| 26. |
- Chung, Sharon A., et al.
(författare)
-
Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti-dsDNA Autoantibody Production
- 2011
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1001323-
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with (Pheterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
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| 27. |
- Gorlova, Olga, et al.
(författare)
-
Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy
- 2011
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:7
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (IcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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| 28. |
- Harley, Isaac T. W., et al.
(författare)
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The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus
- 2010
-
Ingår i: Journal of Biomedicine and Biotechnology. - : Hindawi Limited. - 1110-7243 .- 1110-7251. ; , s. 706825-
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.
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| 29. |
- Hellesen, Carl, et al.
(författare)
-
Fast-ion distributions from third harmonic ICRF heating studied with neutron emission spectroscopy
- 2013
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 53:11, s. 113009-
-
Tidskriftsartikel (refereegranskat)abstract
- The fast-ion distribution from third harmonic ion cyclotron resonance frequency (ICRF) heating on the Joint European Torus is studied using neutron emission spectroscopy with the time-of-flight spectrometer TOFOR. The energy dependence of the fast deuteron distribution function is inferred from the measured spectrum of neutrons born in DD fusion reactions, and the inferred distribution is compared with theoretical models for ICRF heating. Good agreements between modelling and measurements are seen with clear features in the fast-ion distribution function, that are due to the finite Larmor radius of the resonating ions, replicated. Strong synergetic effects between ICRF and neutral beam injection heating were also seen. The total energy content of the fast-ion population derived from TOFOR data was in good agreement with magnetic measurements for values below 350 kJ.
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| 30. |
- Hetzinger, S., et al.
(författare)
-
Coralline algal Barium as indicator for 20th century northwestern North Atlantic surface ocean freshwater variability
- 2013
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- During the past decades climate and freshwater dynamics in the northwestern North Atlantic have undergone major changes. Large-scale freshening episodes, related to polar freshwater pulses, have had a strong influence on ocean variability in this climatically important region. However, little is known about variability before 1950, mainly due to the lack of long-term high-resolution marine proxy archives. Here we present the first multidecadal-length records of annually resolved Ba/Ca variations from Northwest Atlantic coralline algae. We observe positive relationships between algal Ba/Ca ratios from two Newfoundland sites and salinity observations back to 1950. Both records capture episodical multi-year freshening events during the 20th century. Variability in algal Ba/Ca is sensitive to freshwater-induced changes in upper ocean stratification, which affect the transport of cold, Ba-enriched deep waters onto the shelf (highly stratified equals less Ba/Ca). Algal Ba/Ca ratios therefore may serve as a new resource for reconstructing past surface ocean freshwater changes.
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| 31. |
- Hetzinger, S., et al.
(författare)
-
High-resolution analysis of trace elements in crustose coralline algae from the North Atlantic and North Pacific by laser ablation ICP-MS
- 2011
-
Ingår i: Palaeogeography Palaeoclimatology Palaeoecology. - 0031-0182. ; 302:1-2, s. 81-94
-
Tidskriftsartikel (refereegranskat)abstract
- We have investigated the trace elemental composition in the skeleta of two specimens of attached-living coralline algae of the species Clathromorphum compactum from the North Atlantic (Newfoundland) and Clathromorphum nereostratum from the North Pacific/Bering Sea region (Amchitka Island, Aleutians). Samples were analyzed using Laser Ablation-Inductively Coupled Plasma Mass Spectrometry (IA-ICP-MS) yielding for the first time continuous individual trace elemental records of up to 69 years in length. The resulting algal Mg/Ca, Sr/Ca, U/Ca, and Ba/Ca ratios are reproducible within individual sample specimens. Algal Mg/Ca ratios were additionally validated by electron microprobe analyses (Amchitka sample). Algal Sr/Ca, U/Ca, and Ba/Ca ratios were compared to algal Mg/Ca ratios, which previously have been shown to reliably record sea surface temperature (SST). Ratios of Sr/Ca from both Clathromorphum species show a strong positive correlation to temperature-dependent Mg/Ca ratios, implying that seawater temperature plays an important role in the incorporation of Sr into algal calcite. Linear Sr/Ca-SST regressions have provided positive, but weaker relationships as compared to Mg/Ca-SST relationships. Both, algal Mg/Ca and Sr/Ca display clear seasonal cycles. Inverse correlations were found between algal Mg/Ca and U/Ca, Ba/Ca, and correlations to SST are weaker than between Mg/Ca, Sr/Ca and SST. This suggests that the incorporation of U and Ba is influenced by other factors aside from temperature. (C) 2010 Elsevier B.V. All rights reserved.
