| 1. |
- Devarajan, Raman, et al.
(författare)
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Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
- 2023
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:18
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Tidskriftsartikel (refereegranskat)abstract
- The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
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| 2. |
- Thulin, Åsa, et al.
(författare)
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Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein
- 2009
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 7:11, s. 1792-1802
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Tidskriftsartikel (refereegranskat)abstract
- The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain.Using a combination of immunohistochemistry and massspectrometry, we here provide biochemical evidence for thepresence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons.Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+.Previous studies have shown that zinc-dependent bindingof the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis.We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor,which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion.
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| 3. |
- Tuomi, Maria, et al.
(författare)
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Stomping in silence : Conceptualizing trampling effects on soils in polar tundra
- 2021
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Ingår i: Functional Ecology. - : Wiley. - 0269-8463 .- 1365-2435. ; 35:2, s. 306-317
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Forskningsöversikt (refereegranskat)abstract
- Ungulate trampling modifies soils and interlinked ecosystem functions across biomes. Until today, most research has focused on temperate ecosystems and mineral soils while trampling effects on cold and organic matter-rich tundra soils remain largely unknown. We aimed to develop a general model of trampling effects on soil structure, biota, microclimate and biogeochemical processes, with a particular focus on polar tundra soils. To reach this goal, we reviewed literature about the effects of trampling and physical disturbances on soils across biomes and used this to discuss the knowns and unknowns of trampling effects on tundra soils. We identified the following four pathways through which trampling affects soils: (a) soil compaction; (b) reductions in soil fauna and fungi; (c) rapid losses in vegetation biomass and cover; and (d) longer term shifts in vegetation community composition. We found that, in polar tundra, soil responses to trampling pathways 1 and 3 could be characterized by nonlinear dynamics and tundra-specific context dependencies that we formulated into testable hypotheses. In conclusion, trampling may affect tundra soil significantly but many direct, interacting and cascading responses remain unknown. We call for research to advance the understanding of trampling effects on soils to support informed efforts to manage and predict the functioning of tundra systems under global changes. A free Plain Language Summary can be found within the Supporting Information of this article.
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| 4. |
- Ahonen, Saija H K, et al.
(författare)
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Reindeer grazing history determines the responses of subarctic soil fungal communities to warming and fertilization
- 2021
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Ingår i: New Phytologist. - : Wiley. - 1469-8137 .- 0028-646X. ; 232:2, s. 788-801
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Tidskriftsartikel (refereegranskat)abstract
- Composition and functioning of arctic soil fungal communities may alter rapidly due to the ongoing trends of warmer temperatures, shifts in nutrient availability and shrub encroachment. In addition, the communities may also be intrinsically shaped by heavy grazing, which may locally induce an ecosystem change that couples with increased soil temperature and nutrients and where shrub encroachment is less likely to occur than in lightly grazed conditions. We tested how four years of experimental warming and fertilization affected organic soil fungal communities in sites with decadal history of either heavy or light reindeer grazing using high-throughput sequencing of ITS2 rDNA region. Grazing history largely overrode the impacts of short-term warming and fertilization in determining the composition of fungal communities. The less diverse fungal communities under light grazing showed more pronounced responses to experimental treatments when compared to the communities under heavy grazing. Yet, ordination approaches revealed distinct treatment responses under both grazing intensities. If grazing shifts the fungal communities in Arctic ecosystems to a different and more diverse state, this shift may dictate ecosystem responses to further abiotic changes. This inclines that the intensity of grazing cannot be left out when predicting future changes in fungi-driven processes in the tundra.
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| 5. |
- Barthelemy, Hélène, et al.
