2016-11-29It is crucial to fight discrimination in all its forms, but it is unhelpful to exclude conservative voices from debate.
2016-11-30In an era of online discussion, debate must remain nuanced and courteous.
2016-11-30A change in cultural and social factors — such as overcoming a distaste for doggy bags — will be required to shift people’s behaviour.
2016-11-28If politicians can lie without condemnation, what are scientists to do? Kathleen Higgins offers some explanation.
2016-11-30Changing the social status of macaques also changes their immune systems.Low social status has been linked to multiple health problems in humans and other primates, some of which may not be linked to the accessibility of food and other resources.Jenny Tung of Duke
2016-11-30Molecules containing both carbon and silicon have become a standard part of synthetic chemistry, but life uses silicon only in inorganic compounds such as the shells of diatoms.Now, Frances Arnold and her collaborators at the California Institute of Technology in Pasadena have engineered bacteria
2016-11-30Mice with simulated jet lag have an increased risk of developing liver cancer.Sleeping out of step with the day–night cycle has been linked to various health disorders in humans. David Moore, Loning Fu and their colleagues at Baylor College of Medicine in Houston, Texas,
2016-11-30Researchers have for the first time detected temporary changes in Earth's gravitational field just before an earthquake.Jean-Paul Montagner at the CNRS Institute of Earth Physics in Paris and his team analysed gravimetric and seismic data recorded during the massive 2011 Tohoku earthquake in Japan.
2016-11-30Plants and animals will probably be unable to respond to changes in environmental conditions fast enough to keep pace with climate change.Tereza Jezkova and John Wiens of the University of Arizona, Tucson, looked at 56 plant and animal species and documented shifts in their
2016-11-30The muscle that allows mammals to breathe deeply — the diaphragm — may have been present in some reptiles 300 million years ago, about 50 million years before it was thought to have appeared.Markus Lambertz at the University of Bonn in Germany and his
2016-11-30Particles that have linked quantum states, known as 'entangled' particles, can affect each other's states even if they are physically separated. Now scientists have set a record by entangling ten photons — two more than achieved previously.Entangled particles should one day enable quantum computing
2016-11-30Coating metals with a high-quality, single-atom-thick layer of 2D boron nitride can protect them from corrosion.Layers of 2D materials have been touted for use as protective coatings on surfaces but have shown mixed results, with some apparently even increasing corrosion rates in the long
2016-11-30A sensor that sticks to the skin can give colour-coded readouts of ultraviolet light levels from the Sun, the leading cause of skin cancer.John Rogers at the University of Illinois at Urbana–Champaign and his colleagues developed the stretchable device (pictured), which is
2016-11-30Gut microbes and the fatty acids they produce can regulate gene expression by influencing the 3D shape of their hosts' DNA.Intestinal bacteria are known to affect several aspects of host health, including the risk of cardiovascular and metabolic diseases. To study the mechanisms by
2016-11-30The week in science: 25 November–1 December 2016.
2016-11-23The drug, and others based on the ‘amyloid hypothesis’, are still being tested in other, different trials.
2016-11-23Cash to include fund modelled on DARPA, the US defence department’s research arm — but how much will go to basic research is unclear.
2016-11-30Advances in neuroscience are driving the development of therapies that could save thousands of the most vulnerable patients.
2016-11-29British team is first to seek site of 1.5-million-year-old sample.
2016-11-29Next generation of Trojan-horse drugs designed to minimize damage to healthy cells.
2016-11-23String of publications describes attempts — mostly unsuccessful — to use proposed CRISPR rival.
2016-11-28Challenges in preventing pollution from ballast water highlight reforms needed in global shipping regulation, write Zheng Wan and colleagues.
2016-11-30Lawrence Haddad, Corinna Hawkes and colleagues propose ten ways to shift the focus from feeding people to nourishing them.
2016-11-30For sustainable, equitable nutrition we must count the true global costs and benefits of food production, urge Pavan Sukhdev, Peter May and Alexander Müller.
2016-11-30Roger Schonfeld analyses how the sector's scientific books are faring in the digitized, open-access era.
2016-11-30Barbara Kiser reviews five of the week's best science picks.
