An estimated 90 to 95% of Indigenous people in Amazonia died after European contact. This population collapse is postulated to have caused decreases in atmospheric carbon dioxide concentrations at around 1610 CE, as a result of a wave of land abandonment in the wake of disease, slavery, and warfare, whereby the attendant reversion to forest substantially increased terrestrial carbon sequestration. On the basis of 39 Amazonian fossil pollen records, we show that there was no synchronous reforestation event associated with such an atmospheric carbon dioxide response after European arrival in Amazonia. Instead, we find that, at most sites, land abandonment and forest regrowth began about 300 to 600 years before European arrival. Pre-European pandemics, social strife, or environmental change may have contributed to these early site abandonments and ecological shifts.
Islands are among the last regions on Earth settled and transformed by human activities, and they provide replicated model systems for analysis of how people affect ecological functions. By analyzing 27 representative fossil pollen sequences encompassing the past 5000 years from islands globally, we quantified the rates of vegetation compositional change before and after human arrival. After human arrival, rates of turnover accelerate by a median factor of 11, with faster rates on islands colonized in the past 1500 years than for those colonized earlier. This global anthropogenic acceleration in turnover suggests that islands are on trajectories of continuing change. Strategies for biodiversity conservation and ecosystem restoration must acknowledge the long duration of human impacts and the degree to which ecological changes today differ from prehuman dynamics.
Megafauna play important roles in the biosphere, yet little is known about how they shape dryland ecosystems. We report on an overlooked form of ecosystem engineering by donkeys and horses. In the deserts of North America, digging of ≤2-meter wells to groundwater by feral equids increased the density of water features, reduced distances between waters, and, at times, provided the only water present. Vertebrate richness and activity were higher at equid wells than at adjacent dry sites, and, by mimicking flood disturbance, equid wells became nurseries for riparian trees. Our results suggest that equids, even those that are introduced or feral, are able to buffer water availability, which may increase resilience to ongoing human-caused aridification.
Controlling the chiral degree of freedom in matter has long been an important issue for many fields of science. The spin-spiral order, which exhibits a strong magnetoelectric coupling, gives rise to chirality irrespective of the atomic arrangement of matter. Here, we report the resonantly enhanced natural optical activity on the electrically active magnetic excitation, that is, electromagnon, in multiferroic cupric oxide. The electric field control of the natural optical activity is demonstrated through magnetically induced chirality endowed with magnetoelectric coupling. These optical properties inherent to multiferroics may lead to optical devices based on the control of chirality.
Biological ion channels rapidly and selectively gate ion transport through atomic-scale filters to maintain vital life functions. We report an atomic-scale ion transistor exhibiting ultrafast and highly selective ion transport controlled by electrical gating in graphene channels around 3 angstroms in height, made from a single flake of reduced graphene oxide. The ion diffusion coefficient reaches two orders of magnitude higher than the coefficient in bulk water. Atomic-scale ion transport shows a threshold behavior due to the critical energy barrier for hydrated ion insertion. Our in situ optical measurements suggest that ultrafast ion transport likely originates from highly dense packing of ions and their concerted movement inside the graphene channels.
Risks from induced earthquakes are a growing concern that needs effective management. For hydraulic fracturing of the Eagle Ford shale in southern Texas, we developed a risk-informed strategy for choosing red-light thresholds that require immediate well shut-in. We used a combination of datasets to simulate spatially heterogeneous nuisance and damage impacts. Simulated impacts are greater in the northeast of the play and smaller in the southwest. This heterogeneity is driven by concentrations of population density. Spatially varying red-light thresholds normalized on these impacts [moment magnitude (Mw) 2.0 to 5.0] are fairer and safer than a single threshold applied over a broad area. Sensitivity tests indicate that the forecast maximum magnitude is the most influential parameter. Our method provides a guideline for traffic light protocols and managing induced seismicity risks.
Improving materials used to make qubits is crucial to further progress in quantum information processing. Of particular interest are semiconductor-superconductor heterostructures that are expected to form the basis of topological quantum computing. We grew semiconductor indium antimonide nanowires that were coated with shells of tin of uniform thickness. No interdiffusion was observed at the interface between Sn and InSb. Tunnel junctions were prepared by in situ shadowing. Despite the lack of lattice matching between Sn and InSb, a 15-nanometer-thick shell of tin was found to induce a hard superconducting gap, with superconductivity persisting in magnetic field up to 4 teslas. A small island of Sn-InSb exhibits the two-electron charging effect. These findings suggest a less restrictive approach to fabricating superconducting and topological quantum circuits.
