|Nature - Issue - nature.com science feeds|
Crippling the US National Institutes of Health might increase resistance to other attacks on science.
Trump’s pick for the US regulatory agency will bring experience and a clear vision — as well as ties to industry.
New Zealand parrots provide the latest support for a popular theory of crowd behaviour.
Carlos Moedas sees a bold future for the European Research Council and more projects that copy its approach.
A material made of overlapping layers of graphene (atom-thick sheets of carbon) changes colour according to the level of stress applied. This could be used in structures to provide early warning of damage.A team led by Shanglin Gao of the Leibniz Institute of Polymer
Viruses more often evolve by jumping from one host species to another than by remaining within a particular species.Edward Holmes and his colleagues at the University of Sydney in Australia compared the evolutionary histories of 19 virus families with those of their animal or
The build-up of fat cells in the bone marrow could explain why bones grow weaker and heal more slowly with age.Tim Schulz at the German Institute of Human Nutrition in Potsdam-Rehbrücke and his colleagues identified a population of stem-cell-like cells in the bones of
A white dwarf star that circles a black hole every 28 minutes may have the closest orbit of its kind ever seen in our Galaxy.The system, called 47 Tuc X9, is some 4.5 kiloparsecs away. It was already thought to contain two objects orbiting
A cheap, rechargeable sodium-based battery could one day deliver high power at room temperature thanks to its hybrid solid electrolyte.Electrolytes allow electrical charge to flow between a battery's electrodes. Liquid electrolytes can leak and tend to react with sodium metal, an abundant, low-cost material
Mammals might respond to global warming by shrinking in size.During a large warming event called the Palaeocene–Eocene Thermal Maximum (PETM), some 56 million years ago, mammals became smaller. To see how common this climate-driven dwarfing might have been, Abigail D'Ambrosia of the University of
Kingsnakes have superior crushing power, allowing them to squeeze bigger snakes to death, even when these snakes are also constrictors.David Penning at Missouri Southern State University in Joplin and Brad Moon at the University of Louisiana at Lafayette studied 182 snakes from six species,
Fossils of organisms resembling red algae suggest that multicellular life may have emerged on Earth some 400 million years earlier than previously thought.Fossils of the earliest algae— which are closely related to the ancestors of modern plants — are rare and, until now,
Certain combinations of drugs might kill drug-resistant tumours, and a method based on the CRISPR–Cas9 gene-editing system offers a way to find them.Tumours often become resistant to individual drugs, leading clinicians to use combinations of medicines in the hope of thwarting resistance. Michael Bassik
The week in science: 17–23 March 2017.
The Environmental Protection Agency and the National Institutes of Health are big losers— but planetary science at NASA stands to gain.
Immersive experience set to become accessible to all.
President’s impeachment creates opportunity to shift how nation supports basic research.
The indigenous people— known for their click languages — are the first in Africa to draft guidelines for researchers.
Yves Meyer wins the Abel Prize for role in theory with data applications from digital cinema to pinpointing gravitational waves.
Astronomers hope to grab the first images of an event horizon— the point of no return.
An investigation finds that dozens of academic titles offered 'Dr Fraud'— a sham, unqualified scientist — a place on their editorial board. Katarzyna Pisanski and colleagues report.
A global network of cap-and-trade systems would deliver greater complexity and fewer emissions cuts, warns Jessica F. Green.
Anna M. Michalak on the taming and invasion of Earth's largest fresh-water system.
Barbara Kiser reviews five of the week's best science picks.
Nurin Veis tours a show on theories of creativity, curated by a quartet of scientists.