2016-11-30As thousands of scientists and policymakers gather in Mexico this month for the COP13 summit on biodiversity (see www.cbd.int/cop2016), we should take a moment to celebrate the earliest 'tree of life' model of biodiversity.Charles Darwin published the idea of a tree of life
2016-11-30We agree that data alone will not save species (A. M.EllisonNature538, 141;10.1038/538141a2016). However, using data in combination with smart advocacy can make a difference.For example, ecologists specializing in seabirds, fishes and coral reefs shared their
2016-11-30I disagree with Aaron Ellison's contention that biodiversity data only rarely drive conservation decisions (Nature538, 141;10.1038/538141a2016). In China, better data are guiding changes in conservation policies and on-the-ground actions.For instance, huge long-term data sets on species, ecosystems
2016-11-30Aaron Ellison rightly calls for conservation scientists to engage more actively in the political process (Nature538, 141;10.1038/538141a2016). Unfortunately, those doing so can become targets for physical and verbal threats, personal abuse, bullying and trolling on social media.As
2016-11-30Richard Forman and Jianguo Wu identify several zones around the world that might be suitable for future urbanization (Nature537, 608–611;10.1038/537608a2016). We suggest that the problem of supporting a growing population needs to be considered from a
2016-11-30Richard Forman and Jianguo Wu suggest that sustainable city expansion should be restricted to selected urban peripheries (Nature537, 608–611;10.1038/537608a2016). Our investigations across five Indian cities indicate that proper planning of such peri-urban areas is crucial.We
2016-11-30Many of the factors that contributed to Donald Trump's win in the 2016 US presidential election are those that make achievement of the United Nations' Sustainable Development Goals (SDGs) so pressing. Drawn up to end poverty (goal 1) and inequality (goal 10) and to ensure
2016-11-30Unconventional gas extraction ('fracking') is likely to be central to the energy policy of president-elect Donald Trump. I urge the US Congress to tighten current regulations and strike a balance between energy independence and the safeguarding of public health and the environment (see also J.
2016-11-30Contrary to popular opinion, the polls were not wrong in last month's US presidential election (see also Nature539, 339;10.1038/539339a2016). The most recent polls in each state predicted the outcome for individual states — but only when the 95% confidence
2016-11-30Biologist who found unexpected power in protein folding.
2016-11-30Technology and practice can help shy and introverted researchers to succeed when reticence is risky.
2016-11-30Women have fewer co-authors than men over the course of their careers.
2016-11-30The pay gap between men and women in UK science is narrowing.
2016-11-30Order from chaos.
2016-11-30Multiple sclerosis often strikes between the ages of 20 and 40, when people are entering the workforce and raising families.
2016-11-30Emerging evidence points to a viral infection, low levels of vitamin D and genetics as culprits in multiple sclerosis, but how they combine to cause the disease is unclear.
2016-11-30New drugs are beginning to show promise for people with one of the less common, and harder to treat, forms of multiple sclerosis.
2016-11-30It is time for a bolder approach to developing drugs for progressive multiple sclerosis, says Bibi Bielekova.
2016-11-30Could a high-risk treatment play a part in tackling multiple sclerosis?
2016-11-30Dietary changes may be able to alleviate the symptoms of multiple sclerosis, but testing the effects of diet will need a different protocol to the one used for drugs.
2016-11-30arising fromB.Haibe-Kainset al. Nature504, 389–393 (2013); doi:10.1038/nature12831Haibe-Kains et al. reported inconsistency between two large-scale pharmacogenomic studies—the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Project (CGP). Upon careful analysis of the
2016-11-30replying toP.Geeleher, E. R.Gamazon, C.Seoighe, N. J.Cox & R. S.HuangNature540, http://dx.doi.org/10.1038/nature19838 (2016).In the accompanying Comment, Geeleher et al. claim to have discovered overall consistency between the
2016-11-30arising fromB.Haibe-Kainset al. Nature504, 389–393 (2013); doi:10.1038/nature12831The comparative analysis by Haibe-Kains et al. concluded that data from two large-scale studies of cancer cell lines showed highly discordant results for drug sensitivity measurements, whereas
2016-11-30replying toJ. P.Mpindiet al. Nature540, http://dx.doi.org/10.1038/nature20171 (2016).The accompanying Comment by Mpindi et al. is an important contribution to the discussion of pharmacogenomic consistency for several reasons. Mpindi et al. were able
2016-11-30arising fromB.Haibe-Kainset al. Nature504, 389–393 (2013); doi:10.1038/nature12831The Cancer Cell Line Encyclopedia (CCLE) and Cancer Genome Project (CGP) are two independent large-scale efforts to characterize genomes, mRNA expression, and anti-cancer drug dose–responses across cell lines,
2016-11-30replying toM.Bouhaddouet al. Nature540, http://dx.doi.org/10.1038/nature20580 (2016).In the accompanying Comment, the authors make two main claims: (1) that viability metrics computed over the drug concentration range shared between datasets yield higher consistency than the same
2016-11-30Studies of a large frost-filled basin on Pluto show that this feature altered the dwarf planet's spin axis, driving tectonic activity on its surface, and hint at the presence of a subsurface ocean. See Letters p.86, p.90, p.94 & p.97
2016-11-23Mitochondrial organelles — the energy powerhouses of the cell — must divide and fuse dynamically to function. It emerges that two distinct dynamin enzymes enable mitochondrial division. See Letter p.139
2016-11-16Dealing with errors in a quantum computer typically requires complex programming and many additional quantum bits. A technique for controlling errors has been proposed that alleviates both of these problems.
