| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)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. |
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| 3. |
- Khilji, M. S., et al.
(författare)
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The inducible β5i proteasome subunit contributes to proinsulin degradation in GRP94-deficient β-cells and is overexpressed in type 2 diabetes pancreatic islets
- 2020
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Ingår i: American Journal of Physiology - Endocrinology and Metabolism. - 0193-1849. ; 318:6
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Tidskriftsartikel (refereegranskat)abstract
- Proinsulin is a misfolding-prone protein, and its efficient breakdown is critical when β-cells are confronted with high-insulin biosynthetic demands, to prevent endoplasmic reticulum stress, a key trigger of secretory dysfunction and, if uncompensated, apoptosis. Proinsulin degradation is thought to be performed by the constitutively expressed standard proteasome, while the roles of other proteasomes are unknown. We recently demonstrated that deficiency of the proinsulin chaperone glucoseregulated protein 94 (GRP94) causes impaired proinsulin handling and defective insulin secretion associated with a compensated endoplasmic reticulum stress response. Taking advantage of this model of restricted folding capacity, we investigated the role of different proteasomes in proinsulin degradation, reasoning that insulin secretory dynamics require an inducible protein degradation system. We show that the expression of only one enzymatically active proteasome subunit, namely, the inducible β5i-subunit, was increased in GRP94 CRISPR/Cas9 knockout (KO) cells. Additionally, the level of β5i-containing intermediate proteasomes was significantly increased in these cells, as was β5i-related chymotrypsin-like activity. Moreover, proinsulin levels were restored in GRP94 KO upon β5i small interfering RNA-mediated knockdown. Finally, the fraction of β-cells expressing the β5i subunit is increased in human islets from type 2 diabetes patients. We conclude that β5i is an inducible proteasome subunit dedicated to the degradation of mishandled proinsulin. Copyright © 2020 the American Physiological Society.
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| 4. |
- Khilji, M. S., et al.
(författare)
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The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, low concentrations of interleukin 1 beta
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- A central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic beta cells, as this might facilitate autoantigen presentation by beta cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in beta cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes. We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the beta 5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by low concentrations of IL-1 beta stimulating proinsulin biosynthesis. These findings suggest that the beta cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.
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| 5. |
- Pihl, E., et al.
(författare)
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Ten new insights in climate science 2020- A horizon scan
- 2020
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Ingår i: Global Sustainability. - : Cambridge University Press. - 2059-4798.
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Tidskriftsartikel (refereegranskat)abstract
- Non-technical summary We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding of Earth's sensitivity to carbon dioxide, finds that permafrost thaw could release more carbon emissions than expected and that the uptake of carbon in tropical ecosystems is weakening. Adverse impacts on human society include increasing water shortages and impacts on mental health. Options for solutions emerge from rethinking economic models, rights-based litigation, strengthened governance systems and a new social contract. The disruption caused by COVID-19 could be seized as an opportunity for positive change, directing economic stimulus towards sustainable investments. Technical summary A synthesis is made of ten fields within climate science where there have been significant advances since mid-2019, through an expert elicitation process with broad disciplinary scope. Findings include: (1) a better understanding of equilibrium climate sensitivity; (2) abrupt thaw as an accelerator of carbon release from permafrost; (3) changes to global and regional land carbon sinks; (4) impacts of climate change on water crises, including equity perspectives; (5) adverse effects on mental health from climate change; (6) immediate effects on climate of the COVID-19 pandemic and requirements for recovery packages to deliver on the Paris Agreement; (7) suggested long-term changes to governance and a social contract to address climate change, learning from the current pandemic, (8) updated positive cost-benefit ratio and new perspectives on the potential for green growth in the short- A nd long-term perspective; (9) urban electrification as a strategy to move towards low-carbon energy systems and (10) rights-based litigation as an increasingly important method to address climate change, with recent clarifications on the legal standing and representation of future generations. Social media summary Stronger permafrost thaw, COVID-19 effects and growing mental health impacts among highlights of latest climate science.
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| 6. |
- Toledo, A. G., et al.
(författare)
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An affinity chromatography and glycoproteomics workflow to profile the chondroitin sulfate proteoglycans that interact with malarial VAR2CSA in the placenta and in cancer
- 2020
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 30:12, s. 989-1002
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Tidskriftsartikel (refereegranskat)abstract
- Chondroitin sulfate (CS) is the placental receptor for the VAR2CSA malaria protein, expressed at the surface of infected erythrocytes during Plasmodium falciparum infection. Infected cells adhere to syncytiotrophoblasts or get trapped within the intervillous space by binding to a determinant in a 4-O-sulfated CS chains. However, the exact structure of these glycan sequences remains unclear. VAR2CSA-reactive CS is also expressed by tumor cells, making it an attractive target for cancer diagnosis and therapeutics. The identities of the proteoglycans carrying these modifications in placental and cancer tissues remain poorly characterized. This information is clinically relevant since presentation of the glycan chains may be mediated by novel core proteins or by a limited subset of established proteoglycans. To address this question, VAR2CSA-binding proteoglycans were affinity-purified from the human placenta, tumor tissues and cancer cells and analyzed through a specialized glycoproteomics workflow. We show that VAR2CSA-reactive CS chains associate with a heterogenous group of proteoglycans, including novel core proteins. Additionally, this work demonstrates how affinity purification in combination with glycoproteomics analysis can facilitate the characterization of CSPGs with distinct CS epitopes. A similar workflow can be applied to investigate the interaction of CSPGs with other CS binding lectins as well.