DNA modifications vary in form and function but generally do not alter Watson-Crick base pairing. Diaminopurine (Z) is an exception because it completely replaces adenine and forms three hydrogen bonds with thymine in cyanophage S-2L genomic DNA. However, the biosynthesis, prevalence, and importance of Z genomes remain unexplored. Here, we report a multienzyme system that supports Z-genome synthesis. We identified dozens of globally widespread phages harboring such enzymes, and we further verified the Z genome in one of these phages, Acinetobacter phage SH-Ab 15497, by using liquid chromatography with ultraviolet and mass spectrometry. The Z genome endows phages with evolutionary advantages for evading the attack of host restriction enzymes, and the characterization of its biosynthetic pathway enables Z-DNA production on a large scale for a diverse range of applications.
Cells have two purine pathways that synthesize adenine and guanine ribonucleotides from phosphoribose via inosylate. A chemical hybrid between adenine and guanine, 2-aminoadenine (Z), replaces adenine in the DNA of the cyanobacterial virus S-2L. We show that S-2L and Vibrio phage PhiVC8 encode a third purine pathway catalyzed by PurZ, a distant paralog of succinoadenylate synthase (PurA), the enzyme condensing aspartate and inosylate in the adenine pathway. PurZ condenses aspartate with deoxyguanylate into dSMP (N6-succino-2-amino-2'-deoxyadenylate), which undergoes defumarylation and phosphorylation to give dZTP (2-amino-2'-deoxyadenosine-5'-triphosphate), a substrate for the phage DNA polymerase. Crystallography and phylogenetics analyses indicate a close relationship between phage PurZ and archaeal PurA enzymes. Our work elucidates the biocatalytic innovation that remodeled a DNA building block beyond canonical molecular biology.
Bacteriophage genomes harbor the broadest chemical diversity of nucleobases across all life forms. Certain DNA viruses that infect hosts as diverse as cyanobacteria, proteobacteria, and actinobacteria exhibit wholesale substitution of aminoadenine for adenine, thereby forming three hydrogen bonds with thymine and violating Watson-Crick pairing rules. Aminoadenine-encoded DNA polymerases, homologous to the Klenow fragment of bacterial DNA polymerase I that includes 3'-exonuclease but lacks 5'-exonuclease, were found to preferentially select for aminoadenine instead of adenine in deoxynucleoside triphosphate incorporation templated by thymine. Polymerase genes occur in synteny with genes for a biosynthesis enzyme that produces aminoadenine deoxynucleotides in a wide array of Siphoviridae bacteriophages. Congruent phylogenetic clustering of the polymerases and biosynthesis enzymes suggests that aminoadenine has propagated in DNA alongside adenine since archaic stages of evolution.
Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo–electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer—effectively increasing the number of functional spikes and enhancing infectivity—and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.
CRISPR-Cas systems provide RNA-guided adaptive immunity in prokaryotes. We report that the multisubunit CRISPR effector Cascade transcriptionally regulates a toxin-antitoxin RNA pair, CreTA. CreT (Cascade-repressed toxin) is a bacteriostatic RNA that sequesters the rare arginine tRNAUCU (transfer RNA with anticodon UCU). CreA is a CRISPR RNA–resembling antitoxin RNA, which requires Cas6 for maturation. The partial complementarity between CreA and the creT promoter directs Cascade to repress toxin transcription. Thus, CreA becomes antitoxic only in the presence of Cascade. In CreTA-deleted cells, cascade genes become susceptible to disruption by transposable elements. We uncover several CreTA analogs associated with diverse archaeal and bacterial CRISPR-cas loci. Thus, toxin-antitoxin RNA pairs can safeguard CRISPR immunity by making cells addicted to CRISPR-Cas, which highlights the multifunctionality of Cas proteins and the intricate mechanisms of CRISPR-Cas regulation.
