经典100 | NCS： 2025-04-03 期

『Abstract』Bifidobacteria represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest in bifidobacteria as a live biotic therapy, our understanding of colonization, host-microbe interactions, and the health-promoting effects of bifidobacteria is limited. To address these major knowledge gaps, we used a large-scale genetic approach to create a mutant fitness compendium in Bifidobacterium breve . First, we generated a high-density randomly barcoded transposon insertion pool and used it to determine fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. Second, to enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1,462 genes. We leveraged these tools to reveal community- and diet-specific requirements for colonization and to connect the production of immunomodulatory molecules to growth benefits. These resources will catalyze future investigations of this important beneficial microbe.

『Abstract』The genetic information stored in mRNAs is decoded by ribosomes during mRNA translation. mRNAs are typically translated by multiple ribosomes simultaneously, but it is unclear whether and how the activity of different ribosomes on an mRNA is coordinated. Here, we develop an imaging approach based on stopless-ORF circular RNAs (socRNAs) to monitor translation of individual ribosomes in either monosomes or polysomes with very high resolution. Using experiments and simulations, we find that translating ribosomes frequently undergo transient collisions. However, unlike persistent collisions, such transient collisions escape detection by cellular quality control pathways. Rather, transient ribosome collisions promote productive translation by reducing ribosome pausing on problematic sequences, a process we term ribosome cooperativity. Ribosome cooperativity also reduces recycling of ribosomes by quality control pathways, thus enhancing processive translation. Together, our single-ribosome imaging approach reveals that ribosomes cooperate during translation to ensure fast and efficient translation.

『Abstract』The virus particles of human immunodeficiency virus type 1 (HIV-1) are released in an immature, non-infectious form. Proteolytic cleavage of the main structural polyprotein Gag into functional domains induces rearrangement into mature, infectious virions. In immature virus particles, the Gag membrane-binding domain, MA, forms a hexameric protein lattice that undergoes structural transition, following cleavage, into a distinct, mature MA lattice . The mechanism of MA lattice maturation is unknown. Here we show that released spacer peptide 2 (SP2), a conserved peptide of unknown function situated about 300 residues downstream of MA, binds MA to induce structural maturation. By high-resolution in-virus structure determination of MA, we show that MA does not bind lipid into a side pocket as previously thought , but instead binds SP2 as an integral part of the protein–protein interfaces that stabilize the mature lattice. Analysis of Gag cleavage site mutants showed that SP2 release is required for MA maturation, and we demonstrate that SP2 is sufficient to induce maturation of purified MA on lipid monolayers in vitro. SP2-triggered MA maturation correlated with faster fusion of virus with target cells. Our results reveal a new, unexpected interaction between two HIV-1 components, provide a high-resolution structure of mature MA, establish the trigger of MA structural maturation and assign function to the SP2 peptide.

『Abstract』Recent evidence indicates that the emergence of stone tool technology occurred before the appearance of the genus Homo and may potentially be traced back deep into the primate evolutionary line . Conversely, osseous technologies are apparently exclusive of later hominins from approximately 2 million years ago (Ma) , whereas the earliest systematic production of bone tools is currently restricted to European Acheulean sites 400–250 thousand years ago . Here we document an assemblage of bone tools shaped by knapping found within a single stratigraphic horizon at Olduvai Gorge dated to 1.5 Ma. Large mammal limb bone fragments, mostly from hippopotamus and elephant, were shaped to produce various tools, including massive elongated implements. Before our discovery, bone artefact production in pre-Middle Stone Age African contexts was widely considered as episodic, expedient and unrepresentative of early Homo toolkits. However, our results demonstrate that at the transition between the Oldowan and the early Acheulean, East African hominins developed an original cultural innovation that entailed a transfer and adaptation of knapping skills from stone to bone. By producing technologically and morphologically standardized bone tools, early Acheulean toolmakers unravelled technological repertoires that were previously thought to have appeared routinely more than 1 million years later.

『Abstract』Pathogen genomics can provide insights into underlying infectious disease transmission patterns , but new methods are needed to handle modern large-scale pathogen genome datasets and realize this full potential . In particular, genetically proximal viruses should be highly informative about transmission events as genetic proximity indicates epidemiological linkage. Here we use pairs of identical sequences to characterize fine-scale transmission patterns using 114,298 SARS-CoV-2 genomes collected through Washington State (USA) genomic sentinel surveillance with associated age and residence location information between March 2021 and December 2022. This corresponds to 59,660 sequences with another identical sequence in the dataset. We find that the location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postcodes with male prisons, consistent with transmission between prison facilities. We find that transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. Overall, this study improves our ability to use large pathogen genome datasets to understand the determinants of infectious disease spread.

