The limits of free speech p.311

doi: 10.1038/492311a

A burden weighed p.311

doi: 10.1038/492311b

Head of the line p.312

doi: 10.1038/492312a

Mega-array reveals birthplace of giant stars p.319

doi: 10.1038/492319a

Russia shakes up its universities p.320

doi: 10.1038/492320a

Big biotech buys iconic genetics firm p.321

doi: 10.1038/492321a

Global survey reveals impact of disability p.322

doi: 10.1038/492322a

China’s patent boom brings legal wrangles p.323

doi: 10.1038/492323a

2012 in review p.324

doi: 10.1038/492324a

Images of the year p.328

doi: 10.1038/492328a

Nature's 10 p.335

doi: 10.1038/492335a

Thermal physicsQuantum interference heats up p.358

doi: 10.1038/492358a

Neurodevelopmental disordersSignalling pathways of fragile X syndrome p.359

doi: 10.1038/nature11764

Cardiovascular biologyA boost for heart regeneration p.360

doi: 10.1038/nature11763

CancerMetabolism in 'the driver's seat p.362

doi: 10.1038/492362a

EpigeneticsErase for a new start p.363

doi: 10.1038/492363a

Low-temperature physicsCool molecules p.364

doi: 10.1038/492364a

Earth scienceGo with the lows p.365

doi: 10.1038/492365a

2012 Editors' choice p.366

doi: 10.1038/492366a

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

Dynamical age differences among coeval star clusters as revealed by blue stragglers p.393

doi: 10.1038/nature11686

Evaporative cooling of the dipolar hydroxyl radical p.396

doi: 10.1038/nature11718

The Josephson heat interferometer p.401

doi: 10.1038/nature11702

Fractionalized excitations in the spin-liquid state of a kagome-lattice antiferromagnet p.406

doi: 10.1038/nature11659

Quasi-cylindrical wave contribution in experiments on extraordinary optical transmission p.411

doi: 10.1038/nature11669

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

doi: 10.1038/nature11671

Flickering gives early warning signals of a critical transition to a eutrophic lake state p.419

doi: 10.1038/nature11655

Repeated polyploidization of Gossypium genomes and the evolution of spinnable cotton fibres p.423

doi: 10.1038/nature11798

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

doi: 10.1038/nature11617

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

doi: 10.1038/nature11614

Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells p.438

doi: 10.1038/nature11629

Tet1 controls meiosis by regulating meiotic gene expression p.443

doi: 10.1038/nature11709

Structure of the Mediator head module p.448

doi: 10.1038/nature11670

Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning p.452

doi: 10.1038/nature11657