| 1. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Dornelas, M., et al.
(författare)
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BioTIME: A database of biodiversity time series for the Anthropocene
- 2018
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 27:7, s. 760-786
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included: The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain: BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km(2) (158 cm(2)) to 100 km(2) (1,000,000,000,000 cm(2)). Time period and grainBio: TIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement: BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.
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| 6. |
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| 7. |
- Ramilowski, JA, et al.
(författare)
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Functional annotation of human long noncoding RNAs via molecular phenotyping
- 2020
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 30:7, s. 1060-1072
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Tidskriftsartikel (refereegranskat)abstract
- Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.
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| 8. |
- van der Plas, F., et al.
(författare)
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Continental mapping of forest ecosystem functions reveals a high but unrealised potential for forest multifunctionality
- 2018
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 21:1, s. 31-42
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Tidskriftsartikel (refereegranskat)abstract
- Humans require multiple services from ecosystems, but it is largely unknown whether trade-offs between ecosystem functions prevent the realisation of high ecosystem multifunctionality across spatial scales. Here, we combined a comprehensive dataset (28 ecosystem functions measured on 209 forest plots) with a forest inventory dataset (105,316 plots) to extrapolate and map relationships between various ecosystem multifunctionality measures across Europe. These multifunctionality measures reflected different management objectives, related to timber production, climate regulation and biodiversity conservation/recreation. We found that trade-offs among them were rare across Europe, at both local and continental scales. This suggests a high potential for win-win' forest management strategies, where overall multifunctionality is maximised. However, across sites, multifunctionality was on average 45.8-49.8% below maximum levels and not necessarily highest in protected areas. Therefore, using one of the most comprehensive assessments so far, our study suggests a high but largely unrealised potential for management to promote multifunctional forests.
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| 9. |
- 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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| 10. |
- Fritz, M., et al.
(författare)
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Brief Communication : Future avenues for permafrost science from the perspective of early career researchers
- 2015
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Ingår i: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 9:4, s. 1715-1720
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Tidskriftsartikel (refereegranskat)abstract
- Accelerating climate change and increased economic and environmental interests in permafrost-affected regions have resulted in an acute need for more directed permafrost research. In June 2014, 88 early career researchers convened to identify future priorities for permafrost research. This multidisciplinary forum concluded that five research topics deserve greatest attention: permafrost landscape dynamics, permafrost thermal modeling, integration of traditional knowledge, spatial distribution of ground ice, and engineering issues. These topics underline the need for integrated research across a spectrum of permafrost-related domains and constitute a contribution to the Third International Conference on Arctic Research Planning (ICARP III).
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| 11. |
- Kambach, S., et al.
(författare)
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How do trees respond to species mixing in experimental compared to observational studies?
- 2019
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Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 9:19, s. 11254-11265
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Tidskriftsartikel (refereegranskat)abstract
- For decades, ecologists have investigated the effects of tree species diversity on tree productivity at different scales and with different approaches ranging from observational to experimental study designs. Using data from five European national forest inventories (16,773 plots), six tree species diversity experiments (584 plots), and six networks of comparative plots (169 plots), we tested whether tree species growth responses to species mixing are consistent and therefore transferrable between those different research approaches. Our results confirm the general positive effect of tree species mixing on species growth (16% on average) but we found no consistency in species-specific responses to mixing between any of the three approaches, even after restricting comparisons to only those plots that shared similar mixtures compositions and forest types. These findings highlight the necessity to consider results from different research approaches when selecting species mixtures that should maximize positive forest biodiversity and functioning relationships.
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| 12. |
- Hilchenbach, M., et al.