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| 32. |
- Johnson, M. Gatu, et al.
(författare)
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Neutron spectrometry of JET discharges with ICRH-acceleration of helium beam ions
- 2010
-
Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 81:10, s. 10D336-
-
Tidskriftsartikel (refereegranskat)abstract
- Recent experiments at JET aimed at producing He-4 ions in the MeV range through third harmonic ion cyclotron resonance heating (ICRH) acceleration of He-4 beams in a He-4 dominated plasma. MeV range D was also present through parasitic ICRH absorption on residual D. In this contribution, we analyze TOFOR neutron spectrometer data from these experiments. A consistent description of the data is obtained with d(d, n)(3) He and Be-9(alpha, n)C-12 neutron components calculated using Stix distributions for the fast D and He-4, taking finite Larmor radius effects into account and with a ICRH power partition of P-D(RF) = 0.01 X P-4He(RF), in agreement with TOMCAT simulations.
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| 33. |
- Bossini-Castillo, Lara, et al.
(författare)
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A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort
- 2011
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70:4, s. 638-641
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. Methods A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. Results A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). Conclusions The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.
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| 34. |
- Bossini-Castillo, Lara, et al.
(författare)
-
Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population.
- 2011
-
Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 50, s. 1976-1981
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives. The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population.Methods. A total of 3800 SSc patients and 4282 healthy controls of white Caucasian ancestry from eight different European countries were included in the study. The MIF -173 single nucleotide polymorphism (SNP) was selected as genetic marker and genotyped using Taqman 5' allelic discrimination assay.Results. The MIF -173 SNP showed association with SSc [P = 0.04, odds ratio (OR) = 1.10, 95% CI 1.00, 1.19]. Analysis of the MIF -173 polymorphism according to SSc clinical phenotype revealed that the frequency of the -173*C allele was significantly higher in the dcSSc group compared with controls (P = 5.30E-03, OR = 1.21, 95% CI 1.07, 1.38). Conversely, the frequency of the MIF -173*C allele was significantly underrepresented in the lcSSc group compared with dcSSc patients, supporting previous findings [(P = 0.04, OR = 0.86, 95% CI 0.75, 0.99); meta-analysis including previous results (P = 0.005, OR = 0.83, 95% CI 0.73, 0.94)].Conclusion. Our results confirm the role of MIF -173 promoter polymorphism in SSc, and provide evidence of a strong association with the dcSSc subgroup of patients. Hence, the MIF -173 variant is confirmed as a promising clinical phenotype genetic marker.
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| 35. |
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| 36. |
- Eriksson, Jacob, et al.
(författare)
-
Finite Larmor radii effects in fast ion measurements as demonstrated using neutron emission spectrometry of JET plasmas heated with 3rd harmonic ICRF
- 2011
-
Ingår i: 38th EPS Conference on Plasma Physics 2011 (EPS 2011): Europhysics Conference Abstracts. - 2914771681
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- This paper demonstrates how the finite Larmor radii (FLR) of fast ions can affect fast ion measurements by studying data from the neutron time-of-flight spectrometer TOFOR. Neutron spectra were calculated from a model of the fast ion velocity distribution for a JET experiment with 3rd harmonic ICRF heating of deuterium beams. It was found that FLR effects need to be considered to get a good description of the data, if the Larmor radius of the fast ions are comparable to the width of the field of view of the instrument. This applies not only to results from neutron spectrometry but also to other types of fast ion diagnostics.
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| 37. |
- Eriksson, Jacob, et al.
(författare)
-
Finite Larmor radii effects in fast ion measurements with neutron emission spectrometry
- 2013
-
Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 55:1, s. 015008-
-
Tidskriftsartikel (refereegranskat)abstract
- When analysing data from fast ion measurements it is normally assumed that the gyro-phase distribution of the ions is isotropic within the field of view of the measuring instrument. This assumption is not valid if the Larmor radii of the fast ions are comparable to—or larger than—the gradient scale length in the spatial distribution of the ions, and if this scale length is comparable to—or smaller than—the width of the field of view of the measuring instrument. In this paper the effect of such an anisotropy is demonstrated by analysing neutron emission spectrometry data from a JET experiment with deuterium neutral beams together with radiofrequency heating at the third harmonic of the deuterium cyclotron frequency. In the experiment, the neutron time-of-flight spectrometer TOFOR was used to measure the neutrons from the d(d,n) 3 He-reaction. Comparison of the experimental data with Monte Carlo calculations shows that the finite Larmor radii of the fast ions need to be included in the modelling to get a good description of the data. Similar effects are likely to be important for other fast ion diagnostics, such as γ -ray spectroscopy and neutral particle analysis, as well.
