| 1. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Meyer, H., et al.
(author)
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Overview of progress in European medium sized tokamaks towards an integrated plasma-edge/wall solution
- 2017
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In: Nuclear Fusion. - : Institute of Physics Publishing (IOPP). - 0029-5515 .- 1741-4326. ; 57:10
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Journal article (peer-reviewed)abstract
- Integrating the plasma core performance with an edge and scrape-off layer (SOL) that leads to tolerable heat and particle loads on the wall is a major challenge. The new European medium size tokamak task force (EU-MST) coordinates research on ASDEX Upgrade (AUG), MAST and TCV. This multi-machine approach within EU-MST, covering a wide parameter range, is instrumental to progress in the field, as ITER and DEMO core/pedestal and SOL parameters are not achievable simultaneously in present day devices. A two prong approach is adopted. On the one hand, scenarios with tolerable transient heat and particle loads, including active edge localised mode (ELM) control are developed. On the other hand, divertor solutions including advanced magnetic configurations are studied. Considerable progress has been made on both approaches, in particular in the fields of: ELM control with resonant magnetic perturbations (RMP), small ELM regimes, detachment onset and control, as well as filamentary scrape-off-layer transport. For example full ELM suppression has now been achieved on AUG at low collisionality with n = 2 RMP maintaining good confinement H-H(98,H-y2) approximate to 0.95. Advances have been made with respect to detachment onset and control. Studies in advanced divertor configurations (Snowflake, Super-X and X-point target divertor) shed new light on SOL physics. Cross field filamentary transport has been characterised in a wide parameter regime on AUG, MAST and TCV progressing the theoretical and experimental understanding crucial for predicting first wall loads in ITER and DEMO. Conditions in the SOL also play a crucial role for ELM stability and access to small ELM regimes.
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| 3. |
- Meyer, H., et al.
(author)
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Overview of progress in European medium sized tokamaks towards an integrated plasma-edge/wall solution
- 2017
-
In: Nuclear Fusion. - : Institute of Physics Publishing (IOPP). - 0029-5515 .- 1741-4326. ; 57:10
-
Journal article (peer-reviewed)abstract
- Integrating the plasma core performance with an edge and scrape-off layer (SOL) that leads to tolerable heat and particle loads on the wall is a major challenge. The new European medium size tokamak task force (EU-MST) coordinates research on ASDEX Upgrade (AUG), MAST and TCV. This multi-machine approach within EU-MST, covering a wide parameter range, is instrumental to progress in the field, as ITER and DEMO core/pedestal and SOL parameters are not achievable simultaneously in present day devices. A two prong approach is adopted. On the one hand, scenarios with tolerable transient heat and particle loads, including active edge localised mode (ELM) control are developed. On the other hand, divertor solutions including advanced magnetic configurations are studied. Considerable progress has been made on both approaches, in particular in the fields of: ELM control with resonant magnetic perturbations (RMP), small ELM regimes, detachment onset and control, as well as filamentary scrape-off-layer transport. For example full ELM suppression has now been achieved on AUG at low collisionality with n = 2 RMP maintaining good confinement H-H(98,H-y2) approximate to 0.95. Advances have been made with respect to detachment onset and control. Studies in advanced divertor configurations (Snowflake, Super-X and X-point target divertor) shed new light on SOL physics. Cross field filamentary transport has been characterised in a wide parameter regime on AUG, MAST and TCV progressing the theoretical and experimental understanding crucial for predicting first wall loads in ITER and DEMO. Conditions in the SOL also play a crucial role for ELM stability and access to small ELM regimes.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Carlevaro-Fita, J, et al.
(author)
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Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis
- 2020
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1, s. 56-
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Journal article (peer-reviewed)abstract
- Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.
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| 8. |
- Munch Roager, Henrik, et al.
