Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)–biomimetic liposomes encapsulating 2',3'-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine–induced humoral and CD8⁺ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP–adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8⁺ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP–mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

Diapause is a state of suspended development that helps organisms survive extreme environments. How diapause protects living organisms is largely unknown. Using the African turquoise killifish (Nothobranchius furzeri), we show that diapause preserves complex organisms for extremely long periods of time without trade-offs for subsequent adult growth, fertility, and life span. Transcriptome analyses indicate that diapause is an active state, with dynamic regulation of metabolism and organ development genes. The most up-regulated genes in diapause include Polycomb complex members. The chromatin mark regulated by Polycomb, H3K27me3, is maintained at key developmental genes in diapause, and the Polycomb member CBX7 mediates repression of metabolism and muscle genes in diapause. CBX7 is functionally required for muscle preservation and diapause maintenance. Thus, vertebrate diapause is a state of suspended life that is actively maintained by specific chromatin regulators, and this has implications for long-term organism preservation.

Mammalian SWI/SNF family chromatin remodelers, BRG1/BRM-associated factor (BAF) and polybromo-associated BAF (PBAF), regulate chromatin structure and transcription, and their mutations are linked to cancers. The 3.7-angstrom-resolution cryo–electron microscopy structure of human BAF bound to the nucleosome reveals that the nucleosome is sandwiched by the base and the adenosine triphosphatase (ATPase) modules, which are bridged by the actin-related protein (ARP) module. The ATPase motor is positioned proximal to nucleosomal DNA and, upon ATP hydrolysis, engages with and pumps DNA along the nucleosome. The C-terminal α helix of SMARCB1, enriched in positively charged residues frequently mutated in cancers, mediates interactions with an acidic patch of the nucleosome. AT-rich interactive domain-containing protein 1A (ARID1A) and the SWI/SNF complex subunit SMARCC serve as a structural core and scaffold in the base module organization, respectively. Our study provides structural insights into subunit organization and nucleosome recognition of human BAF complex.

Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

Biased agonists of G protein–coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin–biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric G_q protein signaling.

Quantum control of complex objects in the regime of large size and mass provides opportunities for sensing applications and tests of fundamental physics. The realization of such extreme quantum states of matter remains a major challenge. We demonstrate a quantum interface that combines optical trapping of solids with cavity-mediated light-matter interaction. Precise control over the frequency and position of the trap laser with respect to the optical cavity allowed us to laser-cool an optically trapped nanoparticle into its quantum ground state of motion from room temperature. The particle comprises 10⁸ atoms, similar to current Bose-Einstein condensates, with the density of a solid object. Our cooling technique, in combination with optical trap manipulation, may enable otherwise unachievable superposition states involving large masses.

In a magnetic topological insulator, nontrivial band topology combines with magnetic order to produce exotic states of matter, such as quantum anomalous Hall (QAH) insulators and axion insulators. In this work, we probe quantum transport in MnBi₂Te₄ thin flakes—a topological insulator with intrinsic magnetic order. In this layered van der Waals crystal, the ferromagnetic layers couple antiparallel to each other; atomically thin MnBi₂Te₄, however, becomes ferromagnetic when the sample has an odd number of septuple layers. We observe a zero-field QAH effect in a five–septuple-layer specimen at 1.4 kelvin, and an external magnetic field further raises the quantization temperature to 6.5 kelvin by aligning all layers ferromagnetically. The results establish MnBi₂Te₄ as an ideal arena for further exploring various topological phenomena with a spontaneously broken time-reversal symmetry.

The quantum anomalous Hall (QAH) effect combines topology and magnetism to produce precisely quantized Hall resistance at zero magnetic field. We report the observation of a QAH effect in twisted bilayer graphene aligned to hexagonal boron nitride. The effect is driven by intrinsic strong interactions, which polarize the electrons into a single spin- and valley-resolved moiré miniband with Chern number C = 1. In contrast to magnetically doped systems, the measured transport energy gap is larger than the Curie temperature for magnetic ordering, and quantization to within 0.1% of the von Klitzing constant persists to temperatures of several kelvin at zero magnetic field. Electrical currents as small as 1 nanoampere controllably switch the magnetic order between states of opposite polarization, forming an electrically rewritable magnetic memory.

