The Asian hornet, Vespa velutina, is an invasive, globally-distributed predator of European honey bees and other insects. To better under its reproductive biology and to find a specific, effective, and low-impact control method for this species, we identified and tested the key compounds in V. velutina sex pheromone. Virgin gynes (reproductive females) produced this sex pheromone in the sixth intersegmental sternal glands of their abdomens. The active compounds were 4-oxo-octanoic acid (4-OOA, 10.4 μg bee^-1) and 4-oxo-decanoic acid (4-ODA, 13.3 μg bee^-1) at a 0.78 ratio of 4-OOA/4-ODA. We synthesized these compounds and showed that male antennae were highly sensitive to them. Moreover, males were only strongly attracted to a 4-OOA/4-ODA blend at the natural ratio produced by gynes. These results provide the first demonstration of an effective way to lure V. velutina males, and the first chemical identification of a sex pheromone in the eusocial hornets.

In colonial organisms, alarm pheromones can provide a key fitness advantage by enhancing colony defence and warning of danger. Learning which species use alarm pheromone and the key compounds involved therefore enhances our understanding of how this important signal has evolved. However, our knowledge of alarm pheromones is more limited in the social wasps and hornets compared with the social bees and ants. Vespa velutina is an economically important and widespread hornet predator that attacks honey bees and humans. This species is native to Asia and has now invaded Europe. Despite growing interest in V. velutina, it was unknown whether it possessed an alarm pheromone. We show that these hornets use sting venom as an alarm pheromone. Sting venom volatiles were strongly attractive to hornet workers and triggered attacks. Two major venom fractions, consisting of monoketones and diketones, also elicited attack. We used gas chromatography coupled to electroantennographic detection (GC-EAD) to isolate 13 known and 3 unknown aliphatic ketones and alcohols in venom that elicited conspicuous hornet antennal activity. Two of the unknown compounds may be an undecen-2-one and an undecene-2,10-dinone. Three major compounds (heptan-2-one, nonan-2-one and undecan-2-one) triggered attacks, but only nonan-2-one did so at biologically relevant levels (10 hornet equivalents). Nonan-2-one thus deserves particular attention. However, the key alarm releasers for V. velutina remain to be identified. Such identification will help to illuminate the evolution and function of alarm compounds in hornets.

Quantification of cell-free DNA (cfDNA) in circulating blood derived from a transplanted organ is a powerful approach to monitoring post-transplant injury. Genome transplant dynamics (GTD) quantifies donor-derived cfDNA (dd-cfDNA) by taking advantage of single-nucleotide polymorphisms (SNPs) distributed across the genome to discriminate donor and recipient DNA molecules. In its current implementation, GTD requires genotyping of both the transplant recipient and donor. However, in practice, donor genotype information is often unavailable. Here, we address this issue by developing an algorithm that estimates dd-cfDNA levels in the absence of a donor genotype. Our algorithm predicts heart and lung allograft rejection with an accuracy that is similar to conventional GTD. We furthermore refined the algorithm to handle closely related recipients and donors, a scenario that is common in bone marrow and kidney transplantation. We show that it is possible to estimate dd-cfDNA in bone marrow transplant patients that are unrelated or that are siblings of the donors, using a hidden Markov model (HMM) of identity-by-descent (IBD) states along the genome. Last, we demonstrate that comparing dd-cfDNA to the proportion of donor DNA in white blood cells can differentiate between relapse and the onset of graft-versus-host disease (GVHD). These methods alleviate some of the barriers to the implementation of GTD, which will further widen its clinical application.

Competing inhomogeneous orders are a central feature of correlated electron materials, including the high-temperature superconductors. The two-dimensional Hubbard model serves as the canonical microscopic physical model for such systems. Multiple orders have been proposed in the underdoped part of the phase diagram, which corresponds to a regime of maximum numerical difficulty. By combining the latest numerical methods in exhaustive simulations, we uncover the ordering in the underdoped ground state. We find a stripe order that has a highly compressible wavelength on an energy scale of a few kelvin, with wavelength fluctuations coupled to pairing order. The favored filled stripe order is different from that seen in real materials. Our results demonstrate the power of modern numerical methods to solve microscopic models, even in challenging settings.

Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells.

Anthropogenic activities have substantially enhanced the loadings of reactive nitrogen (Nr) in the Earth system since pre-industrial times^1,2, contributing to widespread eutrophication and air pollution^3-6. Increased Nr can also influence global climate through a variety of effects on atmospheric and land processes but the cumulative net climate effect is yet to be unravelled. Here we show that anthropogenic Nr causes a net negative direct radiative forcing of -0.34 [-0.20, -0.50] W m^-2 in the year 2019 relative to the year 1850. This net cooling effect is the result of increased aerosol loading, reduced methane lifetime and increased terrestrial carbon sequestration associated with increases in anthropogenic Nr, which are not offset by the warming effects of enhanced atmospheric nitrous oxide and ozone. Future predictions using three representative scenarios show that this cooling effect may be weakened primarily as a result of reduced aerosol loading and increased lifetime of methane, whereas in particular N₂O-induced warming will probably continue to increase under all scenarios. Our results indicate that future reductions in anthropogenic Nr to achieve environmental protection goals need to be accompanied by enhanced efforts to reduce anthropogenic greenhouse gas emissions to achieve climate change mitigation in line with the Paris Agreement.

Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may affect the efficacy of LV-based cellular therapies.

Unlabelled

The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7A(WT/WT); C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders.

Significance

Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs.

Numerical results for ground-state and excited-state properties (energies, double occupancies, and Matsubara-axis self-energies) of the single-orbital Hubbard model on a two-dimensional square lattice are presented, in order to provide an assessment of our ability to compute accurate results in the thermodynamic limit. Many methods are employed, including auxiliary-field quantum Monte Carlo, bare and bold-line diagrammatic Monte Carlo, method of dual fermions, density matrix embedding theory, density matrix renormalization group, dynamical cluster approximation, diffusion Monte Carlo within a fixed-node approximation, unrestricted coupled cluster theory, and multireference projected Hartree-Fock methods. Comparison of results obtained by different methods allows for the identification of uncertainties and systematic errors. The importance of extrapolation to converged thermodynamic-limit values is emphasized. Cases where agreement between different methods is obtained establish benchmark results that may be useful in the validation of new approaches and the improvement of existing methods.

Nitrous oxide (N2O) is a greenhouse gas and stratospheric ozone-depleting substance with large and growing anthropogenic emissions. Previous studies identified the influx of N2O-depleted air from the stratosphere to partly cause the seasonality in tropospheric N2O (aN2O), but other contributions remain unclear. Here, we combine surface fluxes from eight land and four ocean models from phase 2 of the Nitrogen/N2O Model Intercomparison Project with tropospheric transport modeling to simulate aN2O at eight remote air sampling sites for modern and pre-industrial periods. Models show general agreement on the seasonal phasing of zonal-average N2O fluxes for most sites, but seasonal peak-to-peak amplitudes differ several-fold across models. The modeled seasonal amplitude of surface aN2O ranges from 0.25 to 0.80 ppb (interquartile ranges 21%–52% of median) for land, 0.14–0.25 ppb (17%–68%) for ocean, and 0.28–0.77 ppb (23%–52%) for combined flux contributions. The observed seasonal amplitude ranges from 0.34 to 1.08 ppb for these sites. The stratospheric contributions to aN2O, inferred by the difference between the surface-troposphere model and observations, show 16%–126% larger amplitudes and minima delayed by ∼1 month compared to Northern Hemisphere site observations. Land fluxes and their seasonal amplitude have increased since the pre-industrial era and are projected to grow further under anthropogenic activities. Our results demonstrate the increasing importance of land fluxes for aN2O seasonality. Considering the large model spread, in situ aN2O observations and atmospheric transport-chemistry models will provide opportunities for constraining terrestrial and oceanic biosphere models, critical for projecting carbon-nitrogen cycles under ongoing global warming.