New evidence convincingly shows that metformin, a drug that reduces circulating glucose, acts by inhibiting mitochondrial complex I.

A fundamental requirement for photonic technologies is the ability to control the confinement and propagation of light. Widely used platforms include two-dimensional (2D) optical microcavities in which electromagnetic waves are confined in either metallic or distributed Bragg reflectors. Recently, transition metal dichalcogenides hosting tightly bound excitons with high optical quality have emerged

Multimodal microrobots are of growing interest due to their capabilities to navigate diverse terrains, with promising applications in inspection, exploration, and biomedicine. Despite remarkable progress, it remains challenging to combine the attributes of excellent maneuverability, low power consumption, and high robustness in a single multimodal microrobot. We propose an architected design of a passively

Alongside the Chicxulub meteorite impact, Deccan volcanism is considered a primary trigger for the Cretaceous–Paleogene (K–Pg) mass extinction. Models suggest that volcanic outgassing of carbon and sulfur—potent environmental stressors—drove global temperature change, but the relative timing, duration, and magnitude of such change remains uncertain. Here, we use the organic paleothermometer MBT′ 5me

The orientation and function of smooth muscle in the cervix may contribute to the important biomechanical properties that change during pregnancy. Thus, this study examined the three-dimensional structure, smooth muscle phenotype, and mechanical and contractile functions of the upper and lower cervix of nongravid (not pregnant) and gravid (pregnant) mice. In gravid cervix, we uncovered region-specific

Membrane-based nanofiltration has the potential to revolutionize the large-scale treatment of organic solvents in various applications. However, the widely used commercial membranes suffer from low permeability, narrow structural tunability, and limited chemical resistance. Here, we report a strategy for fabricating covalent organic framework (COF) membranes with solvent-responsive structural flexibility

Dyslexia is a common and partially heritable condition that affects reading ability. In a study of up to 35,231 adults, we explored the structural brain correlates of genetic disposition to dyslexia. Individual dyslexia-disposing genetic variants showed distinct patterns of association with brain structure. Independent component analysis revealed various brain networks that each had their own genomic

Probing ground-state quantum geometry and topology through optical responses is not only of fundamental interest, but it can also offer several practical advantages. Here, using first-principles calculations on thin films of the antiferromagnetic topological insulator MnBi 2 Te 4 , we demonstrate how the generalized optical weight arising from the absorptive part of the optical conductivity can be

Baculovirus is the most studied insect virus owing to a broad ecological distribution and ease of engineering for biotechnological applications. However, its structure and evolutionary place in the virosphere remain enigmatic. Using cryo–electron microscopy, we show that the nucleocapsid forms a covalently cross-linked helical tube protecting a highly compacted 134-kilobase pair DNA genome. The ends

The nucleus is at the nexus of mechanotransduction and the final barrier for most first line chemotherapeutics. Here, we study the intersection between nuclear-cytoskeletal coupling and chemotherapy nuclear internalization. We find that chronic and acute modulation of intracellular filaments changes nuclear influx of doxorubicin (DOX). Rapid changes in cell strain by disruption of cytoskeletal and

Charge transfer or redistribution at oxide heterointerfaces is a critical phenomenon, often leading to remarkable properties such as two-dimensional electron gas and interfacial ferromagnetism. Despite studies on LaNiO 3 /LaFeO 3 superlattices and heterostructures, the direction and magnitude of the charge transfer remain debated, with some suggesting no charge transfer due to the high stability of

Artificial haptics has the potential to revolutionize the way we integrate physical and virtual technologies in our daily lives, with implications for teleoperation, motor skill acquisition, rehabilitation, gaming, interpersonal communication, and beyond. Here, we delve into the intricate interplay between the somatosensory system and engineered haptic inputs for perception and action. We critically

