Junhua Pan, Xinlei Qian, Simon Lattmann, Abbas El Sahili, Tiong Han Yeo, Huan Jia, Tessa Cressey, Barbara Ludeke, Sarah Noton, Marian Kalocsay, Rachel Fearns, Julien Lescar
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause severe respiratory diseases in infants and elder adults1 . Neither a vaccine nor an effective antiviral therapy exists to control RSV or HMPV infections. During viral genome replication and transcription, the tetrameric phosphoprotein P serves as a crucial adaptor between the nucleoprotein-RNA (N-RNA) template and the L protein, which has RNA-dependent RNA polymerase (RdRp), GDP polyribonucleotidyltransferase (PRNTase) and cap-specific methyltransferases (MTases) activities2,3 ...
November 7, 2019: Nature
Weirong Liu, Jonas Cremer, Dengjin Li, Terence Hwa, Chenli Liu
The ability of a species to colonize newly available habitats is crucial to its overall fitness1-3 . In general, motility and fast expansion are expected to be beneficial for colonization and hence for the fitness of an organism4-7 . Here we apply an evolution protocol to investigate phenotypical requirements for colonizing habitats of different sizes during range expansion by chemotaxing bacteria8 . Contrary to the intuitive expectation that faster is better, we show that there is an optimal expansion speed for a given habitat size...
November 6, 2019: Nature
Thomas MacVicar, Yohsuke Ohba, Hendrik Nolte, Fiona Carola Mayer, Takashi Tatsuta, Hans-Georg Sprenger, Barbara Lindner, Yue Zhao, Jiahui Li, Christiane Bruns, Marcus Krüger, Markus Habich, Jan Riemer, Robin Schwarzer, Manolis Pasparakis, Sinika Henschke, Jens C Brüning, Nicola Zamboni, Thomas Langer
Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis1-3 . Here we show that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis...
November 6, 2019: Nature
William B Hamilton, Yaron Mosesson, Rita S Monteiro, Kristina B Emdal, Teresa E Knudsen, Chiara Francavilla, Naama Barkai, Jesper V Olsen, Joshua M Brickman
Central to understanding cellular behaviour in multi-cellular organisms is the question of how a cell exits one transcriptional state to adopt and eventually become committed to another. Fibroblast growth factor-extracellular signal-regulated kinase (FGF -ERK) signalling drives differentiation of mouse embryonic stem cells (ES cells) and pre-implantation embryos towards primitive endoderm, and inhibiting ERK supports ES cell self-renewal1 . Paracrine FGF-ERK signalling induces heterogeneity, whereby cells reversibly progress from pluripotency towards primitive endoderm while retaining their capacity to re-enter self-renewal2 ...
November 6, 2019: Nature
Jonas Cremer, Tomoya Honda, Ying Tang, Jerome Wong-Ng, Massimo Vergassola, Terence Hwa
Bacterial chemotaxis, the directed movement of cells along gradients of chemoattractants, is among the best-characterized subjects in molecular biology1-10 , but much less is known about its physiological roles11 . It is commonly seen as a starvation response when nutrients run out, or as an escape response from harmful situations12-16 . Here we identify an alternative role of chemotaxis by systematically examining the spatiotemporal dynamics of Escherichia coli in soft agar12,17,18 . Chemotaxis in nutrient-replete conditions promotes the expansion of bacterial populations into unoccupied territories well before nutrients run out in the current environment...
November 6, 2019: Nature
Madelaine Böhme, Nikolai Spassov, Jochen Fuss, Adrian Tröscher, Andrew S Deane, Jérôme Prieto, Uwe Kirscher, Thomas Lechner, David R Begun
Many ideas have been proposed to explain the origin of bipedalism in hominins and suspension in great apes (hominids); however, fossil evidence has been lacking. It has been suggested that bipedalism in hominins evolved from an ancestor that was a palmigrade quadruped (which would have moved similarly to living monkeys), or from a more suspensory quadruped (most similar to extant chimpanzees)1 . Here we describe the fossil ape Danuvius guggenmosi (from the Allgäu region of Bavaria) for which complete limb bones are preserved, which provides evidence of a newly identified form of positional behaviour-extended limb clambering...
November 6, 2019: Nature
Shehryar Ahmad, Boyuan Wang, Matthew D Walker, Hiu-Ki R Tran, Peter J Stogios, Alexei Savchenko, Robert A Grant, Andrew G McArthur, Michael T Laub, John C Whitney
Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors1 . One such mechanism involves type VI secretion systems, which bacteria can use to inject antibacterial toxins directly into neighbouring cells. Many of these toxins target the integrity of the cell envelope, but the full range of growth inhibitory mechanisms remains unknown2 . Here we identify a type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa. The crystal structure of Tas1 shows that it is similar to enzymes that synthesize (p)ppGpp, a broadly conserved signalling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress3 ...
