Capturing enzymes under native turnover conditions remains a grand challenge in structural biology. Here, we develop a reaction-based cryo-electron microscopy (cryo-EM) strategy that directly samples Drosophila melanogaster cytidine triphosphate synthase (CTPS) from actively catalyzing mixtures containing only natural substrates and allosteric effectors. By integrating reaction-based sampling with three-dimensional variability analysis, we resolve a continuous conformational spectrum of CTPS dur
Cytidine triphosphate (CTP), a fundamental building block of RNA, plays vital roles in diverse biological processes. CTP synthase (CTPS) is the only known enzyme for de novo synthesis of CTP. Efficient CTPS catalysis requires guanosine triphosphate (GTP) in a dose-dependent, nonconsumptive manner; however, the precise mechanism by which GTP drives CTP formation remains unclear. Here, we integrate a series of cryo-EM structures of Drosophila melanogaster CTPS captured from actively catalyzing sam
Cryptovivipary and vivipary, referred to as (crypto)vivipary, occur across multiple angiosperm lineages and enable embryos to continue developing before dispersal. Yet, this trait raises a fundamental question: how are seed-specific abscisic acid (ABA) responses modulated to support continuous embryonic growth without compromising ABA-dependent vegetative stress tolerance? Here, integrating phylogenomic analyses of independently evolved (crypto)viviparous lineages with spatiotemporal transcripto
The Benjamini-Hochberg (BH) procedure is the standard method for controlling the false discovery rate (FDR) in large-scale studies involving testing multiple hypotheses. Whether the BH procedure controls the FDR for every correlation structure among two-sided Gaussian tests has been a long-standing question, and a positive answer has been believed. Here, we settle the question negatively, by providing examples of Gaussian factor models for which the BH method fails to control the FDR at the nomi
Understanding the structural conformation and dynamics of nucleic acids in solution is critical for the development of nucleic acid therapeutics involving antisense or mRNA therapies, where controlling stability, efficacy, and manufacturability are important. Circular dichroism (CD) spectroscopy allows rapid and nondestructive solution analysis of the spatial arrangements of nucleic acids. While widely used to analyze protein structure, the potential of CD for DNA- and RNA-based pharmaceutical a
Existing models of learning in the brain explain how given circuits learn, but not how biology could assemble those circuits in the first place. To address this gap, we formulate Self-Assembling Learning-the study of how learning systems can emerge from lower-level interactions-and introduce one example mechanism, the Self-Assembling Motif (SAM). SAM is self-assembling at two scales: The motif emerges from initially random connectivity under heterosynaptic plasticity rules, and networks of SAMs,
A growing body of preclinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO 2 ) for rare and common diseases. However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, "hypoxia-in-a-pill" combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2α inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis. Althoug
Transposable elements (TEs) are epigenetically silenced through multiple mechanisms, including heterochromatin formation and DNA methylation. Prior studies have implicated SETDB1 and the Human Silencing Hub (HUSH) complex in heterochromatin formation-based TE repression, but precise characterization of repeat subclass and locus-specific effects for SETDB1 and related mechanisms has been limited by short-read transcriptome mapping. Here, we use long-read RNA sequencing mapped to a telomere-to-tel
Quantum Fisher information (QFI) sets the ultimate precision of optical phase measurements and can reveal multiphoton entanglement. Yet the photon-number fluctuations that encode this sensitivity are difficult to convert into an electrical signal. We theoretically predict that a photodetector utilizing the shot noise of the quantum-geometric shift current of exciton polaritons can measure photon-number statistics and, for pure states, infer the QFI. By solving the Lindblad equation, we obtain th