It is unsurprising that universities have adopted corporate culture (Nature540, 315;10.1038/540315a2016), but surprising that they select such archaic models.Universities corporatize because they must raise funds through teaching, research and commercialization. They need to publish research results openly,
The variable nature of wave power is the main reason why it is expensive and difficult to collect (see Z. L.WangNature542, 159–160;10.1038/542159a2017). Wave-power devices have much more demanding structural requirements than do offshore wind farms,
In my view, you misrepresent aspects of the problems confronting scientists in Turkey (Nature542, 286–288;10.1038/542286a2017). As a Turkish scientist working abroad, I contend that Turkey's government is using its former political ally, the Gülen movement, as
China will conduct its second decadal pollution census in December 2017. This will provide a baseline for measuring the impact of environmental taxes that come into force next year, and for assessing discharge permits that will be issued for all pollution sources by 2020. The
Shirts were a source of inspiration for starch-gel electrophoresis (E.AltschulerNature543, 179;10.1038/543179e2017). They also figured in another pioneering separation technique— polyamide thin-layer chromatography.At the National Taiwan University in 1958, Kung-Tsung Wang and Yao-Tang Lin heard
Inventor of the Science Citation Index.
Conflicts of interest can send a researcher's reputation crashing— but resolving them needn't be as burdensome as it seems.
Saving pygmy blue whales in Sri Lanka's shipping lanes.
“Forty-five minutes exactly, no more.”I'd been trying to gain access to a Mr Singularity ever since the original self-iterated Mr Singularity 2.0, to no avail. The artificial-intelligence cabal knew I would use it to prove that their goal of creating artificial consciousness was inherently
The graphic in the News story‘China seeks cosmic-ray win’ (Nature 543, 300–301; 2017) erroneously gave the surface area of the surface-water Cherenkov detector as 80 m2. In fact, the area is 80,000 m2. The News story ‘Ancient volcanoes
The standard dinosaur evolutionary tree has two key branches: the 'bird-hipped' Ornithischia and the 'reptile-hipped' Saurischia. A revised tree challenges many ideas about the relationships between dinosaur groups. See Article p.501
Genome sequencing of Mycobacterium abscessus strains that infect the lungs suggests a possible shift in the bacterium's mode of infection from environmental acquisition to human transmission. This finding has clinical implications.
The vibrational excitations of nanostructures have been mapped using state-of-the-art electron microscopy. The results improve our understanding of these excitations, which will aid the design of nanostructures. See Letter p.529
A study showing the effects of land-use quality on the productivity of bumblebee colonies highlights the importance of resource availability across space and time in promoting survival over generations. See Letter p.547
Antiretroviral therapy can keep HIV at bay, but a few cells remain infected, so the disease cannot be cured. The discovery of a protein that marks out these infected cells will facilitate crucial studies of this latent viral reservoir. See Letter p.564
For 130 years, dinosaurs have been divided into two distinct clades—Ornithischia and Saurischia. Here we present a hypothesis for the phylogenetic relationships of the major dinosaurian groups that challenges the current consensus concerning early dinosaur evolution and highlights problematic aspects of current cladistic definitions. Our
Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the
Plants live in biogeochemically diverse soils with diverse microbiota. Plant organs associate intimately with a subset of these microbes, and the structure of the microbial community can be altered by soil nutrient content. Plant-associated microbes can compete with the plant and with each other for
The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other
Measurement of spin precession is central to extreme sensing in physics, geophysics, chemistry, nanotechnology and neuroscience, and underlies magnetic resonance spectroscopy. Because there is no spin-angle operator, any measurement of spin precession is necessarily indirect, for example, it may be inferred from spin projectors at different times. Such projectors do not commute, and so quantum measurement back-action—the random change in a quantum state due to measurement—necessarily enters the spin measurement record, introducing errors and limiting sensitivity. Here we show that this disturbance in the spin projector can be reduced below N1/2—the classical limit for N spins—by directing the quantum measurement back-action almost entirely into an unmeasured spin component. This generates a planar squeezed state that, because spins obey non-Heisenberg uncertainty relations, enables simultaneous precise knowledge of spin angle and spin amplitude. We use high-dynamic-range optical quantum non-demolition measurements applied to a precessing magnetic spin ensemble to demonstrate spin tracking with steady-state angular sensitivity 2.9 decibels below the standard quantum limit, simultaneously with amplitude sensitivity 7.0 decibels below the Poissonian variance. The standard quantum limit and Poissonian variance indicate the best possible sensitivity with independent particles. Our method surpasses these limits in non-commuting observables, enabling orders-of-magnitude improvements in sensitivity for state-of-the-art sensing and spectroscopy.