(författare)
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COMET 67P/CHURYUMOV-GERASIMENKO : CLOSE-UP on DUST PARTICLE FRAGMENTS
- 2016
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Ingår i: Astrophysical Journal Letters. - : Institute of Physics Publishing (IOPP). - 2041-8205 .- 2041-8213. ; 816:2
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Tidskriftsartikel (refereegranskat)abstract
- The COmetary Secondary Ion Mass Analyser instrument on board ESA's Rosetta mission has collected dust particles in the coma of comet 67P/Churyumov-Gerasimenko. During the early-orbit phase of the Rosetta mission, particles and particle agglomerates have been imaged and analyzed in the inner coma at distances between 100 km and 10 km off the cometary nucleus and at more than 3 AU from the Sun. We identified 585 particles of more than 14 μm in size. The particles are collected at low impact speeds and constitute a sample of the dust particles in the inner coma impacting and fragmenting on the targets. The sizes of the particles range from 14 μm up to sub-millimeter sizes and the differential dust flux size distribution is fitted with a power law exponent of -3.1. After impact, the larger particles tend to stick together, spread out or consist of single or a group of clumps, and the flocculent morphology of the fragmented particles is revealed. The elemental composition of the dust particles is heterogeneous and the particles could contain typical silicates like olivine and pyroxenes, as well as iron sulfides. The sodium to iron elemental ratio is enriched with regard to abundances in CI carbonaceous chondrites by a factor from ∼1.5 to ∼15. No clear evidence for organic matter has been identified. The composition and morphology of the collected dust particles appear to be similar to that of interplanetary dust particles.
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| 13. |
- O'Connor, M. I., et al.
(författare)
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A general biodiversity-function relationship is mediated by trophic level
- 2017
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Ingår i: Oikos. - : Wiley. - 0030-1299. ; 126:1, s. 18-31
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Tidskriftsartikel (refereegranskat)abstract
- Species diversity affects the functioning of ecosystems, including the efficiency by which communities capture limited resources, produce biomass, recycle and retain biologically essential nutrients. These ecological functions ultimately support the ecosystem services upon which humanity depends. Despite hundreds of experimental tests of the effect of biodiversity on ecosystem function (BEF), it remains unclear whether diversity effects are sufficiently general that we can use a single relationship to quantitatively predict how changes in species richness alter an ecosystem function across trophic levels, ecosystems and ecological conditions. Our objective here is to determine whether a general relationship exists between biodiversity and standing biomass. We used hierarchical mixed effects models, based on a power function between species richness and biomass production (Y = a x S-b), and a database of 374 published experiments to estimate the BEF relationship (the change in biomass with the addition of species), and its associated uncertainty, in the context of environmental factors. We found that the mean relationship (b = 0.26, 95% CI: 0.16, 0.37) characterized the vast majority of observations, was robust to differences in experimental design, and was independent of the range of species richness levels considered. However, the richness-biomass relationship varied by trophic level and among ecosystems; in aquatic systems b was nearly twice as large for consumers (herbivores and detritivores) compared to primary producers; in terrestrial ecosystems, b for detritivores was negative but depended on few studies. We estimated changes in biomass expected for a range of changes in species richness, highlighting that species loss has greater implications than species gains, skewing a distribution of biomass change relative to observed species richness change. When biomass provides a good proxy for processes that underpin ecosystem services, this relationship could be used as a step in modeling the production of ecosystem services and their dependence on biodiversity.
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| 14. |
- Ratcliffe, S., et al.
(författare)
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Biodiversity and ecosystem functioning relations in European forests depend on environmental context
- 2017
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 20:11, s. 1414-1426
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Tidskriftsartikel (refereegranskat)abstract
- The importance of biodiversity in supporting ecosystem functioning is generally well accepted. However, most evidence comes from small-scale studies, and scaling-up patterns of biodiversity-ecosystem functioning (B-EF) remains challenging, in part because the importance of environmental factors in shaping B-EF relations is poorly understood. Using a forest research platform in which 26 ecosystem functions were measured along gradients of tree species richness in six regions across Europe, we investigated the extent and the potential drivers of context dependency of B-EF relations. Despite considerable variation in species richness effects across the continent, we found a tendency for stronger B-EF relations in drier climates as well as in areas with longer growing seasons and more functionally diverse tree species. The importance of water availability in driving context dependency suggests that as water limitation increases under climate change, biodiversity may become even more important to support high levels of functioning in European forests.