Corneal injury–induced fibrosis occurs because of corneal epithelial basement membrane (EBM) injury and defective regeneration. Corneal fibrosis inhibition and transparency restoration depend on reestablished EBM, where the collagen network provides structural stability and heparan sulfate binds corneal epithelium–derived cytokines to regulate homeostasis. Inspired by this, bioactive hydrogels (Hep@Gel)

Phosphatidylserine synthase (PssA) is essential in the biosynthesis of phosphatidylethanolamine, a major phospholipid of bacterial membranes. A peripheral membrane protein PssA can associate with the cellular membrane in its active state or exist in the cytosol in an inactive form. The membrane-bound enzyme acts on cytidine diphosphate diacylglycerol (CDP-DG) to form cytidine monophosphate and a covalent

Mammals can execute intended limb movements despite the fact that spinal reflexes involuntarily modulate muscle activity. To generate appropriate muscle activity, the cortical descending motor output must coordinate with spinal reflexes, yet the underlying neural mechanism remains unclear. We simultaneously recorded activities in motor-related cortical areas, afferent neurons, and forelimb muscles

Exoskeletons offer promising solutions for improving human mobility, but a key challenge is ensuring the controller adapts to changing walking conditions. We present an artificial intelligence (AI)–driven universal exoskeleton system that dynamically switches assistance types between walking modes, modulates assistance levels corresponding to the ground slope, and delivers assistance timely based on

Glycine receptors (GlyRs) regulate motor control and pain processing in the central nervous system through inhibitory synaptic signaling. The subtype GlyRα3 expressed in nociceptive sensory neurons of the spinal dorsal horn is a key regulator of physiological pain perception. Disruption of spinal glycinergic inhibition is associated with chronic inflammatory pain states, making GlyRα3 an attractive

Subsurface environments are among Earth’s largest habitats for microbial life. Yet, until recently, we lacked adequate data to accurately differentiate between globally distributed marine and terrestrial surface and subsurface microbiomes. Here, we analyzed 478 archaeal and 964 bacterial metabarcoding datasets and 147 metagenomes from diverse and widely distributed environments. Microbial diversity

Biological aging clocks produce age estimates that can track with age-related health outcomes. This study aimed to benchmark machine learning algorithms, including regularized regression, kernel-based methods, and ensembles, for developing metabolomic aging clocks from nuclear magnetic resonance spectroscopy data. The UK Biobank data, including 168 plasma metabolites from up to N = 225,212 middle-aged

For millennia, alloying has been the greatest gift from metallurgy to humankind: a process of mixing elements, propelling our society from the Bronze Age to the Space Age. Dealloying, by contrast, acts like a penalty: a corrosive counteracting process of selectively removing elements from alloys or compounds, degrading their structural integrity over time. We show that when these two opposite metallurgical

Podophages are, by far, the least well studied of all the bacteriophages. Despite being classified together due to their short, noncontractile tails, there is a huge amount of diversity among members of this group. Of the podophages, the N4-like Schitoviridae family is the least well studied structurally and is quite divergent from well-characterized podophages such as T7 and P22. In this work, we

The complex neural activity of prefrontal cortex (PFC) is a hallmark of cognitive processes. How these rich dynamics emerge and support neural computations is largely unknown. Here, we infer mechanisms underlying the context-dependent integration of sensory inputs by fitting dynamical models to PFC population responses of behaving monkeys. A class of models implementing linear dynamics driven by external

Protein-protein interaction (PPI) networks, where nodes represent proteins and edges depict myriad interactions among them, are fundamental to understanding the dynamics within biological systems. Despite their pivotal role in modern biology, reliably discerning patterns from these intertwined networks remains a substantial challenge. The essence of the challenge lies in holistically characterizing

De novo peptide design exhibits great potential in materials engineering, particularly for the use of plastic-binding peptides to help remediate microplastic pollution. There are no known peptide binders for many plastics—a gap that can be filled with de novo design. Current computational methods for peptide design exhibit limitations in sampling and scaling that could be addressed with quantum computing

