|Nature - Issue - nature.com science feeds|
Scientists must fight back with the truth about the debunked link between vaccines and autism.
They demonstrate the practice of science at its best.
The potential economic damage from global warming should not be influenced by politics.
Anita Makri argues that the form of science communicated in popular media leaves the public vulnerable to false certainty.
White rhinos can learn about each other by sniffing one another's faeces.Many mammals communicate through smells in their urine. To see whether faeces have a similar role, Courtney Marneweck at the University of KwaZulu-Natal in Pietermaritzburg, South Africa, and her colleagues analysed odours from
The activation of a particular group of brain cells is all it takes to make mice hunt to kill.The brain's central amygdala has long been thought to have a role in producing emotions, particularly fear. To activate this brain region, Ivan de Araujo at
Scientists have braided a molecule into a knot with eight crossings, the most complex yet made in the lab.Flexible polymers can twist themselves into complex knots, but scientists have struggled to create all but the simplest structures. David Leigh and his colleagues at the
Atmospheric methane and other short-lived greenhouse gases are set to keep the global sea level rising for several centuries— even after any potential decline or halt in emissions.Greenhouse gases in the atmosphere cause ocean warming and thermal expansion that results in sea-level rise.
Trees that live in fire-prone areas have evolved thick bark to protect themselves. This trait can be used as an indicator of how resilient a tree species is to increased fire risk under global warming.Adam Pellegrini, now at Stanford University in California, and his
The discovery that extinct marine organisms called trilobites laid eggs provides the first direct evidence for how they reproduced.Trilobites lived between 520 million and 250 million years ago, and are one of the earliest known groups of arthropods (invertebrates, including modern insects, with exoskeletons
Differences between the breeding success of mothers and daughters may have driven the evolution of menopause, according to a study on killer whales.Evolutionary biologists have long puzzled over why females of certain species— humans, killer whales and short-finned pilot whales — stop ovulating
Less than one-quarter of the world's forests show no obvious signs of human activity, and the proportion of undisturbed forest has dropped markedly since the millennium.Peter Potapov at the University of Maryland in College Park and his co-workers used satellite images to identify areas
A high-fat diet speeds tumour growth in mice, but this can be counteracted by drugs that lower levels of a metabolite in the blood.Diet can influence cancer survival, but the molecular reasons are largely unknown. Jing Chen at Emory University in Atlanta, Georgia, and
The week in science: 13–19 January 2017.
Scientists accused of deceiving the public about benefits of transgenic mustard.
An open-science effort to replicate dozens of cancer-biology studies is off to a confusing start.
Publications such as Nature and Science have policies that clash with the global health charity's open-access mandate.
Probe could give early warnings of catastrophic solar storms heading for Earth.
Revised scientific-integrity policy gives researchers more leeway to speak to the press and publish their findings.
Pavo Barišić says he won't step down after a parliamentary ethics committee found he copied another scholar's work.
NASA is now building the rover that it hopes will bring back signs of life on the red planet.
Where did it come from? How do organisms use it without self-destructing? And what else can it do?
Erica Ollmann Saphire and colleagues share lessons in finding treatments fast from the work on Ebola by the Viral Hemorrhagic Fever Immunotherapeutic Consortium.
On Arthur C. Clarke's centenary, Andrew Robinson lauds a prescient, original writer.
Barbara Kiser reviews five of the week's best science picks.
The Brussels Declaration will be published at next month's meeting of the American Association for the Advancement of Science in Boston, Massachusetts. It is a 20-point blueprint for a set of ethics and principles to inform work at the boundaries of science, society and policy.
As officers of the Anthropocene Working Group (AWG; J.Z. and C.W.) and chair of the Subcommission on Quaternary Stratigraphy (SQS; M.J.H.) of the International Commission on Stratigraphy (ICS), we note that the AWG has less power than Erle Ellis and colleagues imply (Nature540
Adding in a wider range of social-science expertise will not, in my view, help efforts to 'formalize the Anthropocene' as a geological age of human influence (E.Elliset al. Nature540, 192–193;10.1038/540192a2016). The authors rightly
By inviting scientists to take their 'red pens to the Internet' and grade online sources of science reporting, Phil Williamson implies that science is the primary and final voice in public discussion (Nature540, 171;10.1038/540171a2016). This disregards other ways
US astronaut and senator.