Two-dimensional materials from layered van der Waals (vdW) crystals hold great promise for electronic, optoelectronic, and quantum devices, but technological implementation will be hampered by the lack of high-throughput techniques for exfoliating single-crystal monolayers with sufficient size and high quality. Here, we report a facile method to disassemble vdW single crystals layer by layer into monolayers with near-unity yield and with dimensions limited only by bulk crystal sizes. The macroscopic monolayers are comparable in quality to microscopic monolayers from conventional Scotch tape exfoliation. The monolayers can be assembled into macroscopic artificial structures, including transition metal dichalcogenide multilayers with broken inversion symmetry and substantially enhanced nonlinear optical response. This approach takes us one step closer to mass production of macroscopic monolayers and bulk-like artificial materials with controllable properties.

Permafrost and methane hydrates are large, climate-sensitive old carbon reservoirs that have the potential to emit large quantities of methane, a potent greenhouse gas, as the Earth continues to warm. We present ice core isotopic measurements of methane (¹⁴C, ¹³C, and D) from the last deglaciation, which is a partial analog for modern warming. Our results show that methane emissions from old carbon reservoirs in response to deglacial warming were small (<19 teragrams of methane per year, 95% confidence interval) and argue against similar methane emissions in response to future warming. Our results also indicate that methane emissions from biomass burning in the pre-Industrial Holocene were 22 to 56 teragrams of methane per year (95% confidence interval), which is comparable to today.

Many animals can associate object shapes with incentives. However, such behavior is possible without storing images of shapes in memory that are accessible to more than one sensory modality. One way to explore whether there are modality-independent internal representations of object shapes is to investigate cross-modal recognition—experiencing an object in one sensory modality and later recognizing it in another. We show that bumble bees trained to discriminate two differently shaped objects (cubes and spheres) using only touch (in darkness) or vision (in light, but barred from touching the objects) could subsequently discriminate those same objects using only the other sensory information. Our experiments demonstrate that bumble bees possess the ability to integrate sensory information in a way that requires modality-independent internal representations.

A myriad of cellular events are regulated by allostery; therefore, evolution of this process is of fundamental interest. Here, we use ancestral sequence reconstruction to resurrect ancestors of two colocalizing proteins, Aurora A kinase and its allosteric activator TPX2 (targeting protein for Xklp2), to experimentally characterize the evolutionary path of allosteric activation. Autophosphorylation of the activation loop is the most ancient activation mechanism; it is fully developed in the oldest kinase ancestor and has remained stable over 1 billion years of evolution. As the microtubule-associated protein TPX2 appeared, efficient kinase binding to TPX2 evolved, likely owing to increased fitness by virtue of colocalization. Subsequently, TPX2-mediated allosteric kinase regulation gradually evolved. Surprisingly, evolution of this regulation is encoded in the kinase and did not arise by a dominating mechanism of coevolution.

Macrocycles can restrict the rotation of substituents through steric repulsions, locking in conformations that provide or enhance the activities of pharmaceuticals, agrochemicals, aroma chemicals, and materials. In many cases, the arrangement of substituents in the macrocycle imparts an element of planar chirality. The difficulty in predicting when planar chirality will arise, as well as the limited number of synthetic methods to impart selectivity, have led to planar chirality being regarded as an irritant. We report a strategy for enantio- and atroposelective biocatalytic synthesis of planar chiral macrocycles. The macrocycles can be formed with high enantioselectivity from simple building blocks and are decorated with functionality that allows one to further modify the macrocycles with diverse structural features.

Mycorrhizal fungi provide plants with a range of benefits, including mineral nutrients and protection from stress and pathogens. Here we synthesize current information about how the presence and type of mycorrhizal association affect plant communities. We argue that mycorrhizal fungi regulate seedling establishment and species coexistence through stabilizing and equalizing mechanisms such as soil nutrient partitioning, feedback to soil antagonists, differential mycorrhizal benefits, and nutrient trade. Mycorrhizal fungi have strong effects on plant population and community biology, with mycorrhizal type–specific effects on seed dispersal, seedling establishment, and soil niche differentiation, as well as interspecific and intraspecific competition and hence plant diversity.

The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα⁺ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.