2016-11-30To reach the cell surface, membrane proteins are first targeted to an organelle called the endoplasmic reticulum. Several targeting pathways are known, but it now emerges that there is yet another pathway. See Letter p.134
2016-11-30Changes in the amount of carbon stored in soil might be a crucial feedback to climate change. Experimental field studies show that warming-induced soil carbon losses are greatest where carbon stocks are largest. See Letter p.104
2016-11-23In the 1980s, the gas surrounding a black hole in a nearby galaxy began to emit much more radiation than before. This change has unexpectedly reversed in the past five years, questioning our understanding of these extreme phenomena.
2016-11-23Little is known about the biological rhythms that emerge from social behaviours in the wild. A study of shorebird pairs shows that rhythms of nest-incubation duties are mainly governed by strategies to avoid predators. See Letter p.109
2016-11-21Organisms use endogenous clocks to anticipate regular environmental cycles, such as days and tides. Natural variants resulting in differently timed behaviour or physiology, known as chronotypes in humans, have not been well characterized at the molecular level. We sequenced the genome of Clunio marinus,
2016-10-24Mitochondria are dynamic organelles that exchange contents and undergo remodelling during cyclic fusion and fission. Genetic mutations in MFN2 (the gene encoding mitofusin 2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A). It has not yet been possible
2016-11-14In all domains of life, selenocysteine (Sec) is delivered to the ribosome by selenocysteine-specific tRNA (tRNASec) with the help of a specialized translation factor, SelB in bacteria. Sec-tRNASec recodes a UGA stop codon next to a downstream mRNA stem–loop. Here we
2016-09-19Pluto has a variety of surface frosts and landforms as well as a complex atmosphere. There is ongoing geological activity related to the massive Sputnik Planitia glacier, mostly made of nitrogen (N2) ice mixed with solid carbon monoxide and methane, covering the 4-kilometre-deep, 1,000-kilometre-wide basin of Sputnik Planitia near the anti-Charon point. The glacier has been suggested to arise from a source region connected to the deep interior, or from a sink collecting the volatiles released planetwide. Thin deposits of N2 frost, however, were also detected at mid-northern latitudes and methane ice was observed to cover most of Pluto except for the darker, frost-free equatorial regions. Here we report numerical simulations of the evolution of N2, methane and carbon monoxide on Pluto over thousands of years. The model predicts N2 ice accumulation in the deepest low-latitude basin and the threefold increase in atmospheric pressure that has been observed to occur since 1988. This points to atmospheric–topographic processes as the origin of Sputnik Planitia’s N2 glacier. The same simulations also reproduce the observed quantities of volatiles in the atmosphere and show frosts of methane, and sometimes N2, that seasonally cover the mid- and high latitudes, explaining the bright northern polar cap reported in the 1990s and the observed ice distribution in 2015. The model also predicts that most of these seasonal frosts should disappear in the next decade.