November 6, 2019: Nature
Filippos Kottakis, Brandon N Nicolay, Ahlima Roumane, Rahul Karnik, Hongcang Gu, Julia M Nagle, Myriam Boukhali, Michele C Hayward, Yvonne Y Li, Ting Chen, Marc Liesa, Peter S Hammerman, Kwok Kin Wong, D Neil Hayes, Orian S Shirihai, Nicholas J Dyson, Wilhelm Haas, Alexander Meissner, Nabeel Bardeesy
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
November 6, 2019: Nature
Yufeng Chen, Huichan Zhao, Jie Mao, Pakpong Chirarattananon, E Farrell Helbling, Nak-Seung Patrick Hyun, David R Clarke, Robert J Wood
Flying insects capable of navigating in highly cluttered natural environments can withstand in-flight collisions because of the combination of their low inertia1 and the resilience of their wings2 , exoskeletons1 and muscles. Current insect-scale (less than ten centimetres long and weighing less than five grams) aerial robots3-6 use rigid microscale actuators, which are typically fragile under external impact. Biomimetic artificial muscles7-10 that are capable of large deformation offer a promising alternative for actuation because they can endure the stresses caused by such impacts...
November 4, 2019: Nature
Adam E Locke, Karyn Meltz Steinberg, Charleston W K Chiang, Susan K Service, Aki S Havulinna, Laurel Stell, Matti Pirinen, Haley J Abel, Colby C Chiang, Robert S Fulton, Anne U Jackson, Chul Joo Kang, Krishna L Kanchi, Daniel C Koboldt, David E Larson, Joanne Nelson, Thomas J Nicholas, Arto Pietilä, Vasily Ramensky, Debashree Ray, Laura J Scott, Heather M Stringham, Jagadish Vangipurapu, Ryan Welch, Pranav Yajnik, Xianyong Yin, Johan G Eriksson, Mika Ala-Korpela, Marjo-Riitta Järvelin, Minna Männikkö, Hannele Laivuori, Susan K Dutcher, Nathan O Stitziel, Richard K Wilson, Ira M Hall, Chiara Sabatti, Aarno Palotie, Veikko Salomaa, Markku Laakso, Samuli Ripatti, Michael Boehnke, Nelson B Freimer
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
November 4, 2019: Nature
Michal Levin, Leon Anavy, Alison G Cole, Eitan Winter, Natalia Mostov, Sally Khair, Naftalie Senderovich, Ekaterina Kovalev, David H Silver, Martin Feder, Selene L Fernandez-Valverde, Nagayasu Nakanishi, David Simmons, Oleg Simakov, Tomas Larsson, Shang-Yun Liu, Ayelet Jerafi-Vider, Karina Yaniv, Joseph F Ryan, Mark Q Martindale, Jochen C Rink, Detlev Arendt, Sandie M Degnan, Bernard M Degnan, Tamar Hashimshony, Itai Yanai
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
October 31, 2019: Nature
Yian Yin, Yang Wang, James A Evans, Dashun Wang
Human achievements are often preceded by repeated attempts that fail, but little is known about the mechanisms that govern the dynamics of failure. Here, building on previous research relating to innovation1-7 , human dynamics8-11 and learning12-17 , we develop a simple one-parameter model that mimics how successful future attempts build on past efforts. Solving this model analytically suggests that a phase transition separates the dynamics of failure into regions of progression or stagnation and predicts that, near the critical threshold, agents who share similar characteristics and learning strategies may experience fundamentally different outcomes following failures...
October 30, 2019: Nature
Oriol Vinyals, Igor Babuschkin, Wojciech M Czarnecki, Michaël Mathieu, Andrew Dudzik, Junyoung Chung, David H Choi, Richard Powell, Timo Ewalds, Petko Georgiev, Junhyuk Oh, Dan Horgan, Manuel Kroiss, Ivo Danihelka, Aja Huang, Laurent Sifre, Trevor Cai, John P Agapiou, Max Jaderberg, Alexander S Vezhnevets, Rémi Leblond, Tobias Pohlen, Valentin Dalibard, David Budden, Yury Sulsky, James Molloy, Tom L Paine, Caglar Gulcehre, Ziyu Wang, Tobias Pfaff, Yuhuai Wu, Roman Ring, Dani Yogatama, Dario Wünsch, Katrina McKinney, Oliver Smith, Tom Schaul, Timothy Lillicrap, Koray Kavukcuoglu, Demis Hassabis, Chris Apps, David Silver
Many real-world applications require artificial agents to compete and coordinate with other agents in complex environments. As a stepping stone to this goal, the domain of StarCraft has emerged as an important challenge for artificial intelligence research, owing to its iconic and enduring status among the most difficult professional esports and its relevance to the real world in terms of its raw complexity and multi-agent challenges. Over the course of a decade and numerous competitions1-3 , the strongest agents have simplified important aspects of the game, utilized superhuman capabilities, or employed hand-crafted sub-systems4 ...
