네이처 컨텐츠

Editorials

Fed up of Earth? Try Mars p.330

Establishing a Martian outpost is likely to bring many of the same societal problems we face on Earth.

doi: 10.1038/539330b

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News

News Features

News & Views

Clear directions for random lasers p.360

Random lasers use disordered structures to produce light, which is usually emitted in many directions. A random laser that can produce a collimated beam offers a wide range of applications, from imaging to security scanning.

Diederik S. Wiersma

doi: 10.1038/nature20477

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Mature proteins braced by a chaperone p.361

Hsp70 chaperone molecules help other proteins to fold, and were thought to bind mainly to unfolded proteins. Single-molecule experiments now suggest that Hsp70s can also stabilize almost fully folded proteins. See Letter p.448

Qinglian Liu & Elizabeth A. Craig

doi: 10.1038/nature20470

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Ions surprise in Earth's deep fluids p.362

Models indicate that there are strong gradients in element concentrations and in the pH of fluids at the slab–mantle interface — a major discontinuity deep within Earth. This transforms our view of global geochemical transport. See Letter p.420

David Dolejš

doi: 10.1038/539362a

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Sleepy and dreamless mutant mice p.364

Sleep in mammals consists of non-rapid-eye-movement and rapid-eye-movement sleep. A large genetic screen reveals that these two sleep states are altered in mice by mutations dubbed Sleepy and Dreamless. See Article p.378

Derk-Jan Dijk & Raphaëlle Winsky-Sommerer

doi: 10.1038/nature20471

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Semiconductors that stretch and heal p.365

Polymeric semiconductors have been prepared whose molecular properties make them stretchable and healable — a milestone in the development of sophisticated organic electronic surfaces that mimic human skin. See Letter p.411

Siegfried Bauer & Martin Kaltenbrunner

doi: 10.1038/539365a

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Deep-sea secrets of butane metabolism p.367

Anaerobic microbes have been found to break down the hydrocarbon butane by a pathway with some similarities to anaerobic methane breakdown. Harnessing the butane pathway might enable biofuel generation. See Article p.396

Stephen W. Ragsdale

doi: 10.1038/539367a

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Review

The effects of Δ9-tetrahydrocannabinol on the dopamine system p.369

A review into the complex effects of Δ9-tetrahydrocannabinol on the dopamine system, examining data from animal and human studies and discussing the necessary future direction of research.

Michael A. P. Bloomfield, Abhishekh H. Ashok, Nora D. Volkow & Oliver D. Howes

doi: 10.1038/nature20153

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Articles

Forward-genetics analysis of sleep in randomly mutagenized mice p.378

Two mutations affecting the sleep–wakefulness balance in mice are detected, showing that the SIK3 protein kinase is essential for determining daily wake time, and the NALCN cation channel regulates the duration of rapid eye movement sleep.

Hiromasa Funato, Chika Miyoshi, Tomoyuki Fujiyama, Takeshi Kanda, Makito Sato, Zhiqiang Wang, Jing Ma, Shin Nakane, Jun Tomita, Aya Ikkyu + et al.

doi: 10.1038/nature20142

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CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells p.384

These preclinical studies outline a CRISPR-based methodology for correcting β-globin gene mutations in haematopoietic stem cells to advance the development of next-generation therapies for β-haemoglobinopathies.

Daniel P. Dever, Rasmus O. Bak, Andreas Reinisch, Joab Camarena, Gabriel Washington, Carmencita E. Nicolas, Mara Pavel-Dinu, Nivi Saxena, Alec B. Wilkens, Sruthi Mantri + et al.

doi: 10.1038/nature20134

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LKB1 loss links serine metabolism to DNA methylation and tumorigenesis p.390

Human tumours with mutations in LKB1 and Kras have a specific hypermetabolic state associated with increased DNA methylation, pointing to potential metabolic and epigenetic vulnerabilities of specific tumours.

Filippos Kottakis, Brandon N. Nicolay, Ahlima Roumane, Rahul Karnik, Hongcang Gu, Julia M. Nagle, Myriam Boukhali, Michele C. Hayward, Yvonne Y. Li, Ting Chen + et al.

doi: 10.1038/nature20132

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Thermophilic archaea activate butane via alkyl-coenzyme M formation p.396

Anaerobic archaea enriched in thermophilic microbial consortia completely degrade butane by modifying mechanisms which were hitherto thought to be specific to methane metabolism.