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| 15. |
- Hornung, K., et al.
(författare)
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Electrical properties of cometary dust particles derived from line shapes of TOF-SIMS spectra measured by the ROSETTA/COSIMA instrument
- 2019
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Ingår i: Planetary and Space Science. - : Elsevier Ltd. - 0032-0633 .- 1873-5088. ; 182
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Tidskriftsartikel (refereegranskat)abstract
- Between Aug. 2014 and Sept. 2016, while ESA's cornerstone mission Rosetta was operating in the vicinity of the nucleus and in the coma of comet 67P/Churyumov-Gerasimenko, the COSIMA instrument collected a large number of dust particles with diameters up to a millimeter. Positive or negative ions were detected by a time-of-flight secondary ion mass spectrometer (TOF-SIMS) and the composition of selected particles was deduced. Many of the negative ion mass spectra show, besides mass peaks at the correct position, an additional, extended contribution at the lower mass side caused by partial charging of the dust. This effect, usually avoided in SIMS applications, can in our case be used to obtain information on the electrical properties of the collected cometary dust particles, such as the specific resistivity (ρr>1.2⋅1010Ωm) and the real part of the relative electrical permittivity (εr<1.2). From these values a lower limit for the porosity is derived (P>0.8).
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| 16. |
- Khudeir, Ali A, et al.
(författare)
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On the cratonization of the Arabian-Nubian Shield: Constraints from gneissic granitoids in south Eastern Desert, Egypt.
- 2021
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Ingår i: Geoscience Frontiers. - : Elsevier. - 1674-9871. ; 12, s. 1-29
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Tidskriftsartikel (refereegranskat)abstract
- The Shaitian granite complex (SGC) spans more than 80 Ma of crustal growth in the Arabian–Nubian Shield insoutheast Egypt. It is a voluminous composite intrusion (60 km2) comprising a host tonalite massif intruded by subordinate dyke-like masses of trondhjemite, granodiorite and monzogranite. The host tonalite, in turn, encloses several, fine-grained amphibolite enclaves. U-Pb zircon dating indicates a wide range of crystallization ages within the SGC (800 ± 18Ma for tonalites; 754± 3.9 Ma for trondhjemite; 738± 3.8 Ma for granodiorite;and 717±3.2 Ma for monzogranite), suggesting crystallization of independent magma pulses. The high positive εNdi (+6 to +8) indicate that the melting sources were dominated by juvenile material without any significant input from older crust. Application of zircon saturation geothermometry indicates increasing temperatures during the generation of melts from 745±31 °C for tonalite to 810±25 °C for trondhjemite; 840±10 °C for granodiorite; and 868±10 °C for monzogranite. The pressure of partial melting is loosely constrained to be below the stability of residual garnet (<10 kbar) as inferred from the almost flat HREE pattern ((Gd/Lu)N=0.9–1.1), but >3kbar for the stability of residual amphibole as inferred from the significantly lower NbN and TaN compared with LREEN and the sub-chondrite Nb/Ta ratios exhibited by the granitic phases. The inverse relation between the generation temperatures and the ages estimates of the granitoid lithologies argue against a significant role of fractional crystallization. The major and trace element contents indicate the emplacement of the SGC within a subduction zone setting. It lacks distinctive features for melt derived from a subducted slab (e.g. high Sr/Y and high (La/Yb)N ratios), and the relatively low MgO and Ni contents in all granite phases within the SGC suggest melting within the lower crust of an island arc overlying a mantle wedge. Comparison with melts produced during melting experiments indicates an amphibolite of basaltic composition is the best candidate as source for the tonalite, trondhjemite and granodiorite magmas whereas the monzogranite magma is most consistent with fusion of a tonalite protolith. Given the overlapping Sm-Nd isotope ratios as well as several trace element ratios between monzogranite and tonalite samples, it is reasonable to suggest that the renewed basaltic underplating may have caused partial melting of tonalite and the emplacement of monzogranite melt within the SGC. The emplacement of potassic granite (monzogranite) melts subsequent to the emplacement of Na-rich granites (tonalite-trondhjemite-granodiorite) most likely suggests major crustal thickening prior to arc collision and amalgamation into the overthickened proto-crust of the Arabian-Nubian shield. Eventually, after complete consolidation, the whole SGC was subjected to regional deformation, most probably during accretion to the Saharan Metacraton (arc–continent collisions) in late Cryogenian-Ediacaran times (650–542 Ma).