『Abstract』The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes . Although many examples of transcriptional metabolic rewiring have been reported , a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)—a high-throughput method combining whole-animal RNA-interference and RNA-sequencing —to around 900 metabolic genes in the nematode Caenorhabditis elegans . We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation–repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.

『Abstract』Metabolic flux, or the rate of metabolic reactions, is one of the most fundamental metrics describing the status of metabolism in living organisms. However, measuring fluxes across the entire metabolic network remains nearly impossible, especially in multicellular organisms. Computational methods based on flux balance analysis have been used with genome-scale metabolic network models to predict network-level flux wiring . However, such approaches have limited power because of the lack of experimental constraints. Here, we introduce a strategy that infers whole-animal metabolic flux wiring from transcriptional phenotypes in the nematode Caenorhabditis elegans . Using a large-scale Worm Perturb-Seq (WPS) dataset for roughly 900 metabolic genes , we show that the transcriptional response to metabolic gene perturbations can be integrated with the metabolic network model to infer a highly constrained, semi-quantitative flux distribution. We discover several features of adult C. elegans metabolism, including cyclic flux through the pentose phosphate pathway, lack of de novo purine synthesis flux and the primary use of amino acids and bacterial RNA as a tricarboxylic acid cycle carbon source, all of which we validate by stable isotope tracing. Our strategy for inferring metabolic wiring based on transcriptional phenotypes should be applicable to a variety of systems, including human cells.

『Abstract』Methane, the main component of natural and shale gas, is a significant carbon source for chemical synthesis. The direct partial oxidation of methane to liquid oxygenates under mild conditions is an attractive pathway, but the inertness of the molecule makes it challenging to achieve simultaneously high conversion and high selectivity towards a single target product. This difficulty is amplified when aiming for more valuable products that require C–C coupling . Whereas selective partial methane oxidation processes have thus typically generated C 1 oxygenates , recent reports have documented photocatalytic methane conversion to the C 2 oxygenate ethanol with low conversions but good-to-high selectivities . Here we show that the intramolecular junction photocatalyst covalent triazine-based framework-1 with alternating benzene and triazine motifs drives methane coupling and oxidation to ethanol with a high selectivity and significantly improved conversion. The heterojunction architecture not only enables efficient and long-lived separation of charges after their generation, but also preferential adsorption of H 2 O and O 2 to the triazine and benzene units, respectively. This dual-site feature separates C–C coupling to form ethane intermediates from the sites where •OH radicals are formed, thereby avoiding over-oxidation. When loaded with Pt to further boost performance, the molecular heterojunction photocatalyst generates ethanol in a packed-bed flow reactor with greatly improved conversion that results in an apparent quantum efficiency of 9.4%. We anticipate that further developing the ‘intramolecular junction’ approach will deliver efficient and selective catalysts for C–C coupling, pertaining, but not limited, to methane conversion to C 2+ chemicals.

『Abstract』Nucleophilic aromatic substitutions (S N Ar) are among the most widely used processes in the pharmaceutical and agrochemical industries , allowing convergent assembly of complex molecules through C–C and C–X (X = O, N, S) bond formation. S N Ar reactions are typically carried out using forcing conditions, involving polar aprotic solvents, stoichiometric bases and elevated temperatures, which do not allow for control over reaction selectivity. Despite the importance of S N Ar chemistry, there are only a handful of selective catalytic methods reported that rely on small organic hydrogen-bonding or phase-transfer catalysts . Here we establish a biocatalytic approach to stereoselective S N Ar chemistry by uncovering promiscuous S N Ar activity in a designed enzyme featuring an activated arginine . This activity was optimized over successive rounds of directed evolution to afford an engineered biocatalyst, S N Ar1.3, that is 160-fold more efficient than the parent and promotes the coupling of electron-deficient arenes with carbon nucleophiles with near-perfect stereocontrol (>99% enantiomeric excess (e.e.)). S N Ar1.3 can operate at a rate of 0.15 s , perform more than 4,000 turnovers and can accept a broad range of electrophilic and nucleophilic coupling partners, including those that allow construction of challenging 1,1-diaryl quaternary stereocentres. Biochemical, structural and computational studies provide insights into the catalytic mechanism of S N Ar1.3, including the emergence of a halide binding pocket shaped by key catalytic residues Arg124 and Asp125. This study brings a landmark synthetic reaction into the realm of biocatalysis to provide an efficient and versatile platform for catalytic S N Ar chemistry.

