Author: Stephen Meyers

The geological record contains evidence of how Earth's climate responded to periodic changes in our planet's orbit and rotation. An investigation reveals how this record can be leveraged to constrain estimates of past climate dynamics.

Author: Sang-Hee Shim

The development of a microscopy technique that enables observation of the interactions between six types of organelle, in 3D and over time, holds promise for improving our understanding of intracellular processes.

Authors: Jennifer Wiseman & Marta Sewilo

New detectors for radio telescopes can map emissions from many different molecules simultaneously across interstellar clouds. One such pioneering study has probed a wide area of a star-forming cloud in the Orion constellation.

Author: Michael Worobey

Evolutionary trees constructed using both newly sequenced and previously available Zika virus genomes reveal how the recent outbreak arose in Brazil and spread across the Americas.

Authors: Peng Liu, Yaoting Ji, Tony Yuen, Elizabeth Rendina-Ruedy, Victoria E. DeMambro, Samarth Dhawan, Wahid Abu-Amer, Sudeh Izadmehr, Bin Zhou, Andrew C. Shin, Rauf Latif, Priyanthan Thangeswaran, Animesh Gupta, Jianhua Li, Valeria Shnayder, Samuel T. Robinson, Yue Eric Yu, Xingjian Zhang, Feiran Yang, Ping Lu, Yu Zhou, Ling-Ling Zhu, Douglas J. Oberlin, Terry F. Davies, Michaela R. Reagan, Aaron Brown, T. Rajendra Kumar, Solomon Epstein, Jameel Iqbal, Narayan G. Avadhani, Maria I. New, Henrik Molina, Jan B. van Klinken, Edward X. Guo, Christoph Buettner, Shozeb Haider, Zhuan Bian, Li Sun, Clifford J. Rosen & Mone Zaidi

Authors: Anna B. Loveland, Gabriel Demo, Nikolaus Grigorieff & Andrei A. Korostelev

Authors: Yan Zhang, Bingfa Sun, Dan Feng, Hongli Hu, Matthew Chu, Qianhui Qu, Jeffrey T. Tarrasch, Shane Li, Tong Sun Kobilka, Brian K. Kobilka & Georgios Skiniotis

Authors: N. R. Faria, J. Quick, I.M. Claro, J. Thézé, J. G. de Jesus, M. Giovanetti, M. U. G. Kraemer, S. C. Hill, A. Black, A. C. da Costa, L. C. Franco, S. P. Silva, C.-H. Wu, J. Raghwani, S. Cauchemez, L. du Plessis, M. P. Verotti, W. K. de Oliveira, E. H. Carmo, G. E. Coelho, A. C. F. S. Santelli, L. C. Vinhal, C. M. Henriques, J. T. Simpson, M. Loose, K. G. Andersen, N. D. Grubaugh, S. Somasekar, C. Y. Chiu, J. E. Muñoz-Medina, C. R. Gonzalez-Bonilla, C. F. Arias, L. L. Lewis-Ximenez, S. A. Baylis, A. O. Chieppe, S. F. Aguiar, C. A. Fernandes, P. S. Lemos, B. L. S. Nascimento, H. A. O. Monteiro, I. C. Siqueira, M. G. de Queiroz, T. R. de Souza, J. F. Bezerra, M. R. Lemos, G. F. Pereira, D. Loudal, L. C. Moura, R. Dhalia, R. F. França, T. Magalhães, E. T. Marques, T. Jaenisch, G. L. Wallau, M. C. de Lima, V. Nascimento, E. M. de Cerqueira, M. M. de Lima, D. L. Mascarenhas, J. P. Moura Neto, A. S. Levin, T. R. Tozetto-Mendoza, S. N. Fonseca, M. C. Mendes-Correa, F. P. Milagres, A. Segurado, E. C. Holmes, A. Rambaut, T. Bedford, M. R. T. Nunes, E. C. Sabino, L. C. J. Alcantara, N. J. Loman & O. G. Pybus

Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil. Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 December 2016) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 2016). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease. However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus.

Authors: Nathan D. Grubaugh, Jason T. Ladner, Moritz U. G. Kraemer, Gytis Dudas, Amanda L. Tan, Karthik Gangavarapu, Michael R. Wiley, Stephen White, Julien Thézé, Diogo M. Magnani, Karla Prieto, Daniel Reyes, Andrea M. Bingham, Lauren M. Paul, Refugio Robles-Sikisaka, Glenn Oliveira, Darryl Pronty, Carolyn M. Barcellona, Hayden C. Metsky, Mary Lynn Baniecki, Kayla G. Barnes, Bridget Chak, Catherine A. Freije, Adrianne Gladden-Young, Andreas Gnirke, Cynthia Luo, Bronwyn MacInnis, Christian B. Matranga, Daniel J. Park, James Qu, Stephen F. Schaffner, Christopher Tomkins-Tinch, Kendra L. West, Sarah M. Winnicki, Shirlee Wohl, Nathan L. Yozwiak, Joshua Quick, Joseph R. Fauver, Kamran Khan, Shannon E. Brent, Robert C. Reiner, Paola N. Lichtenberger, Michael J. Ricciardi, Varian K. Bailey, David I. Watkins, Marshall R. Cone, Edgar W. Kopp, Kelly N. Hogan, Andrew C. Cannons, Reynald Jean, Andrew J. Monaghan, Robert F. Garry, Nicholas J. Loman, Nuno R. Faria, Mario C. Porcelli, Chalmers Vasquez, Elyse R. Nagle, Derek A. T. Cummings, Danielle Stanek, Andrew Rambaut, Mariano Sanchez-Lockhart, Pardis C. Sabeti, Leah D. Gillis, Scott F. Michael, Trevor Bedford, Oliver G. Pybus, Sharon Isern, Gustavo Palacios & Kristian G. Andersen