How can scientists get through to a public that's seemingly indifferent to objective facts?
A social-media professional calls on researchers to speak out for their science.
The Nature Insight 'Frontiers in Biology' aims to cover timely and important developments across biology, ranging from molecular mechanisms to whole-organism physiology and biomedicine.Improvements in sequencing and in methods for enriching and extracting ancient DNA have furthered the temporal and geographic reach of
Advances in the sequencing and the analysis of the genomes of both modern and ancient peoples have facilitated a number of breakthroughs in our understanding of human evolutionary history. These include the discovery of interbreeding between anatomically modern humans and extinct hominins; the development of
A long-term aim of the life sciences is to understand how organismal shape is encoded by the genome. An important challenge is to identify mechanistic links between the genes that control cell-fate decisions and the cellular machines that generate shape, therefore closing the gap between
Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is
Three of the most fundamental questions in biology are how individual cells differentiate to form tissues, how tissues function in a coordinated and flexible fashion and which gene regulatory mechanisms support these processes. Single-cell genomics is opening up new ways to tackle these questions by
A growing number of nucleobase modifications in messenger RNA have been revealed through advances in detection and RNA sequencing. Although some of the biochemical pathways that involve modified bases have been identified, research into the world of RNA modification— the epitranscriptome — is still
Our word is your bond.
The Comment‘Involve social scientists in defining the Anthropocene’ (E. Ellis et al. Nature540, 192–193; 2016) incorrectly stated that proposals for defining this epoch will be put forward for ratification by the International Geological Congress. In fact, they will be put to
'Squeezed' light exhibits smaller quantum fluctuations than no light at all. Localized squeezed regions have now been produced along an infrared light wave and probed with unprecedented time resolution. See Letter p.376
A molecular modification called m6Am has been found to regulate the stability of messenger RNAs in mammalian cells. The mechanism casts fresh light on how reversibly modified RNA bases control the fate of mRNA. See Article p.371
Faced with ever-changing products, consumers can benefit from trying new items. But data collected over almost five years show that, the longer shoppers have been buying a favourite product, the more likely they are to stick with it.
An algorithm has been developed allowing the rational design of origami-inspired materials that can be rearranged to change their properties. This might open the way to strategies for making reconfigurable robots. See Article p.347
Eukaryotic cells, with complex features such as membrane-bound nuclei, evolved from prokaryotic cells that lack these components. A newly identified prokaryotic group reveals intermediate steps in eukaryotic-cell evolution. See Article p.353
Competition between the phospholipase enzyme PLA2G16 and the protein galectin-8 determines whether the RNA-based genomes of picornaviruses can be effectively delivered into host cells. See Letter p.412
50 Years AgoWhen spiders are given lysergic acid they construct webs of more than usual regularity; they become, like man in a similar situation, withdrawn from external stimuli so that their perceptive awareness is reduced, and they cease to adjust their webs to the
Advances in fabrication technologies are enabling the production of architected materials with unprecedented properties. Most such materials are characterized by a fixed geometry, but in the design of some materials it is possible to incorporate internal mechanisms capable of reconfiguring their spatial architecture, and in
The origin and cellular complexity of eukaryotes represent a major enigma in biology. Current data support scenarios in which an archaeal host cell and an alphaproteobacterial (mitochondrial) endosymbiont merged together, resulting in the first eukaryotic cell. The host cell is related to Lokiarchaeota, an archaeal
Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and
In the Drosophila optic lobes, 800 retinotopically organized columns in the medulla act as functional units for processing visual information. The medulla contains over 80 types of neuron, which belong to two classes: uni-columnar neurons have a stoichiometry of one per column, while multi-columnar
Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5′ end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show
