Volume 554 Number 7693



Science needs to redefine excellence p.403

The concept of research excellence is ubiquitous, but its meaning depends on context.

doi: 10.1038/d41586-018-02183-y


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


Why current negative-emissions strategies remain ‘magical thinking’ p.404

Work on how rocks draw carbon from the air shows the scale of the challenge.

doi: 10.1038/d41586-018-02184-x



Italian election leaves science out in the cold p.411

Researchers hold out little hope that the next government will improve their underfunded research system.

doi: 10.1038/d41586-018-02223-7


Physicists plan antimatter’s first outing — in a van p.412

Researchers intend to transport the elusive material between labs and use it to study the strange behaviour of rare radioactive nuclei.

doi: 10.1038/d41586-018-02221-9


Ocean-wide sensor array provides new look at global ocean current p.413

Initial findings hint at the complexity of currents in the North Atlantic that drive the world's weather.

doi: 10.1038/d41586-018-02113-y


CRISPR hack transforms cells into data recorders p.414

Gene-editing tool can be harnessed to give a close-up view of life's most basic processes.

doi: 10.1038/d41586-018-02068-0


Indonesian scientists hamstrung by year-long funding delay p.415

The country's dedicated science fund has failed to raise enough money to finance projects.

doi: 10.1038/d41586-018-02118-7

News Features


Sex and drugs and self-control: how the teen brain navigates risk p.426


doi: 10.1038/d41586-018-02170-3


Who exactly counts as an adolescent? p.429


doi: 10.1038/d41586-018-02169-w

News & Views


In retrospect: Pruning hypothesis comes of age p.438


doi: 10.1038/d41586-018-02053-7


Mechanochemistry: Molecules pressured to react p.468


doi: 10.1038/d41586-018-02047-5


Structural biology: Force-activated ion channels in close-up p.469


doi: 10.1038/d41586-018-01631-z


Pancreatic disease: An inflammatory transcriptional switch p.470


doi: 10.1038/d41586-018-01262-4


Engineering: Neurons mimicked by electronics p.472


doi: 10.1038/d41586-018-02025-x



Importance of investing in adolescence from a developmental science perspective p.441

doi: 10.1038/nature25770


Dynamics of body time, social time and life history at adolescence p.451

doi: 10.1038/nature25750



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.

doi: 10.1038/nature25759



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.

doi: 10.1038/nature25739


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.

doi: 10.1038/nature25453


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.

doi: 10.1038/nature25743



A clumpy and anisotropic galaxy halo at redshift 1 from gravitational-arc tomography p.493

The halo of gas around a galaxy at redshift 1 is clumpy and anisotropic, with little variation in gas velocity, suggesting that it consists of entrained recycled material.

doi: 10.1038/nature25436


A surge of light at the birth of a supernova p.497

The discovery of a newly born type IIb supernova reveals a rapid brightening at optical wavelengths that corresponds to the shock-breakout phase of the explosion.

doi: 10.1038/nature25151


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.

doi: 10.1038/nature25747


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.

doi: 10.1038/nature25765


Palladium-catalysed electrophilic aromatic C–H fluorination p.511

An approach for the direct electrophilic C–H fluorination of arenes is reported, using a palladium catalyst and mild fluorinating reagents.

doi: 10.1038/nature25749


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.

doi: 10.1038/nature25493


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.

doi: 10.1038/nature25508

細胞生物学:組織の硬化はin vivoで細胞の集団移動を引き起こすことにより形態形成を調整する

Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo p.523

Stiffening of the mesoderm owing to an accumulation of cells triggers collective migration of neural crest cells during morphogenesis.

doi: 10.1038/nature25742


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.

doi: 10.1038/nature25506


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.

doi: 10.1038/nature25751


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.

doi: 10.1038/nature25492


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.

doi: 10.1038/nature25501


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.

doi: 10.1038/nature25478

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