| 41. |
- Mariathasan, Sanjeev, et al.
(författare)
-
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
- 2018
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 554:7693, s. 544-548
-
Tidskriftsartikel (refereegranskat)abstract
- Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8 + T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8 + T cells from the tumour parenchyma that were instead found in the fibroblast-and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-Administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-Tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-Tumour immunity by restricting T-cell infiltration.
|
|
| 42. |
- Martijn, Joran, et al.
(författare)
-
Deep mitochondrial origin outside the sampled alphaproteobacteria
- 2018
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 557:7703, s. 101-105
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondria are ATP-generating organelles, the endosymbiotic origin of which was a key event in the evolution of eukaryotic cells(1). Despite strong phylogenetic evidence that mitochondria had an alphaproteobacterial ancestry(2), efforts to pinpoint their closest relatives among sampled alphaproteobacteria have generated conflicting results, complicating detailed inferences about the identity and nature of the mitochondrial ancestor. While most studies support the idea that mitochondria evolved from an ancestor related to Rickettsiales(3-9), an order that includes several host-associated pathogenic and endosymbiotic lineages(10,11), others have suggested that mitochondria evolved from a free-living group(12-14). Here we re-evaluate the phylogenetic placement of mitochondria. We used genome-resolved binning of oceanic metagenome datasets and increased the genomic sampling of Alphaproteobacteria with twelve divergent clades, and one clade representing a sister group to all Alphaproteobacteria. Subsequent phylogenomic analyses that specifically address long branch attraction and compositional bias artefacts suggest that mitochondria did not evolve from Rickettsiales or any other currently recognized alphaproteobacterial lineage. Rather, our analyses indicate that mitochondria evolved from a proteobacterial lineage that branched off before the divergence of all sampled alphaproteobacteria. In light of this new result, previous hypotheses on the nature of the mitochondrial ancestor(6,15,16) should be re-evaluated.
|
|
| 43. |
|
|
| 44. |
- Mathieson, Iain, et al.
(författare)
-
The Genomic History of Southeastern Europe
- 2018
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 555:695, s. 197-203
-
Tidskriftsartikel (refereegranskat)abstract
- Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to understand the dynamics of this process, we analysed genome-wide ancient DNA data from 225 individuals who lived in southeastern Europe and surrounding regions between 12000 and 500 bc. We document a west–east cline of ancestry in indigenous huntergatherers and, in eastern Europe, the early stages in the formation of Bronze Age steppe ancestry. We show that the first farmers of northern and western Europe dispersed through southeastern Europe with limited hunter-gatherer admixture, but that some early groups in the southeast mixed extensively with hunter-gatherers without the sex-biased admixture that prevailed later in the north and west. We also show that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe.
|
|
| 45. |
|
|
| 46. |
- Mirman, Zachary, et al.
(författare)
-
53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in.
- 2018
-
Ingår i: Nature. - : Springer. - 0028-0836 .- 1476-4687. ; 560:7716, s. 112-116
-
Tidskriftsartikel (refereegranskat)abstract
- In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair-which requires a 3' overhang-and classical non-homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3-8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7-SHLD1-SHLD2-SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6-9. Here we address the mechanism by which 53BP1-RIF1-shieldin regulates the generation of recombinogenic 3' overhangs. We report that CTC1-STN1-TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)-primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polα inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST-Polα-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin.
|
|
| 47. |
- Mooley, K., et al.