Squeezed states of electromagnetic radiation have quantum fluctuations below those of the vacuum field. They offer a unique resource for quantum information systems and precision metrology, including gravitational wave detectors, which require unprecedented sensitivity. Since the first experiments on this non-classical form of light, quantum analysis has been based on homodyning techniques and photon correlation measurements. These methods currently function in the visible to near-infrared and microwave spectral ranges. They require a well-defined carrier frequency, and photons contained in a quantum state need to be absorbed or amplified. Quantum non-demolition experiments may be performed to avoid the influence of a measurement in one quadrature, but this procedure comes at the expense of increased uncertainty in another quadrature. Here we generate mid-infrared time-locked patterns of squeezed vacuum noise. After propagation through free space, the quantum fluctuations of the electric field are studied in the time domain using electro-optic sampling with few-femtosecond laser pulses. We directly compare the local noise amplitude to that of bare (that is, unperturbed) vacuum. Our nonlinear approach operates off resonance and, unlike homodyning or photon correlation techniques, without absorption or amplification of the field that is investigated. We find subcycle intervals with noise levels that are substantially less than the amplitude of the vacuum field. As a consequence, there are enhanced fluctuations in adjacent time intervals, owing to Heisenberg’s uncertainty principle, which indicate generation of highly correlated quantum radiation. Together with efforts in the far infrared, this work enables the study of elementary quantum dynamics of light and matter in an energy range at the boundary between vacuum and thermal background conditions.
Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization—a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib—a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis—was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.
The macronutrient phosphorus is thought to limit primary productivity in the oceans on geological timescales. Although there has been a sustained effort to reconstruct the dynamics of the phosphorus cycle over the past 3.5 billion years, it remains uncertain whether phosphorus limitation persisted throughout Earth’s history and therefore whether the phosphorus cycle has consistently modulated biospheric productivity and ocean–atmosphere oxygen levels over time. Here we present a compilation of phosphorus abundances in marine sedimentary rocks spanning the past 3.5 billion years. We find evidence for relatively low authigenic phosphorus burial in shallow marine environments until about 800 to 700 million years ago. Our interpretation of the database leads us to propose that limited marginal phosphorus burial before that time was linked to phosphorus biolimitation, resulting in elemental stoichiometries in primary producers that diverged strongly from the Redfield ratio (the atomic ratio of carbon, nitrogen and phosphorus found in phytoplankton). We place our phosphorus record in a quantitative biogeochemical model framework and find that a combination of enhanced phosphorus scavenging in anoxic, iron-rich oceans and a nutrient-based bistability in atmospheric oxygen levels could have resulted in a stable low-oxygen world. The combination of these factors may explain the protracted oxygenation of Earth’s surface over the last 3.5 billion years of Earth history. However, our analysis also suggests that a fundamental shift in the phosphorus cycle may have occurred during the late Proterozoic eon (between 800 and 635 million years ago), coincident with a previously inferred shift in marine redox states, severe perturbations to Earth’s climate system, and the emergence of animals.
The North Atlantic ocean/atmosphere environment exhibits pronounced interdecadal variability that is known to strongly modulate Atlantic hurricane activity. Variability in sea surface temperature (SST) is correlated with hurricane variability through its relationship with the genesis and thermodynamic potential intensity of hurricanes. Another key factor that governs the genesis and intensity of hurricanes is ambient environmental vertical wind shear (VWS). Warmer SSTs generally correlate with more frequent genesis and greater potential intensity, while VWS inhibits genesis and prevents any hurricanes that do form from reaching their potential intensity. When averaged over the main hurricane-development region in the Atlantic, SST and VWS co-vary inversely, so that the two factors act in concert to either enhance or inhibit basin-wide hurricane activity. Here I show, however, that conditions conducive to greater basin-wide Atlantic hurricane activity occur together with conditions for more probable weakening of hurricanes near the United States coast. Thus, the VWS and SST form a protective barrier along the United States coast during periods of heightened basin-wide hurricane activity. Conversely, during the most-recent period of basin-wide quiescence, hurricanes (and particularly major hurricanes) near the United States coast, although substantially less frequent, exhibited much greater variability in their rate of intensification, and were much more likely to intensify rapidly. Such heightened variability poses greater challenges to operational forecasting and, consequently, greater coastal risk during hurricane events.