Previous evolutionary models of duplicate gene evolution have overlooked the pivotal role of genome architecture. Here, we show that proximity-based regulatory recruitment by distally duplicated genes is an efficient mechanism for modulating tissue-specific production of preexisting proteins. By leveraging genomic asymmetries, we performed a coexpression analysis on Drosophila melanogaster tissue data

Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, Plasmodium falciparum , has developed resistance to nearly all currently available antimalarial drugs. The P. falciparum Niemann-Pick type C1–related (PfNCR1) transporter has been identified as a druggable target, but its structure and

The hydroalkylation reaction of olefins with alkanes is a highly desirable synthetic transformation toward the construction of C(sp 3 )─C(sp 3 ) bonds. However, such transformation has proven to be challenging for unactivated olefins, particularly when the substrates lack directing groups or acidic C(sp 3 )─H bonds. Here, we address this challenge by merging NiH-catalyzed radical relay strategy with

Metal halide perovskite single crystals (SCs) emerge as a promising candidate for ionizing radiation detection. The realization of top-performing radiation detectors typically relies on careful crystal selection from broad candidate groups, as residual strain remains unavoidable during the SC growth process, which often leads to the formation of ferroelastic domains with varied orientations. Here,

Retinitis pigmentosa (RP) is characterized by degeneration of rod and cone photoreceptors that progresses to irreversible blindness. Now, there are no mutation-agnostic approaches to treat RP. Here, we utilized a single adeno-associated virus (AAV)–based CRISPR activation system to activate phosphodiesterase 6B (Pde6b) to mitigate the severe degeneration in Pde6a nmf363 mice. We demonstrate that transcriptional

Striatal cholinergic interneurons (CINs) are key to regulating behavioral flexibility, involving both extinguishing learned actions and adopting new ones. However, the mechanisms driving these processes remain elusive. In this study, we initially demonstrate that chronic alcohol consumption disrupts the burst-pause dynamics of CINs and impairs behavioral flexibility. We next aimed to elucidate the

Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces

Single-nucleotide variants (SNVs) are extremely prevalent in human cancers, although most of these remain clinically unactionable. The programmable RNA nuclease CRISPR-Cas13 has been deployed to specifically target oncogenic RNAs. However, silencing oncogenic SNVs with single-base precision remains extremely challenging due to the intrinsic mismatch tolerance of Cas13. Here, we show that introducing

During the Early Medieval period, the Carpathian Basin witnessed substantial demographic shifts, notably under the Avar dominance for ~250 years, followed by the settlement of early Hungarians in the region during the late 9th century CE. This study presents the genetic analysis of 296 ancient samples, including 103 shotgun-sequenced genomes, from present-day Western Hungary. By using identity-by-descent

The central nervous system represents a major target tissue for therapeutic approach of numerous lysosomal storage disorders. Fabry disease arises from the lack or dysfunction of the lysosomal alpha-galactosidase A (GLA) enzyme, resulting in substrate accumulation and multisystemic clinical manifestations. Current enzyme replacement therapies (ERTs) face limited effectiveness due to poor enzyme biodistribution

Metal-organic networks have attracted widespread interest owing to their hybrid physicochemical properties. Natural biomolecules represent attractive building blocks for these materials because of their inherent biological function and high biocompatibility; however, assembling them into coordination network materials, especially nanoparticles (NPs), is challenging. Herein, we exploit the coordination

Zoonotic influenza A virus (IAV) infections pose a substantial threat to global health. The influenza RNA-dependent RNA polymerase (RdRp) comprises the PB2, PB1, and PA proteins. Of the last four pandemic IAVs, three featured avian-origin PB1 genes. Prior research linked these avian PB1 genes to increased viral fitness when reassorted with human IAV genes. This study evaluated chimeric RdRps with PB1