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| 38. |
- Eriksson, Jacob, et al.
(författare)
-
Neutron spectrometry measurements of energetic deuterons in ICRF heated plasmas with the ITER-like wall at JET
- 2014
-
Ingår i: 41th EPS Conference on Plasma Physics 2014 (EPS 2014): Europhysics Conference Abstracts.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- At JET, experiments have been conducted in order to optimize the performance of ion cyclotron radio-frequency (ICRF) heating in the presence of the newly installed ITER-like wall. The ICRF was tuned to the cyclotron frequency of minority hydrogen (H), which is also the 2nd harmonic of the cyclotron frequency of deuterium (D). The relative H concentration was varied from a few percent up to about 25 percent in a series of plasma discharges and the neutron time-of-flight spectrometer TOFOR was used to measure the energy spectrum of neutrons from the D(D,n)3He reaction during these discharges. It could be seen that the signal from ICRF accelerated deuterons depended strongly on H concentration. This observation indicates that the ICRF power absorbed by D at the 2nd harmonic cyclotron resonance increases with decreasing H concentration. This is in qualitative agreement with theoretical expectations obtained from the plasma wave equation solver TOMCAT.
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| 39. |
- Gamboa, G., et al.
(författare)
-
Mg/Ca ratios in coralline algae record northwest Atlantic temperature variations and North Atlantic Oscillation relationships
- 2010
-
Ingår i: Journal of Geophysical Research-Oceans. - 0148-0227. ; 115
-
Tidskriftsartikel (refereegranskat)abstract
- [1] Climate variability in the North Atlantic has been linked in part to the North Atlantic Oscillation (NAO). The NAO influences marine ecosystems in the northwestern Atlantic and transport variability of the cold Labrador Current. Understanding historic patterns of NAO variability requires long-term and high-resolution climate records that are not available from instrumental data. Here we present the first century-scale proxy record of sea surface temperature (SST) variability from the Newfoundland shelf, a region from which other annual-resolution shallow marine proxies are unavailable. The 116 year record was obtained from three sites along the eastern Newfoundland shelf using laser ablation inductively coupled mass spectrometry-determined Mg/Ca ratios in the crustose coralline alga Clathromorphum compactum. The alga is characterized by a high Mg-calcite skeleton exhibiting annual growth increments and a century-scale lifespan. Results indicate positive correlations between interannual variations in Mg/Ca ratios and both station-based and gridded instrumental SST. In addition, the record shows high spatial correlations to SST across the Newfoundland shelf and the Gulf of St. Lawrence. Before 1950 the Mg/Ca proxy record reveals significant departures from gridded temperature records. While the Newfoundland shelf is generally considered a region of negative correlations to the NAO, the algal time series as well as a recent modeling study suggest a variable negative relationship with the NAO which is strongest after similar to 1960 and before the mid-1930s.
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| 40. |
- Gassner, T., et al.
(författare)
-
Deuterium beam acceleration with 3rd harmonic ion cyclotron resonance heating in Joint European Torus : Sawtooth stabilization and Alfven eigenmodes
- 2012
-
Ingår i: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 19:3, s. 032115-
-
Tidskriftsartikel (refereegranskat)abstract
- Experiments on accelerating NBI-produced deuterium (D) beam ions from their injection energy of similar to 110 keV up to the MeV energy range with 3rd harmonic ion cyclotron resonance heating were performed on the Joint European Torus [P. H. Rebut and B. E. Keen, Fusion Technol. 11, 13 (1987)]. A renewed set of nuclear diagnostics was used for analysing fast D ions during sawtooth stabilization, monster sawtooth crashes, and during excitation of Alfven eigenmodes (AEs) residing inside the q = 1 radius. The measurements and modeling of the fast ions with the nonlinear HAGIS code [S. D. Pinches et al., Comput. Phys. Commun. 111, 133 (1998)] show that monster sawtooth crashes are strongly facilitated by the AE-induced re-distribution of the fast D ions from inside the q = 1 radius to the plasma edge. [http://dx.doi.org/10.1063/1.3696858]
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| 41. |
- Halfar, J., et al.