2016-11-16Pluto is an astoundingly diverse, geologically dynamic world. The dominant feature is Sputnik Planitia—a tear-drop-shaped topographic depression approximately 1,000 kilometres in diameter possibly representing an ancient impact basin. The interior of Sputnik Planitia is characterized by a smooth, craterless plain three to four kilometres beneath the surrounding rugged uplands, and represents the surface of a massive unit of actively convecting volatile ices (N2, CH4 and CO) several kilometres thick. This large feature is very near the Pluto–Charon tidal axis. Here we report that the location of Sputnik Planitia is the natural consequence of the sequestration of volatile ices within the basin and the resulting reorientation (true polar wander) of Pluto. Loading of volatile ices within a basin the size of Sputnik Planitia can substantially alter Pluto’s inertia tensor, resulting in a reorientation of the dwarf planet of around 60 degrees with respect to the rotational and tidal axes. The combination of this reorientation, loading and global expansion due to the freezing of a possible subsurface ocean generates stresses within the planet’s lithosphere, resulting in a global network of extensional faults that closely replicate the observed fault networks on Pluto. Sputnik Planitia probably formed northwest of its present location, and was loaded with volatiles over million-year timescales as a result of volatile transport cycles on Pluto. Pluto’s past, present and future orientation is controlled by feedbacks between volatile sublimation and condensation, changing insolation conditions and Pluto’s interior structure.
2016-11-16The deep nitrogen-covered basin on Pluto, informally named Sputnik Planitia, is located very close to the longitude of Pluto’s tidal axis and may be an impact feature, by analogy with other large basins in the Solar System. Reorientation of Sputnik Planitia arising from tidal and rotational torques can explain the basin’s present-day location, but requires the feature to be a positive gravity anomaly, despite its negative topography. Here we argue that if Sputnik Planitia did indeed form as a result of an impact and if Pluto possesses a subsurface ocean, the required positive gravity anomaly would naturally result because of shell thinning and ocean uplift, followed by later modest nitrogen deposition. Without a subsurface ocean, a positive gravity anomaly requires an implausibly thick nitrogen layer (exceeding 40 kilometres). To prolong the lifetime of such a subsurface ocean to the present day and to maintain ocean uplift, a rigid, conductive water-ice shell is required. Because nitrogen deposition is latitude-dependent, nitrogen loading and reorientation may have exhibited complex feedbacks.
2016-11-30Pluto’s Sputnik Planitia is a bright, roughly circular feature that resembles a polar ice cap. It is approximately 1,000 kilometres across and is centred on a latitude of 25 degrees north and a longitude of 175 degrees, almost directly opposite the side of Pluto that always faces Charon as a result of tidal locking. One explanation for its location includes the formation of a basin in a giant impact, with subsequent upwelling of a dense interior ocean. Once the basin was established, ice would naturally have accumulated there. Then, provided that the basin was a positive gravity anomaly (with or without the ocean), true polar wander could have moved the feature towards the Pluto–Charon tidal axis, on the far side of Pluto from Charon. Here we report modelling that shows that ice quickly accumulates on Pluto near latitudes of 30 degrees north and south, even in the absence of a basin, because, averaged over its orbital period, those are Pluto’s coldest regions. Within a million years of Charon’s formation, ice deposits on Pluto concentrate into a single cap centred near a latitude of 30 degrees, owing to the runaway albedo effect. This accumulation of ice causes a positive gravity signature that locks, as Pluto’s rotation slows, to a longitude directly opposite Charon. Once locked, Charon raises a permanent tidal bulge on Pluto, which greatly enhances the gravity signature of the ice cap. Meanwhile, the weight of the ice in Sputnik Planitia causes the crust under it to slump, creating its own basin (as has happened on Earth in Greenland). Even if the feature is now a modest negative gravity anomaly, it remains locked in place because of the permanent tidal bulge raised by Charon. Any movement of the feature away from 30 degrees latitude is countered by the preferential recondensation of ices near the coldest extremities of the cap. Therefore, our modelling suggests that Sputnik Planitia formed shortly after Charon did and has been stable, albeit gradually losing volume, over the age of the Solar System.
2016-11-30Ghost imaging is a counter-intuitive phenomenon—first realized in quantum optics—that enables the image of a two-dimensional object (mask) to be reconstructed using the spatio-temporal properties of a beam of particles with which it never interacts. Typically, two beams of correlated photons are used: one passes through the mask to a single-pixel (bucket) detector while the spatial profile of the other is measured by a high-resolution (multi-pixel) detector. The second beam never interacts with the mask. Neither detector can reconstruct the mask independently, but temporal cross-correlation between the two beams can be used to recover a ‘ghost’ image. Here we report the realization of ghost imaging using massive particles instead of photons. In our experiment, the two beams are formed by correlated pairs of ultracold, metastable helium atoms, which originate from s-wave scattering of two colliding Bose–Einstein condensates. We use higher-order Kapitza–Dirac scattering to generate a large number of correlated atom pairs, enabling the creation of a clear ghost image with submillimetre resolution. Future extensions of our technique could lead to the realization of ghost interference, and enable tests of Einstein–Podolsky–Rosen entanglement and Bell’s inequalities with atoms.