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital abnormalities. In July 2016, mosquito-borne ZIKV transmission was reported in the continental United States; since then, hundreds of locally acquired infections have been reported in Florida. To gain insights into the timing, source, and likely route(s) of ZIKV introduction, we tracked the virus from its first detection in Florida by sequencing ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least 4 introductions, but potentially as many as 40, contributed to the outbreak in Florida and that local transmission is likely to have started in the spring of 2016—several months before its initial detection. By analysing surveillance and genetic data, we show that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions were linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. Our study provides an understanding of how ZIKV initiates transmission in new regions.

Authors: Jiyeon Kim, Zeping Hu, Ling Cai, Kailong Li, Eunhee Choi, Brandon Faubert, Divya Bezwada, Jaime Rodriguez-Canales, Pamela Villalobos, Yu-Fen Lin, Min Ni, Kenneth E. Huffman, Luc Girard, Lauren A. Byers, Keziban Unsal-Kacmaz, Christopher G. Peña, John V. Heymach, Els Wauters, Johan Vansteenkiste, Diego H. Castrillon, Benjamin P. C. Chen, Ignacio Wistuba, Diether Lambrechts, Jian Xu, John D. Minna & Ralph J. DeBerardinis

Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.

Authors: Isabelle Laforest-Lapointe, Alain Paquette, Christian Messier & Steven W. Kembel

Research on biodiversity and ecosystem functioning has demonstrated links between plant diversity and ecosystem functions such as productivity. At other trophic levels, the plant microbiome has been shown to influence host plant fitness and function, and host-associated microbes have been proposed to influence ecosystem function through their role in defining the extended phenotype of host organisms However, the importance of the plant microbiome for ecosystem function has not been quantified in the context of the known importance of plant diversity and traits. Here, using a tree biodiversity–ecosystem functioning experiment, we provide strong support for the hypothesis that leaf bacterial diversity is positively linked to ecosystem productivity, even after accounting for the role of plant diversity. Our results also show that host species identity, functional identity and functional diversity are the main determinants of leaf bacterial community structure and diversity. Our study provides evidence of a positive correlation between plant-associated microbial diversity and terrestrial ecosystem productivity, and a new mechanism by which models of biodiversity–ecosystem functioning relationships can be improved.

Authors: Alejandra Mendoza, Victoria Fang, Cynthia Chen, Madhavika Serasinghe, Akanksha Verma, James Muller, V. Sai Chaluvadi, Michael L. Dustin, Timothy Hla, Olivier Elemento, Jerry E. Chipuk & Susan R. Schwab

Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer’s patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P1 receptor (S1P1R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer’s patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P1R on T cells, and that the requirement for S1P1R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.

Authors: Hayden C. Metsky, Christian B. Matranga, Shirlee Wohl, Stephen F. Schaffner, Catherine A. Freije, Sarah M. Winnicki, Kendra West, James Qu, Mary Lynn Baniecki, Adrianne Gladden-Young, Aaron E. Lin, Christopher H. Tomkins-Tinch, Simon H. Ye, Daniel J. Park, Cynthia Y. Luo, Kayla G. Barnes, Rickey R. Shah, Bridget Chak, Giselle Barbosa-Lima, Edson Delatorre, Yasmine R. Vieira, Lauren M. Paul, Amanda L. Tan, Carolyn M. Barcellona, Mario C. Porcelli, Chalmers Vasquez, Andrew C. Cannons, Marshall R. Cone, Kelly N. Hogan, Edgar W. Kopp, Joshua J. Anzinger, Kimberly F. Garcia, Leda A. Parham, Rosa M. Gélvez Ramírez, Maria C. Miranda Montoya, Diana P. Rojas, Catherine M. Brown, Scott Hennigan, Brandon Sabina, Sarah Scotland, Karthik Gangavarapu, Nathan D. Grubaugh, Glenn Oliveira, Refugio Robles-Sikisaka, Andrew Rambaut, Lee Gehrke, Sandra Smole, M. Elizabeth Halloran, Luis Villar , Salim Mattar, Ivette Lorenzana, Jose Cerbino-Neto, Clarissa Valim, Wim Degrave, Patricia T. Bozza, Andreas Gnirke, Kristian G. Andersen, Sharon Isern, Scott F. Michael, Fernando A. Bozza, Thiago M. L. Souza, Irene Bosch, Nathan L. Yozwiak, Bronwyn L. MacInnis & Pardis C. Sabeti

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests.