(författare)
-
Coralline algal growth-increment widths archive North Atlantic climate variability
- 2011
-
Ingår i: Palaeogeography Palaeoclimatology Palaeoecology. - 0031-0182. ; 302:1-2, s. 71-80
-
Tidskriftsartikel (refereegranskat)abstract
- Over the past decade coralline algae have increasingly been used as archives of paleoclimate information. Encrusting coralline algae, which deposit annual growth increments in a high Mg-calcite skeleton, are amongst the longest-lived shallow marine organisms. In fact, a live-collected plant has recently been shown to have lived for at least 850 years based on radiometric dating. While a number of investigations have successfully used geochemical information of coralline algal skeletons to reconstruct sea surface temperatures, less attention has been paid to employ growth increment widths as a temperature proxy. Here we explore the relationship between growth and environmental parameters in Clathromorphum compactum collected in the subarctic Northwestern Atlantic. Results indicate that growth-increment widths of individual plants are poorly correlated with instrumental sea surface temperatures (SST). However, an averaged record of multiple growth increment-width time series from a regional network of C. compactum specimens up to 800 km apart reveals strong correlations with annual instrumental SST since 1950. Hence, similar to methods applied in dendrochronology, averaging of multiple sclerochronological records of coralline algae provides accurate climate information. A 115-year growth-increment width master chronology created from modern-collected and museum specimens is highly correlated to multidecadal variability seen in North Atlantic sea surface temperatures. Positive changes in algal growth anomalies record the well-documented regime shift and warming in the northwestern Atlantic during the 1990s. Large positive changes in algal growth anomalies were also present in the 1920s and 1930s, indicating that the impact of a concurrent large-scale regime shift throughout the North Atlantic was more strongly felt in the subarctic Northwestern Atlantic than previously thought, and may have even exceeded the 1990s event with respect to the magnitude of the warming. (C) 2010 Elsevier B.V. All rights reserved.
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| 42. |
- Hellesen, Carl, 1980-, et al.
(författare)
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Measurements of fast ions and their interactions with MHD activity using neutron emission spectroscopy
- 2010
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 50:8, s. 084006-
-
Tidskriftsartikel (refereegranskat)abstract
- Ion cyclotron radio frequency (ICRF) heating can produce fast ion populations with energies reaching up to several megaelectronvolts. Here, we present unique measurements of fast ion distributions from an experiment with 3rd harmonic ICRF heating on deuterium beams using neutron emission spectroscopy (NES). From the experiment, very high DD neutron rates were observed, using only modest external heating powers. This was attributed to acceleration of deuterium beam ions to energies up to about 2-3 MeV, where the DD reactivity is on a par with that of the DT reaction. The high neutron rates allowed for observations of changes in the fast deuterium energy distribution on a time scale of 50 ms. Clear correlations were seen between fast deuterium ions in different energy ranges and magnetohydrodynamic activities, such as monster sawteeth and toroidal Alfven eigen modes (TAE). Specifically, NES data showed that the number of deuterons in the region between 1 and 1.5 MeV were decaying significantly during strong TAE activity, while ions with lower energies around 500 keV were not affected. This was attributed to resonances with the TAE modes.
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| 43. |
- Herman, Jonathan D., et al.
(författare)
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A genomic and evolutionary approach reveals non-genetic drug resistance in malaria
- 2014
-
Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:11, s. 511-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.
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| 44. |
- Hettmann, K., et al.
