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Sökning: L773:0028 0836 OR L773:1476 4687 > (2020)

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1.
  • House, Robert A., et al. (författare)
  • Superstructure control of first-cycle voltage hysteresis in oxygen-redox cathodes
  • 2020
  • Ingår i: Nature. - NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 577:7791, s. 502-508
  • Tidskriftsartikel (refereegranskat)abstract
    • In conventional intercalation cathodes, alkali metal ions can move in and out of a layered material with the charge being compensated for by reversible reduction and oxidation of the transition metal ions. If the cathode material used in a lithium-ion or sodium-ion battery is alkali-rich, this can increase the battery's energy density by storing charge on the oxide and the transition metal ions, rather than on the transition metal alone(1-10). There is a high voltage associated with oxidation of O2- during the first charge, but this is not recovered on discharge, resulting in reduced energy density(11). Displacement of transition metal ions into the alkali metal layers has been proposed to explain the first-cycle voltage loss (hysteresis)(9,12-16). By comparing two closely related intercalation cathodes, Na-0.75[Li0.25Mn0.75]O-2 and Na-0.6[Li0.2Mn0.8]O-2, here we show that the first-cycle voltage hysteresis is determined by the superstructure in the cathode, specifically the local ordering of lithium and transition metal ions in the transition metal layers. The honeycomb superstructure of Na-0.75[Li0.25Mn0.75]O-2, present in almost all oxygen-redox compounds, is lost on charging, driven in part by formation of molecular O-2 inside the solid. The O-2 molecules are cleaved on discharge, reforming O2-, but the manganese ions have migrated within the plane, changing the coordination around O2- and lowering the voltage on discharge. The ribbon superstructure in Na-0.6[Li0.2Mn0.8]O-2 inhibits manganese disorder and hence O-2 formation, suppressing hysteresis and promoting stable electron holes on O2- that are revealed by X-ray absorption spectroscopy. The results show that voltage hysteresis can be avoided in oxygen-redox cathodes by forming materials with a ribbon superstructure in the transition metal layers that suppresses migration of the transition metal. In oxygen-redox intercalation cathodes, voltage hysteresis can be avoided by forming cathode materials with a 'ribbon' superstructure in the transition metal layers that suppresses transition metal migration.
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3.
  • Qureshi, A. A., et al. (författare)
  • The molecular basis for sugar import in malaria parasites
  • 2020
  • Ingår i: Nature. - Nature Research. - 0028-0836 .- 1476-4687. ; 578:7794, s. 321-325
  • Tidskriftsartikel (refereegranskat)abstract
    • Elucidating the mechanism of sugar import requires a molecular understanding of how transporters couple sugar binding and gating events. Whereas mammalian glucose transporters (GLUTs) are specialists1, the hexose transporter from the malaria parasite Plasmodium falciparum PfHT12,3 has acquired the ability to transport both glucose and fructose sugars as efficiently as the dedicated glucose (GLUT3) and fructose (GLUT5) transporters. Here, to establish the molecular basis of sugar promiscuity in malaria parasites, we determined the crystal structure of PfHT1 in complex with d-glucose at a resolution of 3.6 Å. We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures4,5. Nevertheless, engineered PfHT1 mutations made to match GLUT sugar-binding sites did not shift sugar preferences. The extracellular substrate-gating helix TM7b in PfHT1 was positioned in a fully occluded conformation, providing a unique glimpse into how sugar binding and gating are coupled. We determined that polar contacts between TM7b and TM1 (located about 15 Å from d-glucose) are just as critical for transport as the residues that directly coordinate d-glucose, which demonstrates a strong allosteric coupling between sugar binding and gating. We conclude that PfHT1 has achieved substrate promiscuity not by modifying its sugar-binding site, but instead by evolving substrate-gating dynamics.
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4.
  • Qureshi, Abdul Aziz, et al. (författare)
  • The molecular basis for sugar import in malaria parasites
  • 2020
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 578:7794, s. 321-325
  • Tidskriftsartikel (refereegranskat)abstract
    • Elucidating the mechanism of sugar import requires a molecular understanding of how transporters couple sugar binding and gating events. Whereas mammalian glucose transporters (GLUTs) are specialists(1), the hexose transporter from the malaria parasite Plasmodium falciparum PfHT1(2,3) has acquired the ability to transport both glucose and fructose sugars as efficiently as the dedicated glucose (GLUT3) and fructose (GLUT5) transporters. Here, to establish the molecular basis of sugar promiscuity in malaria parasites, we determined the crystal structure of PfHT1 in complex with d-glucose at a resolution of 3.6 angstrom. We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures(4,5). Nevertheless, engineered PfHT1 mutations made to match GLUT sugar-binding sites did not shift sugar preferences. The extracellular substrate-gating helix TM7b in PfHT1 was positioned in a fully occluded conformation, providing a unique glimpse into how sugar binding and gating are coupled. We determined that polar contacts between TM7b and TM1 (located about 15 angstrom from d-glucose) are just as critical for transport as the residues that directly coordinate d-glucose, which demonstrates a strong allosteric coupling between sugar binding and gating. We conclude that PfHT1 has achieved substrate promiscuity not by modifying its sugar-binding site, but instead by evolving substrate-gating dynamics. Crystal structure of the Plasmodium falciparum hexose transporter PfHT1 reveals the molecular basis of its ability to transport multiple types of sugar as efficiently as the dedicated mammalian glucose and fructose transporters.
