Reform regulations to make pet clinical trials easier p.169

doi: 10.1038/540169a

Get water governance on the global agenda p.169

doi: 10.1038/540169b

Turn children on to science through reading p.170

doi: 10.1038/540170a

Europe’s first Mars rover gets funding — despite crash of test craft p.177

doi: 10.1038/nature.2016.21091

North America’s oldest mummy returned to US tribe after genome sequencing p.178

doi: 10.1038/540178a

Mexico proposal to ban human-embryo research would stifle science p.180

doi: 10.1038/540180a

Battle over US overtime pay rules leaves many postdocs in limbo p.181

doi: 10.1038/nature.2016.21084

Deforestation spikes in Brazilian Amazon p.182

doi: 10.1038/nature.2016.21083

Researchers baffled by nationalist surge p.182

doi: 10.1038/540182a

What DNA reveals about St Helena’s freed slaves p.184

doi: 10.1038/540184a

The history of Greenland's ice p.202

doi: 10.1038/540202a

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

doi: 10.1038/540204a

Elemental abundances across cosmic time p.205

doi: 10.1038/540205a

Neural synchronization in Alzheimer's disease p.207

doi: 10.1038/540207a

Forty years of linking orbits to ice ages p.208

doi: 10.1038/540208a

Replacing the cell's power plants p.210

doi: 10.1038/nature20483

Aspiring to naivety p.211

doi: 10.1038/nature20484

Certified randomness in quantum physics p.213

doi: 10.1038/nature20119

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

doi: 10.1038/nature20588

Gamma frequency entrainment attenuates amyloid load and modifies microglia p.230

doi: 10.1038/nature20587

S-2-hydroxyglutarate regulates CD8⁺ T-lymphocyte fate p.236

doi: 10.1038/nature20165

m⁶A modulates neuronal functions and sex determination in Drosophila p.242

doi: 10.1038/nature20568

A massive, quiescent, population II galaxy at a redshift of 2.1 p.248

doi: 10.1038/nature20570

Greenland was nearly ice-free for extended periods during the Pleistocene p.252

doi: 10.1038/nature20146

A persistent and dynamic East Greenland Ice Sheet over the past 7.5 million years p.256

doi: 10.1038/nature20147

Dynamics of a seafloor-spreading episode at the East Pacific Rise p.261

doi: 10.1038/nature20116

Land-use intensification causes multitrophic homogenization of grassland communities p.266

doi: 10.1038/nature20575

Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations p.270

doi: 10.1038/nature20592

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

Microcins mediate competition among Enterobacteriaceae in the inflamed gut p.280

doi: 10.1038/nature20557

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

Host genome integration and giant virus-induced reactivation of the virophage mavirus p.288

doi: 10.1038/nature20593

Designed proteins induce the formation of nanocage-containing extracellular vesicles p.292

doi: 10.1038/nature20607

Capturing pairwise and multi-way chromosomal conformations using chromosomal walks p.296

doi: 10.1038/nature20158

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