Hyoliths are abundant and globally distributed‘shelly’ fossils that appear early in the Cambrian period and can be found throughout the 280 million year span of Palaeozoic strata. The ecological and evolutionary importance of this group has remained unresolved, largely because of their poorly constrained soft anatomy and idiosyncratic scleritome, which comprises an operculum, a conical shell and, in some taxa, a pair of lateral spines (helens). Since their first description over 175 years ago, hyoliths have most often been regarded as incertae sedis, related to molluscs or assigned to their own phylum. Here we examine over 1,500 specimens of the mid-Cambrian hyolith Haplophrentis from the Burgess Shale and Spence Shale Lagerstätten. We reconstruct Haplophrentis as a semi-sessile, epibenthic suspension feeder that could use its helens to elevate its tubular body above the sea floor. Exceptionally preserved soft tissues include an extendable, gullwing-shaped, tentacle-bearing organ surrounding a central mouth, which we interpret as a lophophore, and a U-shaped digestive tract ending in a dorsolateral anus. Together with opposing bilateral sclerites and a deep ventral visceral cavity, these features indicate an affinity with the lophophorates (brachiopods, phoronids and tommotiids), substantially increasing the morphological disparity of this prominent group.
Self-organized regular vegetation patterns are widespread and thought to mediate ecosystem functions such as productivity and robustness, but the mechanisms underlying their origin and maintenance remain disputed. Particularly controversial are landscapes of overdispersed (evenly spaced) elements, such as North American Mima mounds, Brazilian murundus, South African heuweltjies, and, famously, Namibian fairy circles. Two competing hypotheses are currently debated. On the one hand, models of scale-dependent feedbacks, whereby plants facilitate neighbours while competing with distant individuals, can reproduce various regular patterns identified in satellite imagery. Owing to deep theoretical roots and apparent generality, scale-dependent feedbacks are widely viewed as a unifying and near-universal principle of regular-pattern formation despite scant empirical evidence. On the other hand, many overdispersed vegetation patterns worldwide have been attributed to subterranean ecosystem engineers such as termites, ants, and rodents. Although potentially consistent with territorial competition, this interpretation has been challenged theoretically and empirically and (unlike scale-dependent feedbacks) lacks a unifying dynamical theory, fuelling scepticism about its plausibility and generality. Here we provide a general theoretical foundation for self-organization of social-insect colonies, validated using data from four continents, which demonstrates that intraspecific competition between territorial animals can generate the large-scale hexagonal regularity of these patterns. However, this mechanism is not mutually exclusive with scale-dependent feedbacks. Using Namib Desert fairy circles as a case study, we present field data showing that these landscapes exhibit multi-scale patterning—previously undocumented in this system—that cannot be explained by either mechanism in isolation. These multi-scale patterns and other emergent properties, such as enhanced resistance to and recovery from drought, instead arise from dynamic interactions in our theoretical framework, which couples both mechanisms. The potentially global extent of animal-induced regularity in vegetation—which can modulate other patterning processes in functionally important ways—emphasizes the need to integrate multiple mechanisms of ecological self-organization.
Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues. However, the extent and types of genetic variation impacting embryonic gene expression, and their interactions with developmental programs, remain largely unknown. Here we assessed the effect of genetic variation on transcriptional (expression levels) and post-transcriptional (3′ RNA processing) regulation across multiple stages of metazoan development, using 80 inbred Drosophila wild isolates, identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila, we obtain near base-pair resolution, resolving causal mutations in developmental enhancers, validated transcription-factor-binding sites and RNA motifs. This fine-grain mapping uncovered extensive allelic interactions within enhancers that have opposite effects, thereby buffering their impact on enhancer activity. QTL affecting 3′ RNA processing identify new functional motifs leading to transcript isoform diversity and changes in the lengths of 3′ untranslated regions. These results highlight how developmental stage influences the effects of genetic variation and uncover multiple mechanisms that regulate and buffer expression variation during embryogenesis.