(author)
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Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: A randomised cross-over trial
- 2019
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:1, s. 83-93
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Journal article (peer-reviewed)abstract
- Objective T o investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. Design 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of =6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. Results 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. Conclusion C ompared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic lowgrade inflammation.
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| 9. |
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| 10. |
- Hamdi, Yosr, et al.
(author)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Journal article (peer-reviewed)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 11. |
- Hansen, Lea B.S., et al.
(author)
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A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- © 2018, The Author(s). Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.
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| 12. |
- Juul-Pedersen, T., et al.
(author)
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Sedimentation following the spring bloom in Disko Bay, West Greenland, with special emphasis on the role of copepods
- 2006
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In: Marine Ecology-Progress Series. - : Inter-Research Science Center. - 0171-8630 .- 1616-1599. ; 314, s. 239-255
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Journal article (peer-reviewed)abstract
- The sedimentation of particulate organic material was investigated in Disko Bay, West Greenland, during June 2001. Post spring-bloom conditions were encountered, with seasonally decreasing phytoplankton biomass associated with the pycnocline. Calanus finmarchicus, C. glacialis, and C. hyperboreus dominated the zooplankton community, comprising up to 88% of the copepod biomass. Faecal pellet production by C. finmarchicus and C. glacialis was positively correlated to the available food (chlorophyll a > 10 mu m). Results from short-term sediment trap deployments (6 h) showed that particulate organic carbon (POC) sedimentation from the euphotic zone was, on average, 628 mg C m(-2) d(-1), with copepod faecal pellets contributing, on average, 29% of this amount. The faecal pellet contribution to the vertical sinking export of POC was equivalent to that of phytoplankton and amorphous detritus. Yet, on average, 35% of the copepod faecal pellet production was retained within the euphotic zone. The POC: PON (particulate organic nitrogen) ratio of the suspended material in the euphotic zone (8.1 +/- 0.4) was comparable to that of the material collected in the sediment traps just below the euphotic zone (8.0 +/- 0.9). In addition, the daily loss rates of POC and PON within each sampling depth were similar, and the carbon to nitrogen ratio in the sediment traps did not change with depth. These results indicate that the pelagic system had a low retention efficiency of nitrogen just after the spring bloom.
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| 13. |
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| 14. |
- Thor, Peter, 1965, et al.
(author)
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Post-spring bloom community structure of pelagic copepods in the Disko Bay, Western Greenland
- 2005
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In: Journal of Plankton Research. - : Oxford University Press (OUP). - 0142-7873 .- 1464-3774. ; 27:4, s. 341-356
-
Journal article (peer-reviewed)abstract
- Community structure of pelagic copepods was investigated in the upper 200 m in the Disko Bay, Western Greenland, during the post-spring bloom period in June, 2001. This was the first study of the copepod community in West Greenland coastal waters sampled using smaller mesh sizes (50 mu m as opposed to 200 mu m). The mesozooplankton was dominated by copepods who constituted 82% of the total abundance and 95% of the total mesozooplankton biomass (> 50 mu m). Nauplii of Calanus, Pseudocalanus and Oithona dominated by number and the copepodites and adults were dominated by Oithona spp., Oncaea sp., Pseudocalanus sp., harpacticoids, Calanus finmarchicus, C. glacialis, and C. hyperboreus. Multivariate tests showed that the species/stage abundance composition of copepods changed significantly with depth. With one exception, all depth intervals showed unique significantly different compositions. Accordingly, the copepod community structure was influenced primarily by depth rather than by chlorophyll a concentration. Factors other than herbivorous grazing, such as omnivory, predator avoidance or association to marine snow aggregates of specific species, may have influenced the depth distribution of the total copepod community in the Disko Bay. Nevertheless, subsequent Pearson product moment correlations showed positive significant correlations between the vertical distribution of the three Calanus spp. and Pseudocalanus spp. and chlorophyll a concentrations, which points towards these species as prime components in the classic diatom-copepod food chain.