Transcription factor IID (TFIID) recognizes core promoters and supports preinitiation complex (PIC) assembly for RNA polymerase II (Pol II)–mediated eukaryotic transcription. We determined the structures of human TFIID–based PIC in three stepwise assembly states and revealed two-track PIC assembly: stepwise promoter deposition to Pol II and extensive modular reorganization on track I (on TATA–TFIID-binding element promoters) versus direct promoter deposition on track II (on TATA-only and TATA-less promoters). The two tracks converge at an ~50-subunit holo PIC in identical conformation, whereby TFIID stabilizes PIC organization and supports loading of cyclin-dependent kinase (CDK)–activating kinase (CAK) onto Pol II and CAK-mediated phosphorylation of the Pol II carboxyl-terminal domain. Unexpectedly, TBP of TFIID similarly bends TATA box and TATA-less promoters in PIC. Our study provides structural visualization of stepwise PIC assembly on highly diversified promoters.
Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis. Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.
Human health is dependent on a plentiful and nutritious supply of food, primarily derived from crop plants. Rhythmic supply of light as a result of the day and night cycle led to the evolution of circadian clocks that modulate most plant physiology, photosynthesis, metabolism, and development. To regulate crop traits and adaptation, breeders have indirectly selected for variation at circadian genes. The pervasive impact of the circadian system on crops suggests that future food production might be improved by modifying circadian rhythms, engineering the timing of transgene expression, and applying agricultural treatments at the most effective time of day. We describe the applied research required to take advantage of circadian biology in agriculture to increase production and reduce inputs.
Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E–restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E–restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II–restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E–restricted T cells is crucial for RhCMV/SIV vaccine efficacy.
Given vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two critical issues arise: How timing of delivery of the second dose will affect infection dynamics and how it will affect prospects for the evolution of viral immune escape via a buildup of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose as compared with natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short term, focusing on one dose generally decreases infections, but that longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection and find that a one-dose policy may increase the potential for antigenic evolution under certain conditions of partial population immunity. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose and to ramp up vaccination efforts globally.
The temporal order of DNA replication [replication timing (RT)] is correlated with chromatin modifications and three-dimensional genome architecture; however, causal links have not been established, largely because of an inability to manipulate the global RT program. We show that loss of RIF1 causes near-complete elimination of the RT program by increasing heterogeneity between individual cells. RT changes are coupled with widespread alterations in chromatin modifications and genome compartmentalization. Conditional depletion of RIF1 causes replication-dependent disruption of histone modifications and alterations in genome architecture. These effects were magnified with successive cycles of altered RT. These results support models in which the timing of chromatin replication and thus assembly plays a key role in maintaining the global epigenetic state.
Given the increasing interest in keeping global warming below 1.5°C, a key question is what this would mean for China’s emission pathway, energy restructuring, and decarbonization. By conducting a multimodel study, we find that the 1.5°C-consistent goal would require China to reduce its carbon emissions and energy consumption by more than 90 and 39%, respectively, compared with the "no policy" case. Negative emission technologies play an important role in achieving near-zero emissions, with captured carbon accounting on average for 20% of the total reductions in 2050. Our multimodel comparisons reveal large differences in necessary emission reductions across sectors, whereas what is consistent is that the power sector is required to achieve full decarbonization by 2050. The cross-model averages indicate that China’s accumulated policy costs may amount to 2.8 to 5.7% of its gross domestic product by 2050, given the 1.5°C warming limit.
Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets
Motor and sensory functions of the spinal cord are mediated by populations of cardinal neurons arising from separate progenitor lineages. However, each cardinal class is composed of multiple neuronal types with distinct molecular, anatomical, and physiological features, and there is not a unifying logic that systematically accounts for this diversity. We reasoned that the expansion of new neuronal types occurred in a stepwise manner analogous to animal speciation, and we explored this by defining transcriptomic relationships using a top-down approach. We uncovered orderly genetic tiers that sequentially divide groups of neurons by their motor-sensory, local-long range, and excitatory-inhibitory features. The genetic signatures defining neuronal projections were tied to neuronal birth date and conserved across cardinal classes. Thus, the intersection of cardinal class with projection markers provides a unifying taxonomic solution for systematically identifying distinct functional subsets.