『Abstract』Inducing superconducting correlations in chiral edge states is predicted to generate topologically protected zero energy modes with exotic quantum statistics . Experimental efforts so far have focused on engineering interfaces between superconducting materials—typically amorphous metals—and semiconducting quantum Hall or quantum anomalous Hall systems. However, the strong interfacial disorder inherent in this approach can prevent the formation of isolated topological modes . An appealing alternative is to use low-density flat band materials in which the ground state can be tuned between intrinsic superconducting and quantum anomalous Hall states using only the electric field effect. However, quantized transport and superconductivity have not been simultaneously achieved. Here we show that rhombohedral tetralayer graphene aligned to a hexagonal boron nitride substrate hosts a quantized anomalous Hall state at superlattice filling ν = −1 as well as a superconducting state at ν ≈ −3.5 at zero magnetic field. Gate voltage can also be used to actuate non-volatile switching of the chirality in the quantum anomalous Hall state , allowing, in principle, arbitrarily reconfigurable networks of topological edge modes in locally gated devices. Thermodynamic compressibility measurements further show a topologically ordered fractional Chern insulator at ν = 2/3 (ref. )—also stable at zero magnetic field—enabling proximity coupling between superconductivity and fractionally charged edge modes. Finally, we show that, as in rhombohedral bi- and trilayers , integrating a transition metal dichalcogenide layer to the heterostructure nucleates a new superconducting pocket , while leaving the topology of the ν = −1 quantum anomalous Hall state intact. Our results pave the way for a new generation of hybrid interfaces between superconductors and topological edge states in the low disorder limit.

『Abstract』Pan-genomics and genome-editing technologies are revolutionizing breeding of global crops . A transformative opportunity lies in exchanging genotype-to-phenotype knowledge between major crops (that is, those cultivated globally) and indigenous crops (that is, those locally cultivated within a circumscribed area) to enhance our food system. However, species-specific genetic variants and their interactions with desirable natural or engineered mutations pose barriers to achieving predictable phenotypic effects, even between related crops . Here, by establishing a pan-genome of the crop-rich genus Solanum and integrating functional genomics and pan-genetics, we show that gene duplication and subsequent paralogue diversification are major obstacles to genotype-to-phenotype predictability. Despite broad conservation of gene macrosynteny among chromosome-scale references for 22 species, including 13 indigenous crops, thousands of gene duplications, particularly within key domestication gene families, exhibited dynamic trajectories in sequence, expression and function. By augmenting our pan-genome with African eggplant cultivars and applying quantitative genetics and genome editing, we dissected an intricate history of paralogue evolution affecting fruit size. The loss of a redundant paralogue of the classical fruit size regulator CLAVATA3 ( CLV3 ) was compensated by a lineage-specific tandem duplication. Subsequent pseudogenization of the derived copy, followed by a large cultivar-specific deletion, created a single fused CLV3 allele that modulates fruit organ number alongside an enzymatic gene controlling the same trait. Our findings demonstrate that paralogue diversifications over short timescales are underexplored contingencies in trait evolvability. Exposing and navigating these contingencies is crucial for translating genotype-to-phenotype relationships across species.

『Abstract』The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain . Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca . We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations—an extended binding pocket that opens rarely and leads to the conserved signalling residue D (ref. ). We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment. Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors.

