Volume 492 Issue 7429


The limits of free speech p.311

Unregulated drug marketing stifles science and harms patients. To suggest otherwise is an affront to liberty — not a protection of it.

doi: 10.1038/492311a

A burden weighed p.311

Despite some shortcomings, a global study of health metrics should be applauded.

doi: 10.1038/492311b

Head of the line p.312

Japanese scientists deserve support in their bid for the next big collider.

doi: 10.1038/492312a


2012 in review p.324

This epic year for science saw the discovery of the Higgs boson and Curiosity’s arrival on Mars, but researchers also felt the sting of austerity.

doi: 10.1038/492324a

Images of the year p.328

Disintegrating ice, spectacular sunbursts and minuscule lizards are among 2012’s most striking pictures.

doi: 10.1038/492328a

News Features

News & Views

Thermal physicsQuantum interference heats up p.358

A thermal effect predicted more than 40 years ago was nearly forgotten because a related phenomenon stole the limelight. Now experimentally verified, the effect could spur the development of heat-controlling devices. See Letter p.401

doi: 10.1038/492358a

Cardiovascular biologyA boost for heart regeneration p.360

Heart muscle cells die en masse after injury, yet the adult mammalian heart retains little capacity to regenerate them. Regulatory microRNA sequences may stimulate self-renewal of these muscle cells. See Article p.376

doi: 10.1038/nature11763

CancerMetabolism in 'the driver's seat p.362

It is increasingly accepted that metabolic changes in cancer cells can drive tumour formation. The finding that the SIRT6 protein suppresses tumour formation by regulating metabolism adds weight to this view.

doi: 10.1038/492362a

EpigeneticsErase for a new start p.363

Tet proteins regulate gene expression by removing methyl groups from DNA bases. This activity may be a facilitating step in turning on the cell-division pathway that produces sperm and egg cells. See Letter p.443

doi: 10.1038/492363a

Low-temperature physicsCool molecules p.364

A sample of the hydroxyl radical has been cooled to a temperature of a few millikelvin. The result opens the door to observing phenomena such as Bose–Einstein condensation of molecules in their ground state. See Letter p.396

doi: 10.1038/492364a


Seventy-five genetic loci influencing the human red blood cell p.369

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

doi: 10.1038/nature11677

Functional screening identifies miRNAs inducing cardiac regeneration p.376

In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.

doi: 10.1038/nature11739

FMRP targets distinct mRNA sequence elements to regulate protein expression p.382

Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP. Among highly enriched targets, we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1−/− mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders.

doi: 10.1038/nature11737

High-resolution crystal structure of human protease-activated receptor 1 p.387

Protease-activated receptor 1 (PAR1) is the prototypical member of a family of G-protein-coupled receptors that mediate cellular responses to thrombin and related proteases. Thrombin irreversibly activates PAR1 by cleaving the amino-terminal exodomain of the receptor, which exposes a tethered peptide ligand that binds the heptahelical bundle of the receptor to affect G-protein activation. Here we report the 2.2-Å-resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated G-protein-coupled receptors, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent. Protease-activated receptors are important targets for drug development. The structure reported here will aid the development of improved PAR1 antagonists and the discovery of antagonists to other members of this receptor family.

doi: 10.1038/nature11701


Evaporative cooling of the dipolar hydroxyl radical p.396

Evaporative cooling of molecules has not been achieved so far, owing to unfavourable collision properties and trap losses; microwave-forced evaporative cooling of hydroxyl molecules loaded in a magnetic quadrupole trap is now reported.

doi: 10.1038/nature11718

The Josephson heat interferometer p.401

A thermal analogue of a superconducting quantum interference device (SQUID, widely used to measure small magnetic fields) is realized, in which the flow of heat between the superconductors is dependent on the quantum phase difference between them.

doi: 10.1038/nature11702

Laboratory measurements of the viscous anisotropy of olivine aggregates p.415

Measurements of the viscous anisotropy of highly deformed polycrystalline olivine find it to be approximately an order of magnitude larger than that predicted by grain-scale simulations; the maximum degree of anisotropy is reached at geologically low shear strain, such that deforming regions of the Earth’s upper mantle should exhibit significant viscous anisotropy.

doi: 10.1038/nature11671

A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge p.428

High-speed tracking of effortful responses and neuronal activity in rats during a forced swim test identifies medial prefrontal cortex (mPFC) neurons that respond during escape-related swimming but not normal locomotion, and optogenetics shows that mPFC neurons projecting to the brainstem dorsal raphe nucleus, which is implicated in depression, modulate this behavioural response to challenge.

doi: 10.1038/nature11617

Layered reward signalling through octopamine and dopamine in Drosophila p.433

Dopamine is synonymous with reward in mammals but associated with aversive reinforcement in insects, where reward seems to be signalled by octopamine; here it is shown that flies have discrete populations of dopamine neurons representing positive or negative values that are coordinately regulated by octopamine.

doi: 10.1038/nature11614

Tet1 controls meiosis by regulating meiotic gene expression p.443

A loss-of-function approach in mice is used to show that the methylcytosine dioxygenase Tet1 has a role in regulating meiosis and meiotic gene activation in female germ cells; Tet1 deficiency does not greatly affect genome-wide demethylation but has a more specific effect on the expression of a subset of meiotic genes.

doi: 10.1038/nature11709