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| 17. |
- Paquette, J A, et al.
(författare)
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D/H in the refractory organics of comet 67P/Churyumov-Gerasimenko measured by Rosetta/COSIMA
- 2021
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Ingår i: monthly notices of the royal astronomical society. ; 504:4
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Tidskriftsartikel (refereegranskat)abstract
- The D/H ratio is a clue to the origin and evolution of hydrogen-bearing chemical species in Solar system materials. D/H has been observed in the coma of many comets, but most such measurements have been for gaseous water. We present the first in situ measurements of the D/H ratios in the organic refractory component of cometary dust particles collected at very low impact speeds in the coma of comet 67P/Churyumov-Gerasimenko (hereafter 67P) by the COSIMA instrument onboard Rosetta. The values measured by COSIMA are spatial averages over an approximately 35 × 50 µm2 area. The average D/H ratio for the 25 measured particles is (1.57 ± 0.54) × 10−3, about an order of magnitude higher than the Vienna Standard Mean Ocean Water (VSMOW), but more than an order of magnitude lower than the values measured in gas-phase organics in solar-like protostellar regions and hot cores. This relatively high averaged value suggests that refractory carbonaceous matter in comet 67P is less processed than the most primitive insoluble organic matter (IOM) in meteorites, which has a D/H ratio in the range of about 1 to 7 × 10−4. The cometary particles measured in situ also have a higher H/C ratio than the IOM. We deduce that the measured D/H in cometary refractory organics is an inheritance from the presolar molecular cloud from which the Solar system formed. The high D/H ratios observed in the cometary particles challenges models in which high D/H ratios result solely from processes that operated in the protosolar disc.
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| 18. |
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| 20. |
- Bouchard, Frederic, et al.
(författare)
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"Frozen-Ground Cartoons" : Permafrost comics as an innovative tool for polar outreach, education, and engagement
- 2018
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Ingår i: Polar Record. - : Cambridge University Press. - 0032-2474 .- 1475-3057. ; 54:5-6, s. 366-372
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Tidskriftsartikel (refereegranskat)abstract
- Permafrost occupies 20 million square kilometres of Earth's high-latitude and high-altitude landscapes. These regions are sensitive to climate change and human activities; hence, permafrost research is of considerable scientific and societal importance. However, the results of this research are generally not known by the general public. Communicating scientific concepts is an increasingly important task in the research world. Different ways to engage learners and incorporate narratives in teaching materials exist, yet they are generally underused. Here we report on an international scientific outreach project called "Frozen-Ground Cartoons", which aims at making permafrost science accessible and fun for students, teachers, and parents through the creation of comic strips. We present the context in which the project was initiated, as well as recent education and outreach activities. The future phases of the project primarily involve a series of augmented reality materials, such as maps, photos, videos, and 3D drawings. With this project we aim to foster understanding of permafrost research among broader audiences, inspire future permafrost researchers, and raise public and science community awareness of polar science, education, outreach, and engagement.
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| 21. |
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| 22. |
- Hehlmann, Ruediger, et al.