Authors: Laura J. Pollock, Wilfried Thuiller & Walter Jetz

Different facets of biodiversity other than species numbers are increasingly appreciated as critical for maintaining the function of ecosystems and their services to humans. While new international policy and assessment processes such as the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) recognize the importance of an increasingly global, quantitative and comprehensive approach to biodiversity protection, most insights are still focused on a single facet of biodiversity—species. Here we broaden the focus and provide an evaluation of how much of the world’s species, functional and phylogenetic diversity of birds and mammals is currently protected and the scope for improvement. We show that the large existing gaps in the coverage for each facet of diversity could be remedied by a slight expansion of protected areas: an additional 5% of the land has the potential to more than triple the protected range of species or phylogenetic or functional units. Further, the same areas are often priorities for multiple diversity facets and for both taxa. However, we find that the choice of conservation strategy has a fundamental effect on outcomes. It is more difficult (that is, requires more land) to maximize basic representation of the global biodiversity pool than to maximize local diversity. Overall, species and phylogenetic priorities are more similar to each other than they are to functional priorities, and priorities for the different bird biodiversity facets are more similar than those of mammals. Our work shows that large gains in biodiversity protection are possible, while also highlighting the need to explicitly link desired conservation objectives and biodiversity metrics. We provide a framework and quantitative tools to advance these goals for multi-faceted biodiversity conservation.

Authors: Alex M. Valm, Sarah Cohen, Wesley R. Legant, Justin Melunis, Uri Hershberg, Eric Wait, Andrew R. Cohen, Michael W. Davidson, Eric Betzig & Jennifer Lippincott-Schwartz

The organization of the eukaryotic cell into discrete membrane-bound organelles allows for the separation of incompatible biochemical processes, but the activities of these organelles must be coordinated. For example, lipid metabolism is distributed between the endoplasmic reticulum for lipid synthesis, lipid droplets for storage and transport, mitochondria and peroxisomes for β-oxidation, and lysosomes for lipid hydrolysis and recycling. It is increasingly recognized that organelle contacts have a vital role in diverse cellular functions. However, the spatial and temporal organization of organelles within the cell remains poorly characterized, as fluorescence imaging approaches are limited in the number of different labels that can be distinguished in a single image. Here we present a systems-level analysis of the organelle interactome using a multispectral image acquisition method that overcomes the challenge of spectral overlap in the fluorescent protein palette. We used confocal and lattice light sheet instrumentation and an imaging informatics pipeline of five steps to achieve mapping of organelle numbers, volumes, speeds, positions and dynamic inter-organelle contacts in live cells from a monkey fibroblast cell line. We describe the frequency and locality of two-, three-, four- and five-way interactions among six different membrane-bound organelles (endoplasmic reticulum, Golgi, lysosome, peroxisome, mitochondria and lipid droplet) and show how these relationships change over time. We demonstrate that each organelle has a characteristic distribution and dispersion pattern in three-dimensional space and that there is a reproducible pattern of contacts among the six organelles, that is affected by microtubule and cell nutrient status. These live-cell confocal and lattice light sheet spectral imaging approaches are applicable to any cell system expressing multiple fluorescent probes, whether in normal conditions or when cells are exposed to disturbances such as drugs, pathogens or stress. This methodology thus offers a powerful descriptive tool and can be used to develop hypotheses about cellular organization and dynamics.

Authors: Jonathan Green, Atsuko Adachi, Kunal K. Shah, Jonathan D. Hirokawa, Pablo S. Magani & Gaby Maimon

Authors: Hélène Badouin, Jérôme Gouzy, Christopher J. Grassa, Florent Murat, S. Evan Staton, Ludovic Cottret, Christine Lelandais-Brière, Gregory L. Owens, Sébastien Carrère, Baptiste Mayjonade, Ludovic Legrand, Navdeep Gill, Nolan C. Kane, John E. Bowers, Sariel Hubner, Arnaud Bellec, Aurélie Bérard, Hélène Bergès, Nicolas Blanchet, Marie-Claude Boniface, Dominique Brunel, Olivier Catrice, Nadia Chaidir, Clotilde Claudel, Cécile Donnadieu, Thomas Faraut, Ghislain Fievet, Nicolas Helmstetter, Matthew King, Steven J. Knapp, Zhao Lai, Marie-Christine Le Paslier, Yannick Lippi, Lolita Lorenzon, Jennifer R. Mandel, Gwenola Marage, Gwenaëlle Marchand, Elodie Marquand, Emmanuelle Bret-Mestries, Evan Morien, Savithri Nambeesan, Thuy Nguyen, Prune Pegot-Espagnet, Nicolas Pouilly, Frances Raftis, Erika Sallet, Thomas Schiex, Justine Thomas, Céline Vandecasteele, Didier Varès, Felicity Vear, Sonia Vautrin, Martin Crespi, Brigitte Mangin, John M. Burke, Jérôme Salse, Stéphane Muños, Patrick Vincourt, Loren H. Rieseberg & Nicolas B. Langlade