2016-11-30The majority of the Earth’s terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12–17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon–climate feedback that could accelerate climate change.
2016-11-23The behavioural rhythms of organisms are thought to be under strong selection, influenced by the rhythmicity of the environment. Such behavioural rhythms are well studied in isolated individuals under laboratory conditions, but free-living individuals have to temporally synchronize their activities with those of others, including potential mates, competitors, prey and predators. Individuals can temporally segregate their daily activities (for example, prey avoiding predators, subordinates avoiding dominants) or synchronize their activities (for example, group foraging, communal defence, pairs reproducing or caring for offspring). The behavioural rhythms that emerge from such social synchronization and the underlying evolutionary and ecological drivers that shape them remain poorly understood. Here we investigate these rhythms in the context of biparental care, a particularly sensitive phase of social synchronization where pair members potentially compromise their individual rhythms. Using data from 729 nests of 91 populations of 32 biparentally incubating shorebird species, where parents synchronize to achieve continuous coverage of developing eggs, we report remarkable within- and between-species diversity in incubation rhythms. Between species, the median length of one parent’s incubation bout varied from 1–19 h, whereas period length—the time in which a parent’s probability to incubate cycles once between its highest and lowest value—varied from 6–43 h. The length of incubation bouts was unrelated to variables reflecting energetic demands, but species relying on crypsis (the ability to avoid detection by other animals) had longer incubation bouts than those that are readily visible or who actively protect their nest against predators. Rhythms entrainable to the 24-h light–dark cycle were less prevalent at high latitudes and absent in 18 species. Our results indicate that even under similar environmental conditions and despite 24-h environmental cues, social synchronization can generate far more diverse behavioural rhythms than expected from studies of individuals in capti[...]
2016-11-30Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.
2016-11-23Cultured pluripotent stem cells are a cornerstone of regenerative medicine owing to their ability to give rise to all cell types of the body. Although pluripotent stem cells can be propagated indefinitely in vitro, pluripotency is paradoxically a transient state in vivo, lasting 2–3 days around the time of blastocyst implantation. The exception to this rule is embryonic diapause, a reversible state of suspended development triggered by unfavourable conditions. Diapause is a physiological reproductive strategy widely employed across the animal kingdom, including in mammals, but its regulation remains poorly understood. Here we report that the partial inhibition of mechanistic target of rapamycin (mTOR), a major nutrient sensor and promoter of growth, induces reversible pausing of mouse blastocyst development and allows their prolonged culture ex vivo. Paused blastocysts remain pluripotent and competent—able to give rise to embryonic stem (ES) cells and live, fertile mice. We show that both naturally diapaused blastocysts in vivo and paused blastocysts ex vivo display pronounced reductions in mTOR activity, translation, histone modifications associated with gene activity and transcription. Pausing can be induced directly in cultured ES cells and sustained for weeks without appreciable cell death or deviations from cell cycle distributions. We show that paused ES cells display a remarkable global suppression of transcription, maintain a gene expression signature of diapaused blastocysts and remain pluripotent. These results uncover a new pluripotent stem cell state corresponding to the epiblast of the diapaused blastocyst and indicate that mTOR regulates developmental timing at the peri-implantation stage. Our findings have implications in the fields of assisted reproduction, regenerative medicine, cancer, metabolic disorders and ageing.
2016-11-07Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3–MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3–MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.
2016-11-07Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival—mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl−/− macrophages, but not in wild-type, Mlkl−/− or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.
