariane, et al.
(författare)
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Protection Against Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Angiopoietin-Like 4
- 2012
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 125:1, s. 140-149
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Tidskriftsartikel (refereegranskat)abstract
- Background-Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell-cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI. Methods and Results-We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4-deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4-deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4-deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits. Conclusions-These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI.
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| 13. |
- Hudson, Lawrence N., et al.
(författare)
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The PREDICTS database : a global database of how local terrestrial biodiversity responds to human impacts
- 2014
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Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 4:24, s. 4701-4735
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Tidskriftsartikel (refereegranskat)abstract
- Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
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| 14. |
- van der Harst, Pim, et al.
(författare)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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| 15. |
- Abbas, E., et al.
(författare)
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Centrality dependence of the pseudorapidity density distribution for charged particles in Pb-Pb collisions at root s(NN)=2.76 TeV
- 2013
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 726:4-5, s. 610-622
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Tidskriftsartikel (refereegranskat)abstract
- We present the first wide-range measurement of the charged-particle pseudorapidity density distribution, for different centralities (the 0-5%, 5-10%, 10-20%, and 20-30% most central events) in Pb-Pb collisions at root s(NN) = 2.76 TeV at the LHC. The measurement is performed using the full coverage of the ALICE detectors, -5.0 < eta < 5.5, and employing a special analysis technique based on collisions arising from LHC 'satellite' bunches. We present the pseudorapidity density as a function of the number of participating nucleons as well as an extrapolation to the total number of produced charged particles (N-ch = 17165 +/- 772 for the 0-5% most central collisions). From the measured dN(ch)/d eta distribution we derive the rapidity density distribution, dN(ch)/dy, under simple assumptions. The rapidity density distribution is found to be significantly wider than the predictions of the Landau model. We assess the validity of longitudinal scaling by comparing to lower energy results from RHIC. Finally the mechanisms of the underlying particle production are discussed based on a comparison with various theoretical models. (C) 2013 CERN. Published by Elsevier B.V. All rights reserved.
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| 16. |
- Abbas, E., et al.
(författare)
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Charmonium and e(+)e(-) pair photoproduction at mid-rapidity in ultra-peripheral Pb-Pb collisions at root s(NN)=2.76 TeV
- 2013
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 73:11
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Tidskriftsartikel (refereegranskat)abstract
- The ALICE Collaboration at the LHC has measured the J/psi and psi' photoproduction at mid-rapidity in ultra-peripheral Pb-Pb collisions at root s(NN) = 2.76 TeV. The charmonium is identified via its leptonic decay for events where the hadronic activity is required to be minimal. The analysis is based on an event sample corresponding to an integrated luminosity of about 23 mu b(-1). The cross section for coherent and incoherent J/psi production in the rapidity interval -0.9 < y < 0.9, are d sigma(coh)(J/psi)/dy = 2.38(-0.24)(+0.34)(sta + sys) mb and d sigma(inc)(J/psi)/dy = 0.98(-0.17)(+0.19)(sta + sys) mb and , respectively. The results are compared to theoretical models for J/psi production and the coherent cross section is found to be in good agreement with those models incorporating moderate nuclear gluon shadowing at Bjorken-x around 10(-3), such as EPS09 parametrization. In addition the cross section for the process gamma gamma -> e(+)e(-) has been measured and found to be in agreement with models implementing QED at leading order.
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| 17. |
- Abbas, E., et al.
(författare)
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J/psi Elliptic Flow in Pb-Pb Collisions at root s(NN)=2.76 TeV
- 2013
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Ingår i: Physical Review Letters. - 1079-7114. ; 111:16
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first measurement of inclusive J/psi elliptic flow v(2) in heavy-ion collisions at the LHC. The measurement is performed with the ALICE detector in Pb-Pb collisions at root s(NN) = 2.76 TeV in the rapidity range 2.5 < y < 4.0. The dependence of the J/psi v(2) on the collision centrality and on the J/psi transverse momentum is studied in the range 0 <= p(T) < 10 GeV/c. For semicentral Pb-Pb collisions at root s(NN) = 2.76 TeV, an indication of nonzero v(2) is observed with a largest measured value of v(2) = 0.116 +/-0.046(stat) +/- 0.029(syst) for J/psi in the transverse momentum range 2 <= p(T) < 4 GeV/c. The elliptic flow measurement complements the previously reported ALICE results on the inclusive J/psi nuclear modification factor and favors the scenario of a significant fraction of J/psi production from charm quarks in a deconfined partonic phase.
