Volume 520 Number 7547

Editorials

Numbers matter p.263

Researchers need help in making the statistical power of animal experiments clear.

doi: 10.1038/520263b

Close the deal p.263

Science-based evidence and enlightened diplomacy have brought within reach a historic opportunity for nuclear détente with Iran. It must be seized.

doi: 10.1038/520263a

News

News Features

The Ras renaissance p.278

Thirty years of pursuit have failed to yield a drug to take on one of the deadliest families of cancer-causing proteins. Now some researchers are taking another shot.

doi: 10.1038/520278a

Voices of Hubble p.282

As the venerable space telescope turns 25 this month, key scientists and engineers recount the highs and lows of its stellar career.

doi: 10.1038/520282a

News & Views

The complex seeds of metastasis p.298

Analyses of prostate-cancer metastases reveal a complex cellular architecture, and show that secondary sites can be seeded by multiple cell populations derived from both the primary tumour and other metastases. See Letter p.353

doi: 10.1038/nature14377

A new recipe for Earth formation p.299

Experimental results suggest that if Earth initially grew by the accumulation of highly chemically reduced material, its core could contain enough uranium to drive the planet's magnetic field throughout Earth's history. See Letter p.337

doi: 10.1038/520299a

An extravascular route for tumour cells p.300

Molecular tracing of populations of breast-cancer cells in a primary tumour in mice reveals that two proteins, Serpine2 and Slpi, enable tumour cells to form vascular-like networks, facilitating perfusion and metastasis. See Letter p.358

doi: 10.1038/nature14382

Streamlining drug synthesis p.302

Drug manufacture can benefit from flow synthesis, in which raw materials are fed into a sequence of reactors, producing the drug as a continuous output. A flow strategy that capitalizes on solid catalysts has now been realized. See Letter p.329

doi: 10.1038/520302a

A weighty mass difference p.303

The neutron–proton mass difference, one of the most consequential parameters of physics, has now been calculated from fundamental theories. This landmark calculation portends revolutionary progress in nuclear physics.

doi: 10.1038/nature14381

Recovering the potential of coral reefs p.304

An analysis of fish declines in coral reefs shows that simple fishing limits and implementation of marine protected areas can be enough to support recovery of coral ecosystem resilience. See Letter p.341

doi: 10.1038/nature14384

Analysis

Articles

Crystal structures of the human adiponectin receptors p.312

The crystal structures of the human adiponectin receptors AdipoR1 and AdipoR2 are solved at 2.9 and 2.4 Å resolution, respectively; the structural and functional information may aid the development and optimization of adiponectin receptor agonists for the treatment of obesity-related diseases.

doi: 10.1038/nature14301

Letters

An ultrafast rechargeable aluminium-ion battery p.325

An aluminium-ion battery is reported that can charge within one minute, and offers improved cycle life compared to previous devices; it operates through the electrochemical deposition and dissolution of aluminium at the anode, and the intercalation/de-intercalation of chloroaluminate anions into a novel graphitic-foam cathode.

doi: 10.1038/nature14340

Icebergs not the trigger for North Atlantic cold events p.333

A delay between surface cooling and the arrival of ice-rafted debris at a site southwest of Iceland over the past four glacial cycles implies that icebergs typically arrived too late to have triggered cooling, although the freshwater derived from melting icebergs may provide a positive feedback for cold stadial conditions.

doi: 10.1038/nature14330

A Mercury-like component of early Earth yields uranium in the core and high mantle 142Nd p.337

Recent 142Nd isotope data indicate that the silicate Earth (its crust plus the mantle) has a samarium to neodymium elemental ratio (Sm/Nd) that is greater than that of the supposed chondritic building blocks of the planet. This elevated Sm/Nd has been ascribed either to a ‘hidden’ reservoir in the Earth or to loss of an early-formed terrestrial crust by impact ablation. Since removal of crust by ablation would also remove the heat-producing elements—potassium, uranium and thorium—such removal would make it extremely difficult to balance terrestrial heat production with the observed heat flow. In the ‘hidden’ reservoir alternative, a complementary low-Sm/Nd layer is usually considered to reside unobserved in the silicate lower mantle. We have previously shown, however, that the core is a likely reservoir for some lithophile elements such as niobium. We therefore address the question of whether core formation could have fractionated Nd from Sm and also acted as a sink for heat-producing elements. We show here that addition of a reduced Mercury-like body (or, alternatively, an enstatite-chondrite-like body) rich in sulfur to the early Earth would generate a superchondritic Sm/Nd in the mantle and an 142Nd/144Nd anomaly of approximately +14 parts per million relative to chondrite. In addition, the sulfur-rich core would partition uranium strongly and thorium slightly, supplying a substantial part of the ‘missing’ heat source for the geodynamo.