The domesticated sunflower, Helianthus annuus L., is a global oil crop that has promise for climate change adaptation, because it can maintain stable yields across a wide variety of environmental conditions, including drought. Even greater resilience is achievable through the mining of resistance alleles from compatible wild sunflower relatives, including numerous extremophile species. Here we report a high-quality reference for the sunflower genome (3.6 gigabases), together with extensive transcriptomic data from vegetative and floral organs. The genome mostly consists of highly similar, related sequences and required single-molecule real-time sequencing technologies for successful assembly. Genome analyses enabled the reconstruction of the evolutionary history of the Asterids, further establishing the existence of a whole-genome triplication at the base of the Asterids II clade and a sunflower-specific whole-genome duplication around 29 million years ago. An integrative approach combining quantitative genetics, expression and diversity data permitted development of comprehensive gene networks for two major breeding traits, flowering time and oil metabolism, and revealed new candidate genes in these networks. We found that the genomic architecture of flowering time has been shaped by the most recent whole-genome duplication, which suggests that ancient paralogues can remain in the same regulatory networks for dozens of millions of years. This genome represents a cornerstone for future research programs aiming to exploit genetic diversity to improve biotic and abiotic stress resistance and oil production, while also considering agricultural constraints and human nutritional needs.

Authors: Julia Bailey-Serres & Wenbo Ma

Plants precisely express some immune regulators by controlling the translation of messenger RNA into protein. This insight enabled a disease-resistant rice to be engineered without compromised productivity.

Authors: Carolina Guibentif & Berthold Göttgens

Haematopoietic stem cells give rise to all lineages of blood cell, and their production in vitro has been a long-sought goal of stem-cell biology. Two groups now achieve this feat through different means.

Authors: Raphael Lis, Charles C. Karrasch, Michael G. Poulos, Balvir Kunar, David Redmond, Jose G. Barcia Duran, Chaitanya R. Badwe, William Schachterle, Michael Ginsberg, Jenny Xiang, Arash Rafii Tabrizi, Koji Shido, Zev Rosenwaks, Olivier Elemento, Nancy A. Speck, Jason M. Butler, Joseph M. Scandura & Shahin Rafii

Authors: Mary Philip, Lauren Fairchild, Liping Sun, Ellen L. Horste, Steven Camara, Mojdeh Shakiba, Andrew C. Scott, Agnes Viale, Peter Lauer, Taha Merghoub, Matthew D. Hellmann, Jedd D. Wolchok, Christina S. Leslie & Andrea Schietinger

Authors: Ryohichi Sugimura, Deepak Kumar Jha, Areum Han, Clara Soria-Valles, Edroaldo Lummertz da Rocha, Yi-Fen Lu, Jeremy A. Goettel, Erik Serrao, R. Grant Rowe, Mohan Malleshaiah, Irene Wong, Patricia Sousa, Ted N. Zhu, Andrea Ditadi, Gordon Keller, Alan N. Engelman, Scott B. Snapper, Sergei Doulatov & George Q. Daley

Authors: Haonan Zhang, Anna Qiao, Dehua Yang, Linlin Yang, Antao Dai, Chris de Graaf, Steffen Reedtz-Runge, Venkatasubramanian Dharmarajan, Hui Zhang, Gye Won Han, Thomas D. Grant, Raymond G. Sierra, Uwe Weierstall, Garrett Nelson, Wei Liu, Yanhong Wu, Limin Ma, Xiaoqing Cai, Guangyao Lin, Xiaoai Wu, Zhi Geng, Yuhui Dong, Gaojie Song, Patrick R. Griffin, Jesper Lau, Vadim Cherezov, Huaiyu Yang, Michael A. Hanson, Raymond C. Stevens, Qiang Zhao, Hualiang Jiang, Ming-Wei Wang & Beili Wu

Authors: Shinjae Chung, Franz Weber, Peng Zhong, Chan Lek Tan, Thuc Nghi Nguyen, Kevin T. Beier, Nikolai Hörmann, Wei-Cheng Chang, Zhe Zhang, Johnny Phong Do, Shenqin Yao, Michael J. Krashes, Bosiljka Tasic, Ali Cetin, Hongkui Zeng, Zachary A. Knight, Liqun Luo & Yang Dan

In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep. However, the sleep-active neurons are spatially intermingled with wake-active neurons, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.