The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota, which has an important role in human health and nutrition. The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host. The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci, with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA–SusG. Glycan degradation mainly occurs intracellularly and depends on the import of oligosaccharides by an outer membrane protein complex composed of an extracellular SusD-like lipoprotein and an integral membrane SusC-like TonB-dependent transporter. The presence of the partner SusD-like lipoprotein is the major feature that distinguishes SusC-like proteins from previously characterized TonB-dependent transporters. Many sequenced gut Bacteroides spp. encode over 100 SusCD pairs, of which the majority have unknown functions and substrate specificities. The mechanism by which extracellular substrate binding by SusD proteins is coupled to outer membrane passage through their cognate SusC transporter is unknown. Here we present X-ray crystal structures of two functionally distinct SusCD complexes purified from Bacteroides thetaiotaomicron and derive a general model for substrate translocation. The SusC transporters form homodimers, with each β-barrel protomer tightly capped by SusD. Ligands are bound at the SusC–SusD interface in a large solvent-excluded cavity. Molecular dynamics simulations and single-channel electrophysiology reveal a ‘pedal bin’ mechanism, in which SusDmoves away from SusC in a hinge-like fashion in the absence of ligand to expose the substrate-binding site to the extracellular milieu. These data provide mechanistic insights into outer membrane nutrient import by members of the microbiota, an area of major importance for understanding human–microbiota symbiosis.
Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non-enveloped viruses, their biology has been extensively studied. Although a range of different cell-surface receptors are bound by different picornaviruses, it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8, 9, 10, 11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle. We find that PLA2G16 functions early during infection, enabling virion-mediated genome delivery into the cytoplasm, but not in any virion-assigned step, such as cell binding, endosomal trafficking or pore formation. To resolve this paradox, we screened for suppressors of theΔPLA2G16 phenotype and identified a mechanism previously implicated in the clearance of intracellular bacteria. The sensor of this mechanism, galectin-8 (encoded by LGALS8), detects permeated endosomes and marks them for autophagic degradation, whereas PLA2G16 facilitates viral genome translocation and prevents clearance. This study uncovers two competing processes triggered by virus entry: activation of a pore-activated clearance pathway and recruitment of a phospholipase to enable genome release.
As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.
Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways but is often difficult to define or predict. Here we report the development of a mass spectrometry platform to determine simultaneously the presence of interfacial lipids and oligomeric stability and to uncover how lipids act as key regulators of membrane-protein association. Evaluation of oligomeric strength for a dataset of 125α-helical oligomeric membrane proteins reveals an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT, one of the proteins with the lowest oligomeric stability), we founda precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid-binding sites or expression in cardiolipin-deficient Escherichia coli abrogated dimer formation. Molecular dynamics simulation revealed that cardiolipin acts as a bidentate ligand, bridging across subunits. Subsequently, we show that for the Vibrio splendidus sugar transporter SemiSWEET, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids are essential for dimerization of the Na+/H+ antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for the substantially more stable homologous Thermus thermophilus protein NapA. We found that lipid binding is obligatory for dimerization of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids, we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of α-helical membrane proteins, including G-protein-coupled receptors.
|Nature - AOP - nature.com science feeds|
When some cancer cells delete a tumour-suppressor gene, they also delete nearby genes. It emerges that one of these latter genes has a key metabolic role, revealing a therapeutic opportunity that might be relevant for many tumours.
It emerges that phage viruses, which infect bacteria, use small peptides to communicate with each other. This observation of intercellular communication also reveals how viruses make a key developmental decision.
Materials called hydrogels have potential applications as scaffolds for tissue engineering, but methods are needed to assemble them into complex structures that mimic those found in nature. Just such a method has now been reported.
