Volume 518 Issue 7538


Telling stories p.137

The UK Research Excellence Framework’s focus on impact is a useful reminder of all the ways that science can help society — both economically and by other means.

doi: 10.1038/518137a

Spot the difference p.137

The US measles outbreak highlights why most states should reconsider their vaccination rules.

doi: 10.1038/518137b

A single light p.138

A year of illumination switches on with a Nature special issue.

doi: 10.1038/518138a


News Features

Light fantastic p.153

Scientists are pushing the properties of light to new extremes. A special issue explores these frontiers.

doi: 10.1038/518153a

Leading lights p.154

Shape it, squeeze it, energize it or tie it into knots. Scientists are taking light to new extremes.

doi: 10.1038/518154a

Super vision p.158

Using techniques adapted from astronomy, physicists are finding ways to see through opaque materials such as living tissue.

doi: 10.1038/518158a

News & Views

The oldest cosmic light p.170

The cosmic microwave background is a faint glow of light left over from the Big Bang. It fills the entire sky and records the Universe's early history. Two independent experts outline what we know about this ancient light, both theoretically and observationally.

doi: 10.1038/518170a

Death drags down the neighbourhood p.171

An analysis of dying cells reveals that they play an active part in modifying tissue shape by pulling on neighbouring cells. This induces neighbouring cells to contract at their apices, which results in tissue folding. See Letter p.245

doi: 10.1038/nature14198

Sibling rivalry begins at birth p.173

High-resolution astronomical observations of a nearby molecular gas cloud have revealed a quadruplet of stars in the act of formation. The system is arguably the youngest multiple star system detected so far. See Letter p.213

doi: 10.1038/518173a

Familiar ends with alternative endings p.174

The faithful propagation of species requires a complex balance of DNA-repair pathways to maintain genome integrity. New work sheds light on one such poorly understood pathway and its role in certain cancers. See Letters p.254 & p.258

doi: 10.1038/nature14200

When carbon escaped from the sea p.176

A record of boron isotopes in fossils of microscopic plankton provides fresh evidence that some ocean regions were a source of carbon dioxide to the atmosphere when Earth warmed at the end of the last ice age. See Letter p.219

doi: 10.1038/518176a

Cold shock protects the brain p.177

A protein released during hypothermia has been found to affect the progression of neurodegenerative disease in mice by sparing neurons from death and preserving the connections between them. See Letter p.236

doi: 10.1038/nature14195



New genetic loci link adipose and insulin biology to body fat distribution p.187

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

doi: 10.1038/nature14132

Genetic studies of body mass index yield new insights for obesity biology p.197

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

doi: 10.1038/nature14177

Shearing-induced asymmetry in entorhinal grid cells p.207

Grid cells are cells of the brain’s internal map of space that fire when an animal is in a location corresponding to the vertices of a hexagonal grid pattern tiling the entire environment; how the pattern is mapped onto the external environment has remained a mystery, however, new studies in rat reveal that the axes of the grid are determined by the boundaries of the external environment and provide insight into the rotation of the grid axis in relation to these boundaries.

doi: 10.1038/nature14151


The formation of a quadruple star system with wide separation p.213

Observations of a wide-separation quadruple system in the Perseus star-forming region reveal a young protostar and three gravitationally bound dense gas condensations; each condensation is expected to form a star and the closest pair will form a bound binary, while the quadruple stellar system itself is bound but unstable on timescales of 500,000 years.

doi: 10.1038/nature14166

Recharge of a subglacial lake by surface meltwater in northeast Greenland p.223

Observations of rapid, persistent elevation gains that occur on the ice surface above a subglacial lake as the lake is refilled with surface meltwater during the summer melt period in Greenland show that surface meltwater may be trapped and stored at the bed of an ice sheet, affecting ice dynamics downstream.

doi: 10.1038/nature14116

Homo erectus at Trinil on Java used shells for tool production and engraving p.228

Argon and luminescence dating of fossil shell infills from Trinil in Java, where Homo erectus lived, reveals that the hominin-bearing deposits are younger than previously thought; perforated shells, a shell tool and an engraved shell indicate that Homo erectus ate freshwater mussels, used their shells as tools and was able to create abstract engravings.

doi: 10.1038/nature13962

Grid cell symmetry is shaped by environmental geometry p.232

Neuronal grid cells fire in a spatial grid pattern laid out across the surface of a familiar environment, however the role of environmental boundaries in the construction of this pattern is not well understood; this study shows that the grid pattern orients to the walls of polarized environments such as squares but not circles and that the hexagonal grid symmetry is permanently broken in highly polarized environments such as trapezoids.

doi: 10.1038/nature14153

RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration p.236

Structural synaptic plasticity and remodelling are features of the healthy adult brain and are seen during hibernation; a hibernation-inspired model of mouse cooling used to study synaptic regeneration has identified the ‘cold-shock’ RNA-binding protein, RBM3, as a regulator of synaptic assembly, deficiency of which contributes to synapse loss in neurodegenerative disease.

doi: 10.1038/nature14142

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor p.240

Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

doi: 10.1038/nature13948

Apico-basal forces exerted by apoptotic cells drive epithelium folding p.245

Apoptotic cell death is required for morphogenesis of the developing leg joint of fruitflies; using this model system, the authors show here that within apoptotic cells a transient pulling force exerted through a highly dynamic apico-basal myosin II cable-like structure acts as a mechanical signal to increase tissue tension and modify tissue shape.

doi: 10.1038/nature14152

RNA helicase DDX21 coordinates transcription and ribosomal RNA processing p.249

DEAD-box RNA helicase DDX21 is involved in both the transcription and RNA processing of ribosomal genes in human cells, sensing the transcriptional status of both RNA polymerase I and RNA polymerase II and associating with non-coding RNAs involved in ribonucleoprotein formation, possibly allowing for coordinated regulation of protein synthesis.

doi: 10.1038/nature13923

Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination p.254

The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Polθ; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Polθ has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.

doi: 10.1038/nature14157

Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair p.258

Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. Previous studies have implicated the DNA polymerase θ (Polθ also known as POLQ, encoded by POLQ) in a pathway required for the repair of DNA double-strand breaks, referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway. Whether Polθ interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Polθ expression in EOCs. Knockdown of Polθ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Polθ in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Polθ contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Polθ-mediated repair in EOCs, and identify Polθ as a novel druggable target for cancer therapy.

doi: 10.1038/nature14184