Authors: Lei Geng, Lee T. Murray, Loretta J. Mickley, Pu Lin, Qiang Fu, Andrew J. Schauer & Becky Alexander

The abundance of tropospheric oxidants, such as ozone (O3) and hydroxyl (OH) and peroxy radicals (HO2 + RO2), determines the lifetimes of reduced trace gases such as methane and the production of particulate matter important for climate and human health. The response of tropospheric oxidants to climate change is poorly constrained owing to large uncertainties in the degree to which processes that influence oxidants may change with climate and owing to a lack of palaeo-records with which to constrain levels of atmospheric oxidants during past climate transitions. At present, it is thought that temperature-dependent emissions of tropospheric O3 precursors and water vapour abundance determine the climate response of oxidants, resulting in lower tropospheric O3 in cold climates while HOx (= OH + HO2 + RO2) remains relatively buffered. Here we report observations of oxygen-17 excess of nitrate (a proxy for the relative abundance of atmospheric O3 and HOx) from a Greenland ice core over the most recent glacial–interglacial cycle and for two Dansgaard–Oeschger events. We find that tropospheric oxidants are sensitive to climate change with an increase in the O3/HOx ratio in cold climates, the opposite of current expectations. We hypothesize that the observed increase in O3/HOx in cold climates is driven by enhanced stratosphere-to-troposphere transport of O3, and that reactive halogen chemistry is also enhanced in cold climates. Reactive halogens influence the oxidative capacity of the troposphere directly as oxidants themselves and indirectly via their influence on O3 and HOx. The strength of stratosphere-to-troposphere transport is largely controlled by the Brewer–Dobson circulation, which may be enhanced in colder climates owing to a stronger meridional gradient of sea surface temperatures, with implications for the response of tropospheric oxidants and stratospheric thermal and mass balance. These two processes may represent important, yet relatively unexplored, climate feedback mechanisms during major climate transitions.

Authors: Sydney R. Gordon, Roy L. Maute, Ben W. Dulken, Gregor Hutter, Benson M. George, Melissa N. McCracken, Rohit Gupta, Jonathan M. Tsai, Rahul Sinha, Daniel Corey, Aaron M. Ring, Andrew J. Connolly & Irving L. Weissman

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin’s lymphoma. Although it is well established that PD-1–PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1–PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1–PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.

Authors: Ayuna Hattori, Makoto Tsunoda, Takaaki Konuma, Masayuki Kobayashi, Tamas Nagy, John Glushka, Fariba Tayyari, Daniel McSkimming, Natarajan Kannan, Arinobu Tojo, Arthur S. Edison & Takahiro Ito

Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2–BCAT1 axis drives cancer progression in myeloid leukaemia.

Authors: Edward L. Huttlin, Raphael J. Bruckner, Joao A. Paulo, Joe R. Cannon, Lily Ting, Kurt Baltier, Greg Colby, Fana Gebreab, Melanie P. Gygi, Hannah Parzen, John Szpyt, Stanley Tam, Gabriela Zarraga, Laura Pontano-Vaites, Sharan Swarup, Anne E. White, Devin K. Schweppe, Ramin Rad, Brian K. Erickson, Robert A. Obar, K. G. Guruharsha, Kejie Li, Spyros Artavanis-Tsakonas, Steven P. Gygi & J. Wade Harper

The physiology of a cell can be viewed as the product of thousands of proteins acting in concert to shape the cellular response. Coordination is achieved in part through networks of protein–protein interactions that assemble functionally related proteins into complexes, organelles, and signal transduction pathways. Understanding the architecture of the human proteome has the potential to inform cellular, structural, and evolutionary mechanisms and is critical to elucidating how genome variation contributes to disease. Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification–mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome, and constitutes, to our knowledge, the largest such network so far. With more than 56,000 candidate interactions, BioPlex 2.0 contains more than 29,000 previously unknown co-associations and provides functional insights into hundreds of poorly characterized proteins while enhancing network-based analyses of domain associations, subcellular localization, and co-complex formation. Unsupervised Markov clustering of interacting proteins identified more than 1,300 protein communities representing diverse cellular activities. Genes essential for cell fitness are enriched within 53 communities representing central cellular functions. Moreover, we identified 442 communities associated with more than 2,000 disease annotations, placing numerous candidate disease genes into a cellular framework. BioPlex 2.0 exceeds previous experimentally derived interaction networks in depth and breadth, and will be a valuable resource for exploring the biology of incompletely characterized proteins and for elucidating larger-scale patterns of proteome organization.

Authors: Yang Liu, Jianying Liu, Senyan Du, Chao Shan, Kaixiao Nie, Rudian Zhang, Xiao-Feng Li, Renli Zhang, Tao Wang, Cheng-Feng Qin, Penghua Wang, Pei-Yong Shi & Gong Cheng