Interleukin-17 functions as a neuromodulator in the roundworm Caenorhabditis elegans, acting directly on RMG hub interneurons to alter their response properties and contribution to behaviour.
Some phages—viruses that infect bacteria—encode peptides that are secreted from infected cells and that, beyond a certain threshold, stimulate other viruses to switch from the lytic (killing the host cell) to lysogenic (dormant) phase.
The first high-resolution (3.5 Å) structure of a full-length cyclic-nucleotide-gated channel, revealing an unconventional, voltage-insensitive voltage-sensor domain and a unique coupling mechanism between cyclic-nucleotide-binding and pore-opening.
A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids toα-ketoglutarate (α-KG) thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime ‘collateral lethality’ therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease.
Discovering ways to control the magnetic state of media with the lowest possible production of heat and at the fastest possible speeds is important in the study of fundamental magnetism, with clear practical potential. In metals, it is possible to switch the magnetization between two stable states (and thus to record magnetic bits) using femtosecond circularly polarized laser pulses. However, the switching mechanisms in these materials are directly related to laser-induced heating close to the Curie temperature. Although several possible routes for achieving all-optical switching in magnetic dielectrics have been discussed, no recording has hitherto been demonstrated. Here we describe ultrafast all-optical photo-magnetic recording in transparent films of the dielectric cobalt-substituted garnet. A single linearly polarized femtosecond laser pulse resonantly pumps specific d−d transitions in the cobalt ions, breaking the degeneracy between metastable magnetic states. By changing the polarization of the laser pulse, we deterministically steer the net magnetization in the garnet, thus writing ‘0’ and ‘1’ magnetic bits at will. This mechanism outperforms existing alternatives in terms of the speed of the write–read magnetic recording event (less than 20 picoseconds) and the unprecedentedly low heat load (less than 6 joules per cubic centimetre).
Large interannual variations in the measured growth rate of atmospheric carbon dioxide (CO2) originate primarily from fluctuations in carbon uptake by land ecosystems. It remains uncertain, however, to what extent temperature and water availability control the carbon balance of land ecosystems across spatial and temporal scales. Here we use empirical models based on eddy covariance data and process-based models to investigate the effect of changes in temperature and water availability on gross primary productivity (GPP), terrestrial ecosystem respiration (TER) and net ecosystem exchange (NEE) at local and global scales. We find that water availability is the dominant driver of the local interannual variability in GPP and TER. To a lesser extent this is true also for NEE at the local scale, but when integrated globally, temporal NEE variability is mostly driven by temperature fluctuations. We suggest that this apparent paradox can be explained by two compensatory water effects. Temporal water-driven GPP and TER variations compensate locally, dampening water-driven NEE variability. Spatial water availability anomalies also compensate, leaving a dominant temperature signal in the year-to-year fluctuations of the land carbon sink. These findings help to reconcile seemingly contradictory reports regarding the importance of temperature and water in controlling the interannual variability of the terrestrial carbon balance. Our study indicates that spatial climate covariation drives the global carbon cycle response.
The Southern Ocean houses a diverse and productive community of organisms. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean.
Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination, the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand–receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type ‘winner’ and the polarity-deficient ‘loser’ clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans-activation of Sas–PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas–PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.
Translation of RNA into proteins is a fundamental process for all cells. Analysis of a mouse model of skin cancer uncovers an atypical RNA-translation program that has a vital role in tumour formation.
The translation of upstream open reading frames in skin tumour models protects some cancer-related mRNAs from global reductions in protein synthesis during the early stages of tumour initiation, suggesting that unconventional translation has a crucial role in tumorigenesis.