(författare)
-
A mildly relativistic wide-angle outflow in the neutron-star merger event GW170817
- 2018
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 554:7691, s. 207-210
-
Tidskriftsartikel (refereegranskat)abstract
- GW170817 was the first gravitational-wave detection of a binary neutron-star merger. It was accompanied by radiation across the electromagnetic spectrum and localized to the galaxy NGC 4993 at a distance of 40 megaparsecs. It has been proposed that the observed γ-ray, X-ray and radio emission is due to an ultra-relativistic jet being launched during the merger (and successfully breaking out of the surrounding material), directed away from our line of sight (off-axis). The presence of such a jet is predicted from models that posit neutron-star mergers as the drivers of short hard-γ-ray bursts. Here we report that the radio light curve of GW170817 has no direct signature of the afterglow of an off-axis jet. Although we cannot completely rule out the existence of a jet directed away from the line of sight, the observed γ-ray emission could not have originated from such a jet. Instead, the radio data require the existence of a mildly relativistic wide-angle outflow moving towards us. This outflow could be the high-velocity tail of the neutron-rich material that was ejected dynamically during the merger, or a cocoon of material that breaks out when a jet launched during the merger transfers its energy to the dynamical ejecta. Because the cocoon model explains the radio light curve of GW170817, as well as the γ-ray and X-ray emission (and possibly also the ultraviolet and optical emission), it is the model that is most consistent with the observational data. Cocoons may be a ubiquitous phenomenon produced in neutron-star mergers, giving rise to a hitherto unidentified population of radio, ultraviolet, X-ray and γ-ray transients in the local Universe.
|
|
| 48. |
- Mooley, K., et al.
(författare)
-
Superluminal motion of a relativistic jet in the neutron-star merger GW170817
- 2018
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 561:7723, s. 355-359
-
Tidskriftsartikel (refereegranskat)abstract
- The binary neutron-star merger GW1708171was accompanied by radiation across the electromagnetic spectrum2and localized2to the galaxy NGC 4993 at a distance3of about 41 megaparsecs from Earth. The radio and X-ray afterglows of GW170817 exhibited delayed onset4–7, a gradual increase8in the emission with time (proportional to t0.8) to a peak about 150 days after the merger event9, followed by a relatively rapid decline9,10. So far, various models have been proposed to explain the afterglow emission, including a choked-jet cocoon4,8,11–13and a successful-jet cocoon4,8,11–18(also called a structured jet). However, the observational data have remained inconclusive10,15,19,20as to whether GW170817 launched a successful relativistic jet. Here we report radio observations using very long-baseline interferometry. We find that the compact radio source associated with GW170817 exhibits superluminal apparent motion between 75 days and 230 days after the merger event. This measurement breaks the degeneracy between the choked- and successful-jet cocoon models and indicates that, although the early-time radio emission was powered by a wide-angle outflow8(a cocoon), the late-time emission was most probably dominated by an energetic and narrowly collimated jet (with an opening angle of less than five degrees) and observed from a viewing angle of about 20 degrees. The imaging of a collimated relativistic outflow emerging from GW170817 adds substantial weight to the evidence linking binary neutron-star mergers and short γ-ray bursts.
|
|
| 49. |
- Muhlemann, B., et al.
(författare)
-
Ancient hepatitis B viruses from the Bronze Age to the Medieval period
- 2018
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 557:7705, s. 418-423
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatitis B virus (HBV) is a major cause of human hepatitis. There is considerable uncertainty about the timescale of its evolution and its association with humans. Here we present 12 full or partial ancient HBV genomes that are between approximately 0.8 and 4.5 thousand years old. The ancient sequences group either within or in a sister relationship with extant human or other ape HBV clades. Generally, the genome properties follow those of modern HBV. The root of the HBV tree is projected to between 8.6 and 20.9 thousand years ago, and we estimate a substitution rate of 8.04 x 10(-6-)1.51 x 10(-5) nucleotide substitutions per site per year. In several cases, the geographical locations of the ancient genotypes do not match present-day distributions. Genotypes that today are typical of Africa and Asia, and a subgenotype from India, are shown to have an early Eurasian presence. The geographical and temporal patterns that we observe in ancient and modern HBV genotypes are compatible with well-documented human migrations during the Bronze and Iron Ages(1,2). We provide evidence for the creation of HBV genotype A via recombination, and for a long-term association of modern HBV genotypes with humans, including the discovery of a human genotype that is now extinct. These data expose a complexity of HBV evolution that is not evident when considering modern sequences alone.
|
|
| 50. |
- Nerini, Francesco Fuso
(författare)
-
Use SDGs to guide climate action
- 2018
-
Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 557:7703, s. 31-31
-
Tidskriftsartikel (refereegranskat)
|
|