(författare)
-
The geochemistry of Tl and its isotopes during magmatic and hydrothermal processes: The peralkaline Ilimaussaq complex, southwest Greenland
- 2014
-
Ingår i: Chemical Geology. - : Elsevier BV. - 0009-2541. ; 366, s. 1-13
-
Tidskriftsartikel (refereegranskat)abstract
- We use thallium (Tl) concentrations, K/Rb, K/Tl and Rb/Tl ratios and Tl isotopes in minerals from the alkaline to peralkaline Ilimaussaq complex (South Greenland) to trace magmatic differentiation, crustal assimilation, magmatic degassing, ore precipitation and hydrothermal metasomatism. Closed-system magmatic differentiation is marked by a coherent decrease of K/Tl- and K/Rb-ratios, whereas crustal assimilation results in a strong Tl-enrichment, causing low K/Tl-ratios compared to K/Rb-ratios. Thallium isotopes show only slight changes during orthomagmatic differentiation and the assimilation of crustal material cannot be traced, since the isotopic composition of the average crust is within the range of the mantle and mantle-derived rocks. Magmatic degassing, however, increases Rb/Tl-ratios and changes the isotopic composition of Tl. The released fluids are enriched in Tl, characterized by high 205Tl/203Tl ratios and can precipitate Tl-rich sulfide and silicate minerals as indicated by some late-magmatic hydrothermal veins, which contain a conspicuous assemblage of Tl-Fe-Cu-sulfides (thalcusite, djerfisherite, chalcothallite). The oxidative alteration of these assemblages at high pH results in small-scale redistribution of Tl. Thallium released by this process is entrained into late-stage Tl-enriched astrophyllite. © 2013 Elsevier B.V.
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| 45. |
- Moller, Anders Pape, et al.
(författare)
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Clutch-size variation in Western Palaearctic secondary hole-nesting passerine birds in relation to nest box design
- 2014
-
Ingår i: Methods in Ecology and Evolution. - 2041-210X. ; 5:4, s. 353-362
-
Tidskriftsartikel (refereegranskat)abstract
- Secondary hole-nesting birds that do not construct nest holes themselves and hence regularly breed in nest boxes constitute important model systems for field studies in many biological disciplines with hundreds of scientists and amateurs involved. Those research groups are spread over wide geographic areas that experience considerable variation in environmental conditions, and researchers provide nest boxes of varying designs that may inadvertently introduce spatial and temporal variation in reproductive parameters. We quantified the relationship between mean clutch size and nest box size and material after controlling for a range of environmental variables in four of the most widely used model species in the Western Palaearctic: great tit Parus major, blue tit Cyanistes caeruleus, pied flycatcher Ficedula hypoleuca and collared flycatcher F.albicollis from 365 populations and 79610 clutches. Nest floor area and nest box material varied non-randomly across latitudes and longitudes, showing that scientists did not adopt a random box design. Clutch size increased with nest floor area in great tits, but not in blue tits and flycatchers. Clutch size of blue tits was larger in wooden than in concrete nest boxes. These findings demonstrate that the size of nest boxes and material used to construct nest boxes can differentially affect clutch size in different species. The findings also suggest that the nest box design may affect not only focal species, but also indirectly other species through the effects of nest box design on productivity and therefore potentially population density and hence interspecific competition.
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| 46. |
- Moller, Anders P., et al.
(författare)
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Variation in clutch size in relation to nest size in birds
- 2014
-
Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 4:18, s. 3583-3595
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Tidskriftsartikel (refereegranskat)abstract
- Nests are structures built to support and protect eggs and/or offspring from predators, parasites, and adverse weather conditions. Nests are mainly constructed prior to egg laying, meaning that parent birds must make decisions about nest site choice and nest building behavior before the start of egg-laying. Parent birds should be selected to choose nest sites and to build optimally sized nests, yet our current understanding of clutch size-nest size relationships is limited to small-scale studies performed over short time periods. Here, we quantified the relationship between clutch size and nest size, using an exhaustive database of 116 slope estimates based on 17,472 nests of 21 species of hole and non-hole-nesting birds. There was a significant, positive relationship between clutch size and the base area of the nest box or the nest, and this relationship did not differ significantly between open nesting and hole-nesting species. The slope of the relationship showed significant intraspecific and interspecific heterogeneity among four species of secondary hole-nesting species, but also among all 116 slope estimates. The estimated relationship between clutch size and nest box base area in study sites with more than a single size of nest box was not significantly different from the relationship using studies with only a single size of nest box. The slope of the relationship between clutch size and nest base area in different species of birds was significantly negatively related to minimum base area, and less so to maximum base area in a given study. These findings are consistent with the hypothesis that bird species have a general reaction norm reflecting the relationship between nest size and clutch size. Further, they suggest that scientists may influence the clutch size decisions of hole-nesting birds through the provisioning of nest boxes of varying sizes.
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| 47. |
- Nowaczyk, N. R., et al.