Peatlands are carbon-rich ecosystems that cover just three per cent of Earth’s land surface, but store one-third of soil carbon. Peat soils are formed by the build-up of partially decomposed organic matter under waterlogged anoxic conditions. Most peat is found in cool climatic regions where unimpeded decomposition is slower, but deposits are also found under some tropical swamp forests. Here we present field measurements from one of the world’s most extensive regions of swamp forest, the Cuvette Centrale depression in the central Congo Basin. We find extensive peat deposits beneath the swamp forest vegetation (peat defined as material with an organic matter content of at least 65 per cent to a depth of at least 0.3 metres). Radiocarbon dates indicate that peat began accumulating from about 10,600 years ago, coincident with the onset of more humid conditions in central Africa at the beginning of the Holocene. The peatlands occupy large interfluvial basins, and seem to be largely rain-fed and ombrotrophic-like (of low nutrient status) systems. Although the peat layer is relatively shallow (with a maximum depth of 5.9 metres and a median depth of 2.0 metres), by combining in situ and remotely sensed data, we estimate the area of peat to be approximately 145,500 square kilometres (95 per cent confidence interval of 131,900–156,400 square kilometres), making the Cuvette Centrale the most extensive peatland complex in the tropics. This area is more than five times the maximum possible area reported for the Congo Basin in a recent synthesis ofpantropical peat extent. We estimate that the peatlands store approximately 30.6 petagrams (30.6 × 1015 grams) of carbon belowground (95 per cent confidence interval of 6.3–46.8 petagrams of carbon)—a quantity that is similar to the above-ground carbon stocks of the tropical forests of the entire Congo Basin. Our result for the Cuvette Centrale increases the best estimate of global tropical peatland carbon stocks by 36 per cent, to 104.7 petagrams of carbon (minimum estimate of 69.6 petagrams of carbon; maximum estimate of 129.8 petagrams of carbon). This stored carbon is vulnerable to land-use change and any future reduction in precipitation.
The critical role in surface reactions and heterogeneous catalysis of metal atoms with low coordination numbers, such as found at atomic steps and surface defects, is firmly established. But despite the growing availability of tools that enable detailed in situ characterization, so far it has not been possible to document this role directly. Surface properties can be mapped with high spatial resolution, and catalytic conversion can be tracked with a clear chemical signature; however, the combination of the two, which would enable high-spatial-resolution detection of reactions on catalytic surfaces, has rarely been achieved. Single-molecule fluorescence spectroscopy has been used to image and characterize single turnover sites at catalytic surfaces, but is restricted to reactions that generate highly fluorescing product molecules. Herein the chemical conversion of N-heterocyclic carbene molecules attached to catalytic particles is mapped using synchrotron-radiation-based infrared nanospectroscopy with a spatial resolution of 25 nanometres, which enabled particle regions that differ in reactivity to be distinguished. These observations demonstrate that, compared to the flat regions on top of the particles, the peripheries of the particles—which contain metal atoms with low coordination numbers—are more active in catalysing oxidation and reduction of chemically active groups in surface-anchored N-heterocyclic carbene molecules.
Quality control mechanisms intervene appropriately when defective translation events occur, in order to preserve the integrity of protein synthesis. Rescue of ribosomes translating on messenger RNAs that lack stop codons is one of the co-translational quality control pathways. In many bacteria, ArfA recognizes stalled ribosomes and recruits the release factor RF2, which catalyses the termination of protein synthesis. Although an induced-fit mechanism of nonstop mRNA surveillance mediated by ArfA and RF2 has been reported, the molecular interaction between ArfA and RF2 in the ribosome that is responsible for the mechanism is unknown. Here we report an electron cryo-microscopy structure of ArfA and RF2 in complex with the 70S ribosome bound to a nonstop mRNA. The structure, which is consistent with our kinetic and biochemical data, reveals the molecular interactions that enable ArfA to specifically recruit RF2, not RF1, into the ribosome and to enable RF2 to release the truncated protein product in this co-translational quality control pathway. The positively charged C-terminal domain of ArfA anchors in the mRNA entry channel of the ribosome. Furthermore, binding of ArfA and RF2 induces conformational changes in the ribosomal decoding centre that are similar to those seen in other protein-involved decoding processes. Specific interactions between residues in the N-terminal domain of ArfA and RF2 help RF2 to adopt a catalytically competent conformation for peptide release. Our findings provide a framework for understanding recognition of the translational state of the ribosome by new proteins, and expand our knowledge of the decoding potential of the ribosome.
