Volume 513 Number 7516

Editorials

There is life after academia p.5

With high numbers of postdocs emerging from universities, prospective PhD students must be prepared for the fact that they will probably not end up with a career in research.

doi: 10.1038/513005a

The digital toolbox p.6

A new section of Nature examines the software and websites that make research easier.

doi: 10.1038/513006b

Heavenly homes p.6

The discovery of our Galaxy’s place in the Universe adds detail to our address.

doi: 10.1038/513006a

News

News Features

The ones who got away p.20

Sometimes, the brightest stars in science decide to leave. Nature finds out where they go.

doi: 10.1038/513020a

The lingering questions p.24

In the haze of incomplete data, scientists are divided over the risks and benefits of electronic cigarettes.

doi: 10.1038/513024a

News & Views

How plumes help to break plates p.36

Computer models show how hot material that rises from Earth's interior is affected by plate tectonics, producing unexpected irregularities in Earth's topography and assisting in the break-up of continental plates. See Letter p.85

doi: 10.1038/513036a

Dynasty of the plastic fish p.37

Ambitious experimental and morphological studies of a modern fish show how developmental flexibility may have helped early 'fishapods' to make the transition from finned aquatic animals to tetrapods that walk on land. See Article p.54

doi: 10.1038/nature13743

A guardian angel of cell integrity p.38

The finding that RIPK1, an integral protein in cell-death pathways, also functions to preserve the body's epithelial-cell barriers challenges the idea that cell death and survival are regulated by distinct factors. See Letters p.90 & p.95

doi: 10.1038/513038a

Edit the genome to understand it p.40

Genome editing followed by sequencing has now been used to engineer and analyse every variation of several stretches of human DNA in living cells, providing insight into the function of each constituent nucleotide molecule. See Letter p.120

doi: 10.1038/nature13659

Meet the Laniakea supercluster p.41

An analysis of a three-dimensional map of galaxies and their velocities reveals the hitherto unknown edges of the large system of galaxies in which we live — dubbed the Laniakea supercluster. See Letter p.71

doi: 10.1038/513041a

How fluorescent RNA gets its glow p.42

Fluorescent tags are proving invaluable for tracking RNA molecules in cells. Two sets of crystal structures for one such tag — an RNA motif that fluoresces when bound to a dye — will aid the development of even better markers.

doi: 10.1038/513042a

Review

Migrations and dynamics of the intertropical convergence zone p.45

The intertropical convergence zone, where global rainfall is greatest, is a narrow belt of clouds usually centred about six degrees north of the Equator; this Review links its migrations on various timescales to the atmospheric energy balance.

doi: 10.1038/nature13636

Articles

Developmental plasticity and the origin of tetrapods p.54

The most primitive extant bony fish, Polypterus, exhibits adaptive plasticity for life on land when raised on land rather than in water, suggesting that environmentally induced phenotypic plasticity might have facilitated the macroevolutionary transition to life on land.

doi: 10.1038/nature13708

Letters

The Laniakea supercluster of galaxies p.71

Examination of a three-dimensional map of galaxies and their velocities shows a surface bounding the motions of galaxies that are inward after removal of the mean cosmic expansion and long-range flows; the galaxies within this surface lie within our home supercluster.

doi: 10.1038/nature13674

A 400-solar-mass black hole in the galaxy M82 p.74

The discovery of two stable peaks at frequencies with a ratio of 3:2 in the power spectrum of X-ray emission from the brightest X-ray source in galaxy M82 suggests that, if the relationship between frequency and mass that holds for stellar-mass black holes can be extended to intermediate masses, the black hole believed to be the source of the emission has a mass approximately 400 times that of the Sun.

doi: 10.1038/nature13710

Asymmetric three-dimensional topography over mantle plumes p.85

Three-dimensional numerical models of the interaction of a mantle plume with a rheologically realistic lithosphere predict complex surface evolution very different from the smooth, radially symmetric patterns usually assumed to be the signature of a mantle upwelling, with strongly asymmetric small-scale three-dimensional features such as rifts and linear fault structures.

doi: 10.1038/nature13703

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies p.105

BRAF mutations occur frequently in melanomas, but patients generally develop resistance to agents targeting mutant BRAF; now, the persistent formation of the translation initiation complex eIF4F has been described as an indicator of multiple mechanisms of resistance that arise in BRAF-mutated tumours and as a promising therapeutic target.

doi: 10.1038/nature13572

Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer p.110

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.

doi: 10.1038/nature13441

Saturation editing of genomic regions by multiplex homology-directed repair p.120

The authors perform saturation mutagenesis of genomic regions in their native endogenous chromosomal context by using CRISPR/Cas9 RNA-guided cleavage and multiplex homology-directed repair; its utility is demonstrated by measuring the effects of hundreds to thousands of genomic edits to BRCA1 and DBR1 on splicing and cellular fitness, respectively.

doi: 10.1038/nature13695