| 21. |
- Forrest, ARR, et al.
(författare)
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A promoter-level mammalian expression atlas
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 507:7493, s. 462-
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Tidskriftsartikel (refereegranskat)
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| 22. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 23. |
- Gal-Yam, Avishay, et al.
(författare)
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A Wolf-Rayet-like progenitor of SN 2013cu from spectral observations of a stellar wind
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 509:7501, s. 471-
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Tidskriftsartikel (refereegranskat)abstract
- The explosive fate of massive Wolf-Rayet stars(1) (WRSs) is a key open question in stellar physics. An appealing option is that hydrogen-deficient WRSs are the progenitors of some hydrogen-poor supernova explosions of types IIb, Ib and Ic (ref. 2). A blue object, having luminosity and colours consistent with those of some WRSs, has recently been identified in pre-explosion images at the location of a supernova of type Ib (ref. 3), but has not yet been conclusively determined to have been the progenitor. Similar work has so far only resulted in non-detections(4). Comparison of early photometric observations of type Ic supernovae with theoretical models suggests that the progenitor stars had radii of less than 1012 centimetres, as expected for some WRSs(5). The signature of WRSs, their emission line spectra, cannot be probed by such studies. Here we report the detection of strong emission lines in a spectrum of type IIb supernova 2013cu (iPTF13ast) obtained approximately 15.5 hours after explosion (by 'flash spectroscopy', which captures the effects of the supernova explosion shock breakout flash on material surrounding the progenitor star). We identify Wolf-Rayet-like wind signatures, suggesting a progenitor of the WN(h) subclass (those WRSs with winds dominated by helium and nitrogen, with traces of hydrogen). The extent of this dense wind may indicate increased mass loss from the progenitor shortly before its explosion, consistent with recent theoretical predictions(6).
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| 24. |
- Gall, Christa, et al.
(författare)
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Rapid formation of large dust grains in the luminous supernova 2010j1
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7509, s. 326-
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Tidskriftsartikel (refereegranskat)abstract
- The origin of dust in galaxies is still a mystery(1-4). The majority of the refractory elements are produced in supernova explosions, but it is unclear how and where dust grains condense and grow, and how they avoid destruction in the harsh environments of star-forming galaxies. The recent detection of 0.1 to 0.5 solar masses of dust in nearby supernova remnants(5-7) suggests in situ dust formation, while other observations reveal very little dust in supernovae in the first few years after explosion(1,8,10). Observations of the spectral evolution of the bright SN 2010j1 have been interpreted as pre-existing dust(11), dust formationlz(12,13) or no dust at all(14). Here we report the rapid (40 to 240 days) formation of dust in its dense circumstellar medium. The wavelength-dependent extinction of this dust reveals the presence of very large (exceeding one micrometre) grains, which resist destruction(15). At later times (500 to 900 days), the near-infrared thermal emission shows an accelerated growth in dust mass, marking the transition of the dust source from the circumstellar medium to the ejecta. This provides the link between the early and late dust mass evolution in supernovae with dense circumstellar media.
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| 25. |
- Gnad, T., et al.
(författare)
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Adenosine activates brown adipose tissue and recruits beige adipocytes via A(2A) receptors
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 516:7531, s. 395-
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies(1-5). Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of beta-adrenergic receptors(1-5). Because BAT therapies based on cold exposureor beta-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat(6-8). However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A(2A) receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A(2A) receptors in mice causes adecrease in BAT-dependent thermogenesis, whereas treatment with A(2A) agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A(2A) receptors or injection of lentiviral vectors expressing the A(2A) receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A(2A) agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A(2A) signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
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| 26. |
- Handa, I. Tanya, et al.
(författare)
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Consequences of biodiversity loss for litter decomposition across biomes
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 509:7499, s. 218-221
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Tidskriftsartikel (refereegranskat)abstract
- The decomposition of dead organic matter is a major determinant of carbon and nutrient cycling in ecosystems, and of carbon fluxes between the biosphere and the atmosphere(1-3). Decomposition is driven by a vast diversity of organisms that are structured in complex food webs(2,4). Identifying the mechanisms underlying the effects of biodiversity on decomposition is critical(4-6) given the rapid loss of species worldwide and the effects of this loss on human well-being(7-9). Yet despite comprehensive syntheses of studies on how biodiversity affects litter decomposition(4-6,10), key questions remain, including when, where and how biodiversity has a role and whether general patterns and mechanisms occur across ecosystems and different functional types of organism(4,9-12). Here, in field experiments across five terrestrial and aquatic locations, ranging from the subarctic to the tropics, we show that reducing the functional diversity of decomposer organisms and plant litter types slowed the cycling of litter carbon and nitrogen. Moreover, we found evidence of nitrogen transfer from the litter of nitrogen-fixing plants to that of rapidly decomposing plants, but not between other plant functional types, highlighting that specific interactions in litter mixtures control carbon and nitrogen cycling during decomposition. The emergence of this general mechanism and the coherence of patterns across contrasting terrestrial and aquatic ecosystems suggest that biodiversity loss has consistent consequences for litter decomposition and the cycling of major elements on broad spatial scales.
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| 27. |
- Ho, Joshua W. K., et al.
(författare)
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Comparative analysis of metazoan chromatin organization
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 512:7515, s. 449-U507
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Tidskriftsartikel (refereegranskat)abstract
- Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms(1-3). Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths(4,5). To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.
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| 28. |
- Holmes, Emily A., et al.
(författare)
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A call for mental-health science
- 2014
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 511:7509, s. 287-289
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 29. |
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| 30. |
- Jones, Owen R., et al.
(författare)
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Diversity of ageing across the tree of life
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 505:7482, s. 169-
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Tidskriftsartikel (refereegranskat)abstract
- Evolution drives, and is driven by, demography. A genotype moulds its phenotype's age patterns of mortality and fertility in an environment; these two patterns in turn determine the genotype's fitness in that environment. Hence, to understand the evolution of ageing, age patterns of mortality and reproduction need to be compared for species across the tree of life. However, few studies have done so and only for a limited range of taxa. Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga. Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species, including increasing, constant, decreasing, humped and bowed trajectories for both long-and short-lived species. This diversity challenges theoreticians to develop broader perspectives on the evolution of ageing and empiricists to study the demography of more species.
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