Photosystem II (PSII) splits water in oxygenic photosynthesis on Earth. The structure and function of the C 4 S 4 M 2 -type PSII-LHCII (light-harvesting complex II) megacomplexes from the wild-type and PsbR-deletion mutant plants are studied through electron microscopy (EM), structural mass spectrometry, and ultrafast fluorescence spectroscopy [time-resolved fluorescence (TRF)]. The cryo-EM structure

Archaea share genomic similarities with Eukarya and cellular architectural similarities with Bacteria, though archaeal and bacterial surface layers (S-layers) differ. Using cellular cryo–electron tomography, we visualized the S-layer lattice surrounding Methanospirillum hungatei , a methanogenic archaeon. Though more compact than known structures, M. hungatei ’s S-layer is a flexible hexagonal lattice

The ribosomal RNA (rRNA) is one of the most heavily modified RNA species in nature. Although we have advanced knowledge of the sites, functions, and the enzymology of many of the rRNA modifications from all kingdoms of life, we lack basic understanding of many of those that are not universally present. A single N 3 modified uridine base (m 3 U) was identified to be present on the 28 S rRNA from humans

Down syndrome (DS), caused by trisomy 21 (T21), results in immune and metabolic dysregulation. People with DS experience co-occurring conditions at higher rates than the euploid population. However, the interplay between immune and metabolic alterations and the clinical manifestations of DS are poorly understood. Here, we report an integrated analysis of immunometabolic pathways in DS. Using multi-omics

Modulating the endogenous stores of gastrointestinal hormones is considered a promising strategy to mimic gut endocrine function, improving metabolic dysfunction. Here, we exploit mouse and human knock-in and knockout intestinal organoids and show that agents used as commercial lipid excipients can activate nutrient-sensitive receptors on enteroendocrine cells (EECs) and, when formulated as lipid nanocarriers

Mixotrophic protists combine photosynthesis with the ingestion of prey to thrive in resource-limited conditions in the ocean. Yet, how they fine-tune resource investments between their two different metabolic strategies remains unclear. Here, we present a modeling framework (Mixotroph Optimal Contributions to Heterotrophy and Autotrophy) that predicts the optimal (growth-maximizing) investments of

Atrial fibrillation leads to severe diseases such as heart failure and strokes. While catheter ablation is prevalent for the treatment, existing techniques hardly can achieve both tissue selectivity and ablation uniformity. Here, we propose a bioinspired strategy for balloon-based pulsed field ablation (PFA) systems based on “flounder” electrodes. Inspired by a flounder skeleton and citrus peels, the

Tissue-resident memory T (T RM ) cells preferentially reside in peripheral tissues, serving as key players in tumor immunity and immunotherapy. The lack of effective approaches for expanding T RM cells and delivering these cells in vivo hinders the exploration of T RM cell–mediated cancer immunotherapy. Here, we report a nanoparticle artificial antigen-presenting cell (nano-aAPC) ex vivo expansion

Oxytocin (OT) neurons in the hypothalamic paraventricular nucleus (PVH) play an important role in various physiological and behavioral processes, including the initiation of milk ejection and the regulation of maternal behaviors. However, their activity patterns at the single-cell level remain poorly understood. Using microendoscopic Ca 2+ imaging in freely moving mouse dams, we demonstrate highly

Multiple antibiotic resistances are a major global health threat. The predominant tool for adaptation in Gram-negative bacteria is the integron. Under stress, it rearranges gene cassettes to offer an escape using the tyrosine recombinase IntI, recognizing folded DNA hairpins, the attC sites. Four recombinases and two attC sites form the synaptic complex. Yet, for unclear reasons, the recombination

The spatiotemporal configuration of genes with distal regulatory elements is believed to be crucial for transcriptional control, but full mechanistic understanding is lacking. We combine simultaneous live tracking of pairs of genomic loci and nascent transcripts with molecular dynamics simulations to assess the Sox2 gene and its enhancer. We find that both loci exhibit more constrained mobility than