Imaging of vibrational excitations in and near nanostructures is essential for developing low-loss infrared nanophotonics, controlling heat transport in thermal nanodevices, inventing new thermoelectric materials and understanding nanoscale energy transport. Spatially resolved electron energy loss spectroscopy has previously been used to image plasmonic behaviour in nanostructures in an electron microscope, but hitherto it has not been possible to map vibrational modes directly in a single nanostructure, limiting our understanding of phonon coupling with photons and plasmons. Here we present spatial mapping of optical and acoustic, bulk and surface vibrational modes in magnesium oxide nanocubes using an atom-wide electron beam. We find that the energy and the symmetry of the surface polariton phonon modes depend on the size of the nanocubes, and that they are localized to the surfaces of the nanocube. We also observe a limiting of bulk phonon scattering in the presence of surface phonon modes. Most phonon spectroscopies are selectively sensitive to either surface or bulk excitations; therefore, by demonstrating the excitation of both bulk and surface vibrational modes using a single probe, our work represents advances in the detection and visualization of spatially confined surface and bulk phonons in nanostructures.
A wide variety of high-performance applications require materials for which shape control is maintained under substantial stress, and that have minimal density. Bio-inspired hexagonal and square honeycomb structures and lattice materials based on repeating unit cells composed of webs or trusses, when made from materials of high elastic stiffness and low density, represent some of the lightest, stiffest and strongest materials available today. Recent advances in 3D printing and automated assembly have enabled such complicated material geometries to be fabricated at low (and declining) cost. These mechanical metamaterials have properties that are a function of their mesoscale geometry as well as their constituents, leading to combinations of properties that are unobtainable in solid materials; however, a material geometry that achieves the theoretical upper bounds for isotropic elasticity and strain energy storage (the Hashin–Shtrikman upper bounds) has yet to be identified. Here we evaluate the manner in which strain energy distributes under load in a representative selection of material geometries, to identify the morphological features associated with high elastic performance. Using finite-element models, supported by analytical methods, and a heuristic optimization scheme, we identify a material geometry that achieves the Hashin–Shtrikman upper bounds on isotropic elastic stiffness. Previous work has focused on truss networks and anisotropic honeycombs, neither of which can achieve this theoretical limit.We find that stiff but well distributed networks of plates are required to transfer loads efficiently between neighbouring members. The resulting low-density mechanical metamaterials have many advantageous properties: their mesoscale geometry can facilitate large crushing strains with high energy absorption, optical bandgaps and mechanically tunable acoustic bandgaps, high thermal insulation, buoyancy, and fluid storage and transport. Our relatively simple design can be manufactured using origami-like sheet folding and bonding methods.
In chemical syntheses, the activation of carbon–hydrogen (C–H) bonds converts them directly into carbon–carbon or carbon–heteroatom bonds without requiring any prior functionalization. C–H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C–H bond in a substrate can be activated by using a ‘directing’ (usually a functional) group to obtain the desired product selectively. The applicability of such a C–H activation reaction can be severely curtailed by the distance of the C–H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C–H bonds of a substrate has been exploited to achieve meta-selective C–H activation by using a covalently attached, U-shaped template. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C–H bonds. Using this strategy, we demonstrate remote, site-selective C–H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.
The chemical composition of Earth’s lower mantle can be constrained by combining seismological observations with mineral physics elasticity measurements. However, the lack of laboratory data for Earth’s most abundant mineral, (Mg,Fe,Al)(Al,Fe,Si)O3 bridgmanite (also known as silicate perovskite), has hampered any conclusive result. Here we report single-crystal elasticity data on (Al,Fe)-bearing bridgmanite (Mg0.9Fe0.1Si0.9Al0.1)O3 measured using high-pressure Brillouin spectroscopy and X-ray diffraction. Our measurements show that the elastic behaviour of (Al,Fe)-bearing bridgmanite is markedly different from the behaviour of the MgSiO3 endmember. We use our data to model seismic wave velocities in the top portion of the lower mantle, assuming a pyrolitic mantle composition and accounting for depth-dependent changes in iron partitioning between bridgmanite and ferropericlase. We find excellent agreement between our mineral physics predictions and the seismic Preliminary Reference Earth Model down to at least 1,200 kilometres depth, indicating chemical homogeneity of the upper and shallow lower mantle. A high Fe3+/Fe2+ ratio of about two in shallow-lower-mantle bridgmanite is required to match seismic data, implying the presence of metallic iron in an isochemical mantle. Our calculated velocities are in increasingly poor agreement with those of the lower mantle at depths greater than 1,200 kilometres, indicating either a change in bridgmanite cation ordering or a decrease in the ferric iron content of the lower mantle.