Systemic therapy for breast cancer has evolved rapidly since 2020, driven by the expansion of targeted therapies, antibody-drug conjugates, and immunotherapy across biologic subtypes. The integration of tumor molecular profiling and germline testing has enabled increasingly personalized, biomarker-guided treatment strategies. In hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, cyclin-dependent kinase 4 and 6 inhibitors remain foundational, whereas phos
Fast radio bursts (FRBs) are millisecond-duration radio transients from extragalactic sources. Their frequency and polarization properties are affected by plasma and magnetic fields along the line of sight to Earth. We report radio observations of FRB 20240304B and near-infrared follow-up to identify its host galaxy. The host is a low-mass, clumpy, star-forming galaxy at redshift 2.148 ± 0.0013, corresponding to 3 billion years after the Big Bang. This FRB occurred during the peak of cosmic
The generation and manipulation of entanglement with low error are essential in quantum information systems. In practice, two-qubit entangling gates constitute a dominant error source, limiting circuit depths and performance in fault-tolerant architectures. Using a neutral-atom quantum processor, we realized entangling controlled- Z gates with a high-Rabi-frequency smooth-amplitude pulse, employing state-selective readout and qubit reuse for fast calibration, and achieved a fidelity of 99.854(4)
Low-symmetry materials unlock rich Berry curvature physics and anomalous transport phenomena that are forbidden in high-symmetry quantum systems through rigorous crystalline symmetry constraints. Current approaches rely on external fields or complex heterogeneous stacking to break crystalline symmetries, which hinders scalable device integration. In this work, we demonstrate surface premelting engineering to create wafer-scale low-symmetry graphene on germanium-110 [Ge(110)]. Controlled premelti
The origin of Bronze Age tin is one of the most compelling mysteries in global archaeology. A number of studies were carried out to identify fingerprints to determine tin sources, but all failed to suit the contexts of Bronze Age China. This study provides the first comprehensive provenance analysis of the tin ore utilized during the Shang dynasty of China. Using U-Pb dating analysis on cassiterite grains surviving in various contexts including primary smelting site, metal resource hoard, and br
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that detects aberrant DNA and activates the STING-dependent innate immune response. Although cGAS is predominantly localized in the nucleus under physiological conditions, its nuclear function remains incompletely understood. Here, we identify nuclear cGAS as a transcriptional repressor that restrains inflammatory gene expression independently of STING signaling. Using macrophages challenged with lipopolysaccharide (LPS), we found that cGA
Post-transcriptional transfer RNA (tRNA) modifications dynamically regulate translational capacity, yet whether the tRNA epitranscriptome is temporally coordinated with gene expression programs during bacterial growth remains unknown. Here, we combine time-resolved nanopore tRNA sequencing, liquid chromatography-tandem mass spectrometry modification profiling, transcriptomics, and proteomics across the Pseudomonas aeruginosa PA14 growth cycle to show that tRNA-modifying enzymes, the correspondin
Giredestrant and everolimus target the estrogen receptor (ER) pathway and the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, respectively, which are implicated in endocrine-therapy resistance. In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had disease progression or recurrence after receipt of a
Menopause is an important biological transition with up to 72 symptoms that shapes aging trajectories across organs and encompasses ~40% of the female lifespan. Although menopause awareness is increasing, research on strategies for menopause symptom management and optimizing health in the postmenopausal period is lacking. This Review highlights that menopause characteristics, such as type, timing, and symptom burden, influence health outcomes and later-life disease risk. Similarly, menopause hor