Crustal thickness and elevation variations control mountain building and climate change at convergent margins. As an archetypal Andean-type convergent margin, eastern Asia preserves voluminous magmas ideal for quantifying these processes and their impacts on climate. Here, we use Sr/Y and Ce/Y proxies to show that the crust experienced alternating thickening and thinning during the Late Mesozoic. We

Biological age, which reflects the physiological state of an individual, offers a better predictive value than chronological age for age-related diseases and mortality. Nonetheless, determining accurate functional features of biological age remains challenging due to the multifactorial nature of aging. Here, we established a unique mouse cohort comprising 1576 male and female outbred SWISS mice subjected

The detection of mid-infrared (MIR) light is technologically important for applications such as night vision, imaging, sensing, and thermal metrology. Traditional MIR photodetectors either require cryogenic cooling or have sophisticated device structures involving complex nanofabrication. Here, we conceive spectrally tunable MIR detection by using two-dimensional metal halide perovskites (2D-MHPs)

The angular optical trap (AOT) is a powerful technique for measuring the DNA topology and rotational mechanics of fundamental biological processes. Realizing the full potential of the AOT requires rapid torsional control of these processes. However, existing AOT quartz cylinders are limited in their ability to meet the high rotation rate requirement while minimizing laser-induced photodamage. In this

Efforts to understand how Pleistocene climate changes were translated into fluctuations in ice sheet extent and volume are limited by a lack of consensus about the glacial history of the North Sea. Here, we use high-resolution 3D seismic data to interpret the landforms and sediments of the central North Sea in unprecedented detail. In contrast to previous interpretations of multiple extensive early

Leveraging the unique properties of quantum entanglement, quantum entanglement distribution networks support multiple quantum information applications and are essential to the development of quantum networks. However, practical implementation poses fundamental challenges to network scalability and flexibility. Here, we propose a reconfigurable entanglement distribution network scheme based on tunable

Cisplatin-based chemotherapy is used across many common tumor types, but resistance reduces the likelihood of long-term survival. We previously found the puromycin-sensitive aminopeptidase, NPEPPS, as a druggable driver of cisplatin resistance in vitro and in vivo and in patient-derived organoids. Here, we present a general mechanism where NPEPPS interacts with the volume-regulated anion channels (VRACs)

Proper axonal myelination and function of the vertebrate central nervous system rely largely on the timely differentiation of oligodendrocytes (OLs), yet key regulatory factors remain enigmatic. Our study reveals neural zinc finger (Nzf2) as a crucial orchestrator that controls the timing of OL differentiation both during development and myelin repair, contrasting with its previously suggested role

High-performance membrane-based H 2 /CO 2 separation offers a promising way to reduce the energy costs of precombustion capture. Current membranes, often made from two-dimensional laminates like metal-organic frameworks, have limitations due to complex fabrication methods requiring high temperatures, organic solvents, and long synthesis time. These processes often result in poor H 2 /CO 2 selectivity

Similar to cellulose synthases (CESAs), cellulose synthase–like D (CSLD) proteins synthesize β-1,4-glucan in plants. CSLDs are important for tip growth and cytokinesis, but it was unknown whether they form membrane complexes in vivo or produce microfibrillar cellulose. We produced viable CESA-deficient mutants of the moss Physcomitrium patens to investigate CSLD function without interfering CESA activity

Geologic hydrogen could be a low-carbon primary energy resource; however, the magnitude of Earth’s subsurface endowment has not yet been assessed. Knowledge of the occurrence and behavior of natural hydrogen on Earth has been combined with information from geologic analogs to construct a mass balance model to predict the resource potential. Given the associated uncertainty, stochastic model results

Eukaryotes carry three types of structural maintenance of chromosome (SMC) protein complexes, condensin, cohesin, and SMC5/6, which are ATP-dependent motor proteins that remodel the genome via DNA loop extrusion (LE). SMCs modulate DNA supercoiling but remains incompletely understood how this is achieved. Using a single-molecule magnetic tweezers assay that directly measures how much twist is induced