Volume 540 Number 7632

Editorials

News

News Features

News & Views

The history of Greenland's ice p.202

Global sea levels would rise by several metres if the Greenland Ice Sheet melted completely. Two studies have examined its past behaviour in an effort to evaluate its vulnerability in a warming world — and have come to seemingly conflicting conclusions. Two geochemists and a glaciologist discuss the issues. See Letters p.252 & p.256

doi: 10.1038/540202a

A parasite's parasite saves host's neighbours p.204

Viruses can be attacked by parasitic viruses, which compete with them for cellular resources. It emerges that one such parasitic virus can defend a host-cell population from a viral attack. See Letter p.288

doi: 10.1038/540204a

Elemental abundances across cosmic time p.205

The chemical composition of a massive galaxy in the early Universe reveals an extremely short period of star formation. This result could challenge our ideas about the evolution of galaxies and of the Universe itself. See Letter p.248

doi: 10.1038/540205a

Neural synchronization in Alzheimer's disease p.207

Electrical oscillations generated by neural circuits are disrupted in Alzheimer's disease. Restoring these oscillations in mouse models activates immune cells to clear disease-associated amyloid-β protein from the brain. See Article p.230

doi: 10.1038/540207a

Forty years of linking orbits to ice ages p.208

In 1976, it was demonstrated that tiny wobbles in Earth's orbit led to the great ice-age cycles of the past few million years. This finding had wide implications for climate science and the details remain hotly debated today.

doi: 10.1038/540208a

Replacing the cell's power plants p.210

Nuclear DNA from human eggs that harbour mutations in the DNA of organelles called mitochondria has been successfully transferred to donor eggs, bringing the prospect of therapy for mitochondrial diseases a step closer. See Letter p.270

doi: 10.1038/nature20483

Aspiring to naivety p.211

Human stem cells that can give rise to every cell type in the body are major players in biomedical research. A molecular analysis of human embryos might help to make these cultured cells more authentic imitations of their in vivo counterparts.

doi: 10.1038/nature20484

Reviews

Certified randomness in quantum physics p.213

Quantum technology enables new methods for generating of randomness with minimal assumptions, certified by the violation of a Bell inequality, which opens up new theoretical and experimental research directions and leads to new challenges.

doi: 10.1038/nature20119

Safeguarding pollinators and their values to human well-being p.220

Wild and managed pollinators are threatened by pressures such as environmental changes and pesticides, leading to risks for pollinator-dependent crop production, meaning more research and better policies are needed to safeguard pollinators and their services.

doi: 10.1038/nature20588

Articles

Letters

Intronic polyadenylation of PDGFRα in resident stem cells attenuates muscle fibrosis p.276

Platelet-derived growth factor receptor α (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signalling through this receptor promotes muscle development in growing embryos and angiogenesis in regenerating adult muscle. However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show in mice that PDGFRα signalling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. We found that FAPs produce multiple transcriptional variants of Pdgfra with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signalling and to prevent FAP over-activation. Moreover, increasing the expression of this isoform limits fibrosis in vivo in mice, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem-cell populations.

doi: 10.1038/nature20160

Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys p.284

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost) and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.

doi: 10.1038/nature20583

m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination p.301

N6-methyladenosine (m6A) is the most common internal modification of eukaryotic messenger RNA (mRNA) and is decoded by YTH domain proteins. The mammalian mRNA m6A methylosome is a complex of nuclear proteins that includes METTL3 (methyltransferase-like 3), METTL14, WTAP (Wilms tumour 1-associated protein) and KIAA1429. Drosophila has corresponding homologues named Ime4 and KAR4 (Inducer of meiosis 4 and Karyogamy protein 4), and Female-lethal (2)d (Fl(2)d) and Virilizer (Vir). In Drosophila, fl(2)d and vir are required for sex-dependent regulation of alternative splicing of the sex determination factor Sex lethal (Sxl). However, the functions of m6A in introns in the regulation of alternative splicing remain uncertain. Here we show that m6A is absent in the mRNA of Drosophila lacking Ime4. In contrast to mouse and plant knockout models, Drosophila Ime4-null mutants remain viable, though flightless, and show a sex bias towards maleness. This is because m6A is required for female-specific alternative splicing of Sxl, which determines female physiognomy, but also translationally represses male-specific lethal 2 (msl-2) to prevent dosage compensation in females. We further show that the m6A reader protein YT521-B decodes m6A in the sex-specifically spliced intron of Sxl, as its absence phenocopies Ime4 mutants. Loss of m6A also affects alternative splicing of additional genes, predominantly in the 5′ untranslated region, and has global effects on the expression of metabolic genes. The requirement of m6A and its reader YT521-B for female-specific Sxl alternative splicing reveals that this hitherto enigmatic mRNA modification constitutes an ancient and specific mechanism to adjust levels of gene expression.

doi: 10.1038/nature20577