Controlling the directionality of emitted far-field thermal radiation is a fundamental challenge. Photonic strategies enable angular selectivity of thermal emission over narrow bandwidths, but thermal radiation is a broadband phenomenon. The ability to constrain emitted thermal radiation to fixed narrow angular ranges over broad bandwidths is an important, but lacking, capability. We introduce gradient epsilon-near-zero (ENZ) materials that enable broad-spectrum directional control of thermal emission. We demonstrate two emitters consisting of multiple oxides that exhibit high (>0.7, >0.6) directional emissivity (60° to 75°, 70° to 85°) in the p-polarization for a range of wavelengths (10.0 to 14.3 micrometers, 7.7 to 11.5 micrometers). This broadband directional emission enables meaningful radiative heat transfer primarily in the high emissivity directions. Decoupling the conventional limitations on angular and spectral response improves performance for applications such as thermal camouflaging, solar heating, radiative cooling, and waste heat recovery.
The "magic methyl" effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp3)–H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light–initiated triplet energy transfer promotes homolysis of the O–O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C–H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.
The nonlinear scaling of complexity with the increased number of components in integrated photonics is a major obstacle impeding large-scale, phase-locked laser arrays. Here, we develop a higher-dimensional supersymmetry formalism for precise mode control and nonlinear power scaling. Our supersymmetric microlaser arrays feature phase-locked coherence and synchronization of all of the evanescently coupled microring lasers—collectively oscillating in the fundamental transverse supermode—which enables high-radiance, small-divergence, and single-frequency laser emission with a two-orders-of-magnitude enhancement in energy density. We also demonstrate the feasibility of structuring high-radiance vortex laser beams, which enhance the laser performance by taking full advantage of spatial degrees of freedom of light. Our approach provides a route for designing large-scale integrated photonic systems in both classical and quantum regimes.
Josephson junctions are superconducting devices used as high-sensitivity magnetometers and voltage amplifiers as well as the basis of high-performance cryogenic computers and superconducting quantum computers. Although device performance can be degraded by the generation of quasiparticles formed from broken Cooper pairs, this phenomenon also opens opportunities to sensitively detect electromagnetic radiation. We demonstrate single near-infrared photon detection by coupling photons to the localized surface plasmons of a graphene-based Josephson junction. Using the photon-induced switching statistics of the current-biased device, we reveal the critical role of quasiparticles generated by the absorbed photon in the detection mechanism. The photon sensitivity will enable a high-speed, low-power optical interconnect for future superconducting computing architectures.
Understanding when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We used a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated before the time of the most recent common ancestor of all sequenced SARS-CoV-2 genomes. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province, China. By characterizing the likely dynamics of the virus before it was discovered, we show that more than two-thirds of SARS-CoV-2–like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.
Groundwater wells supply water to billions of people, but they can run dry when water tables decline. Here, we analyzed construction records for ~39 million globally distributed wells. We show that 6 to 20% of wells are no more than 5 meters deeper than the water table, implying that millions of wells are at risk of running dry if groundwater levels decline by only a few meters. Further, newer wells are not being constructed deeper than older wells in some of the places experiencing significant groundwater level declines, suggesting that newer wells are at least as likely to run dry as older wells if groundwater levels continue to decline. Poor water quality in deep aquifers and the high costs of well construction limit the effectiveness of tapping deep groundwater to stave off the loss of access to water as wells run dry.
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice
The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopamine receptor (D2R) modulation. Inhibiting the ISR inverted the sign of D2R modulation of CIN firing and evoked dopamine release and altered skill learning. Thus, a noncanonical, steady-state mode of ISR activation is found in CINs, revealing a neuromodulatory role for the ISR in learning.
Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage–positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 lineage–negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents Engrailed-1 activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).
Plants constantly experience fluctuating internal and external mechanical cues, ranging from nanoscale deformation of wall components, cell growth variability, nutating stems, and fluttering leaves to stem flexion under tree weight and wind drag. Developing plants use such fluctuations to monitor and channel their own shape and growth through a form of proprioception. Fluctuations in mechanical cues may also be actively enhanced, producing oscillating behaviors in tissues. For example, proprioception through leaf nastic movements may promote organ flattening. We propose that fluctuation-enhanced proprioception allows plant organs to sense their own shapes and behave like active materials with adaptable outputs to face variable environments, whether internal or external. Because certain shapes are more amenable to fluctuations, proprioception may also help plant shapes to reach self-organized criticality to support such adaptability.