Zika virus (ZIKV) remained obscure until the recent explosive outbreaks in French Polynesia (2013–2014) and South America (2015–2016). Phylogenetic studies have shown that ZIKV has evolved into African and Asian lineages. The Asian lineage of ZIKV was responsible for the recent epidemics in the Americas. However, the underlying mechanisms through which ZIKV rapidly and explosively spread from Asia to the Americas are unclear. Non-structural protein 1 (NS1) facilitates flavivirus acquisition by mosquitoes from an infected mammalian host and subsequently enhances viral prevalence in mosquitoes. Here we show that NS1 antigenaemia determines ZIKV infectivity in its mosquito vector Aedes aegypti, which acquires ZIKV via a blood meal. Clinical isolates from the most recent outbreak in the Americas were much more infectious in mosquitoes than the FSS13025 strain, which was isolated in Cambodia in 2010. Further analyses showed that these epidemic strains have higher NS1 antigenaemia than the FSS13025 strain because of an alanine-to-valine amino acid substitution at residue 188 in NS1. ZIKV infectivity was enhanced by this amino acid substitution in the ZIKV FSS13025 strain in mosquitoes that acquired ZIKV from a viraemic C57BL/6 mouse deficient in type I and II interferon (IFN) receptors (AG6 mouse). Our results reveal that ZIKV evolved to acquire a spontaneous mutation in its NS1 protein, resulting in increased NS1 antigenaemia. Enhancement of NS1 antigenaemia in infected hosts promotes ZIKV infectivity and prevalence in mosquitoes, which could have facilitated transmission during recent ZIKV epidemics.

Authors: Gaojie Song, Dehua Yang, Yuxia Wang, Chris de Graaf, Qingtong Zhou, Shanshan Jiang, Kaiwen Liu, Xiaoqing Cai, Antao Dai, Guangyao Lin, Dongsheng Liu, Fan Wu, Yiran Wu, Suwen Zhao, Li Ye, Gye Won Han, Jesper Lau, Beili Wu, Michael A. Hanson, Zhi-Jie Liu, Ming-Wei Wang & Raymond C. Stevens

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V–VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

Authors: Rupert Sutherland, John Townend, Virginia Toy, Phaedra Upton, Jamie Coussens, Michael Allen, Laura-May Baratin, Nicolas Barth, Leeza Becroft, Carolin Boese, Austin Boles, Carolyn Boulton, Neil G. R. Broderick, Lucie Janku-Capova, Brett M. Carpenter, Bernard Célérier, Calum Chamberlain, Alan Cooper, Ashley Coutts, Simon Cox, Lisa Craw, Mai-Linh Doan, Jennifer Eccles, Dan Faulkner, Jason Grieve, Julia Grochowski, Anton Gulley, Arthur Hartog, Jamie Howarth, Katrina Jacobs, Tamara Jeppson, Naoki Kato, Steven Keys, Martina Kirilova, Yusuke Kometani, Rob Langridge, Weiren Lin, Timothy Little, Adrienn Lukacs, Deirdre Mallyon, Elisabetta Mariani, Cécile Massiot, Loren Mathewson, Ben Melosh, Catriona Menzies, Jo Moore, Luiz Morales, Chance Morgan, Hiroshi Mori, Andre Niemeijer, Osamu Nishikawa, David Prior, Katrina Sauer, Martha Savage, Anja Schleicher, Douglas R. Schmitt, Norio Shigematsu, Sam Taylor-Offord, Damon Teagle, Harold Tobin, Robert Valdez, Konrad Weaver, Thomas Wiersberg, Jack Williams, Nick Woodman & Martin Zimmer

Temperature and fluid pressure conditions control rock deformation and mineralization on geological faults, and hence the distribution of earthquakes. Typical intraplate continental crust has hydrostatic fluid pressure and a near-surface thermal gradient of 31 ± 15 degrees Celsius per kilometre. At temperatures above 300–450 degrees Celsius, usually found at depths greater than 10–15 kilometres, the intra-crystalline plasticity of quartz and feldspar relieves stress by aseismic creep and earthquakes are infrequent. Hydrothermal conditions control the stability of mineral phases and hence frictional–mechanical processes associated with earthquake rupture cycles, but there are few temperature and fluid pressure data from active plate-bounding faults. Here we report results from a borehole drilled into the upper part of the Alpine Fault, which is late in its cycle of stress accumulation and expected to rupture in a magnitude 8 earthquake in the coming decades. The borehole (depth 893 metres) revealed a pore fluid pressure gradient exceeding 9 ± 1 per cent above hydrostatic levels and an average geothermal gradient of 125 ± 55 degrees Celsius per kilometre within the hanging wall of the fault. These extreme hydrothermal conditions result from rapid fault movement, which transports rock and heat from depth, and topographically driven fluid movement that concentrates heat into valleys. Shear heating may occur within the fault but is not required to explain our observations. Our data and models show that highly anomalous fluid pressure and temperature gradients in the upper part of the seismogenic zone can be created by positive feedbacks between processes of fault slip, rock fracturing and alteration, and landscape development at plate-bounding faults.

Authors: Guoyong Xu, George H. Greene, Heejin Yoo, Lijing Liu, Jorge Marqués, Jonathan Motley & Xinnian Dong

In the absence of specialized immune cells, the need for plants to reprogram transcription to transition from growth-related activities to defence is well understood. However, little is known about translational changes that occur during immune induction. Using ribosome footprinting, here we perform global translatome profiling on Arabidopsis exposed to the microbe-associated molecular pattern elf18. We find that during this pattern-triggered immunity, translation is tightly regulated and poorly correlated with transcription. Identification of genes with altered translational efficiency leads to the discovery of novel regulators of this immune response. Further investigation of these genes shows that messenger RNA sequence features are major determinants of the observed translational efficiency changes. In the 5′ leader sequences of transcripts with increased translational efficiency, we find a highly enriched messenger RNA consensus sequence, R-motif, consisting of mostly purines. We show that R-motif regulates translation in response to pattern-triggered immunity induction through interaction with poly(A)-binding proteins. Therefore, this study provides not only strong evidence, but also a molecular mechanism, for global translational reprogramming during pattern-triggered immunity in plants.