Stationary entanglement between the motion of macroscopic objects and light is a long-standing goal of quantum optomechanics, with implications for both fundamental tests of quantum physics and emerging quantum technologies. We report the generation of quantum entanglement between the center-of-mass motion of a nanosphere levitated in an optical tweezer inside an optical cavity and the electromagnetic field. Using heterodyne detection, we reconstructed the full set of optomechanical correlations
Enhancing toughness in nanocomposites often involves viscoelastic organic phases, but this typically reduces stiffness. We describe a high-modulus toughening mechanism in mature Cristaria plicata nacre arising from a crystalline organic-inorganic framework composed of aragonite nanorods alternately integrated with intratabular biomolecular crystallites. Due to the critical slip-length effect, these crystalline units approach the theoretical limits of modulus and strength. The nanoconfined biomol
Optical frequency combs (OFCs) are frequency rulers essential for precision metrology, next-generation navigation and testing of fundamental physics 1 . Despite intense efforts, chip-integrated OFCs remain laboratory-bound, unable to fulfil their promise of compact and cost-effective deployment. Although improvements in fabrication and integration are important, a conceptual limitation has stymied progress: on-chip OFC architectures have aimed to miniaturize their table-top counterparts and reli
Abstract The dazzling stripes found on zebras and snakes have long been thought to interfere with predator motion perception 1,2 , but this hypothesis has received little empirical support so far 3 . Butterflies show enormously diverse and high-contrast wing patterns, the function of which has inspired intense theoretical debate and research 4 . Here we suggest that butterfly wing patterns work in tandem with flight dynamics to create visual illusions that confuse predators. We use multiple line
Insecticide resistance poses a major challenge to global pest management, yet its cascading effects on ecological networks remain poorly understood. Here, we show that target-site-resistant herbivorous insects can accumulate unmetabolized insecticides and inadvertently function as "toxic prey," impairing the fitness of their natural enemies. Using neonicotinoid- and spinosyn-resistant Myzus persicae and genetically modified Drosophila melanogaster , we demonstrate that resistant hosts surviving
Humans collaborating with AI hold the promise of achieving superior outcomes compared to either acting alone (i.e., human-AI synergy). However, the conditions that facilitate such synergy when humans are advised by AI are not well understood. A recent meta-analysis showed that, on average, human-AI combinations do not outperform the better individual agent. We argue that this pessimistic conclusion arises from insufficient attention to human learning in experimental designs. To substantiate this
In congenital handlessness, where individuals rely on their feet for compensatory manual functions, reorganization in the primary somatosensory cortex (SI) appears to be limited to local shifts by adjacent body parts. It remains unclear how congenital handlessness and lifelong compensatory foot use shape the sensorimotor system beyond SI, and whether compensatory abilities can drive broader functional reorganization. Here, we used task-based and resting-state functional MRI (fMRI) to investigate
The cGAS (cyclic GMP-AMP synthase)-STING (Stimulator of interferon genes) pathway plays a central role in antiviral innate immunity in vertebrates. Recent studies have shown that invertebrates possess a related cGLR (cGAS-like receptor)-STING pathway. However, due to the lack of direct evidence demonstrating viral evasion of cGLR-STING-mediated immunity, the functional importance of cGLR-STING pathway in antiviral responses remains uncertain in invertebrates. Here, we show that an insect picorna
Tony Leggett (1938-2026) was one of the great theoretical physicists of his generation, specializing in the quantum mechanics of fluids and solids. Rightly recognized by the 2003 Nobel Prize in Physics for his explanation of the experiments discovering the superfluidity of helium-3, he will be remembered equally for his pioneering inquiries into the transition from the quantum to the classical world and the extent to which we can observe quantum phenomena on macroscopic scales.