(författare)
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Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic-phase chronic myeloid leukemia in routine clinical practice : SIMPLICITY
- 2019
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Ingår i: American Journal of Hematology. - : WILEY. - 0361-8609 .- 1096-8652. ; 94:1, s. 46-54
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Tidskriftsartikel (refereegranskat)abstract
- SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor (TKI) use and management patterns in patients with chronic phase-chronic myeloid leukemia in the US and Europe in routine clinical practice. Herein we describe interruptions, discontinuations and switching of TKI therapy during the initial 2 years of treatment among 1121 patients prospectively enrolled between October 1, 2010 and March 7, 2017. Patient characteristics were broadly similar between the imatinib (n = 370), dasatinib (n = 376), and nilotinib (n = 375) cohorts. Treatment interruptions occurred in 16.4% (year 1) and 4.0% (year 2) of patients, mainly attributed to hematologic intolerances. Treatment discontinuations occurred in 21.8% (year 1) and 10.2% (year 2) of patients, with the highest rate within the first 3 months for intolerance. Switching of TKI was seen in 17.8% (year 1) and 9.5% (year 2) of patients. Significant associations were found between TKI switching and female gender (year 1), age >= 65 years at diagnosis (year 2) and treatment with imatinib (year 2). Intolerance was the most common reason given for patients discontinuing and for switching TKI therapy; however resistance was also cited. Lack of response monitoring in routine clinical practice may have resulted in lower identification of resistance in this dataset. Data from SIMPLICITY suggest that, in routine clinical practice, intolerance and resistance to TKIs influence decisions to change treatment. Changes in TKI therapy are frequent, with nearly a third of patients discontinuing their first-line TKI.
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| 23. |
- Isnard, R., et al.
(författare)
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H/C elemental ratio of the refractory organic matter in cometary particles of 67P/Churyumov-Gerasimenko
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 630
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Tidskriftsartikel (refereegranskat)abstract
- Context. Because comets are part of the most primitive bodies of our solar system, establishing their chemical composition and comparing them to other astrophysical bodies gives new constraints on the formation and evolution of organic matter throughout the solar system. For two years, the time-of-flight secondary ion mass spectrometer COmetary Secondary Ion Mass Analyzer (COSIMA) on board the Rosetta orbiter performed in situ analyses of the dust particles ejected from comet 67P/Churyumov-Gerasimenko (67P). Aims. The aim is to determine the H/C elemental ratio of the refractory organic component contained in cometary particles of 67P. Methods. We analyzed terrestrial and extraterrestrial calibration samples using the COSIMA ground-reference model. Exploiting these calibration samples, we provide calibration lines in both positive and negative ion registration modes. Thus, we are now able to measure the cometary H/C elemental ratio. Results. The mean H/C value is 1.04 +/- 0.16 based on 33 different cometary particles. Consequently, the H/C atomic ratio is on average higher in cometary particles of 67P than in even the most primitive insoluble organic matter extracted from meteorites. Conclusions. These results imply that the refractory organic matter detected in dust particles of 67P is less unsaturated than the material in meteorites.
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| 24. |
- Israeli-Korn, SD, et al.
(författare)
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Intersegmental coordination patterns are differently affected in Parkinson's disease and cerebellar ataxia
- 2019
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Ingår i: Journal of neurophysiology. - : American Physiological Society. - 1522-1598 .- 0022-3077. ; 121:2, s. 672-689
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Tidskriftsartikel (refereegranskat)abstract
- The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane’s orientation and other parameters pertinent to this law in patients with idiopathic Parkinson’s disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al. 2009). In the present study, we compared the planarity index (PI), covariation plane (CVP) orientation, and CVP orientation predicted by the model in 11 PD patients, 8 CA patients, and two groups of healthy subjects matched for age, height, weight, and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti-parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD-off-med compared with Ctrl_PD and in CA vs. Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. NEW & NOTEWORTHY Kinematic and muscular synergies may have a role in overcoming motor redundancies, which may be reflected in intersegmental covariation. Basal ganglia and cerebellar networks were suggested to be involved in crafting and modulating synergies. We thus compared intersegmental coordination in Parkinson’s disease and cerebellar disease patients and found opposite effects in some aspects. Further research integrating muscle activities as well as biomechanical and neural control modeling are needed to account for these findings.
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| 25. |
- Mustjoki, S., et al.
(författare)
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Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy
- 2009
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 23:8, s. 1398-1405
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Tidskriftsartikel (refereegranskat)abstract
- Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile. Leukemia (2009) 23, 1398-1405; doi:10.1038/leu.2009.46; published online 19 March 2009
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