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5.
  • Shahnawaz, Mohammad, et al. (författare)
  • Discriminating alpha-synuclein strains in Parkinsons disease and multiple system atrophy
  • 2020
  • Ingår i: Nature. - NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687.
  • Tidskriftsartikel (refereegranskat)abstract
    • Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of alpha-synuclein, including Parkinsons disease, dementia with Lewy bodies and multiple system atrophy(1). Clinically, it is challenging to differentiate Parkinsons disease and multiple system atrophy, especially at the early stages of disease(2). Aggregates of alpha-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of alpha-synuclein that can self-propagate and spread from cell to cell(3-6). Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect alpha-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity(7,8). Here we show that the alpha-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinsons disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinsons disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that alpha-synuclein aggregates that are associated with Parkinsons disease and multiple system atrophy correspond to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of alpha-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinsons disease and multiple system atrophy. Protein misfolding cyclic amplification (PMCA) technology can discriminate between patients with Parkinsons disease and patients with multiple system atrophy on the basis of the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid.
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6.
  • Squazzoni, Flaminio, et al. (författare)
  • Unlock ways to share data on peer review
  • 2020
  • Ingår i: Nature. - Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 578:7796, s. 512-514
  • Tidskriftsartikel (refereegranskat)
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7.
  • Wåhlin, Anna, 1970-, et al. (författare)
  • Ice front blocking of ocean heat transport to an Antarctic ice shelf
  • 2020
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 578, s. 568-571
  • Tidskriftsartikel (refereegranskat)abstract
    • Mass loss from the Antarctic Ice Sheet to the ocean has increased in recent decades, largely because the thinning of its floating ice shelves has allowed the outflow of grounded ice to accelerate. Enhanced basal melting of the ice shelves is thought to be the ultimate driver of change, motivating a recent focus on the processes that control ocean heat transport onto and across the seabed of the Antarctic continental shelf towards the ice. However, the shoreward heat flux typically far exceeds that required to match observed melt rates, suggesting that other critical controls exist. Here we show that the depth-independent (barotropic) component of the heat flow towards an ice shelf is blocked by the marked step shape of the ice front, and that only the depth-varying (baroclinic) component, which is typically much smaller, can enter the sub-ice cavity. Our results arise from direct observations of the Getz Ice Shelf system and laboratory experiments on a rotating platform. A similar blocking of the barotropic component may occur in other areas with comparable ice–bathymetry configurations, which may explain why changes in the density structure of the water column have been found to be a better indicator of basal melt rate variability than the heat transported onto the continental shelf. Representing the step topography of the ice front accurately in models is thus important for simulating ocean heat fluxes and induced melt rates.
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8.
  • Burmann, Björn Marcus, et al. (författare)
  • Regulation of alpha-synuclein by chaperones in mammalian cells
  • 2020
  • Ingår i: Nature. - 0028-0836. ; 577:7788, s. 127-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein alpha-synuclein(1). The aggregation propensity of alpha-synuclein in cells is modulated by specific factors that include post-translational modifications(2,3), Abelson-kinase-mediated phosphorylation(4,5) and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear(6-8). Here we systematically characterize the interaction of molecular chaperones with alpha-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in alpha-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of alpha-synuclein. NMR experiments(9) in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between alpha-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90 beta, results in transient membrane binding and triggers a remarkable re-localization of alpha-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of alpha-synuclein at Tyr39 directly impairs the interaction of alpha-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of alpha-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.
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9.
  • Cabrita, Rita, et al. (författare)
  • Tertiary lymphoid structures improve immunotherapy and survival in melanoma
  • 2020
  • Ingår i: Nature. - Nature Publishing Group. - 0028-0836. ; 577:7791, s. 561-565
  • Tidskriftsartikel (refereegranskat)abstract
    • Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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10.
  • Campbell, Peter J., et al. (författare)
  • Pan-cancer analysis of whole genomes
  • 2020
  • Ingår i: Nature. - Nature Publishing Group. - 1476-4687. ; 578, s. 82-93
  • 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 scale. 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 promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes.
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