『Abstract』A supersolid is a counter-intuitive phase of matter in which its constituent particles are arranged into a crystalline structure, yet they are free to flow without friction. This requires the particles to share a global macroscopic phase while being able to reduce their total energy by spontaneous, spatial self-organization. The existence of the supersolid phase of matter was speculated more than 50 years ago . However, only recently has there been convincing experimental evidence, mainly using ultracold atomic Bose–Einstein condensates (BECs) coupled to electromagnetic fields. There, various guises of the supersolid were created using atoms coupled to high-finesse cavities , with large magnetic dipole moments , and spin–orbit-coupled, two-component systems showing stripe phases . Here we provide experimental evidence of a new implementation of the supersolid phase in a driven-dissipative, non-equilibrium context based on exciton–polaritons condensed in a topologically non-trivial, bound state in the continuum (BiC) with exceptionally low losses, realized in a photonic-crystal waveguide. We measure the density modulation of the polaritonic state indicating the breaking of translational symmetry with a precision of several parts in a thousand. Direct access to the phase of the wavefunction allows us to also measure the local coherence of the supersolid. We demonstrate the potential of our synthetic photonic material to host phonon dynamics and a multimode excitation spectrum.

『Abstract』Seawater electrolysis powered by renewable electricity provides an attractive strategy for producing green hydrogen . However, direct seawater electrolysis faces many challenges, primarily arising from corrosion and competing reactions at the anode caused by the abundance of halide ions (Cl , Br ) in seawater . Previous studies on seawater electrolysis have mainly focused on the anode development, because the cathode operates at reducing potentials, which is not subject to electrode dissolution or chloride corrosion reactions during seawater electrolysis . However, renewable energy sources are intermittent, variable and random, which cause frequent start–shutdown operations if renewable electricity is used to drive seawater electrolysis. Here we first unveil dynamic evolution and degradation of seawater splitting cathode in intermittent electrolysis and, accordingly, propose construction of a catalyst’s passivation layer to maintain the hydrogen evolution performance during operation. An in situ-formed phosphate passivation layer on the surface of NiCoP–Cr 2 O 3 cathode can effectively protect metal active sites against oxidation during frequent discharge processes and repel halide ion adsorption on the cathode during shutdown conditions. We demonstrate that electrodes optimized using this design strategy can withstand fluctuating operation at 0.5 A cm for 10,000 h in alkaline seawater, with a voltage increase rate of only 0.5% khr . The newly discovered challenge and our proposed strategy herein offer new insights to facilitate the development of practical seawater splitting technologies powered by renewable electricity.

『Abstract』Carbohydrates are an abundant, inexpensive and renewable biomass feedstock that could be a cornerstone for sustainable chemical manufacturing, but scalable and environmentally friendly methods that leverage these feedstocks are lacking. For example, 1-allyl sorbitol is the foundational building block for the polypropylene clarifying agent Millad NX 8000, which is produced on the multi-metric ton scale annually, but the manufacturing process at present requires superstoichiometric amounts of tin . The NX 8000 additives dominate about 80% of the global clarified polypropylene market and are used in concentrations of 0.01–1% during polypropylene production to improve its transparency and resistance to high temperatures, translating to 300–30,000 metric tons annually. The market volume of polypropylene in 2022 was approximately 79.01 million metric tons (MMT), with demand expected to rise by nearly 33% to 105 MMT by 2030 (ref. ). The cost and sustainability benefits of clarified polypropylene are driving this demand, necessitating more clarifying agents . Here we report a high-yielding allylation of unprotected carbohydrates in water using a catalytic amount of indium metal and either allylboronic acid or the pinacol ester (allylBpin) as donors. Aldohexoses, aminohexoses, ketohexoses and aldopentoses are all allylated in high yield under mild conditions and the indium metal is recoverable and reusable with no loss of catalytic activity. Leveraging these features, this process was translated to a scalable continuous synthesis of 1-allyl sorbitol in flow with high yield and productivity through Bayesian optimization of reaction parameters.

『Abstract』Superconducting (SC) states that break space-group symmetries of the underlying crystal can exhibit nontrivial spatial modulation of the order parameter. Previously, such states were intimately associated with the breaking of translational symmetry , resulting in the density-wave orders , with wavelengths spanning several unit cells . However, a related basic concept has long been overlooked : when only intra-unit-cell symmetries of the space group are broken, the SC states can show a distinct type of nontrivial modulation preserving long-range lattice translation. Here we refer to this new concept as the pair density modulation (PDM) and report the first observation of a PDM state in exfoliated thin flakes of the iron-based superconductor FeTe 0.55 Se 0.45 . Using scanning tunnelling microscopy (STM), we discover robust SC gap modulation with the wavelength corresponding to the lattice periodicity and the amplitude exceeding 30 % of the gap average. Notably, we find that the observed modulation originates from the large difference in SC gaps on the two nominally equivalent iron sublattices. The experimental findings, backed up by model calculations, suggest that, in contrast to the density-wave orders, the PDM state is driven by the interplay of sublattice symmetry breaking and a peculiar nematic distortion specific to the thin flakes. Our results establish new frontiers for exploring the intertwined orders in strong-correlated electronic systems and open a new chapter for iron-based superconductors.

