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Diversity in sight p.418

A systematic analysis of bipolar cells, which act as a central signalling conduit in the retina, reveals that the neurons' diverse responses to light are generated largely by feedback from neighbouring amacrine cells. See Article p.439

Richard H. Masland

doi: 10.1038/nature21498

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Predictable ice ages on a chaotic planet p.419

Statistical analysis has revealed a simple rule for the occurrence of warm periods during the Quaternary, whereas on much longer timescales geological data have confirmed that the Solar System is chaotic. See Article p.427 & Letter p.468

Didier Paillard

doi: 10.1038/542419a

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RNA editing packs a one-two punch p.420

Optimal protein synthesis requires bases in transfer RNAs to be modified. A key modification has been shown to involve an unusual two-step mechanism that entails the sequential activities of two enzymes. See Letter p.494

William T. Yewdell & Jayanta Chaudhuri

doi: 10.1038/542420a

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Earth's seven sisters p.421

Seven small planets whose surfaces could harbour liquid water have been spotted around a nearby dwarf star. If such a configuration is common in planetary systems, our Galaxy could be teeming with Earth-like planets. See Letter p.456

Ignas A. G. Snellen

doi: 10.1038/542421a

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Organic analogues of graphene p.423

Chemists have long aspired to synthesize two-dimensional polymers that are fully conjugated — an attribute that imparts potentially useful properties. Just such a material has been prepared using a solid-state polymerization reaction.

Maryam Ebrahimi & Federico Rosei

doi: 10.1038/nature21503

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A targeted treatment with off-target risks p.424

It emerges that blood-cancer-targeting drugs that block a tumour-survival pathway also activate a mutation-causing enzyme in mice and in human cells. This might have implications for the clinical use of these drugs. See Letter p.489

David A. Fruman & Susan O'Brien

doi: 10.1038/nature21504

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Articles

A simple rule to determine which insolation cycles lead to interglacials p.427

A simple model, based on only summer insolation energy and time since the previous deglaciation, correctly predicts the deglaciation history of the past 2.6 million years, including the change in frequency of glacial–interglacial cycles about one million years ago.

P. C. Tzedakis, M. Crucifix, T. Mitsui & E. W. Wolff

doi: 10.1038/nature21364

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Inhibition decorrelates visual feature representations in the inner retina p.439

The functional diversity of bipolar cells, which split visual inputs into different excitatory channels within the retina, arises from centre–surround interactions in their receptive fields that tune both spatial and temporal signalling.

Katrin Franke, Philipp Berens, Timm Schubert, Matthias Bethge, Thomas Euler & Tom Baden

doi: 10.1038/nature21394

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Sterile protection against human malaria by chemoattenuated PfSPZ vaccine p.445

Immunization with Plasmodium falciparum sporozoites under chemoprophylaxis can protect against controlled human malaria infection with the same strain for at least 10 weeks, and protection correlates with polyfunctional T-cell memory.

Benjamin Mordmüller, Güzin Surat, Heimo Lagler, Sumana Chakravarty, Andrew S. Ishizuka, Albert Lalremruata, Markus Gmeiner, Joseph J. Campo, Meral Esen, Adam J. Ruben + et al.

doi: 10.1038/nature21060

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Adipose-derived circulating miRNAs regulate gene expression in other tissues p.450

Adipose tissue is a major source of circulating exosomal miRNAs, which contribute to the regulation of gene expression in distant tissues and organs.

Thomas Thomou, Marcelo A. Mori, Jonathan M. Dreyfuss, Masahiro Konishi, Masaji Sakaguchi, Christian Wolfrum, Tata Nageswara Rao, Jonathon N. Winnay, Ruben Garcia-Martin, Steven K. Grinspoon + et al.

doi: 10.1038/nature21365

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Letters

Seven temperate terrestrial planets around the nearby ultracool dwarf star TRAPPIST-1 p.456

Last year, three Earth-sized planets were discovered to be orbiting the nearby Jupiter-sized star TRAPPIST-1; now, follow-up photometric observations from the ground and from space show that there are at least seven Earth-sized planets in this star system, and that they might be the right temperature to harbour liquid water on their surfaces.