Insect pollinators such as bumblebees (Bombus spp.) are in global decline. A major cause of this decline is habitat loss due to agricultural intensification. A range of global and national initiatives aimed at restoring pollinator habitats and populations have been developed. However, the success of these initiatives depends critically upon understanding how landscape change affects key population-level parameters, such as survival between lifecycle stages, in target species. This knowledge is lacking for bumblebees, because of the difficulty of systematically finding and monitoring colonies in the wild. We used a combination of habitat manipulation, land-use and habitat surveys, molecular genetics and demographic and spatial modelling to analyse between-year survival of family lineages in field populations of three bumblebee species. Here we show that the survival of family lineages from the summer worker to the spring queen stage in the following year increases significantly with the proportion of high-value foraging habitat, including spring floral resources, within 250–1,000 m of the natal colony. This provides evidence for a positive impact of habitat quality on survival and persistence between successive colony cycle stages in bumblebee populations. These findings also support the idea that conservation interventions that increase floral resources at a landscape scale and throughout the season have positive effects on wild pollinators in agricultural landscapes.
The human genome encodes some 350 Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), the products of a rapidly evolving gene family that has been traced back to early tetrapods. The function of most KZFPs is unknown, but a few have been demonstrated to repress transposable elements in embryonic stem (ES) cells by recruiting the transcriptional regulator TRIM28 and associated mediators of histone H3 Lys9 trimethylation (H3K9me3)-dependent heterochromatin formation and DNA methylation. Depletion of TRIM28 in human or mouse ES cells triggers the upregulation of a broad range of transposable elements, and recent data based on a few specific examples have pointed to an arms race between hosts and transposable elements as an important driver of KZFP gene selection. Here, to obtain a global view of this phenomenon, we combined phylogenetic and genomic studies to investigate the evolutionary emergence of KZFP genes in vertebrates and to identify their targets in the human genome. First, we unexpectedly reassigned the root of the family to a common ancestor of coelacanths and tetrapods. Second, although we confirmed that the majority of KZFPs bind transposable elements and pinpoint cases of ongoing co-evolution, we found that most of their transposable element targets have lost all transposition potential. Third, by examining the interplay between human KZFPs and other transcriptional modulators, we obtained evidence that KZFPs exploit evolutionarily conserved fragments of transposable elements as regulatory platforms long after the arms race against these genetic invaders has ended. Together, our results demonstrate that KZFPs partner with transposable elements to build a largely species-restricted layer of epigenetic regulation.
