| 1841. |
- Rasmussen, RD, et al.
(författare)
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BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 13398-
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Tidskriftsartikel (refereegranskat)abstract
- Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.
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| 1842. |
- Ravikumar, Sadhana, et al.
(författare)
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Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.
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| 1843. |
- Ray, Robert P, et al.
(författare)
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Enhanced flight performance by genetic manipulation of wing shape in Drosophila.
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Insect wing shapes are remarkably diverse and the combination of shape and kinematics determines both aerial capabilities and power requirements. However, the contribution of any specific morphological feature to performance is not known. Using targeted RNA interference to modify wing shape far beyond the natural variation found within the population of a single species, we show a direct effect on flight performance that can be explained by physical modelling of the novel wing geometry. Our data show that altering the expression of a single gene can significantly enhance aerial agility and that the Drosophila wing shape is not, therefore, optimized for certain flight performance characteristics that are known to be important. Our technique points in a new direction for experiments on the evolution of performance specialities in animals.
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| 1844. |
- Raykova, Doroteya, 1986-, et al.
(författare)
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A method for Boolean analysis of protein interactions at a molecular level
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Determination of interactions between native proteins in cells is important for understanding function. Here the authors report MolBoolean as a method to detect interactions between endogenous proteins in subcellular compartments, using antibody-DNA conjugates for identification and signal amplification. Determining the levels of protein-protein interactions is essential for the analysis of signaling within the cell, characterization of mutation effects, protein function and activation in health and disease, among others. Herein, we describe MolBoolean - a method to detect interactions between endogenous proteins in various subcellular compartments, utilizing antibody-DNA conjugates for identification and signal amplification. In contrast to proximity ligation assays, MolBoolean simultaneously indicates the relative abundances of protein A and B not interacting with each other, as well as the pool of A and B proteins that are proximal enough to be considered an AB complex. MolBoolean is applicable both in fixed cells and tissue sections. The specific and quantifiable data that the method generates provide opportunities for both diagnostic use and medical research.
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| 1845. |
- Redjai Sani, Sohrab, et al.
(författare)
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Mutually synchronized bottom-up multi-nanocontact spin-torque oscillators
- 2013
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4, s. 2731-
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Tidskriftsartikel (refereegranskat)abstract
- Spin-torque oscillators offer a unique combination of nanosize, ultrafast modulation rates and ultrawide band signal generation from 100 MHz to close to 100 GHz. However, their low output power and large phase noise still limit their applicability to fundamental studies of spin-transfer torque and magnetodynamic phenomena. A possible solution to both problems is the spin-wave-mediated mutual synchronization of multiple spin-torque oscillators through a shared excited ferromagnetic layer. To date, synchronization of high-frequency spin-torque oscillators has only been achieved for two nanocontacts. As fabrication using expensive top-down lithography processes is not readily available to many groups, attempts to synchronize a large number of nanocontacts have been all but abandoned. Here we present an alternative, simple and cost-effective bottom-up method to realize large ensembles of synchronized nanocontact spin-torque oscillators. We demonstrate mutual synchronization of three high-frequency nanocontact spin-torque oscillators and pairwise synchronization in devices with four and five nanocontacts.
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| 1846. |
- Rehn, Alexandra, et al.
(författare)
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A methylated lysine is a switch point for conformational communication in the chaperone Hsp90
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Methylation of a conserved lysine in C-terminal domain of the molecular chaperone Hsp90 was shown previously to affect its in vivo function. However, the underlying mechanism remained elusive. Through a combined experimental and computational approach, this study shows that this site is very sensitive to sidechain modifications and crucial for Hsp90 activity in vitro and in vivo. Our results demonstrate that this particular lysine serves as a switch point for the regulation of Hsp90 functions by influencing its conformational cycle, ATPase activity, co-chaperone regulation, and client activation of yeast and human Hsp90. Incorporation of the methylated lysine via genetic code expansion specifically shows that upon modification, the conformational cycle of Hsp90 is altered. Molecular dynamics simulations including the methylated lysine suggest specific conformational changes that are propagated through Hsp90. Thus, methylation of the C-terminal lysine allows a precise allosteric tuning of Hsp90 activity via long distances. Methylation of a lysine residue in Hsp90 is a recently discovered post-translational modification but the mechanistic effects of this modification have remained unknown so far. Here the authors combine biochemical and biophysical approaches, molecular dynamics (MD) simulations and functional experiments with yeast and show that this lysine is a switch point, which specifically modulates conserved Hsp90 functions including co-chaperone regulation and client activation.