『Abstract』Deracemization is an emerging strategy for generating enantioenriched compounds wherein the two enantiomers of a readily available racemic starting material are transformed into a single enantiomer, typically through the action of a light-induced catalyst . Excellent proof of principle for this potentially powerful approach to asymmetric catalysis has been described ; nevertheless, substantial challenges have not yet been addressed, including the exploitation of carbon–heteroatom (rather than only carbon–hydrogen and carbon–carbon) bond cleavage to achieve deracemization, as well as the development of processes that provide broad classes of useful enantioenriched compounds and tetrasubstituted stereocentres. Here we describe a straightforward method that addresses these challenges, using a chiral copper catalyst, generated in situ from commercially available components, to achieve the photoinduced deracemization of tertiary (and secondary) alkyl halides through carbon–halogen bond cleavage. Mechanistic studies (including the independent synthesis of postulated intermediates, photophysical, spectroscopic and reactivity studies, and density functional theory calculations) provide support for the key steps and intermediates in our proposed catalytic cycle, as well as insight into the origin of enantioselectivity.

『Abstract』Hardware implementations of artificial neural networks (ANNs)—the most advanced of which are made of millions of electronic neurons interconnected by hundreds of millions of electronic synapses—have achieved higher energy efficiency than classical computers in some small-scale data-intensive computing tasks . State-of-the-art neuromorphic computers, such as Intel’s Loihi or IBM’s NorthPole , implement ANNs using bio-inspired neuron- and synapse-mimicking circuits made of complementary metal–oxide–semiconductor (CMOS) transistors, at least 18 per neuron and six per synapse. Simplifying the structure and size of these two building blocks would enable the construction of more sophisticated, larger and more energy-efficient ANNs. Here we show that a single CMOS transistor can exhibit neural and synaptic behaviours if biased in a specific (unconventional) manner. By connecting one additional CMOS transistor in series, we build a versatile 2-transistor-cell that exhibits adjustable neuro-synaptic response (which we named neuro-synaptic random access memory cell, or NS-RAM cell). This electronic performance comes with a yield of 100% and an ultra-low device-to-device variability, owing to the maturity of the silicon CMOS platform used—no materials or devices alien to the CMOS process are required. These results represent a short-term solution for the implementation of efficient ANNs and an opportunity in terms of CMOS circuit design and optimization for artificial intelligence applications.

『Abstract』A quantum network provides an infrastructure that connects quantum devices with revolutionary computing, sensing and communication capabilities. A quantum satellite constellation offers a solution to facilitate the quantum network on a global scale . The Micius satellite has verified the feasibility of satellite quantum communications ; however, scaling up quantum satellite constellations is challenging, requiring small lightweight satellites, portable ground stations and real-time secure key exchange. Here we tackle these challenges and report the development of a quantum microsatellite capable of performing space-to-ground quantum key distribution using portable ground stations. The microsatellite payload weighs approximately 23 kilograms, and the portable ground station weighs about 100 kilograms, representing reductions by more than 1 and 2 orders of magnitude, respectively. Using this set-up, we demonstrate satellite-based quantum key distribution with multiple ground stations and achieve the sharing of up to 1.07 million bits of secure keys during a single satellite pass. In addition, we multiplex bidirectional satellite–ground optical communication with quantum communication, enabling key distillation and secure communication in real time. Also, a secret key, enabling one-time pad encryption of images, is created between China and South Africa at locations separated by over 12,900 kilometres on Earth. The compact quantum payload can be readily assembled on existing space stations or small satellites , paving the way for a satellite-constellation-based quantum and classical network for widespread real-life applications.