Marine phytoplankton inhabit a dynamic environment where turbulence, together with nutrient and light availability, shapes species fitness, succession and selection. Many species of phytoplankton are motile and undertake diel vertical migrations to gain access to nutrient-rich deeper layers at night and well-lit surface waters during the day. Disruption of this migratory strategy by turbulence is considered to be an important cause of the succession between motile and non-motile species when conditions turn turbulent. However, this classical view neglects the possibility that motile species may actively respond to turbulent cues to avoid layers of strong turbulence. Here we report that phytoplankton, including raphidophytes and dinoflagellates, can actively diversify their migratory strategy in response to hydrodynamic cues characteristic of overturning by Kolmogorov-scale eddies. Upon experiencing repeated overturning with timescales and statistics representative of ocean turbulence, an upward-swimming population rapidly (5–60 min) splits into two subpopulations, one swimming upward and one swimming downward. Quantitative morphological analysis of the harmful-algal-bloom-forming raphidophyte Heterosigma akashiwo together with a model of cell mechanics revealed that this behaviour was accompanied by a modulation of the cells’ fore–aft asymmetry. The minute magnitude of the required modulation, sufficient to invert the preferential swimming direction of the cells, highlights the advanced level of control that phytoplankton can exert on their migratory behaviour. Together with observations of enhanced cellular stress after overturning and the typically deleterious effects of strong turbulence on motile phytoplankton, these results point to an active adaptation of H. akashiwo to increase the chance of evading turbulent layers by diversifying the direction of migration within the population, in a manner suggestive of evolutionary bet-hedging. This migratory behaviour relaxes the boundaries between the fluid dynamic niches of motile and non-motile phytoplankton, and highlights that rapid responses to hydrodynamic cues are important survival strategies for phytoplankton in the ocean.
Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemiapersisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.
The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.
The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice. Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3′ untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4–NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required forthe survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFβ superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line.
Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m6A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+ transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) and the demethylase FTO (fat mass and obesity-associated protein). In theabsence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m6A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase. DNA polymerase κ (Pol κ), which has been implicated in both nucleotide excision repair and trans-lesion synthesis, required the catalytic activity of METTL3 for immediate localization to ultraviolet-induced DNA damage sites. Importantly, Pol κ overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we haveuncovered a novel function for RNA m6A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m6A RNA serves as a beacon for the selective, rapid recruitment of Pol κ to damage sites to facilitate repair and cell survival.
|Nature - AOP - nature.com science feeds|
Crystal structures and DFT calculations suggest a possible mechanism for diiron enzyme arene hydroxylation.
The biosynthesis of oxetanocin A involves OxsB, a B12-dependent S-adenosylmethionine radical enzyme, which catalyses an unusual ring contraction of a 2′-deoxyadenosine phosphate.
Recent observations have revealed massive galactic molecular outflows that may have the physical conditions (high gas densities) required to form stars. Indeed, several recent models predict that such massive outflows may ignite star formation within the outflow itself. This star-formation mode, in which stars form with high radial velocities, could contribute to the morphological evolution of galaxies, to the evolution in size and velocity dispersion of the spheroidal component of galaxies, and would contribute to the population of high-velocity stars, which could even escape the galaxy. Such star formation could provide in situ chemical enrichment of the circumgalactic and intergalactic medium (through supernova explosions of young stars on large orbits), and some models also predict it to contribute substantially to the star-formation rate observed in distant galaxies. Although there exists observational evidence for star formation triggered by outflows or jets into their host galaxy, as a consequence of gas compression, evidence for star formation occurring within galactic outflows is still missing. Here we report spectroscopic observations that unambiguously reveal star formation occurring in a galactic outflow at a redshift of 0.0448. The inferred star-formation rate in the outflow is larger than 15 solar masses per year. Star formation may also be occurring in other galactic outflows, but may have been missed by previous observations owing to the lack of adequate diagnostics.
A polysaccharide called rhamnogalacturonan II is a major component of some fruits, but humans rely on their gut microbiota to digest it. The microbes and processes responsible for this digestion have now been revealed.
Structural insights into adiponectin receptors provide evidence that these proteins have an inherent enzymatic activity, which gives them the ability to propagate signalling by their ligand, the hormone adiponectin.
The sign of a material's charge carriers is usually reflected in the sign of the 'Hall voltage'. But for a structure inspired by chain mail, altering its geometry inverts the Hall voltage, even if the charge carriers are unchanged.
Marine protected areas are being implemented at an accelerating pace, and hold promise for restoring damaged ecosystems. But glaring shortfalls in staffing and funding often lead to suboptimal outcomes.
Although 71% of marine protected areas are benefiting fish populations, their effects are highly variable, with staff capacity proving to be the most important explanatory variable.
Use of a head-mounted miniature microscope in awake, behaving mice reveals that neural ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli in a way that matches models of supervised learning.