Rafael Laso-Pérez, Gunter Wegener, Katrin Knittel, Friedrich Widdel, Katie J. Harding, Viola Krukenberg, Dimitri V. Meier, Michael Richter, Halina E. Tegetmeyer, Dietmar Riedel + et al.

doi: 10.1038/nature20152

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Letters

Tidal evolution of the Moon from a high-obliquity, high-angular-momentum Earth p.402

A model of the Moon’s tidal evolution, starting from the fast-spinning, high-obliquity Earth that would be expected after a giant impact, reveals that solar perturbations on the Moon’s orbit naturally produce the current lunar inclination and Earth’s low obliquity.

Matija Ćuk, Douglas P. Hamilton, Simon J. Lock & Sarah T. Stewart

doi: 10.1038/nature19846

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Nanoscale thermal imaging of dissipation in quantum systems p.407

A cryogenic thermal imaging technique that uses a superconducting quantum interference device fabricated on the tip of a sharp pipette can be used to image the thermal signature of extremely low power nanometre-scale dissipation processes.

D. Halbertal, J. Cuppens, M. Ben Shalom, L. Embon, N. Shadmi, Y. Anahory, H. R. Naren, J. Sarkar, A. Uri, Y. Ronen + et al.

doi: 10.1038/nature19843

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Intrinsically stretchable and healable semiconducting polymer for organic transistors p.411

Introducing non-covalent crosslinking moieties to polymer semiconductors produces a stretchable and healable material suitable for wearable electronics.

Jin Young Oh, Simon Rondeau-Gagné, Yu-Cheng Chiu, Alex Chortos, Franziska Lissel, Ging-Ji Nathan Wang, Bob C. Schroeder, Tadanori Kurosawa, Jeffrey Lopez, Toru Katsumata + et al.

doi: 10.1038/nature20102

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Amazon boundary layer aerosol concentration sustained by vertical transport during rainfall p.416

Rapid vertical transport of small aerosol particles from the free troposphere to the atmospheric boundary layer occurs during precipitation and maintains the population of aerosol particles over Amazonia.

Jian Wang, Radovan Krejci, Scott Giangrande, Chongai Kuang, Henrique M. J. Barbosa, Joel Brito, Samara Carbone, Xuguang Chi, Jennifer Comstock, Florian Ditas + et al.

doi: 10.1038/nature19819

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Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development p.433

Transcription of a long non-coding RNA, known as upperhand (Uph) located upstream of the HAND2 transcription factor is required to maintain transcription of the Hand2 gene by RNA polymerase, and blockade of Uph expression leads to heart defects and embryonic lethality in mice.

Kelly M. Anderson, Douglas M. Anderson, John R. McAnally, John M. Shelton, Rhonda Bassel-Duby & Eric N. Olson

doi: 10.1038/nature20128

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PI3Kγ is a molecular switch that controls immune suppression p.437

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.

Megan M. Kaneda, Karen S. Messer, Natacha Ralainirina, Hongying Li, Christopher J. Leem, Sara Gorjestani, Gyunghwi Woo, Abraham V. Nguyen, Camila C. Figueiredo, Philippe Foubert + et al.

doi: 10.1038/nature19834

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Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells p.443

Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.

Olivier De Henau, Matthew Rausch, David Winkler, Luis Felipe Campesato, Cailian Liu, Daniel Hirschhorn Cymerman, Sadna Budhu, Arnab Ghosh, Melissa Pink, Jeremy Tchaicha + et al.

doi: 10.1038/nature20554

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Alternative modes of client binding enable functional plasticity of Hsp70 p.448

Hsp70 binds unfolded protein segments in its groove, but can also bind and stabilize folded protein structures, owing to its moveable lid, with ATP hydrolysis and co-chaperones allowing control of these contrasting effects.

Alireza Mashaghi, Sergey Bezrukavnikov, David P. Minde, Anne S. Wentink, Roman Kityk, Beate Zachmann-Brand, Matthias P. Mayer, Günter Kramer, Bernd Bukau & Sander J. Tans

doi: 10.1038/nature20137

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Local regulation of gene expression by lncRNA promoters, transcription and splicing p.452

Various cis-regulatory functions of genomic loci that produce long non-coding RNAs are revealed, including instances where their promoters have enhancer-like activity and the lncRNA transcripts themselves are not required for activity.

Jesse M. Engreitz, Jenna E. Haines, Elizabeth M. Perez, Glen Munson, Jenny Chen, Michael Kane, Patrick E. McDonel, Mitchell Guttman & Eric S. Lander

doi: 10.1038/nature20149

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