Cell fate perturbations underlie many human diseases, including breast cancer. Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5, 6), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-α (ERα) signalling. In the presence of LATS, ERα was targeted for ubiquitination and Ddb1–cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERα and the Hippo effectors YAP and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.
Males of many polygynous species compete for access to fertile females without providing them with resources other than sperm and without investing in care for the offspring (male dominance polygyny). In such systems, local competition for access to females is intense and typically only a few males obtain matings, leading to strong sexual selection. Sampling multiple breeding areas could then provide a mechanism for males to increase their chances to reproduce. However, little is known about such sampling behaviour and about the spatial scale at which males compete. Here we show that most males of a migratory, polygynous shorebird, the pectoral sandpiper (Calidris melanotos), that arrived at a known breeding location in northern Alaska subsequently moved through a considerable part of the entire species’ breeding range (up to 13,045 km in a four-week period), sampling as many as 23 additional potential breeding sites. Our data suggest that males do not have a final breeding destination after migration from their wintering quarters, but make nomadic movements that are probably not a consequence of breeding failure. Tenure, the duration of stay at a site, correlated strongly with the number of breeding females at the site, suggesting that decisions to leave are dependent on local mating opportunities. Nomadic movements may allow males to display and sire offspring at multiple sites withina single breeding season. Sexual selection may then favour high-performance males that are able to reduce sleep to compete locally and to fly long distances between breeding sites, leading to a population with unrestricted interbreeding and without local adaptation and speciation.
The lymphangiogenic factor PROX1 transcriptionally upregulates CPT1A, a rate-controlling enzyme in fatty acidβ-oxidation, and this co-regulates lymphatic endothelial cell differentiation by epigenetic control of lymphatic gene expression, demonstrating a role for metabolism in developmental biology.
Some CLC proteins are channels that conduct chloride ions passively, whereas others are active co-transporters, a difference that has been hard to understand given their high degree of sequence homology; now, cryo-electron microscopy is used to determine the structure of a mammalian CLC channel, shedding light on this question.
Engineered spin–orbit coupling (SOC) in cold-atom systems can enable the study of new synthetic materials and complex condensed matter phenomena. However, spontaneous emission in alkali-atom spin–orbit-coupled systems is hindered by heating, limiting the observation of many-body effects and motivating research into potential alternatives. Here we demonstrate that spin–orbit-coupled fermions can be engineered to occur naturally in a one-dimensional optical lattice clock. In contrast to previous SOC experiments, here the SOC is both generated and probed using a direct ultra-narrow optical clock transition between two electronic orbital states in 87Sr atoms. We use clock spectroscopy to prepare lattice band populations, internal electronic states and quasi-momenta, and to produce spin–orbit-coupled dynamics. The exceptionally long lifetime of the excited clock state (160 seconds) eliminates decoherence and atom loss from spontaneous emission at all relevant experimental timescales, allowing subsequent momentum- and spin-resolved in situ probing of the SOC band structure and eigenstates. We use these capabilities to study Bloch oscillations, spin–momentum locking and Van Hove singularitiesin the transition density of states. Our results lay the groundwork for using fermionic optical lattice clocks to probe new phases of matter.
Neutrinos are much lighter than the other constituents of matter. One explanation for this could be that neutrinos are their own antiparticles and belong to a new class of 'Majorana' particle. An experiment sets strong constraints on this scenario.
The human dispersal out of Africa that populated the world was probably paced by climate changes. This is the inference drawn from computer modelling of climate variability during the time of early human migration.
Underactivity of the transcription factor p53 can lead to tumour development. The discovery that the SET protein binds to and inhibits p53 points to a way to unleash the tumour suppressor's activity.
Deadly coral snakes warn predators through striking red-black banding. New data confirm that many harmless snakes have evolved to resemble coral snakes, and suggest that the evolution of this Batesian mimicry is not always a one-way street.