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Temperate rainforests near the South Pole during peak Cretaceous warmth 期刊论文
NATURE, 2020, 580 (7801) : 81-+
作者:  Johann P. Klages;  Ulrich Salzmann;  Torsten Bickert;  Claus-Dieter Hillenbrand;  Karsten Gohl;  Gerhard Kuhn;  Steven M. Bohaty;  ;  rgen Titschack;  Juliane Mü;  ller;  Thomas Frederichs;  Thorsten Bauersachs;  Werner Ehrmann;  Tina van de Flierdt;  Patric Simõ;  es Pereira;  Robert D. Larter;  Gerrit Lohmann;  Igor Niezgodzki;  Gabriele Uenzelmann-Neben;  Maximilian Zundel;  Cornelia Spiegel;  Chris Mark;  David Chew;  Jane E. Francis;  Gernot Nehrke;  Florian Schwarz;  James A. Smith;  Tim Freudenthal;  Oliver Esper;  Heiko Pä;  like;  Thomas A. Ronge;  Ricarda Dziadek
收藏  |  浏览/下载:13/0  |  提交时间:2020/05/13

The mid-Cretaceous period was one of the warmest intervals of the past 140 million years(1-5), driven by atmospheric carbon dioxide levels of around 1,000 parts per million by volume(6). In the near absence of proximal geological records from south of the Antarctic Circle, it is disputed whether polar ice could exist under such environmental conditions. Here we use a sedimentary sequence recovered from the West Antarctic shelf-the southernmost Cretaceous record reported so far-and show that a temperate lowland rainforest environment existed at a palaeolatitude of about 82 degrees S during the Turonian-Santonian age (92 to 83 million years ago). This record contains an intact 3-metre-long network of in situ fossil roots embedded in a mudstone matrix containing diverse pollen and spores. A climate model simulation shows that the reconstructed temperate climate at this high latitude requires a combination of both atmospheric carbon dioxide concentrations of 1,120-1,680 parts per million by volume and a vegetated land surface without major Antarctic glaciation, highlighting the important cooling effect exerted by ice albedo under high levels of atmospheric carbon dioxide.


  
Germline Elongator mutations in Sonic Hedgehog medulloblastoma 期刊论文
NATURE, 2020, 580 (7803) : 396-+
作者:  Helmrich, S.;  Arias, A.;  Lochead, G.;  Wintermantel, T. M.;  Buchhold, M.;  Diehl, S.;  Whitlock, S.
收藏  |  浏览/下载:16/0  |  提交时间:2020/07/03

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.


  
MAFG-driven astrocytes promote CNS inflammation 期刊论文
NATURE, 2020, 578 (7796) : 593-+
作者:  Clark, Peter U.;  He, Feng;  Golledge, Nicholas R.;  Mitrovica, Jerry X.;  Dutton, Andrea;  Hoffman, Jeremy S.;  Dendy, Sarah
收藏  |  浏览/下载:39/0  |  提交时间:2020/07/03

Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis(2), but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2 alpha to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2 alpha and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.


Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.


  
Processive extrusion of polypeptide loops by a Hsp100 disaggregase 期刊论文
NATURE, 2020, 578 (7794) : 317-+
作者:  Zhao, Peishen;  Liang, Yi-Lynn;  Belousoff, Matthew J.;  Deganutti, Giuseppe;  Fletcher, Madeleine M.;  Willard, Francis S.;  Bell, Michael G.;  Christe, Michael E.;  Sloop, Kyle W.;  Inoue, Asuka;  Truong, Tin T.;  Clydesdale, Lachlan;  Furness, Sebastian G. B.;  Christopoulos, Arthur;  Wang, Ming-Wei;  Miller, Laurence J.;  Reynolds, Christopher A.;  Danev, Radostin;  Sexton, Patrick M.;  Wootten, Denise
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

The ability to reverse protein aggregation is vital to cells(1,2). Hsp100 disaggregases such as ClpB and Hsp104 are proposed to catalyse this reaction by translocating polypeptide loops through their central pore(3,4). This model of disaggregation is appealing, as it could explain how polypeptides entangled within aggregates can be extracted and subsequently refolded with the assistance of Hsp70(4,5). However, the model is also controversial, as the necessary motor activity has not been identified(6-8) and recent findings indicate non-processive mechanisms such as entropic pulling or Brownian ratcheting(9,10). How loop formation would be accomplished is also obscure. Indeed, cryo-electron microscopy studies consistently show single polypeptide strands in the Hsp100 pore(11,12). Here, by following individual ClpB-substrate complexes in real time, we unambiguously demonstrate processive translocation of looped polypeptides. We integrate optical tweezers with fluorescent-particle tracking to show that ClpB translocates both arms of the loop simultaneously and switches to single-arm translocation when encountering obstacles. ClpB is notably powerful and rapid  it exerts forces of more than 50 pN at speeds of more than 500 residues per second in bursts of up to 28 residues. Remarkably, substrates refold while exiting the pore, analogous to co-translational folding. Our findings have implications for protein-processing phenomena including ubiquitin-mediated remodelling by Cdc48 (or its mammalian orthologue p97)(13) and degradation by the 26S proteasome(14).


A combination of optical tweezers and fluorescent-particle tracking is used to dissect the dynamics of the Hsp100 disaggregase ClpB, and show that the processive extrusion of polypeptide loops is the mechanistic basis of its activity.


  
Antagonistic cooperativity between crystal growth modifiers 期刊论文
NATURE, 2020, 577 (7791) : 497-+
作者:  Ma, Wenchuan;  Lutsko, James F.;  Rimer, Jeffrey D.;  Vekilov, Peter G.
收藏  |  浏览/下载:9/0  |  提交时间:2020/07/03

Inhibitor pairs that suppress the crystallization of haematin, which is a part of malaria parasites'  physiology, show unexpected antagonism due to attenuation of step pinning by kink blockers.


Ubiquitous processes in nature and the industry exploit crystallization from multicomponent environments(1-5)  however, laboratory efforts have focused on the crystallization of pure solutes(6,7) and the effects of single growth modifiers(8,9). Here we examine the molecular mechanisms employed by pairs of inhibitors in blocking the crystallization of haematin, which is a model organic compound with relevance to the physiology of malaria parasites(10,11). We use a combination of scanning probe microscopy and molecular modelling to demonstrate that inhibitor pairs, whose constituents adopt distinct mechanisms of haematin growth inhibition, kink blocking and step pinning(12,13), exhibit both synergistic and antagonistic cooperativity depending on the inhibitor combination and applied concentrations. Synergism between two crystal growth modifiers is expected, but the antagonistic cooperativity of haematin inhibitors is not reflected in current crystal growth models. We demonstrate that kink blockers reduce the line tension of step edges, which facilitates both the nucleation of crystal layers and step propagation through the gates created by step pinners. The molecular viewpoint on cooperativity between crystallization modifiers provides guidance on the pairing of modifiers in the synthesis of crystalline materials. The proposed mechanisms indicate strategies to understand and control crystallization in both natural and engineered systems, which occurs in complex multicomponent media(1-3,8,9). In a broader context, our results highlight the complexity of crystal-modifier interactions mediated by the structure and dynamics of the crystal interface.


  
Using all data to improve seasonal sea surface temperature predictions: A combination-based model forecast with unequal observation lengths 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2018, 38 (8) : 3215-3223
作者:  Khan, Mohammad Zaved Kaiser;  Sharma, Ashish;  Mehrotra, Rajeshwar
收藏  |  浏览/下载:0/0  |  提交时间:2019/04/09
model combination  seasonal prediction  sea surface temperature  unequal data length