(författare)
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Short- and long-term plant and microbial uptake of 15N-labelled urea in a mesic tundra heath, West Greenland
- 2024
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Ingår i: Polar Biology. - : Springer Nature. - 0722-4060 .- 1432-2056. ; 47:1, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Terrestrial animals are key elements in the cycling of elements in the Arctic where nutrient availability is low. Waste production by herbivores, in particular urine deposition, has a crucial role for nitrogen (N) recycling, still, it remains largely unexplored. Also, experimental evidence is biased toward short-term studies and Arctic regions under high herbivore pressure. In this study, we aimed to examine the fate of N derived from urine in a nutrient poor tundra heath in West Greenland, with historical low level of herbivory. We performed a pulse labelling with 15N-urea over the plant canopy and explored ecosystem N partition and retention in the short-term (2 weeks and 1 year) and longer-term (5 years). We found that all vascular plants, irrespective of their traits, could rapidly take up N-urea, but mosses and lichens were even more efficient. Total 15N enrichment was severely reduced for all plants 5 years after tracer addition, with the exception of cryptogams, indicating that non-vascular plants constituted a long-term sink of 15N-urea. The 15N recovery was also high in the litter suggesting high N immobilization in this layer, potentially delaying the nutrients from urine entering the soil compartment. Long-term 15N recovery in soil microbial biomass was minimal, but as much as 30% of added 15N remained in the non-microbial fraction after 5 years. Our results demonstrate that tundra plants that have evolved under low herbivory pressure are well adapted to quickly take advantage of labile urea, with urine having only a transient effect on soil nutrient availability.
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| 6. |
- Gavazov, Konstantin, 1983-, et al.
(författare)
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Plant-microbial linkages underpin carbon sequestration in contrasting mountain tundra vegetation types
- 2022
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Ingår i: Soil Biology and Biochemistry. - : Elsevier. - 0038-0717 .- 1879-3428. ; 165
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Tidskriftsartikel (refereegranskat)abstract
- Tundra ecosystems hold large stocks of soil organic matter (SOM), likely due to low temperatures limiting rates of microbial SOM decomposition more than those of SOM accumulation from plant primary productivity and microbial necromass inputs. Here we test the hypotheses that distinct tundra vegetation types and their carbon supply to characteristic rhizosphere microbes determine SOM cycling independent of temperature. In the subarctic Scandes, we used a three-way factorial design with paired heath and meadow vegetation at each of two elevations, and with each combination of vegetation type and elevation subjected during one growing season to either ambient light (i.e., ambient plant productivity), or 95% shading (i.e., reduced plant productivity). We assessed potential above- and belowground ecosystem linkages by uni- and multivariate analyses of variance, and structural equation modelling. We observed direct coupling between tundra vegetation type and microbial community composition and function, which underpinned the ecosystem's potential for SOM storage. Greater primary productivity at low elevation and ambient light supported higher microbial biomass and nitrogen immobilisation, with lower microbial mass-specific enzymatic activity and SOM humification. Congruently, larger SOM at lower elevation and in heath sustained fungal-dominated microbial communities, which were less substrate-limited, and invested less into enzymatic SOM mineralisation, owing to a greater carbon-use efficiency (CUE). Our results highlight the importance of tundra plant community characteristics (i.e., productivity and vegetation type), via their effects on soil microbial community size, structure and physiology, as essential drivers of SOM turnover. The here documented concerted patterns in above- and belowground ecosystem functioning is strongly supportive of using plant community characteristics as surrogates for assessing tundra carbon storage potential and its evolution under climate and vegetation changes.
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| 7. |
- Gylling, Mikhail, et al.
(författare)
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The hypoparathyroidism of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protective effect of male sex
- 2003
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - 0021-972X .- 1945-7197. ; 88:10, s. 4602-4608
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, hypoparathyroidism (HP) is the most common endocrine component. It occurs in most (but not all) patients. Determinants of its occurrence are unknown, and there is no proof for its autoimmune nature. Recently, the Ca(2+)-sensing receptor (CaSR) was reported to be an autoantigen in HP. With our group of 90 patients, we aimed at identifying the determinants and pathomechanism of HP. For the determinants, we evaluated gender and the HLA class II. For the pathomechanism, we searched for parathyroid autoantibodies, including antibodies against CaSR and PTH. Also, we studied whether AIRE is expressed in the human parathyroid, because its absence could be a pathogenetic factor. We found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped HP, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs. 7% of females. In contrast, we found no linkage to the HLA class II. By immunofluorescence, 19% of the patients had antibodies to parathyroid epithelia. By immunoblotting, these recognized several parathyroid proteins. No antibodies were observed against the CaSR or PTH. By RT-PCR, AIRE mRNA was not found in the parathyroid.
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| 8. |
- Kirchhoff, Leah, et al.