Michaël Gillon, Amaury H. M. J. Triaud, Brice-Olivier Demory, Emmanuël Jehin, Eric Agol, Katherine M. Deck, Susan M. Lederer, Julien de Wit, Artem Burdanov, James G. Ingalls + et al.

doi: 10.1038/nature21360

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Static non-reciprocity in mechanical metamaterials p.461

Suitably engineered mechanical metamaterials show static non-reciprocity—that is, the transmission of motion from one side to the other depends on the direction of that motion.

Corentin Coulais, Dimitrios Sounas & Andrea Alù

doi: 10.1038/nature21044

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Onset of the aerobic nitrogen cycle during the Great Oxidation Event p.465

Nitrogen isotope data from sediments deposited during the earliest stage of the Great Oxidation Event show evidence for the emergence of a pervasive aerobic marine nitrogen cycle.

Aubrey L. Zerkle, Simon W. Poulton, Robert J. Newton, Colin Mettam, Mark W. Claire, Andrey Bekker & Christopher K. Junium

doi: 10.1038/nature20826

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m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition p.475

The maternal-to-zygotic transition (MZT) is one of the most profound and tightly orchestrated processes during the early life of embryos, yet factors that shape the temporal pattern of vertebrate MZT are largely unknown. Here we show that over one-third of zebrafish maternal messenger RNAs (mRNAs) can be N6-methyladenosine (m6A) modified, and the clearance of these maternal mRNAs is facilitated by an m6A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m6A-modified maternal mRNAs and impedes zygotic genome activation. These embryos fail to initiate timely MZT, undergo cell-cycle pause, and remain developmentally delayed throughout larval life. Our study reveals m6A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m6A mRNA methylation in transcriptome switching and animal development.

Boxuan Simen Zhao, Xiao Wang, Alana V. Beadell, Zhike Lu, Hailing Shi, Adam Kuuspalu, Robert K. Ho & Chuan He

doi: 10.1038/nature21355

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Metabolic gatekeeper function of B-lymphoid transcription factors p.479

The B-lymphoid transcription factors PAX5 and IKZF1 restrict the supply of glucose and energy to B cells to levels that are not enough to fuel a driver-oncogene, thereby acting as tumour suppressors and sensitizing acute lymphoblastic leukaemia B cells to glucocorticoid therapy.

Lai N. Chan, Zhengshan Chen, Daniel Braas, Jae-Woong Lee, Gang Xiao, Huimin Geng, Kadriye Nehir Cosgun, Christian Hurtz, Seyedmehdi Shojaee, Valeria Cazzaniga + et al.

doi: 10.1038/nature21076

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Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer p.484

The gene CHD1 is synthetic essential in PTEN-deficient prostate and breast cancers.

Di Zhao, Xin Lu, Guocan Wang, Zhengdao Lan, Wenting Liao, Jun Li, Xin Liang, Jasper Robin Chen, Sagar Shah, Xiaoying Shang + et al.

doi: 10.1038/nature21357

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Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells p.489

Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton’s tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.

Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B. Blasco, Fernanda Langellotto + et al.

doi: 10.1038/nature21406

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Editing and methylation at a single site by functionally interdependent activities p.494

The C-to-U deamination at position 32 of tRNAThr in Trypanosoma brucei requires two enzymatic activities and proceeds via formation of a 3-methylcytosine intermediate, supporting the notion of a coupled modification system.

Mary Anne T. Rubio, Kirk W. Gaston, Katherine M. McKenney, Ian M. C. Fleming, Zdeněk Paris, Patrick A. Limbach & Juan D. Alfonzo

doi: 10.1038/nature21396

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Basis of catalytic assembly of the mitotic checkpoint complex p.498

The near-complete in vitro reconstitution of the mitotic spindle assembly checkpoint reveals how the assembly of its effector, the mitotic checkpoint complex, is catalysed.

Alex C. Faesen, Maria Thanasoula, Stefano Maffini, Claudia Breit, Franziska Müller, Suzan van Gerwen, Tanja Bange & Andrea Musacchio

doi: 10.1038/nature21384

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