October 30, 2019: Nature
Julie A Harris, Stefan Mihalas, Karla E Hirokawa, Jennifer D Whitesell, Hannah Choi, Amy Bernard, Phillip Bohn, Shiella Caldejon, Linzy Casal, Andrew Cho, Aaron Feiner, David Feng, Nathalie Gaudreault, Charles R Gerfen, Nile Graddis, Peter A Groblewski, Alex M Henry, Anh Ho, Robert Howard, Joseph E Knox, Leonard Kuan, Xiuli Kuang, Jerome Lecoq, Phil Lesnar, Yaoyao Li, Jennifer Luviano, Stephen McConoughey, Marty T Mortrud, Maitham Naeemi, Lydia Ng, Seung Wook Oh, Benjamin Ouellette, Elise Shen, Staci A Sorensen, Wayne Wakeman, Quanxin Wang, Yun Wang, Ali Williford, John W Phillips, Allan R Jones, Christof Koch, Hongkui Zeng
The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource1 , involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron...
October 30, 2019: Nature
Xuefei Zhang, Yu Zhang, Zhaoqing Ba, Nia Kyritsis, Rafael Casellas, Frederick W Alt
Antibody class switch recombination (CSR) in B lymphocytes replaces immunoglobulin heavy chain locus (Igh) Cμ constant region exons (CH s) with one of six CH s lying 100-200 kb downstream1 . Each CH is flanked upstream by an I promoter and long repetitive switch (S) region1 . Cytokines and activators induce activation-induced cytidine deaminase (AID)2 and I-promoter transcription, with 3' IgH regulatory region (3' IgHRR) enhancers controlling the latter via I-promoter competition for long-range 3' IgHRR interactions3-8 ...
October 30, 2019: Nature
John D Strickley, Jonathan L Messerschmidt, Mary E Awad, Tiancheng Li, Tatsuya Hasegawa, Dat Thinh Ha, Henry W Nabeta, Paul A Bevins, Kenneth H Ngo, Maryam M Asgari, Rosalynn M Nazarian, Victor A Neel, Alfred Bennett Jenson, Joongho Joh, Shadmehr Demehri
Immunosuppression increases the risk of cancers that are associated with viral infection1 . In particular, the risk of squamous cell carcinoma of the skin-which has been associated with beta human papillomavirus (β-HPV) infection-is increased by more than 100-fold in immunosuppressed patients2-4 . Previous studies have not established a causative role for HPVs in driving the development of skin cancer. Here we show that T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts, and the loss of this immunity-rather than the oncogenic effect of HPVs-causes the markedly increased risk of skin cancer in immunosuppressed patients...
October 30, 2019: Nature
Jude Canon, Karen Rex, Anne Y Saiki, Christopher Mohr, Keegan Cooke, Dhanashri Bagal, Kevin Gaida, Tyler Holt, Charles G Knutson, Neelima Koppada, Brian A Lanman, Jonathan Werner, Aaron S Rapaport, Tisha San Miguel, Roberto Ortiz, Tao Osgood, Ji-Rong Sun, Xiaochun Zhu, John D McCarter, Laurie P Volak, Brett E Houk, Marwan G Fakih, Bert H O'Neil, Timothy J Price, Gerald S Falchook, Jayesh Desai, James Kuo, Ramaswamy Govindan, David S Hong, Wenjun Ouyang, Haby Henary, Tara Arvedson, Victor J Cee, J Russell Lipford
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2 . The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5 . Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development...
October 30, 2019: Nature
Shabih Shakeel, Eeson Rajendra, Pablo Alcón, Francis O'Reilly, Dror S Chorev, Sarah Maslen, Gianluca Degliesposti, Christopher J Russo, Shaoda He, Chris H Hill, J Mark Skehel, Sjors H W Scheres, Ketan J Patel, Juri Rappsilber, Carol V Robinson, Lori A Passmore
The Fanconi anaemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks, and responds to replication stress1,2 . Genetic inactivation of this pathway by mutation of genes encoding FA complementation group (FANC) proteins impairs development, prevents blood production and promotes cancer1,3 . The key molecular step in the FA pathway is the monoubiquitination of a pseudosymmetric heterodimer of FANCD2-FANCI4,5 by the FA core complex-a megadalton multiprotein E3 ubiquitin ligase6,7 ...
October 30, 2019: Nature
Benjamin D Ross, Adrian J Verster, Matthew C Radey, Danica T Schmidtke, Christopher E Pope, Lucas R Hoffman, Adeline M Hajjar, S Brook Peterson, Elhanan Borenstein, Joseph D Mougous
The human gastrointestinal tract consists of a dense and diverse microbial community, the composition of which is intimately linked to health. Extrinsic factors such as diet and host immunity are insufficient to explain the constituents of this community, and direct interactions between co-resident microorganisms have been implicated as important drivers of microbiome composition. The genomes of bacteria derived from the gut microbiome contain several pathways that mediate contact-dependent interbacterial antagonism1-3 ...
October 30, 2019: Nature
Zhaoyang Li, Cen Wang, Ziying Wang, Chenggang Zhu, Jie Li, Tian Sha, Lixiang Ma, Chao Gao, Yi Yang, Yimin Sun, Jian Wang, Xiaoli Sun, Chenqi Lu, Marian Difiglia, Yanai Mei, Chen Ding, Shouqing Luo, Yongjun Dang, Yu Ding, Yiyan Fei, Boxun Lu
Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)1 and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington's disease, an incurable neurodegenerative disorder2 ...
October 30, 2019: Nature
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