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| 18. |
- Abbas, E., et al.
(författare)
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Mid-rapidity anti-baryon to baryon ratios in pp collisions at root s=0.9, 2.76 and 7 TeV measured by ALICE
- 2013
-
Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 73:7
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Tidskriftsartikel (refereegranskat)abstract
- The ratios of yields of anti-baryons to baryons probes the mechanisms of baryon-number transport. Results for (p) over bar /p, (Lambda) over bar/Lambda, (Xi) over bar (+)/(Xi) over bar (-) and (Omega) over bar (+)/(Omega) over bar (-) in pp collisions at root s = 0.9, 2.76 and 7 TeV, measured with the ALICE detector at the LHC, are reported. Within the experimental uncertainties and ranges covered by our measurement, these ratios are independent of rapidity, transverse momentum and multiplicity for all measured energies. The results are compared to expectations from event generators, such as PYTHIA and HIJING/B, that are used to model the particle production in pp collisions. The energy dependence of (p) over bar /p, (Lambda) over bar/(Lambda) over bar, (Xi) over bar (+)/(Xi) over bar (-) and (Omega) over bar (+)/(Omega) over bar (-), reaching values compatible with unity for root s = 7 TeV, complement the earlier (p) over bar /p measurement of ALICE. These dependencies can be described by exchanges with the Regge-trajectory intercept of alpha(J) approximate to 0.5, which are suppressed with increasing rapidity interval Delta y. Any significant contribution of an exchange not suppressed at large Delta y (reached at LHC energies) is disfavoured.
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| 19. |
- Abbas, E., et al.
(författare)
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Performance of the ALICE VZERO system
- 2013
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- ALICE is an LHC experiment devoted to the study of strongly interacting matter in proton-proton, proton-nucleus and nucleus-nucleus collisions at ultra-relativistic energies. The ALICE VZERO system, made of two scintillator arrays at asymmetric positions, one on each side of the interaction point, plays a central role in ALICE. In addition to its core function as a trigger source, the VZERO system is used to monitor LHC beam conditions, to reject beam-induced backgrounds and to measure basic physics quantities such as luminosity, particle multiplicity, centrality and event plane direction in nucleus-nucleus collisions. After describing the VZERO system, this publication presents its performance over more than four years of operation at the LHC.
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| 20. |
- Abelev, B., et al.
(författare)
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Centrality dependence of pi, K, and p production in Pb-Pb collisions at root s(NN)=2.76 TeV
- 2013
-
Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 88:4
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Tidskriftsartikel (refereegranskat)abstract
- In this paper measurements are presented of pi(+/-), K-+/-, p, and (p) over bar production at midrapidity (vertical bar y vertical bar < 0.5), in Pb-Pb collisions at root s(NN) = 2.76 TeV as a function of centrality. The measurement covers the transverse-momentum (p(T)) range from 100, 200, and 300 MeV/c up to 3, 3, and 4.6 GeV/c for pi, K, and p, respectively. The measured p(T) distributions and yields are compared to expectations based on hydrodynamic, thermal and recombination models. The spectral shapes of central collisions show a stronger radial flow than measured at lower energies, which can be described in hydrodynamic models. In peripheral collisions, the p(T) distributions are not well reproduced by hydrodynamic models. Ratios of integrated particle yields are found to be nearly independent of centrality. The yield of protons normalized to pions is a factor similar to 1.5 lower than the expectation from thermal models.
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