(författare)
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Microbial community composition unaffected by mycorrhizal plant removal in sub-arctic tundra
- 2024
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Ingår i: Fungal ecology. - 1754-5048 .- 1878-0083. ; 69
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Tidskriftsartikel (refereegranskat)abstract
- Vegetation changes in a warming Arctic may affect plant-associated soil microbial communities with possible consequences for the biogeochemical cycling of carbon (C) and nitrogen (N). In a sub-arctic tundra heath, we factorially removed plant species with ecto- and ericoid mycorrhizal associations. After two years, we explored how mycorrhizal type-specific plant removal influences microbial communities, soil and microbial C and N pools, and extracellular enzymatic activities. Removal of ecto- and ericoid mycorrhizal plants did not change the soil fungal or bacterial community composition or their extracellular enzyme activities. However, ericoid plant removal decreased microbial C:N ratio, suggesting a stoichiometric effect decoupled from microbial community composition. In other words, microbial communities appear to show initial plasticity in response to major changes in tundra vegetation. This highlights the importance of longer-term perspectives when investigating the effects of vegetation changes on biogeochemical processes in Arctic ecosystems.
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| 9. |
- Monteux, Sylvain, 1989-, et al.
(författare)
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Controlling biases in targeted plant removal experiments
- 2024
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Ingår i: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 242:4, s. 1835-1845
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Tidskriftsartikel (refereegranskat)abstract
- Targeted removal experiments are a powerful tool to assess the effects of plant species or (functional) groups on ecosystem functions. However, removing plant biomass in itself can bias the observed responses. This bias is commonly addressed by waiting until ecosystem recovery, but this is inherently based on unverified proxies or anecdotal evidence. Statistical control methods are efficient, but restricted in scope by underlying assumptions.We propose accounting for such biases within the experimental design, using a gradient of biomass removal controls. We demonstrate the relevance of this design by presenting (1) conceptual examples of suspected biases and (2) how to observe and control for these biases.Using data from a mycorrhizal association-based removal experiment, we show that ignoring biomass removal biases (including by assuming ecosystem recovery) can lead to incorrect, or even contrary conclusions (e.g. false positive and false negative). Our gradient design can prevent such incorrect interpretations, regardless of whether aboveground biomass has fully recovered.Our approach provides more objective and quantitative insights, independently assessed for each variable, than using a proxy to assume ecosystem recovery. Our approach circumvents the strict statistical assumptions of, for example, ANCOVA and thus offers greater flexibility in data analysis.
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| 10. |
- Rocher-Ros, Gerard, et al.
(författare)
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Metabolism overrides photo-oxidation in CO2 dynamics of Arctic permafrost streams
- 2021
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Ingår i: Limnology and Oceanography. - : John Wiley & Sons. - 0024-3590 .- 1939-5590. ; 66:S1, s. S169-S181
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Tidskriftsartikel (refereegranskat)abstract
- Global warming is enhancing the mobilization of organic carbon (C) from Arctic soils into streams, where it can be mineralized to CO2 and released to the atmosphere. Abiotic photo‐oxidation might drive C mineralization, but this process has not been quantitatively integrated with biological processes that also influence CO2 dynamics in aquatic ecosystems. We measured CO2 concentrations and the isotopic composition of dissolved inorganic C (δ13CDIC) at diel resolution in two Arctic streams, and coupled this with whole‐system metabolism estimates to assess the effect of biotic and abiotic processes on stream C dynamics. CO2 concentrations consistently decreased from night to day, a pattern counter to the hypothesis that photo‐oxidation is the dominant source of CO2. Instead, the observed decrease in CO2 during daytime was explained by photosynthetic rates, which were strongly correlated with diurnal changes in δ13CDIC values. However, on days when modeled photosynthetic rates were near zero, there was still a significant diel change in δ13CDIC values, suggesting that metabolic estimates are partly masked by O2 consumption from photo‐oxidation. Our results suggest that 6–12 mmol CO2‐C m−2 d−1 may be generated from photo‐oxidation, a range that corresponds well to previous laboratory measurements. Moreover, ecosystem respiration rates were 10 times greater than published photo‐oxidation rates for these Arctic streams, and accounted for 33–80% of total CO2 evasion. Our results suggest that metabolic activity is the dominant process for CO2 production in Arctic streams. Thus, future aquatic CO2 emissions may depend on how biotic processes respond to the ongoing environmental change.
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