(författare)
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Chronology of Lake El'gygytgyn sediments - a combined magnetostratigraphic, palaeoclimatic and orbital tuning study based on multi-parameter analyses
- 2013
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 9:6, s. 2413-2432
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Tidskriftsartikel (refereegranskat)abstract
- A 318-metre-long sedimentary profile drilled by the International Continental Scientific Drilling Program (ICDP) at Site 5011-1 in Lake El'gygytgyn, Far East Russian Arctic, has been analysed for its sedimentologic response to global climate modes by chronostratigraphic methods. The 12 km wide lake is sited off-centre in an 18 km large crater that was created by the impact of a meteorite 3.58 Ma ago. Since then sediments have been continuously deposited. For establishing their chronology, major reversals of the earth's magnetic field provided initial tie points for the age model, confirming that the impact occurred in the earliest geomagnetic Gauss chron. Various stratigraphic parameters, reflecting redox conditions at the lake floor and climatic conditions in the catchment were tuned synchronously to Northern Hemisphere insolation variations and the marine oxygen isotope stack, respectively. Thus, a robust age model comprising more than 600 tie points could be defined. It could be shown that deposition of sediments in Lake El'gygytgyn occurred in concert with global climatic cycles. The upper similar to 160m of sediments represent the past 3.3 Ma, equivalent to sedimentation rates of 4 to 5 cm ka(-1), whereas the lower 160m represent just the first 0.3 Ma after the impact, equivalent to sedimentation rates in the order of 45 cm ka(-1). This study also provides orbitally tuned ages for a total of 8 tephras deposited in Lake El'gygytgyn.
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| 48. |
- Piper, Brian J., et al.
(författare)
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Non-replication of an association of Apolipoprotein E2 with sinistrality
- 2013
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Ingår i: Laterality. - 1357-650X .- 1464-0678. ; 18:2, s. 251-261
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Tidskriftsartikel (refereegranskat)abstract
- A recent report found that left-handed adolescents were more than three times more likely to have an Apolipoprotein (APOE) E2 allele. This study was unable to replicate this association in young adults (N=166). A meta-analysis of nine other datasets (N=360 to 7559, Power > 0.999) including that of National Alzheimer's Coordinating Center also failed to find an over-representation of E2 among left-handers indicating that this earlier outcome was most likely a statistical artefact.
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| 49. |
- Riddle, Nicole C, et al.
(författare)
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Plasticity in patterns of histone modifications and chromosomal proteins in Drosophila heterochromatin
- 2011
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 21:2, s. 147-163
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Tidskriftsartikel (refereegranskat)abstract
- Eukaryotic genomes are packaged in two basic forms, euchromatin and heterochromatin. We have examined the composition and organization of Drosophila melanogaster heterochromatin in different cell types using ChIP-array analysis of histone modifications and chromosomal proteins. As anticipated, the pericentric heterochromatin and chromosome 4 are on average enriched for the "silencing" marks H3K9me2, H3K9me3, HP1a, and SU(VAR)3-9, and are generally depleted for marks associated with active transcription. The locations of the euchromatin-heterochromatin borders identified by these marks are similar in animal tissues and most cell lines, although the amount of heterochromatin is variable in some cell lines. Combinatorial analysis of chromatin patterns reveals distinct profiles for euchromatin, pericentric heterochromatin, and the 4th chromosome. Both silent and active protein-coding genes in heterochromatin display complex patterns of chromosomal proteins and histone modifications; a majority of the active genes exhibit both "activation" marks (e.g., H3K4me3 and H3K36me3) and "silencing" marks (e.g., H3K9me2 and HP1a). The hallmark of active genes in heterochromatic domains appears to be a loss of H3K9 methylation at the transcription start site. We also observe complex epigenomic profiles of intergenic regions, repeated transposable element (TE) sequences, and genes in the heterochromatic extensions. An unexpectedly large fraction of sequences in the euchromatic chromosome arms exhibits a heterochromatic chromatin signature, which differs in size, position, and impact on gene expression among cell types. We conclude that patterns of heterochromatin/euchromatin packaging show greater complexity and plasticity than anticipated. This comprehensive analysis provides a foundation for future studies of gene activity and chromosomal functions that are influenced by or dependent upon heterochromatin.
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| 50. |
- Rogers, Kathleen E., et al.
(författare)
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Novel Cruzain Inhibitors for the Treatment of Chagas' Disease
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 80:3, s. 398-405
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Tidskriftsartikel (refereegranskat)abstract
- The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T.similar to cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas disease.
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