네이처 컨텐츠

Editorials

Adolescence research must grow up p.403

Young people get a raw deal from society. Targeted study and approaches as part of a new global effort are urgently needed to help them.

doi: 10.1038/d41586-018-02185-w

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News

News Features

News & Views

Pruning hypothesis comes of age p.438

The idea that disrupted pruning of neuronal connections in the brain during adolescence is a cause of schizophrenia was proposed in 1983. This proved prescient, as subsequent imaging, genetic and molecular research has shown.

doi: 10.1038/d41586-018-02053-7

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Molecules pressured to react p.468

Crystals have been made that undergo reactions when compressed. Computational simulations of these processes provide much-needed atomic-level insight into the mechanisms of mechanically induced reactions.

doi: 10.1038/d41586-018-02047-5

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Force-activated ion channels in close-up p.469

Piezo proteins allow cells to sense forces by letting ions pass through the cell membrane in response to mechanical stimuli. Three structures of a Piezo protein shed light on how this crucial process works.

doi: 10.1038/d41586-018-01631-z

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An inflammatory transcriptional switch p.470

The mouse pancreas adopts a pre-inflammatory state in response to a chemical injury or the loss of one copy of the gene Nr5a2. This state might predispose mice, and possibly humans, to pancreatitis and pancreatic cancer.

doi: 10.1038/d41586-018-01262-4

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Neurons mimicked by electronics p.472

Electronic devices can currently emulate only basic functions of biological neurons. Devices called memtransistors could overcome this limitation and give rise to improvements in artificial-intelligence systems.

doi: 10.1038/d41586-018-02025-x

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Perspectives

Analysis

Adolescence and the next generation OPEN p.458

Investing in adolescents as the parents of the next generation is important for the wellbeing of current and future generations.

George C. Patton, Craig A. Olsson, Vegard Skirbekk, Richard Saffery, Mary E. Wlodek, Peter S. Azzopardi, Marcin Stonawski, Bruce Rasmussen, Elizabeth Spry, Kate Francis + et al.

doi: 10.1038/nature25759

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Articles

A molecular atlas of cell types and zonation in the brain vasculature p.475

Single-cell transcriptomic analysis of the murine blood–brain barrier provides molecular definitions of the main vascular cell types, classifies perivascular cell types and sheds light on the organization of the arteriovenous axis.

Michael Vanlandewijck, Liqun He, Maarja Andaloussi Mäe, Johanna Andrae, Koji Ando, Francesca Del Gaudio, Khayrun Nahar, Thibaud Lebouvier, Bàrbara Laviña, Leonor Gouveia + et al.

doi: 10.1038/nature25739

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Structure of the mechanically activated ion channel Piezo1 p.481

The cryo-electron microscopy structure of full-length mouse Piezo1 reveals six Piezo repeats, and 26 transmembrane helices per protomer, and shows that a kinked helical beam and anchor domain link the Piezo repeats to the pore and control gating allosterically.

Kei Saotome, Swetha E. Murthy, Jennifer M. Kefauver, Tess Whitwam, Ardem Patapoutian & Andrew B. Ward

doi: 10.1038/nature25453

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Structure and mechanogating mechanism of the Piezo1 channel p.487

The electron cryo-microscopy structure of full-length mouse Piezo1 reveals unique topological features such as the repetitive transmembrane helical units that constitute the highly curved transmembrane region, and identifies regions and single residues that are crucial for the mechanical activation of the channel.

Qiancheng Zhao, Heng Zhou, Shaopeng Chi, Yanfeng Wang, Jianhua Wang, Jie Geng, Kun Wu, Wenhao Liu, Tingxin Zhang, Meng-Qiu Dong + et al.

doi: 10.1038/nature25743

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Letters

Multi-terminal memtransistors from polycrystalline monolayer molybdenum disulfide p.500

Polycrystalline monolayer molybdenum disulfide is used to fabricate a multi-terminal device combining a memristor and a transistor, which can mimic biological neurons with multiple synapses for neuromorphic computing applications.

Vinod K. Sangwan, Hong-Sub Lee, Hadallia Bergeron, Itamar Balla, Megan E. Beck, Kan-Sheng Chen & Mark C. Hersam

doi: 10.1038/nature25747

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Sterically controlled mechanochemistry under hydrostatic pressure p.505

‘Molecular anvil’ molecules consisting of a compressible mechanophore and incompressible ligands react under hydrostatic pressure to produce elemental metal via an unexplored mechanism.

Hao Yan, Fan Yang, Ding Pan, Yu Lin, J. Nathan Hohman, Diego Solis-Ibarra, Fei Hua Li, Jeremy E. P. Dahl, Robert M. K. Carlson, Boryslav A. Tkachenko + et al.

doi: 10.1038/nature25765

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Meridional overturning circulation conveys fast acidification to the deep Atlantic Ocean p.515

There has been a reduction of about forty per cent in the transport of carbonate ions to the deep North Atlantic Ocean since preindustrial times, severely endangering cold-water corals.

