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Dirk Loeffler, Arne Wehling, Florin Schneiter, Yang Zhang, Niklas Müller-Bötticher, Philipp S Hoppe, Oliver Hilsenbeck, Konstantinos D Kokkaliaris, Max Endele, Timm Schroeder
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
September 13, 2019: Nature
Yunlu Kang, Rui Liu, Jing-Xiang Wu, Lei Chen
Soluble guanylate cyclase (sGC) is the primary nitric oxide (NO) sensor. It plays a central role in NO signalling and is implicated in many essential physiological processes and disease conditions. The binding of NO leads to a significant boost in sGC enzymatic activity. However, the mechanism of NO activation remains incompletely understood. Here we report the cryo-electron microscopy structures of the human sGC α1β1 heterodimer in different functional states. These structures revealed that the transducer module bridges the NO sensor module and the catalytic module...
September 12, 2019: Nature
Enrico Cappellini, Frido Welker, Luca Pandolfi, Jazmín Ramos-Madrigal, Diana Samodova, Patrick L Rüther, Anna K Fotakis, David Lyon, J Víctor Moreno-Mayar, Maia Bukhsianidze, Rosa Rakownikow Jersie-Christensen, Meaghan Mackie, Aurélien Ginolhac, Reid Ferring, Martha Tappen, Eleftheria Palkopoulou, Marc R Dickinson, Thomas W Stafford, Yvonne L Chan, Anders Götherström, Senthilvel K S S Nathan, Peter D Heintzman, Joshua D Kapp, Irina Kirillova, Yoshan Moodley, Jordi Agusti, Ralf-Dietrich Kahlke, Gocha Kiladze, Bienvenido Martínez-Navarro, Shanlin Liu, Marcela Sandoval Velasco, Mikkel-Holger S Sinding, Christian D Kelstrup, Morten E Allentoft, Ludovic Orlando, Kirsty Penkman, Beth Shapiro, Lorenzo Rook, Love Dalén, M Thomas P Gilbert, Jesper V Olsen, David Lordkipanidze, Eske Willerslev
The sequencing of ancient DNA has enabled the reconstruction of speciation, migration and admixture events for extinct taxa1 . However, the irreversible post-mortem degradation2 of ancient DNA has so far limited its recovery-outside permafrost areas-to specimens that are not older than approximately 0.5 million years (Myr)3 . By contrast, tandem mass spectrometry has enabled the sequencing of approximately 1.5-Myr-old collagen type I4 , and suggested the presence of protein residues in fossils of the Cretaceous period5 -although with limited phylogenetic use6 ...
September 11, 2019: Nature
Fabio Puddu, Mareike Herzog, Alexandra Selivanova, Siyue Wang, Jin Zhu, Shir Klein-Lavi, Molly Gordon, Roi Meirman, Gonzalo Millan-Zambrano, Iñigo Ayestaran, Israel Salguero, Roded Sharan, Rong Li, Martin Kupiec, Stephen P Jackson
Despite major progress in defining the functional roles of genes, a complete understanding of their influences is far from being realized, even in relatively simple organisms. A major milestone in this direction arose via the completion of the yeast Saccharomyces cerevisiae gene-knockout collection (YKOC), which has enabled high-throughput reverse genetics, phenotypic screenings and analyses of synthetic-genetic interactions1-3 . Ensuing experimental work has also highlighted some inconsistencies and mistakes in the YKOC, or genome instability events that rebalance the effects of specific knockouts4-6 , but a complete overview of these is lacking...
September 11, 2019: Nature
Yu Zhang, Xuefei Zhang, Zhaoqing Ba, Zhuoyi Liang, Edward W Dring, Hongli Hu, Jiangman Lou, Nia Kyritsis, Jeffrey Zurita, Muhammad S Shamim, Aviva Presser Aiden, Erez Lieberman Aiden, Frederick W Alt
The RAG endonuclease initiates Igh V(D)J assembly in B cell progenitors by joining D segments to JH segments, before joining upstream VH segments to DJH intermediates1 . In mouse progenitor B cells, the CTCF-binding element (CBE)-anchored chromatin loop domain2 at the 3' end of Igh contains an internal subdomain that spans the 5' CBE anchor (IGCR1)3 , the DH segments, and a RAG-bound recombination centre (RC)4 . The RC comprises the JH -proximal D segment (DQ52), four JH segments, and the intronic enhancer (iEμ)5 ...
September 11, 2019: Nature
Parimal Samir, Sannula Kesavardhana, Deanna M Patmore, Sebastien Gingras, R K Subbarao Malireddi, Rajendra Karki, Clifford S Guy, Benoit Briard, David E Place, Anannya Bhattacharya, Bhesh Raj Sharma, Amanda Nourse, Sharon V King, Aaron Pitre, Amanda R Burton, Stephane Pelletier, Richard J Gilbertson, Thirumala-Devi Kanneganti
The cellular stress response has a vital role in regulating homeostasis by modulating cell survival and death. Stress granules are cytoplasmic compartments that enable cells to survive various stressors. Defects in the assembly and disassembly of stress granules are linked to neurodegenerative diseases, aberrant antiviral responses and cancer1-5 . Inflammasomes are multi-protein heteromeric complexes that sense molecular patterns that are associated with damage or intracellular pathogens, and assemble into cytosolic compartments known as ASC specks to facilitate the activation of caspase-1...
