From work emerging through the middle of the 20th century, the essence of meaning has become widely accepted as being described by the three orthogonal dimensions of valence, arousal, and dominance. These essential dimensions have become the cornerstone of sentiment analysis across many fields. By reexamining first types and then tokens for the English language, and through the use of automatically annotated histograms-"ousiograms"-we find here that the essence of meaning conveyed by words is instead best described by a goodness-power-aggression-danger-structure (GPADS) circumplex framework; that large-scale English language corpora reveal a systematic bias toward safe, low-danger words; and that the power-danger-structure framework is the minimal framework that represents essential meaning. We find remarkable congruences between the GPADS framework and other spaces including mental states and fictional archetypes, and we construct and demonstrate a prototype ousiometer.

The South Pole-Aitken (SPA) basin-forming impact was a critical event in the Moon's history. Despite being the oldest and largest acknowledged basin, critical details including the impactor's size, nature, direction, and fate of the ejecta remain uncertain. Here, we simulate SPA's formation and resultant crustal structure. We find that SPA's observed shape of an ellipse tapered toward the south is best reproduced by a 260-km-diameter differentiated impactor striking with a north-to-south trajectory. In this scenario, the impact disperses lunar mantle materials in the cross-range and the downrange directions away from the lunar farside. Much of the mantle ejecta collapses into the basin interior, consistent with the distribution inferred from gravity. These results suggest that the Artemis landing sites near the lunar south pole should contain abundant SPA ejecta including mantle materials. Samples returned from these regions should therefore reveal the age of SPA and the composition of the lunar mantle.

Antarctic sea ice extent began declining in 2015, reaching its minimum in the post-1970s observational era in 2023. To diagnose the drivers of this decline, we analyze an observationally constrained sea ice-ocean model spanning 2013-2023 and identify three distinct phases of sea ice retreat. First, intensifying westerlies preconditioned the Southern Ocean via increased upwelling of warm, saline circumpolar deep water (CDW). Second, strong winds in 2015-2016 enhanced the mixing of CDW into the upper ocean, thereby initiating sea ice loss, particularly in East Antarctica. Third, sustained mixing of CDW into the surface layer, combined with reduced equatorward sea ice-derived freshwater export, maintained an unprecedentedly low sea ice state. East Antarctic sea ice loss was primarily subsurface driven via enhanced upward CDW flux, whereas West Antarctic sea ice loss was also forced by longwave radiative flux anomalies. Our findings suggest that persistent upwelling-favorable conditions under anthropogenic forcing may push the Southern Ocean into a prolonged low sea ice state.

Cancer therapeutics frequently fail in clinical trials because of poor therapeutic index (efficacy-to-toxicity ratio). We systematically identified targets likely to have a good therapeutic index, revealing insulin receptor substrate 4 (IRS4) as a dependency in IRS4-expressing cancers. Pan-cancer analysis of pediatric-enriched cancers revealed IRS4 expression consistent with dependency in 68% of choroid plexus, 37% of malignant rhabdoid, 31% of NUT midline, and 5% of osteosarcomas, while in adult cancers, it was expressed in 8% of uterine leiomyosarcomas and 1 to 2% of lung squamous, stomach, and breast carcinomas. IRS4 expression in adult tumors was associated with enhancer hijacking rearrangements, including recurrent GATA3-IRS4 and ANKRD30A-IRS4 in breast cancer, while rhabdoid and NUT midline cancers expressed IRS4 epigenetically. IRS4 fueled cancer dependency through PI3K-Akt activation, and domain analysis revealed the PH and PTB domains, which have a predicted drug pocket, to be dispensable, suggesting degradation-based modalities. These data reveal IRS4 as a target in IRS4-expressing cancers and suggest inhibitory approaches.

Medical microrobots have strong potential for targeted therapeutic delivery; however, current systems achieve only physical targeting, and once at the target site, they are unable to distinguish healthy cells from cancerous ones because of the lack of biological selectivity. Here, we present a biohybrid microrobot system that combines magnetic targeting with biological selectivity. The microrobots are derived from human embryonic kidney cells genetically engineered to produce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a molecule that induces cancer cell death in multiple tumor types without damaging healthy cells. Engineered cells are then conjugated to biocompatible magnetic Janus particles-silica beads half-coated with FePt nanofilms-to enable external magnetic control. With magnetic fields, the microrobots accumulate around the tumor spheroids and continuously release TRAIL for several days, leading to selective cancer cell death while avoiding damage to healthy cells. This study combines microrobotics with genetically engineered cell therapies to achieve a targeted, prolonged, and cancer-selective therapeutic delivery.