LACTB modulates mitochondrial lipid metabolism and changes the differentiation state of breast cancer cells, thereby negatively affecting the growth of various tumorigenic, but not non-tumorigenic, cells both in vitro and in vivo.
The hierarchical deconstruction of the complex pectic glycan rhamnogalacturonan-II by the human gut bacterium Bacteroides thetaiotaomicron reveals seven new families of glycoside hydrolases and three catalytic functions not previously observed.
Energy–structure–function maps that describe the possible structures and properties of molecular crystals are developed, and these maps are used to guide the experimental discovery of porous materials with specific functions.
Somatic cells acquire mutations throughout the course of an individual’s life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adulttissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4+ T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.
Platelets are critical for haemostasis, thrombosis, and inflammatory responses, but the events that lead to mature platelet production remain incompletely understood. The bone marrow has been proposed to be a major site of platelet production, although there is indirect evidence that the lungs might also contribute to platelet biogenesis. Here, by directly imaging the lung microcirculation in mice, we show that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Megakaryocytes that release platelets in the lungs originate from extrapulmonary sites such as the bone marrow; we observed large megakaryocytes migrating out of the bone marrow space. The contribution of the lungs to platelet biogenesis is substantial, accounting for approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature megakaryocytes along with haematopoietic progenitors in the extravascular spaces of the lungs. Under conditions of thrombocytopenia and relative stem cell deficiency in the bone marrow, these progenitors can migrate out of the lungs, repopulate the bone marrow, completely reconstitute blood platelet counts, and contribute to multiple haematopoietic lineages. These results identify the lungs as a primary site of terminal platelet production and an organ with considerable haematopoietic potential.
Polymer electrolyte membrane fuel cells (PEMFCs) running on hydrogen are attractive alternative power supplies for a range of applications, with in situ release of the required hydrogen from a stable liquid offering one way of ensuring its safe storage and transportation before use. The use of methanol is particularly interesting in this regard, because it is inexpensive and can reform itself with water to release hydrogen with a high gravimetric density of 18.8 per cent by weight. But traditional reforming of methanol steam operates at relatively high temperatures (200–350 degrees Celsius), so the focus for vehicle and portable PEMFC applications has been on aqueous-phase reforming of methanol (APRM). This method requires less energy, and the simpler and more compact device design allows direct integration into PEMFC stacks. There remains, however, the need for an efficient APRM catalyst. Here we report that platinum (Pt) atomically dispersed on α-molybdenum carbide (α-MoC) enables low-temperature (150–190 degrees Celsius), base-free hydrogen production through APRM, with an average turnover frequency reaching 18,046 moles of hydrogen per mole of platinum per hour. We attribute this exceptional hydrogen production—which far exceeds that of previously reported low-temperature APRM catalysts—to the outstanding ability of α-MoC to induce water dissociation, and to the fact that platinum and α-MoC act in synergy to activate methanol and then to reform it.
Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain. However, the molecular mechanisms by which ADIPORs function are not known. Here we describe the crystal structure of ADIPOR2 bound to a FFA molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. We also identify a ceramide binding pose and propose a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, we present a revised ADIPOR1 crystal structure exhibiting a seven-transmembrane-domain architecture that is clearly distinct from that of ADIPOR2. In this structure, no FFA is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so we suspect that the two distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and further studies will be required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs. These insights into ADIPOR function will enable the structure-based design of potent modulators of these clinically relevant enzymes.
Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR–ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.