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| 15. |
- Hansen, A. B., et al.
(author)
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DIAGNOSIS OF ENDOCRINE DISEASE : Sex steroid action in adolescence: too much, too little; too early, too late
- 2021
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In: European Journal of Endocrinology. - 1479-683X. ; 184:1, s. 17-28
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Research review (peer-reviewed)abstract
- Abstract: This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient's motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.
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| 16. |
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| 17. |
- Williams, S., et al.
(author)
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Comparison of climate signals obtained from encrusting and free-living rhodolith coralline algae
- 2018
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In: Chemical Geology. - : Elsevier BV. - 0009-2541. ; 476, s. 418-428
-
Journal article (peer-reviewed)abstract
- Coralline algae have been used for sclerochronological studies throughout the last decade. These studies have focused on two different growth morphologies of the photosynthetic coralline algae: massive crusts forming small buildups on hard substrate, and free-living branching algal nodules, known as rhodoliths. The latter are generally found on soft-substrate, where they are frequently overturned by water movement and bottom feeding organisms, leaving one side of the rhodolith partially buried in the sediment at any given time. Here we test whether either of these growth morphologies is more suitable for proxy reconstructions by comparing Mg/Ca ratios - a temperature proxy - in multiple replicates of rhodoliths of Lithothamnion glaciale and in rhodoliths as well as encrusting specimens of Clathromorphum compactum. With both species being widespread throughout the Temperate and Arctic regions, we have chosen two North Atlantic localities at Nuuk Fjord, Greenland (Subarctic), and off the southeastern coast of Newfoundland, Canada (Temperate), for this study. Two to three Mg/Ca ratio transects spanning 18 years of growth were analysed on multiple specimens with encrusting morphologies and along different sides of rhodoliths using laser ablation inductively coupled mass spectrometry and compared to remotely sensed sea surface temperature (SST) data. The length of the common time span used for comparison was limited by growth interruptions in rhodoliths. Furthermore, our comparison is based on the assumption that rhodolith growth increments are annual - an assumption that has recently been challenged by mesocosm studies. Monthly Mg/Ca values from multiple transects within each individual were compared and in samples from Nuuk fjord significant correlations were found in 4 of 4 encrusting C. compactum, 4 of 4 C. compactum rhodoliths, and 2 of 3 L. glaciale rhodoliths. In Newfoundland significant correlations were found in 6 of 6 encrusting C. compactum comparisons (average: r = 0.61, p < 0.001), and in 6 of 6 L. glaciale rhodolith comparisons (average: r = 0.43, p < 0.001) for monthly resolved time series. The monthly Mg/Ca ratios (n = 216) from each morphology were compared with instrumental Reynolds SST yielding the following correlations: encrusting C. compactum (r = 0.64, p < 0.001), C. compactum rhodolith (r = 0.62, p < 0.001) and L. glaciale (r = 0.58, p < 0.001). In Newfoundland both morphologies indicate a similar strength in recording SST: encrusting C. compactum (r = 0.85, p < 0.001) and rhodolith-forming L. glaciale (r = 0.84, p < 0.001). In summary, Mg/Ca ratios derived from both coralline algal growth forms can yield SST information, however, massive encrusting forms generally yield higher correlations to SST than transects measured on individual rhodoliths, which only allowed for the generation of short uninterrupted time series due to frequent growth irregularities.
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| 18. |
- Williams, S., et al.