Authors: Guoyong Xu, Meng Yuan, Chaoren Ai, Lijing Liu, Edward Zhuang, Sargis Karapetyan, Shiping Wang & Xinnian Dong

Controlling plant disease has been a struggle for humankind since the advent of agriculture. Studies of plant immune mechanisms have led to strategies of engineering resistant crops through ectopic transcription of plants’ own defence genes, such as the master immune regulatory gene NPR1 (ref. 1). However, enhanced resistance obtained through such strategies is often associated with substantial penalties to fitness, making the resulting products undesirable for agricultural applications. To remedy this problem, we sought more stringent mechanisms of expressing defence proteins. On the basis of our latest finding that translation of key immune regulators, such as TBF1 (ref. 3), is rapidly and transiently induced upon pathogen challenge (see accompanying paper), we developed a ‘TBF1-cassette’ consisting of not only the immune-inducible promoter but also two pathogen-responsive upstream open reading frames (uORFsTBF1) of the TBF1 gene. Here we demonstrate that inclusion of uORFsTBF1-mediated translational control over the production of snc1-1 (an autoactivated immune receptor) in Arabidopsis thaliana and AtNPR1 in rice enables us to engineer broad-spectrum disease resistance without compromising plant fitness in the laboratory or in the field. This broadly applicable strategy may lead to decreased pesticide use and reduce the selective pressure for resistant pathogens.

Authors: Susan C. Anenberg, Joshua Miller, Ray Minjares, Li Du, Daven K. Henze, Forrest Lacey, Christopher S. Malley, Lisa Emberson, Vicente Franco, Zbigniew Klimont & Chris Heyes

Vehicle emissions contribute to fine particulate matter (PM2.5) and tropospheric ozone air pollution, affecting human health, crop yields and climate worldwide. On-road diesel vehicles produce approximately 20 per cent of global anthropogenic emissions of nitrogen oxides (NOx), which are key PM2.5 and ozone precursors. Regulated NOx emission limits in leading markets have been progressively tightened, but current diesel vehicles emit far more NOx under real-world operating conditions than during laboratory certification testing. Here we show that across 11 markets, representing approximately 80 per cent of global diesel vehicle sales, nearly one-third of on-road heavy-duty diesel vehicle emissions and over half of on-road light-duty diesel vehicle emissions are in excess of certification limits. These excess emissions (totalling 4.6 million tons) are associated with about 38,000 PM2.5- and ozone-related premature deaths globally in 2015, including about 10 per cent of all ozone-related premature deaths in the 28 European Union member states. Heavy-duty vehicles are the dominant contributor to excess diesel NOx emissions and associated health impacts in almost all regions. Adopting and enforcing next-generation standards (more stringent than Euro 6/VI) could nearly eliminate real-world diesel-related NOx emissions in these markets, avoiding approximately 174,000 global PM2.5- and ozone-related premature deaths in 2040. Most of these benefits can be achieved by implementing Euro VI standards where they have not yet been adopted for heavy-duty vehicles.

Authors: Ching-Ju Tsai, Joerg Standfuss & Robert M. Glaeser

G-protein-coupled receptors are biological targets for drug discovery. Developments in cryo-electron microscopy have enabled the solution of the structure of a class B receptor in complex with its signalling protein. Two biologists and a microscopist explain the exciting implications of this work.

Authors: T. D. Jones, D. R. Davies, I. H. Campbell, G. Iaffaldano, G. Yaxley, S. C. Kramer & C. R. Wilson

Mantle plumes are buoyant upwellings of hot rock that transport heat from Earth’s core to its surface, generating anomalous regions of volcanism that are not directly associated with plate tectonic processes. The best-studied example is the Hawaiian–Emperor chain, but the emergence of two sub-parallel volcanic tracks along this chain, Loa and Kea, and the systematic geochemical differences between them have remained unexplained. Here we argue that the emergence of these tracks coincides with the appearance of other double volcanic tracks on the Pacific plate and a recent azimuthal change in the motion of the plate. We propose a three-part model that explains the evolution of Hawaiian double-track volcanism: first, mantle flow beneath the rapidly moving Pacific plate strongly tilts the Hawaiian plume and leads to lateral separation between high- and low-pressure melt source regions; second, the recent azimuthal change in Pacific plate motion exposes high- and low-pressure melt products as geographically distinct volcanoes, explaining the simultaneous emergence of double-track volcanism across the Pacific; and finally, secondary pyroxenite, which is formed as eclogite melt reacts with peridotite, dominates the low-pressure melt region beneath Loa-track volcanism, yielding the systematic geochemical differences observed between Loa- and Kea-type lavas. Our results imply that the formation of double-track volcanism is transitory and can be used to identify and place temporal bounds on plate-motion changes.