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| 7. |
- Ahnberg, H., et al.
(författare)
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Stabilising effects of different binders in some Swedish soils
- 2003
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Ingår i: Ground Improvement. - : Thomas Telford Ltd.. - 1365-781X .- 1751-7621. ; 7:1, s. 9-23
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Tidskriftsartikel (refereegranskat)abstract
- In Sweden, lime and lime-cement have been used for several decades as stabilising agents in deep stabilisation of soft soils. More recently, other types of binder have come into use, but so far only to a limited extent. In order to gather experience about the effect of various binders, laboratory tests have been performed on different types of soil stabilised with a range of binders. Lime, cement, fly ash and blast furnace slag in different combinations together with different admixtures, such as gypsum, silica fume and calcium chloride, have been used in the investigations. The variation in strength with type of binder has been studied, and comparisons have also been made with results from some previous investigations using different binders. The tests showed that there is no optimal, universal binder for stabilisation of the soils. Whereas some binders are robust, yielding good results in most types of soil, there are also binders that produce very good results in certain soils but poor results in others. Both similarities and differences in effects were found for different binders.
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| 8. |
- Boström, C., et al.
(författare)
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Distribution, structure and function of Nordic eelgrass (Zostera marina) ecosystems: Implications for coastal management and conservation
- 2014
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Ingår i: Aquatic conservation. - : Wiley. - 1052-7613. ; 24:3, s. 410-434
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Forskningsöversikt (refereegranskat)abstract
- This paper focuses on the marine foundation eelgrass species, Zostera marina, along a gradient from the northern Baltic Sea to the north-east Atlantic. This vast region supports a minimum of 1480km2 eelgrass (maximum >2100km2), which corresponds to more than four times the previously quantified area of eelgrass in Western Europe. Eelgrass meadows in the low salinity Baltic Sea support the highest diversity (4-6 spp.) of angiosperms overall, but eelgrass productivity is low (<2g dw m-2 d-1) and meadows are isolated and genetically impoverished. Higher salinity areas support monospecific meadows, with higher productivity (3-10g dw m-2 d-1) and greater genetic connectivity. The salinity gradient further imposes functional differences in biodiversity and food webs, in particular a decline in number, but increase in biomass of mesograzers in the Baltic. Significant declines in eelgrass depth limits and areal cover are documented, particularly in regions experiencing high human pressure. The failure of eelgrass to re-establish itself in affected areas, despite nutrient reductions and improved water quality, signals complex recovery trajectories and calls for much greater conservation effort to protect existing meadows. The knowledge base for Nordic eelgrass meadows is broad and sufficient to establish monitoring objectives across nine national borders. Nevertheless, ensuring awareness of their vulnerability remains challenging. Given the areal extent of Nordic eelgrass systems and the ecosystem services they provide, it is crucial to further develop incentives for protecting them. © 2014 The Authors.
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| 9. |
- Chandrasekaran, Abinaya, et al.
(författare)
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Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3
- 2021
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; , s. 2736-2751
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration.
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| 10. |
- Gunnarsson, Fredrik, 1983, et al.
(författare)
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Lean NOx reduction over Ag/alumina catalysts via ethanol-SCR using ethanol/gasoline blends
- 2017
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Ingår i: Applied Catalysis B: Environmental. - : Elsevier BV. - 0926-3373 .- 1873-3883. ; 202, s. 42-50
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Tidskriftsartikel (refereegranskat)abstract
- This study focuses on the activity for lean NOx reduction over sol-gel synthesized silver alumina (Ag/Al2O3) catalysts, with and without platinum doping, using ethanol (EtOH), EtOH/C3H6 and EtOH/gasoline blends as reducing agents. The effect of ethanol concentration, both by varying the hydrocarbon-to-NOx ratio and by alternating the gasoline concentration in the EtOH/gasoline mixture, is investigated. High activity for NOx reduction is demonstrated for powder catalysts for EtOH and EtOH/C3H6 as well as for monolith coated catalysts (EtOH and EtOH/gasoline). The results show that pure Ag/Al2O3 catalysts display higher NOx reduction and lower light-off temperature as compared to the platinum doped samples. The 4 wt.% Ag/Al2O3 catalyst displays 100% reduction in the range 340-425 degrees C, with up to 37% selectivity towards NH3. These results are also supported by DRIFTS (Diffuse reflection infrared Fourier transform spectroscopy) experiments. The high ammonia formation could, in combination with an NH3-SCR catalyst, be utilized to construct a NOx reduction system with lower fuel penalty cf. stand alone HC-SCR. In addition, it would result in an overall decrease in CO2 emissions.
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