(author)
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Coralline Algae Archive Fjord Surface Water Temperatures in Southwest Greenland
- 2018
-
In: Journal of Geophysical Research-Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953. ; 123:8, s. 2617-2626
-
Journal article (peer-reviewed)abstract
- One of the most dramatic signs of ongoing global change is the mass loss of the Greenland Ice Sheet and the resulting rise in sea level, whereby most of the recent ice sheet mass loss can be attributed to an increase in meltwater runoff. The retreat and thinning of Greenland glaciers has been caused by rising air and ocean temperatures over the past decades. Despite the global scale impact of the changing ice sheet balance, estimates of glacial runoff in Greenland rarely extend past several decades, thus limiting our understanding of long-term glacial response to temperature. Here we present a 42-year long annually resolved red coralline algal Mg/Ca proxy temperature record from a southwestern Greenland fjord, with temperature ranging from 1.5 to 4 degrees C (standard error = 1.06 degrees C). This temperature time series in turn tracks the general trend of glacial runoff from four West Greenland glaciers discharging freshwater into the fjord (all p < 0.001). The algal time series further exhibits significant correlations to Irminger Sea temperature patterns, which are transmitted to western Greenland fjords via the West Greenland Current. The 42-year long record demonstrates the potential of annual increment forming coralline algae, which are known to live up to 650 years and which are abundant along the Greenland coastline, for reconstructing time series of sea surface temperature.
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| 19. |
- Williams, S., et al.
(author)
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Reprint of Comparison of climate signals obtained from encrusting and free-living rhodolith coralline algae
- 2019
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In: Chemical Geology. - : Elsevier BV. - 0009-2541. ; 526, s. 175-185
-
Journal article (peer-reviewed)abstract
- Coralline algae have been used for sclerochronological studies throughout the last decade. These studies have focused on two different growth morphologies of the photosynthetic coralline algae: massive crusts forming small buildups on hard substrate, and free-living branching algal nodules, known as rhodoliths. The latter are generally found on soft-substrate, where they are frequently overturned by water movement and bottom feeding organisms, leaving one side of the rhodolith partially buried in the sediment at any given time. Here we test whether either of these growth morphologies is more suitable for proxy reconstructions by comparing Mg/Ca ratios - a temperature proxy - in multiple replicates of rhodoliths of Lithothamnion glaciale and in rhodoliths as well as encrusting specimens of Clathromorphum compactum. With both species being widespread throughout the Temperate and Arctic regions, we have chosen two North Atlantic localities at Nuuk Fjord, Greenland (Subarctic), and off the southeastern coast of Newfoundland, Canada (Temperate), for this study. Two to three Mg/Ca ratio transects spanning 18 years of growth were analysed on multiple specimens with encrusting morphologies and along different sides of rhodoliths using laser ablation inductively coupled mass spectrometry and compared to remotely sensed sea surface temperature (SST) data. The length of the common time span used for comparison was limited by growth interruptions in rhodoliths. Furthermore, our comparison is based on the assumption that rhodolith growth increments are annual - an assumption that has recently been challenged by mesocosm studies. Monthly Mg/Ca values from multiple transects within each individual were compared and in samples from Nuuk fjord significant correlations were found in 4 of 4 encrusting C. compactum, 4 of 4 C. compactum rhodoliths, and 2 of 3 L. glaciale rhodoliths. In Newfoundland significant correlations were found in 6 of 6 encrusting C. compactum comparisons (average: r = 0.61, p < 0.001), and in 6 of 6 L. glaciale rhodolith comparisons (average: r= 0.43, p < 0.001) for monthly resolved time series. The monthly Mg/Ca ratios (n = 216) from each morphology were compared with instrumental Reynolds SST yielding the following correlations: encrusting C. compactum (r = 0.64, p < 0.001), C. compactum rhodolith (r = 0.62, p < 0.001) and L. glaciale (r = 0.58, p < 0.001). In Newfoundland both morphologies indicate a similar strength in recording SST: encrusting C. compactum (r = 0.85, p < 0.001) and rhodolith-forming L. glaciale (r= 0.84, p < 0.001). In summary, Mg/Ca ratios derived from both coralline algal growth forms can yield SST information, however, massive encrusting forms generally yield higher correlations to SST than transects measured on individual rhodoliths, which only allowed for the generation of short uninterrupted time series due to frequent growth irregularities.
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