Genetic mutations in myosin, the motor protein that powers the heartbeat, are linked to inherited hypertrophic and dilated cardiomyopathies. Mavacamten and omecamtiv mecarbil are therapeutic, myosin-targeted drugs designed to treat these myopathies, but their mechanism of action has remained unclear. Using single-particle cryo-EM, we determined near-atomic resolution structures of wild-type, mavacamten-bound, and omecamtiv mecarbil–bound myosin molecules. Across all conditions, we observe two distinct, alternate conformations of myosin, not previously reported. We show how mavacamten stabilizes one conformation by reinforcing key electrostatic interfaces in the molecule, whereas omecamtiv mecarbil weakens these interfaces, favoring the second structure. This remodeling elucidates previously unclear allosteric mechanisms through which these drugs either inhibit or enhance myosin activity, countering the deleterious impacts of disease. These findings reveal how drugs modulate myosin structure to control cardiac contractility.

Methanotrophic bacteria are the primary organisms that consume atmospheric methane (CH4) and have potential to mitigate climate-active gases. However, a limited understanding of the genetic determinants of methanotrophy hinders the development of biotechnologies leveraging these unique microbes. Here, we developed and optimized a CRISPR interference (CRISPRi) system to enable functional genomic screening in methanotrophic bacteria. We built a genome-wide single guide RNA (sgRNA) library in the industrial methanotroph, Methylococcus capsulatus, consisting of ~45,000 unique sgRNAs mediating inducible, CRISPRi-dependent transcriptional repression. A selective screen during growth on CH4 identified genes associated with essential methanotrophic bacterial processes and previously unidentified essential gene candidates, highlighting the utility of CRISPRi for functional genetic screening in methanotrophs. The CRISPRi screen also led to nitrate mineral salts medium optimization to improve methanotroph biomass productivity from CH4. Collectively, our results show that the CRISPRi system and sgRNA library developed here can be used for facile gene-function analyses and genomic screening to identify genetic determinants of methanotrophy and isolation of improved methanotroph biocatalysts.

Interleukin-10 (IL-10) production by B cells plays a critical role in regulating inflammatory responses, yet the mechanisms controlling its expression remain poorly understood. We identified a conserved noncoding sequence (CNS-9) as an essential regulatory element for IL-10 expression in mouse B cells. Comprehensive genomic analyses revealed that CNS-9 functions as an enhancer bound by the transcription factor NFATc1, which facilitates chromatin looping between CNS-9 and the IL-10 promoter to drive transcription. Flow cytometry analyses identified B1a cells as the predominant source of B cell-derived IL-10, with this production critically dependent on NFATc1-mediated CNS-9 regulation. In a mouse model of LPS-induced sepsis, deletion of CNS-9, B cell-specific NFATc1, or both resulted in reduced IL-10 production, exacerbated inflammatory responses, and decreased survival. Furthermore, we demonstrated that the human homolog, CNS-12, functions similarly through NFATc1-dependent mechanisms. These findings establish a conserved regulatory pathway controlling IL-10 expression in B cells with notable implications for inflammatory disease pathogenesis and potential therapeutic interventions.

The mid-lithosphere discontinuity (MLD) is a fundamental yet enigmatic seismic boundary within Earth's lithosphere, whose origin remains debated despite decades of study. Using thermomechanical models with self-consistent grain-size evolution, we propose a previously unrecognized mechanism for MLD formation. Plate deformation induces pronounced grain-size reduction within the brittle-ductile transition, generating permeability barriers that trap ascending fluids. These fluid-rich layers reproduce the observed seismic velocity drops. Their depth scales with lithospheric thickness and thermal structure and is fine-tuned by rheology evolution through brittle-ductile partitioning. The interplay between grain-size reduction and fluid accumulation imparts dual mechanical behavior to the MLD, stabilizing it within cold, ancient lithosphere or enabling localized failure under thermal perturbation. This framework identifies grain-scale processes as the primary control on MLD formation and links mantle-lithosphere coupling to planetary lithospheric evolution.

Observation of the universe demands telescopes with high resolution. In the optical band, traditional interference requires bringing interfering fields together, which limits the resolution due to the restricted length of baseline. Here we demonstrate the very long-baseline interferometer (VLBI) in optical band, where two interfering fields never met each other. In particular, we report the first quantum interference observation when the input of VLBI is single-photon state. Interference is recovered after measuring the amplitudes of photon fields and digitally processing the signals of quantum receivers. Moreover, we analyze interference in time and spectral domains for broadband thermal light input and show that the ultrahigh spectral resolution can improve the precision of radial velocity to 0.08centimeters per second, which is 2 orders of magnitude better than that achievable at the current stage. Further, we apply the spectrally resolved interference in distinguishing two independent sources with angular resolutions beyond diffraction limit. Our investigations have a profound effect on the VLBI, quantum optics, and precision measurement.