doi: 10.1038/nature14350

Recovery potential of the world's coral reef fishes p.341

Continuing degradation of coral reef ecosystems has generated substantial interest in how management can support reef resilience. Fishing is the primary source of diminished reef function globally, leading to widespread calls for additional marine reserves to recover fish biomass and restore key ecosystem functions. Yet there are no established baselines for determining when these conservation objectives have been met or whether alternative management strategies provide similar ecosystem benefits. Here we establish empirical conservation benchmarks and fish biomass recovery timelines against which coral reefs can be assessed and managed by studying the recovery potential of more than 800 coral reefs along an exploitation gradient. We show that resident reef fish biomass in the absence of fishing (B0) averages ∼1,000 kg ha−1, and that the vast majority (83%) of fished reefs are missing more than half their expected biomass, with severe consequences for key ecosystem functions such as predation. Given protection from fishing, reef fish biomass has the potential to recover within 35 years on average and less than 60 years when heavily depleted. Notably, alternative fisheries restrictions are largely (64%) successful at maintaining biomass above 50% of B0, sustaining key functions such as herbivory. Our results demonstrate that crucial ecosystem functions can be maintained through a range of fisheries restrictions, allowing coral reef managers to develop recovery plans that meet conservation and livelihood objectives in areas where marine reserves are not socially or politically feasible solutions.

doi: 10.1038/nature14358

The evolutionary history of lethal metastatic prostate cancer p.353

The subclonal composition of human prostate tumours and their metastases has been mapped by whole-genome sequencing, thus establishing the evolutionary trees behind the development and spread of these cancers; an important observation was that metastases could be re-seeded multiple times, and spread from one tumour to another was frequently seen.

doi: 10.1038/nature14347

A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis p.358

Different clones of a mammary tumour cell line possess differential abilities to contribute to the formation of metastasis; the expression of Serpine2 and Slp1 proteins drives vascular mimicry and metastasis to the lung, with similar associations observed in human data sets, and these proteins also function as anticoagulants, thus further promoting extravasation of tumour cells.

doi: 10.1038/nature14403

Therapy-induced tumour secretomes promote resistance and tumour progression p.368

Tumour cells respond to an effective, targeted drug treatment with BRAF, ALK or EGFR kinase inhibitors by inducing a complex network of secreted signals that promote tumour growth, dissemination and metastasis of drug-resistant cancer cell clones, and increase the survival of drug-sensitive tumour cells, potentially contributing to incomplete tumour regression.

doi: 10.1038/nature14336

β-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis p.383

Non-ribosomal peptide synthetases are giant enzymes composed of modules that house repeated sets of functional domains, which select, activate and couple amino acids drawn from a pool of nearly 500 potential building blocks. The structurally and stereochemically diverse peptides generated in this manner underlie the biosynthesis of a large sector of natural products. Many of their derived metabolites are bioactive such as the antibiotics vancomycin, bacitracin, daptomycin and the β-lactam-containing penicillins, cephalosporins and nocardicins. Penicillins and cephalosporins are synthesized from a classically derived non-ribosomal peptide synthetase tripeptide (from δ-(l-α-aminoadipyl)–l-cysteinyl–d-valine synthetase). Here we report an unprecedented non-ribosomal peptide synthetase activity that both assembles a serine-containing peptide and mediates its cyclization to the critical β-lactam ring of the nocardicin family of antibiotics. A histidine-rich condensation domain, which typically performs peptide bond formation during product assembly, also synthesizes the embedded four-membered ring. We propose a mechanism, and describe supporting experiments, that is distinct from the pathways that have evolved to the three other β-lactam antibiotic families: penicillin/cephalosporins, clavams and carbapenems. These findings raise the possibility that β-lactam rings can be regio- and stereospecifically integrated into engineered peptides for application as, for example, targeted protease inactivators.

doi: 10.1038/nature14100