September 11, 2019: Nature
G Miniutti, R D Saxton, M Giustini, K D Alexander, R P Fender, I Heywood, I Monageng, M Coriat, A K Tzioumis, A M Read, C Knigge, P Gandhi, M L Pretorius, B Agís-González
In the past two decades, high-amplitude electromagnetic outbursts have been detected from dormant galaxies and often attributed to the tidal disruption of a star by the central black hole1,2 . X-ray emission from the Seyfert 2 galaxy GSN 069 (2MASX J01190869-3411305) at a redshift of z = 0.018 was first detected in July 2010 and implies an X-ray brightening by a factor of more than 240 over ROSAT observations performed 16 years earlier3,4 . The emission has smoothly decayed over time since 2010, possibly indicating a long-lived tidal disruption event5 ...
September 11, 2019: Nature
Haig Aghajanian, Toru Kimura, Joel G Rurik, Aidan S Hancock, Michael S Leibowitz, Li Li, John Scholler, James Monslow, Albert Lo, Wei Han, Tao Wang, Kenneth Bedi, Michael P Morley, Ricardo A Linares Saldana, Nikhita A Bolar, Kendra McDaid, Charles-Antoine Assenmacher, Cheryl L Smith, Dagmar Wirth, Carl H June, Kenneth B Margulies, Rajan Jain, Ellen Puré, Steven M Albelda, Jonathan A Epstein
Fibrosis is observed in nearly every form of myocardial disease1 . Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2 . However, clinical interventions and therapies that target fibrosis remain limited3 . Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice...
September 11, 2019: Nature
Rutger D Luteijn, Shivam A Zaver, Benjamin G Gowen, Stacia K Wyman, Nick E Garelis, Liberty Onia, Sarah M McWhirter, George E Katibah, Jacob E Corn, Joshua J Woodward, David H Raulet
The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2 . Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3 . The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP)4-7 . This cyclic dinucleotide (CDN) activates STING8 , which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response...
September 11, 2019: Nature
Yi Zheng, Xufeng Xue, Yue Shao, Sicong Wang, Sajedeh Nasr Esfahani, Zida Li, Jonathon M Muncie, Johnathon N Lakins, Valerie M Weaver, Deborah L Gumucio, Jianping Fu
Early human embryonic development involves extensive lineage diversification, cell-fate specification and tissue patterning1 . Despite its basic and clinical importance, early human embryonic development remains relatively unexplained owing to interspecies divergence2,3 and limited accessibility to human embryo samples. Here we report that human pluripotent stem cells (hPSCs) in a microfluidic device recapitulate, in a highly controllable and scalable fashion, landmarks of the development of the epiblast and amniotic ectoderm parts of the conceptus, including lumenogenesis of the epiblast and the resultant pro-amniotic cavity, formation of a bipolar embryonic sac, and specification of primordial germ cells and primitive streak cells...
September 11, 2019: Nature
Kim Newton, Katherine E Wickliffe, Debra L Dugger, Allie Maltzman, Merone Roose-Girma, Monika Dohse, László Kőműves, Joshua D Webster, Vishva M Dixit
The aspartate-specific cysteine protease caspase-8 suppresses necroptotic cell death mediated by RIPK3 and MLKL. Indeed, mice that lack caspase-8 die in a RIPK3- and MLKL-dependent manner during embryogenesis1-3 . In humans, caspase-8 deficiency is associated with immunodeficiency4 or very early onset inflammatory bowel disease5 . The substrates that are cleaved by caspase-8 to prevent necroptosis in vivo have not been defined. Here we show that knock-in mice that express catalytically inactive caspase-8(C362A) die as embryos owing to MLKL-dependent necroptosis, similar to caspase-8-deficient mice...
September 11, 2019: Nature
Cédric Aria, Jean-Bernard Caron
The chelicerates are a ubiquitous and speciose group of animals that has a considerable ecological effect on modern terrestrial ecosystems-notably as predators of insects and also, for instance, as decomposers1 . The fossil record shows that chelicerates diversified early in the marine ecosystems of the Palaeozoic era, by at least the Ordovician period2 . However, the timing of chelicerate origins and the type of body plan that characterized the earliest members of this group have remained controversial. Although megacheirans3-5 have previously been interpreted as chelicerate-like, and habeliidans6 (including Sanctacaris7,8 ) have been suggested to belong to their immediate stem lineage, evidence for the specialized feeding appendages (chelicerae) that are diagnostic of the chelicerates has been lacking...