Mg 3 (Sb, Bi) 2 has emerged as a promising material due to its favorable combination of high thermoelectric performance and ductility. However, a key question remains regarding how plastic deformation affects its thermoelectric properties. Here we investigate the evolution of deformation-induced defects and their influence on the transport and mechanical properties of Mg 3 (Sb, Bi) 2 . Compressive deformation introduces high densities of dislocations and deformation twins, accompanied by a prono
Retatrutide is a triple-receptor agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. In this phase 3, randomized, double-blind trial, we assigned adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide (at a dose of 4 mg, 9 mg, or 12 mg) or placebo for 80 weeks. Primary outcomes (evaluated in the 9-mg and 12-mg groups each vs. placebo) were the percent change in body weight and the change in the WOM
Wavelike bosonic particles can accumulate in a single mode characterized by a particular wavelength, and such condensates are at the heart of phenomena such as superconductivity and superfluidity where usually a single complex number describes their state. If there are several flavors of excitations or particles, a vector containing several complex numbers can characterize multicomponent condensation, thus opening new possibilities for textures, dynamics, and devices. Thus far, multicomponent co
People often cooperate out of concern for their reputation. The corresponding theory of indirect reciprocity predicts that such cooperation can only evolve if people's opinions of each other are sufficiently correlated. This correlation, however, can be difficult to achieve when individuals form their opinions independently from one another, as in private assessment models. In that case, errors can generate disagreements that propagate throughout a population. Here, we identify a simple mechanis
Shoot branching patterns and their diversity arise from variable activities of axillary meristems (AMs). A common feature of flowering plants is delayed AM initiation and growth during the vegetative phase, followed by a sudden and rapid acceleration of apical AM initiation during the reproductive phase. The mechanisms underlying this pronounced developmental shift are poorly understood. During tomato floral transition, the primary shoot meristem (PSM) terminates in a flower after producing two
David Botstein, who died on February 27, 2026, was a towering figure in the field of modern molecular genetics. His research career was largely focused on the development of methods to better understand biological systems, beginning with his early work on Salmonella phage P22 and yeast, where he exploited the use of conditional lethal mutations as suppressors to identify genes with common functions and to order them in a pathway. He is best remembered for developing restriction fragment length p
We pioneered a strategy based on low-frequency vibronic coupling to design narrowband room-temperature phosphorescent (RTP) materials. Here we select coronene derivative (CoDe) system and report that attaching aroyl group to the coronene core disrupts its intrinsic symmetry and introduces abundant low-frequency vibrational modes, thereby affording efficient room-temperature phosphorescence with a full width at half maximum (FWHM) of approximately 25 nm or narrower. In CoDe systems functionalized
DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3A R882H ) mutation, a hot-spot mutation in acute myeloid leukemia and developmental disorders, exerts a dominant-negative effect in DNMT3A-mediated DNA methylation through promoting high-order protein assembly. However, due to the lack of structural knowledge on DNMT3A homo-oligomers, the mechanism behind wild-type DNMT3A
Twenty-five years after the draft of the human genome sequence, genomics has revolutionized many areas of biology, the diagnosis of familial and early-onset diseases, and the development of targeted therapies, particularly in oncology. Genomic knowledge has had little effect on the diagnosis and treatment of most common adult-onset conditions. Genomewide association studies have revealed that for these conditions, thousands of genetic variants of small effect underpin the polygenic nature of ris
Transposable elements mobilize within and occasionally between genomes, including from host to virus. We identified two insertions of the human BC200 noncoding RNA gene in the poxvirus molluscum contagiosum virus (MCV), which were likely acquired through long interspersed nuclear element 1 (LINE-1 or L1)–mediated retrotransposition during modern human history. Although BC200 was co-opted approximately 40 million years ago to regulate neuronal translation, we show that it never lost its mobilizat
The study of twisted two-dimensional (2D) materials, in which twisting layers create moiré superlattices, has created opportunities for investigating topological phases and strongly correlated physics. The broader potential of a seemingly infinite set of twistable 2D materials remains largely unexplored. Here, we define “theoretically twistable materials” as single- or multilayer structures that allow for the construction of simple continuum models of their moiré structures. Our high-throughput
We report on the role of the homeobox gene goosecoid ( gsc ) within an epistatic pathway that mediates body axis formation in Xenopus . Embryos depleted of β-catenin form exclusively ventral structures and lack all traces of axial structures. Microinjection of gsc mRNA rescues an entire body axis with head and trunk-tail. This remarkable activity is shared with the homeobox gene siamois ( sia ) and growth factors of the Nodal family. Using a Gsc antisense morpholino, we showed that dorsalization