Colloidal quantum dots (CQDs) feature a low degeneracy of electronic states at the band edges compared with the corresponding bulk material, as well as a narrow emission linewidth. Unfortunately for potential laser applications, this degeneracy is incompletely lifted in the valence band, spreading the hole population among several states at room temperature. This leads to increased optical gain thresholds, demanding high photoexcitation levels to achieve population inversion (more electrons in excited states than in ground states—the condition for optical gain). This, in turn, increases Auger recombination losses, limiting the gain lifetime to sub-nanoseconds and preventing steady laser action. State degeneracy also broadens the photoluminescence linewidth at the single-particle level. Here we demonstrate a way to decrease the band-edge degeneracy and single-dot photoluminescence linewidth in CQDs by means of uniform biaxial strain. We have developed a synthetic strategy that we term facet-selective epitaxy: we first switch off, and then switch on, shell growth on the (0001) facet of wurtzite CdSe cores, producing asymmetric compressive shells that create built-in biaxial strain, while still maintaining excellent surface passivation (preventing defect formation, which otherwise would cause non-radiative recombination losses). Our synthesis spreads the excitonic fine structure uniformly and sufficiently broadly that it prevents valence-band-edge states from being thermally depopulated. We thereby reduce the optical gain threshold and demonstrate continuous-wave lasing from CQD solids, expanding the library of solution-processed materials that may be capable of continuous-wave lasing. The individual CQDs exhibit an ultra-narrow single-dot linewidth, and we successfully propagate this into the ensemble of CQDs.
The enteric nervous system of jawed vertebrates arises primarily from vagal neural crest cells that migrate to the foregut and subsequently colonize and innervate the entire gastrointestinal tract. Here we examine development of the enteric nervous system in the basal jawless vertebrate the sea lamprey (Petromyzon marinus) to gain insight into its evolutionary origin. Surprisingly, we find no evidence for the existence of a vagally derived enteric neural crest population in the lamprey. Rather, labelling with the lipophilic dye DiI shows that late-migrating cells, originating from the trunk neural tube and associated with nerve fibres, differentiate into neurons within the gut wall and typhlosole. We propose that these trunk-derived neural crest cells may be homologous to Schwann cell precursors, recently shown in mammalian embryos to populate post-embryonic parasympathetic ganglia, including enteric ganglia. Our results suggest that neural-crest-derived Schwann cell precursors made an important contribution to the ancient enteric nervous system of early jawless vertebrates, a role that was largely subsumed by vagal neural crest cells in early gnathostomes.
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b+Gr1+) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.
The human brain contains approximately 60 billion cerebellar granule cells, which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes. Although evidence suggests a role for the cerebellum in cognition, granule cells are known to encode only sensory and motor context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.
A zeolite with structure type MFI is an aluminosilicate or silicate material that has a three-dimensionally connected pore network, which enables molecular recognition in the size range 0.5–0.6 nm. These micropore dimensions are relevant for many valuable chemical intermediates, and therefore MFI-type zeolites are widely used in the chemical industry as selective catalysts or adsorbents. As with all zeolites, strategies to tailor them for specific applications include controllingtheir crystal size and shape. Nanometre-thick MFI crystals (nanosheets) have been introduced in pillared and self-pillared (intergrown) architectures, offering improved mass-transfer characteristics for certain adsorption and catalysis applications. Moreover, single (non-intergrown and non-layered)nanosheets have been used to prepare thin membranes that could be used to improve the energy efficiency of separation processes. However, until now, single MFI nanosheets have been prepared using a multi-step approach based on the exfoliation of layered MFI, followed by centrifugation to remove non-exfoliated particles. This top-down method is time-consuming, costly and low-yield and it produces fragmented nanosheets with submicrometre lateral dimensions. Alternatively, direct (bottom-up) synthesis could produce high-aspect-ratio zeolite nanosheets, with improved yield and at lower cost. Herewe use a nanocrystal-seeded growth method triggered by a single rotational intergrowth to synthesize high-aspect-ratio MFI nanosheets with a thickness of 5 nanometres (2.5 unit cells). These high-aspect-ratio nanosheets allow the fabrication of thin and defect-free coatings that effectively coverporous substrates. These coatings can be intergrown to produce high-flux and ultra-selective MFI membranes that compare favourably with other MFI membranes prepared from existing MFI materials (such as exfoliated nanosheets or nanocrystals).