2016-11-30In eukaryotes, up to one-third of cellular proteins are targeted to the endoplasmic reticulum, where they undergo folding, processing, sorting and trafficking to subsequent endomembrane compartments. Targeting to the endoplasmic reticulum has been shown to occur co-translationally by the signal recognition particle (SRP) pathway or post-translationally by the mammalian transmembrane recognition complex of 40 kDa (TRC40) and homologous yeast guided entry of tail-anchored proteins (GET) pathways. Despite the range of proteins that can be catered for by these two pathways, many proteins are still known to be independent of both SRP and GET, so there seems to be a critical need for an additional dedicated pathway for endoplasmic reticulum relay. We set out to uncover additional targeting proteins using unbiased high-content screening approaches. To this end, we performed a systematic visual screen using the yeast Saccharomyces cerevisiae, and uncovered three uncharacterized proteins whose loss affected targeting. We suggest that these proteins work together and demonstrate that they function in parallel with SRP and GET to target a broad range of substrates to the endoplasmic reticulum. The three proteins, which we name Snd1, Snd2 and Snd3 (for SRP-independent targeting), can synthetically compensate for the loss of both the SRP and GET pathways, and act as a backup targeting system. This explains why it has previously been difficult to demonstrate complete loss of targeting for some substrates. Our discovery thus puts in place an essential piece of the endoplasmic reticulum targeting puzzle, highlighting how the targeting apparatus of the eukaryotic cell is robust, interlinked and flexible.
2016-10-31Mitochondria cannot be generated de novo; they must grow, replicate their genome, and divide in order to be inherited by each daughter cell during mitosis. Mitochondrial division is a structural challenge that requires the substantial remodelling of membrane morphology. Although division factors differ across organisms, the need for multiple constriction steps and a dynamin-related protein (Drp1, Dnm1 in yeast) has been conserved. In mammalian cells, mitochondrial division has been shown to proceed with at least two sequential constriction steps: the endoplasmic reticulum and actin must first collaborate to generate constrictions suitable for Drp1 assembly on the mitochondrial outer membrane; Drp1 then further constricts membranes until mitochondrial fission occurs. In vitro experiments, however, indicate that Drp1 does not have the dynamic range to complete membrane fission. In contrast to Drp1, the neuron-specific classical dynamin dynamin-1 (Dyn1) has been shown to assemble on narrower lipid profiles and facilitate spontaneous membrane fission upon GTP hydrolysis. Here we report that the ubiquitously expressed classical dynamin-2 (Dyn2) is a fundamental component of the mitochondrial division machinery. A combination of live-cell and electron microscopy in three different mammalian cell lines reveals that Dyn2 works in concert with Drp1 to orchestrate sequential constriction events that build up to division. Our work underscores the biophysical limitations of Drp1 and positions Dyn2, which has intrinsic membrane fission properties, at the final step of mitochondrial division.
2016-11-16Targeted genome editing via engineered nucleases is an exciting area of biomedical research and holds potential for clinical applications. Despite rapid advances in the field, in vivo targeted transgene integration is still infeasible because current tools are inefficient, especially for non-dividing cells, which compose most adult tissues. This poses a barrier for uncovering fundamental biological principles and developing treatments for a broad range of genetic disorders. Based on clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) technology, here we devise a homology-independent targeted integration (HITI) strategy, which allows for robust DNA knock-in in both dividing and non-dividing cells in vitro and, more importantly, in vivo (for example, in neurons of postnatal mammals). As a proof of concept of its therapeutic potential, we demonstrate the efficacy of HITI in improving visual function using a rat model of the retinal degeneration condition retinitis pigmentosa. The HITI method presented here establishes new avenues for basic research and targeted gene therapies.
2016-10-05Nature536, 479–483 (2016); doi:10.1038/nature19084In this Letter, during the production process, one of the images in Fig. 3a was inadvertently labelled with the incorrect PDAC cell line name. The second picture from the left should have been
2016-10-05Nature535, 111–116 (2016); doi:10.1038/nature18590In this Article, owing to a typesetter error the ‘received date’ was incorrectly shown as ‘6 March 2015’ instead of ‘6 March 2016’; this has been corrected in the online versions of the
2016-10-19Nature535, 136–139 (2016); doi:10.1038/nature18010In this Letter, the 60-subunit protein assembly presented more strongly resembles a wireframe dodecahedron than an icosahedron. We thank the reader who drew this to our attention and we agree that all instances
2016-10-19Nature537, 544–547 (2016); doi:10.1038/nature19353In this Letter, the ArrayExpress accession number provided for the gene expression data for Sdhb-deficient cells should have been ‘ E-MTAB-4349’, rather than the Affymetrix GeneChip platform accession ‘A-AFFY-130’; this has been