Authors: Cheng Gong, Lin Li, Zhenglu Li, Huiwen Ji, Alex Stern, Yang Xia, Ting Cao, Wei Bao, Chenzhe Wang, Yuan Wang, Z. Q. Qiu, R. J. Cava, Steven G. Louie, Jing Xia & Xiang Zhang

The realization of long-range ferromagnetic order in two-dimensional van der Waals crystals, combined with their rich electronic and optical properties, could lead to new magnetic, magnetoelectric and magneto-optic applications. In two-dimensional systems, the long-range magnetic order is strongly suppressed by thermal fluctuations, according to the Mermin–Wagner theorem; however, these thermal fluctuations can be counteracted by magnetic anisotropy. Previous efforts, based on defect and composition engineering, or the proximity effect, introduced magnetic responses only locally or extrinsically. Here we report intrinsic long-range ferromagnetic order in pristine Cr2Ge2Te6 atomic layers, as revealed by scanning magneto-optic Kerr microscopy. In this magnetically soft, two-dimensional van der Waals ferromagnet, we achieve unprecedented control of the transition temperature (between ferromagnetic and paramagnetic states) using very small fields (smaller than 0.3 tesla). This result is in contrast to the insensitivity of the transition temperature to magnetic fields in the three-dimensional regime. We found that the small applied field leads to an effective anisotropy that is much greater than the near-zero magnetocrystalline anisotropy, opening up a large spin-wave excitation gap. We explain the observed phenomenon using renormalized spin-wave theory and conclude that the unusual field dependence of the transition temperature is a hallmark of soft, two-dimensional ferromagnetic van der Waals crystals. Cr2Ge2Te6 is a nearly ideal two-dimensional Heisenberg ferromagnet and so will be useful for studying fundamental spin behaviours, opening the door to exploring new applications such as ultra-compact spintronics.

Authors: Yi-Lynn Liang, Maryam Khoshouei, Mazdak Radjainia, Yan Zhang, Alisa Glukhova, Jeffrey Tarrasch, David M. Thal, Sebastian G. B. Furness, George Christopoulos, Thomas Coudrat, Radostin Danev, Wolfgang Baumeister, Laurence J. Miller, Arthur Christopoulos, Brian K. Kobilka, Denise Wootten, Georgios Skiniotis & Patrick M. Sexton

Authors: Michael R. Hall, Kevin M. Kocot, Kenneth W. Baughman, Selene L. Fernandez-Valverde, Marie E. A. Gauthier, William L. Hatleberg, Arunkumar Krishnan, Carmel McDougall, Cherie A. Motti, Eiichi Shoguchi, Tianfang Wang, Xueyan Xiang, Min Zhao, Utpal Bose, Chuya Shinzato, Kanako Hisata, Manabu Fujie, Miyuki Kanda, Scott F. Cummins, Noriyuki Satoh, Sandie M. Degnan & Bernard M. Degnan

The crown-of-thorns starfish (COTS, the Acanthaster planci species group) is a highly fecund predator of reef-building corals throughout the Indo-Pacific region. COTS population outbreaks cause substantial loss of coral cover, diminishing the integrity and resilience of reef ecosystems. Here we sequenced genomes of COTS from the Great Barrier Reef, Australia and Okinawa, Japan to identify gene products that underlie species-specific communication and could potentially be used in biocontrol strategies. We focused on water-borne chemical plumes released from aggregating COTS, which make the normally sedentary starfish become highly active. Peptide sequences detected in these plumes by mass spectrometry are encoded in the COTS genome and expressed in external tissues. The exoproteome released by aggregating COTS consists largely of signalling factors and hydrolytic enzymes, and includes an expanded and rapidly evolving set of starfish-specific ependymin-related proteins. These secreted proteins may be detected by members of a large family of olfactory-receptor-like G-protein-coupled receptors that are expressed externally, sometimes in a sex-specific manner. This study provides insights into COTS-specific communication that may guide the generation of peptide mimetics for use on reefs with COTS outbreaks.

Author: Giorgio Gratta

Neutrinos are much lighter than the other constituents of matter. One explanation for this could be that neutrinos are their own antiparticles and belong to a new class of 'Majorana' particle. An experiment sets strong constraints on this scenario.

Authors: Peter B. deMenocal & Chris Stringer

The human dispersal out of Africa that populated the world was probably paced by climate changes. This is the inference drawn from computer modelling of climate variability during the time of early human migration.

Author: Michelle C. Barton

Underactivity of the transcription factor p53 can lead to tumour development. The discovery that the SET protein binds to and inhibits p53 points to a way to unleash the tumour suppressor's activity.

Author: David W. Pfennig

Deadly coral snakes warn predators through striking red-black banding. New data confirm that many harmless snakes have evolved to resemble coral snakes, and suggest that the evolution of this Batesian mimicry is not always a one-way street.