Establishing the relationship between rates of change in species richness and biotic and abiotic environmental change is a major goal of evolutionary biology. Although exquisite fossil and geological records provide insight in rare cases, most groups lack high-quality fossil records. Consequently, biologists typically rely on molecular phylogenies to study the diversity dynamics of clades, usually by correlating changes in diversification rate with environmental or trait shifts. However, inferences drawn from molecular phylogenies can be limited owing to the challenge of accounting for extinct species, making it difficult to accurately determine the underlying diversity dynamics that produce them. Here, using a geologically informed model of the relationship between changing island area and species richness for the Hawaiian archipelago, we infer the rates of species richness change for 14 endemic groups over their entire evolutionary histories without the need for fossil data, or molecular phylogenies. We find that these endemic clades underwent evolutionary radiations characterized by initially increasing rates of species accumulation, followed by slow-downs. In fact, for most groups on most islands, their time of evolutionary expansion has long past, and they are now undergoing previously unrecognized long-term evolutionary decline. Our results show how landscape dynamism can drive evolutionary dynamics over broad timescales, including driving species loss that is not readily detected using molecular phylogenies, or without a rich fossil record. We anticipate that examination of other clades where the relationship between environmental change and species richness change can be quantified will reveal that many other living groups have also experienced similarly complex evolutionary trajectories, including long-term and ongoing evolutionary decline.
A chromosome conformation capture method in which single cells are first imaged and then processed enables intact genome folding to be studied at a scale of 100 kb, validated, and analysed to generate hypotheses about 3D genomic interactions and organisation.
ATP binding cassette (ABC) transporters of the exporter class harness the energy of ATP hydrolysis in the nucleotide-binding domains (NBDs) to power the energetically uphill efflux of substrates by a dedicated transmembrane domain (TMD). Although numerous investigations have described the mechanism of ATP hydrolysis and defined the architecture of ABC exporters, a detailed structural dynamic understanding of the transduction of ATP energy to the work of substrate translocation remains elusive. Here we used double electron–electron resonance and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein (Pgp; also known as ABCB1), which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy. Pairs of spin labels were introduced at residues selected to track the putative inward-facing to outward-facing transition. Our findings illuminate how ATP energy is harnessed in the NBDs in a two-stroke cycle and elucidate the consequent conformational motion that reconfigures the TMD, two criticalaspects of Pgp transport mechanism. Along with a fully atomistic model of the outward-facing conformation in membranes, the insight into Pgp conformational dynamics harmonizes mechanistic and structural data into a novel perspective on ATP-coupled transport and reveals mechanistic divergence withinthe efflux class of ABC transporters.
Analysis of Aboriginal Australian mitochondrial genomes shows geographic patterns and deep splits across the major haplogroups that indicate a single, rapid migration along the coasts around 49–45 ka, followed by longstanding persistence in discrete geographic areas.
Recent genomic data have revealed multiple interactions between Neanderthals and modern humans, but there is currently little genetic evidence regarding Neanderthal behaviour, diet, or disease. Here we describe the shotgun-sequencing of ancient DNA from five specimens of Neanderthal calcified dental plaque (calculus) and the characterization of regional differences in Neanderthal ecology. At Spy cave, Belgium, Neanderthal diet was heavily meat based and included woolly rhinoceros and wild sheep (mouflon), characteristic of a steppe environment. In contrast, no meat was detected in the diet of Neanderthals from El Sidrón cave, Spain, and dietary components of mushrooms, pine nuts, and moss reflected forest gathering. Differences in diet were also linked to an overall shift in the oral bacterial community (microbiota) and suggested that meat consumption contributed to substantial variation within Neanderthal microbiota. Evidence for self-medication was detected in an El Sidrón Neanderthal with a dental abscess and a chronic gastrointestinal pathogen (Enterocytozoon bieneusi). Metagenomic data from this individual also contained a nearly complete genome of the archaeal commensal Methanobrevibacter oralis (10.2× depth of coverage)—the oldest draft microbial genome generated to date, at around 48,000 years old. DNA preserved within dental calculus represents a notable source of information about the behaviour and health of ancient hominin specimens, as well as a unique system that is useful for the study of long-term microbial evolution.
Cryo-electron microscopy maps of the fission yeast Mediator complex and of a Mediator–RNA polymerase II holoenzyme reveal how changes in the Med14 subunit enable large-scale rearrangements of the Mediator structure that are essential for holoenzyme formation.
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.