September 11, 2019: Nature
Quinn Burlingame, Xiaheng Huang, Xiao Liu, Changyeong Jeong, Caleb Coburn, Stephen R Forrest
Organic photovoltaic cells are now approaching commercially viable efficiencies, particularly for applications that make use of their unique potential for flexibility and semitransparency1-3 . However, their reliability remains a major concern, as even the most stable devices reported so far degrade within only a few years4-8 . This has led to the belief that short operational lifetimes are an intrinsic disadvantage of devices that are fabricated using weakly bonded organic materials-an idea that persists despite the rapid growth and acceptance of organic light-emitting devices, which can achieve lifetimes of several million hours9 ...
September 9, 2019: Nature
Jinbao Xiang, Ming Shang, Yu Kawamata, Helena Lundberg, Solomon H Reisberg, Miao Chen, Pavel Mykhailiuk, Gregory Beutner, Michael R Collins, Alyn Davies, Matthew Del Bel, Gary M Gallego, Jillian E Spangler, Jeremy Starr, Shouliang Yang, Donna G Blackmond, Phil S Baran
Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2 . Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids...
September 9, 2019: Nature
Mingyang Guo, Fabian Böttcher, Jens Hertkorn, Jan-Niklas Schmidt, Matthias Wenzel, Hans Peter Büchler, Tim Langen, Tilman Pfau
A supersolid is a counter-intuitive state of matter that combines the frictionless flow of a superfluid with the crystal-like periodic density modulation of a solid1,2 . Since the first prediction in the 1950s3 , experimental efforts to realize this state have focused mainly on helium, where supersolidity remains elusive4 . Recently, supersolidity has also been studied intensively in ultracold quantum gases, and some of its defining properties have been induced in spin-orbit coupled Bose-Einstein condensates (BECs)5,6 and BECs coupled to two crossed optical cavities7,8 ...
September 9, 2019: Nature
L Tanzi, S M Roccuzzo, E Lucioni, F Famà, A Fioretti, C Gabbanini, G Modugno, A Recati, S Stringari
The paradoxical supersolid phase of matter, possessing the apparently incompatible properties of crystalline order and superfluidity, was predicted 50 years ago1-3 in the context of solid helium4-8 . Ultracold quantum gases have recently shown the appearance of the periodic order typical of a crystal, due to various types of controllable interactions9-13 . A crucial feature of a D-dimensional supersolid is the occurrence of up to D+1 gapless excitations reflecting the Goldstone modes associated with the spontaneous breaking of two continuous symmetries: the breaking of phase invariance, corresponding to the locking of the phase of the atomic wave functions at the origin of superfluid phenomena, and the breaking of translational invariance due to the lattice structure of the system...
September 9, 2019: Nature
Alicia Lardennois, Gabriella Pásti, Teresa Ferraro, Flora Llense, Pierre Mahou, Julien Pontabry, David Rodriguez, Samantha Kim, Shoichiro Ono, Emmanuel Beaurepaire, Christelle Gally, Michel Labouesse
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
September 6, 2019: Nature
Xueni Li, Shiheng Liu, Lingdi Zhang, Aaron Issaian, Ryan C Hill, Sara Espinosa, Shasha Shi, Yanxiang Cui, Kalli Kappel, Rhiju Das, Kirk C Hansen, Z Hong Zhou, Rui Zhao
The molecular mechanisms of exon definition and back-splicing are fundamental unanswered questions in pre-mRNA splicing. Here we report cryo-electron microscopy structures of the yeast spliceosomal E complex assembled on introns, providing a view of the earliest event in the splicing cycle that commits pre-mRNAs to splicing. The E complex architecture suggests that the same spliceosome can assemble across an exon, and that it either remodels to span an intron for canonical linear splicing (typically on short exons) or catalyses back-splicing to generate circular RNA (on long exons)...
September 4, 2019: Nature
Zhe Chen, Chuanming Zhou, Xunlai Yuan, Shuhai Xiao
The origin of motility in bilaterian animals represents an evolutionary innovation that transformed the Earth system. This innovation probably occurred in the late Ediacaran period-as evidenced by an abundance of trace fossils (ichnofossils) dating to this time, which include trails, trackways and burrows1-3 . However, with few exceptions4-8 , the producers of most of the late Ediacaran ichnofossils are unknown, which has resulted in a disconnection between the body- and trace-fossil records. Here we describe the fossil of a bilaterian of the terminal Ediacaran period (dating to 551-539 million years ago), which we name Yilingia spiciformis (gen...
September 4, 2019: Nature
Daniel N Weinberg, Simon Papillon-Cavanagh, Haifen Chen, Yuan Yue, Xiao Chen, Kartik N Rajagopalan, Cynthia Horth, John T McGuire, Xinjing Xu, Hamid Nikbakht, Agata E Lemiesz, Dylan M Marchione, Matthew R Marunde, Matthew J Meiners, Marcus A Cheek, Michael-Christopher Keogh, Eric Bareke, Anissa Djedid, Ashot S Harutyunyan, Nada Jabado, Benjamin A Garcia, Haitao Li, C David Allis, Jacek Majewski, Chao Lu
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis1-4 . They are also implicated in human developmental disorders and cancers5-8 , supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies9-11 ...
September 4, 2019: Nature
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