Réunion Island experienced a massive chikungunya virus epidemic in 2024-2025, with >54,000 confirmed cases. This is the second major chikungunya epidemic on the island, following the first one that peaked 20 years ago. It has been asserted that this new outbreak finds its origin in a single introduction event into the island, offering an opportunity to exploit viral genomic data to understand the epidemiological and dispersal dynamics of the introduced transmission chain. We sequenced &g
Understanding how phosphoenolpyruvate (PEP) binding induces the large open-to-closed conformational transition of bacterial Enzyme I (EI) has remained a long-standing problem in structural biology. In EI, PEP binds the C-terminal EIC domain, yet catalysis requires docking of the distant N-terminal EIN domain, which carries the active-site H189 residue, onto EIC. How this local binding event is coupled to global domain rearrangement has been unclear. Here, we combine experimental Chemical Shift C
Time boundaries (TBs), temporal analogues of spatial interfaces, offer a powerful handle to engineer quantum systems. However, unlike the well-developed stationary scattering theory at spatial interfaces, a unified framework for quantum scattering at TBs has been missing. Here we develop a Bloch-wave scattering theory for TBs by introducing a temporal scattering matrix [Formula: see text] between incoming and outgoing Bloch channels. We uncover topological resonant transmissions (RTs)-poles of [
Locally broken symmetries are used across fields to transport matter, particles, and information in preferential directions. Beyond local mechanisms, spatially distributed nonlinearities in crystalline media have enabled nonreciprocal transport, a rectification mechanism that operates continuously across scales and frequencies. Here, we show that this concept applies beyond condensed matter, to fluid transport in living organisms and artificial systems. We take the example of the lymphatic vascu
Glycyl radical enzymes (GREs) catalyze challenging chemical reactions using a posttranslationally installed glycyl radical cofactor. One such enzyme, indoleacetate decarboxylase (IAD), performs the radical-based decarboxylation of indole-3-acetate (I3A) to form the malodorant molecule skatole. In addition to being an odor nuisance, skatole is a human and livestock lung toxin, a suspected carcinogen, and a mosquito attractant, all of which impact human health, agriculture, food production, and wa
Complete phononic band gaps-frequency intervals that exclude elastic waves of every polarization-have so far been realized only in periodic phononic crystals, whose band structures are direction-dependent and defect-sensitive. Disordered stealthy hyperuniform composites have produced complete and isotropic photonic band gaps, but analogous elastic designs have so far fallen short. Here we show that pushing such composites to the ultradense inclusion packing fractions recently shown to be achieva
The hydroperoxy radical (HO 2 ) self-reaction is an important radical termination pathway under low-NO tropospheric conditions and a major gas-phase source of hydrogen peroxide (H 2 O 2 ), a key oxidant reservoir. Here we determine HO 2 self-reaction kinetics across atmospherically relevant temperatures and pressures and over a range of water vapor and methanol concentrations, using a collinear photolysis–probe geometry with cross-validated ultraviolet and mid-infrared absorption. The resulting
CREBBP is among the most frequently mutated genes in human cancer and encodes a lysine acetyltransferase (KAT) protein that acetylates histones and nonhistone proteins to drive transcriptional activation. Mutations of CREBBP most frequently result in missense changes affecting the active site within the KAT domain. However, there has not yet been comprehensive biochemical, structural, and functional studies to determine the impact of recurrent KAT-domain variants. Here we show that the most freq
Whether screening with blood-based early-detection tests for multiple cancers in addition to usual care has clinical utility is unknown. In a randomized, controlled trial conducted in England, we obtained peripheral blood from persons 50 to 77 years of age at up to three annual visits. After baseline blood collection, participants were randomly assigned in a 1:1 ratio to the intervention group (participants whose blood was tested) or the control group (participants whose blood was stored). Parti
Population data at small area scales are essential for effective decision-making, influencing public health, disaster response, and resource allocation, among others. While national censuses remain the cornerstone of population data, they are often constrained by high costs, infrequent collection cycles, and coverage gaps, which can hinder timely data availability. To address these challenges, geospatial statistical approaches using limited microcensus surveys have been demonstrated as a reliabl
Ultracold dipolar molecules hold great promise for the creation of exotic quantum states of matter, but the realization of long-lived molecular bulk samples with strong dipole-dipole interactions has remained challenging. In this work, we realized a collisionally stable gas of ultracold ground state molecules with a lifetime of several seconds. Utilizing double-microwave dressing, we achieved an extreme suppression of inelastic two- and three-body losses by factors of more than 10,000 and 1000,