Fiz F. Perez, Marcos Fontela, Maribel I. García-Ibáñez, Herlé Mercier, Anton Velo, Pascale Lherminier, Patricia Zunino, Mercedes de la Paz, Fernando Alonso-Pérez, Elisa F. Guallart + et al.

doi: 10.1038/nature25493

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Global patterns of tropical forest fragmentation p.519

Satellite data and modelling reveal that tropical forest fragments have similar size distributions across continents, and that forest fragmentation is close to a critical point, beyond which fragment numbers will strongly increase.

Franziska Taubert, Rico Fischer, Jürgen Groeneveld, Sebastian Lehmann, Michael S. Müller, Edna Rödig, Thorsten Wiegand & Andreas Huth

doi: 10.1038/nature25508

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Peptidoglycan synthesis drives an FtsZ-treadmilling-independent step of cytokinesis p.528

Peptidoglycan is the main component of the bacterial wall and protects cells from the mechanical stress that results from high intracellular turgor. Peptidoglycan biosynthesis is very similar in all bacteria; bacterial shapes are therefore mainly determined by the spatial and temporal regulation of peptidoglycan synthesis rather than by the chemical composition of peptidoglycan. The form of rod-shaped bacteria, such as Bacillus subtilis or Escherichia coli, is generated by the action of two peptidoglycan synthesis machineries that act at the septum and at the lateral wall in processes coordinated by the cytoskeletal proteins FtsZ and MreB, respectively. The tubulin homologue FtsZ is the first protein recruited to the division site, where it assembles in filaments—forming the Z ring—that undergo treadmilling and recruit later divisome proteins. The rate of treadmilling in B. subtilis controls the rates of both peptidoglycan synthesis and cell division. The actin homologue MreB forms discrete patches that move circumferentially around the cell in tracks perpendicular to the long axis of the cell, and organize the insertion of new cell wall during elongation. Cocci such as Staphylococcus aureus possess only one type of peptidoglycan synthesis machinery, which is diverted from the cell periphery to the septum in preparation for division. The molecular cue that coordinates this transition has remained elusive. Here we investigate the localization of S. aureus peptidoglycan biosynthesis proteins and show that the recruitment of the putative lipid II flippase MurJ to the septum, by the DivIB–DivIC–FtsL complex, drives peptidoglycan incorporation to the midcell. MurJ recruitment corresponds to a turning point in cytokinesis, which is slow and dependent on FtsZ treadmilling before MurJ arrival but becomes faster and independent of FtsZ treadmilling after peptidoglycan synthesis activity is directed to the septum, where it provides additional force for cell envelope constriction.

João M. Monteiro, Ana R. Pereira, Nathalie T. Reichmann, Bruno M. Saraiva, Pedro B. Fernandes, Helena Veiga, Andreia C. Tavares, Margarida Santos, Maria T. Ferreira, Vânia Macário + et al.

doi: 10.1038/nature25506

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Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas p.533

In mouse pancreas cells with only one copy of the Nr5a2 gene, the orphan nuclear receptor NR5A2 undergoes a marked transcriptional shift from differentiation-specific to inflammatory genes, which results in an epithelial-cell-autonomous basal pre-inflammatory state.

Isidoro Cobo, Paola Martinelli, Marta Flández, Latifa Bakiri, Mingfeng Zhang, Enrique Carrillo-de-Santa-Pau, Jinping Jia, Víctor J. Sánchez-Arévalo Lobo, Diego Megías, Irene Felipe + et al.

doi: 10.1038/nature25751

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TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis p.538

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. Inhibition of the PD-1–PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.

Daniele V. F. Tauriello, Sergio Palomo-Ponce, Diana Stork, Antonio Berenguer-Llergo, Jordi Badia-Ramentol, Mar Iglesias, Marta Sevillano, Sales Ibiza, Adrià Cañellas, Xavier Hernando-Momblona + et al.

doi: 10.1038/nature25492

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TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells p.544

Therapeutic antibodies that block the programmed death-1 (PD-1)–programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.

Sanjeev Mariathasan, Shannon J. Turley, Dorothee Nickles, Alessandra Castiglioni, Kobe Yuen, Yulei Wang, Edward E. Kadel III, Hartmut Koeppen, Jillian L. Astarita, Rafael Cubas + et al.

doi: 10.1038/nature25501

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MEK drives BRAF activation through allosteric control of KSR proteins p.549

KSR–MEK complexes allosterically activate BRAF through the action of N-terminal regulatory region and kinase domain contacts, thus challenging the accepted role of KSR as a scaffold for MEK recruitment to RAF.

Hugo Lavoie, Malha Sahmi, Pierre Maisonneuve, Sara A. Marullo, Neroshan Thevakumaran, Ting Jin, Igor Kurinov, Frank Sicheri & Marc Therrien

doi: 10.1038/nature25478

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