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| 1847. |
- Reichstein, Birte, 1983-, et al.
(författare)
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Ontogenetic asymmetry modulates population biomass production and response to harvest
- 2015
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Patterns in biomass production are determined by resource input (productivity) and trophic transfer efficiency. At fixed resource input, variation in consumer biomass production has been related to food quality, metabolic type and diversity among species. In contrast, intraspecific variation in individual body size because of ontogenetic development, which characterizes the overwhelming majority of taxa, has been largely neglected. Here we show experimentally in a long-term multigenerational study that reallocating constant resource input in a two-stage consumer system from an equal resource delivery to juveniles and adults to an adult-biased resource delivery is sufficient to cause more than a doubling of total consumer biomass. We discuss how such changes in consumer stage-specific resource allocation affect the likelihood for alternative stable states in harvested populations as a consequence of stage-specific overcompensation in consumer biomass and thereby the risk of catastrophic collapses in exploited populations.
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| 1848. |
- Reid, A. H., et al.
(författare)
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Beyond a phenomenological description of magnetostriction
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Magnetostriction, the strain induced by a change in magnetization, is a universal effect in magnetic materials. Owing to the difficulty in unraveling its microscopic origin, it has been largely treated phenomenologically. Here, we show how the source of magnetostriction-the underlying magnetoelastic stress-can be separated in the time domain, opening the door for an atomistic understanding. X-ray and electron diffraction are used to separate the subpicosecond spin and lattice responses of FePt nanoparticles. Following excitation with a 50-fs laser pulse, time-resolved X-ray diffraction demonstrates that magnetic order is lost within the nanoparticles with a time constant of 146 fs. Ultrafast electron diffraction reveals that this demagnetization is followed by an anisotropic, three-dimensional lattice motion. Analysis of the size, speed, and symmetry of the lattice motion, together with ab initio calculations accounting for the stresses due to electrons and phonons, allow us to reveal the magnetoelastic stress generated by demagnetization.
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| 1849. |
- Reid, Cameron J, et al.
(författare)
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A role for ColV plasmids in the evolution of pathogenic Escherichia coli ST58
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli ST58 has recently emerged as a globally disseminated uropathogen that often progresses to sepsis. Unlike most pandemic extra-intestinal pathogenic E. coli (ExPEC), which belong to pathogenic phylogroup B2, ST58 belongs to the environmental/commensal phylogroup B1. Here, we present a pan-genomic analysis of a global collection of 752 ST58 isolates from diverse sources. We identify a large ST58 sub-lineage characterized by near ubiquitous carriage of ColV plasmids, which carry genes encoding virulence factors, and by a distinct accessory genome including genes typical of the Yersiniabactin High Pathogenicity Island. This sub-lineage includes three-quarters of all ExPEC sequences in our study and has a broad host range, although poultry and porcine sources predominate. By contrast, strains isolated from cattle often lack ColV plasmids. Our data indicate that ColV plasmid acquisition contributed to the divergence of the major ST58 sub-lineage, and different sub-lineages inhabit poultry, swine and cattle.
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| 1850. |
- Reiling, Linda, et al.
(författare)
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Targets of complement-fixing antibodies in protective immunity against malaria in children
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies against P. falciparum merozoites fix complement to inhibit blood-stage replication in naturally-acquired and vaccine-induced immunity; however, specific targets of these functional antibodies and their importance in protective immunity are unknown. Among malaria-exposed individuals, we show that complement-fixing antibodies to merozoites are more strongly correlated with protective immunity than antibodies that inhibit growth quantified using the current reference assay for merozoite vaccine evaluation. We identify merozoite targets of complement-fixing antibodies and identify antigen-specific complement-fixing antibodies that are strongly associated with protection from malaria in a longitudinal study of children. Using statistical modelling, combining three different antigens targeted by complement-fixing antibodies could increase the potential protective effect to over 95%, and we identify antigens that were common in the most protective combinations. Our findings support antibody-complement interactions against merozoite antigens as important anti-malaria immune mechanisms, and identify specific merozoite antigens for further evaluation as vaccine candidates.
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