『Abstract』Temporary pacemakers are essential for the care of patients with short-lived bradycardia in post-operative and other settings . Conventional devices require invasive open-heart surgery or less invasive endovascular surgery, both of which are challenging for paediatric and adult patients . Other complications include risks of infections, lacerations and perforations of the myocardium, and of displacements of external power supplies and control systems. Here we introduce a millimetre-scale bioresorbable optoelectronic system with an onboard power supply and a wireless, optical control mechanism with generalized capabilities in electrotherapy and specific application opportunities in temporary cardiac pacing. The extremely small sizes of these devices enable minimally invasive implantation, including percutaneous injection and endovascular delivery. Experimental studies demonstrate effective pacing in mouse, rat, porcine, canine and human cardiac models at both single-site and multi-site locations. Pairing with a skin-interfaced wireless device allows autonomous, closed-loop operation upon detection of arrhythmias. Further work illustrates opportunities in combining these miniaturized devices with other medical implants, with an example of arrays of pacemakers for individual or collective use on the frames of transcatheter aortic valve replacement systems, to provide unique solutions that address risks for atrioventricular block following surgeries. This base technology can be readily adapted for a broad range of additional applications in electrotherapy, such as nerve and bone regeneration, wound therapy and pain management.

『Abstract』Two-dimensional (2D) metals are appealing for many emergent phenomena and have recently attracted research interests . Unlike the widely studied 2D van der Waals (vdW) layered materials, 2D metals are extremely challenging to achieve, because they are thermodynamically unstable . Here we develop a vdW squeezing method to realize diverse 2D metals (including Bi, Ga, In, Sn and Pb) at the ångstrom thickness limit. The achieved 2D metals are stabilized from a complete encapsulation between two MoS 2 monolayers and present non-bonded interfaces, enabling access to their intrinsic properties. Transport and Raman measurements on monolayer Bi show excellent physical properties, for example, new phonon mode, enhanced electrical conductivity, notable field effect and large nonlinear Hall conductivity. Our work establishes an effective route for implementing 2D metals, alloys and other 2D non-vdW materials, potentially outlining a bright vision for a broad portfolio of emerging quantum, electronic and photonic devices.

『Abstract』The goal of future quantum networks is to enable new internet applications that are impossible to achieve using only classical communication . Up to now, demonstrations of quantum network applications and functionalities on quantum processors have been performed in ad hoc software that was specific to the experimental setup, programmed to perform one single task (the application experiment) directly into low-level control devices using expertise in experimental physics. Here we report on the design and implementation of an architecture capable of executing quantum network applications on quantum processors in platform-independent high-level software. We demonstrate the capability of the architecture to execute applications in high-level software by implementing it as a quantum network operating system—QNodeOS—and executing test programs, including a delegated computation from a client to a server on two quantum network nodes based on nitrogen-vacancy (NV) centres in diamond . We show how our architecture allows us to maximize the use of quantum network hardware by multitasking different applications. Our architecture can be used to execute programs on any quantum processor platform corresponding to our system model, which we illustrate by demonstrating an extra driver for QNodeOS for a trapped-ion quantum network node based on a single Ca atom . Our architecture lays the groundwork for computer science research in quantum network programming and paves the way for the development of software that can bring quantum network technology to society.

『Abstract』Interfacial water exhibits rich and complex behaviour , playing an important part in chemistry, biology, geology and engineering. However, there is still much debate on the fundamental properties of water at hydrophobic interfaces, such as orientational ordering, the concentration of hydronium and hydroxide, improper hydrogen bonds and the presence of large electric fields . This controversy arises from the challenges in measuring interfacial systems, even with the most advanced experimental techniques and theoretical approaches available. Here we report on an in-solution, interface-selective Raman spectroscopy method using multivariate curve resolution to probe hexadecane-in-water emulsions, aided by a monomer-field theoretical model for Raman spectroscopy . Our results indicate that oil–water emulsion interfaces can exhibit reduced tetrahedral order and weaker hydrogen bonding, along with a substantial population of free hydroxyl groups that experience about 95 cm redshift in their stretching mode compared with planar oil–water interfaces. Given the known electrostatic zeta potential characteristic of oil droplets , we propose the existence of a strong electric field (about 50–90 MV cm ) emanating from the oil phase. This field is inferred indirectly but supported by control experiments and theoretical estimates. These observations are either absent or opposite in the molecular hydrophobic interface formed by small solutes or at planar oil–water interfaces. Instead, water structural disorder and enhanced electric fields emerge as unique features of the mesoscale interface in oil–water emulsions, potentially contributing to the accelerated chemical reactivity observed at hydrophobic–water interfaces .

『Abstract』One of the main interpretations of deep-rooted geophysical structures in the mantle is that they stem from the top-down solidification of the primitive basal magma ocean of Earth above the core . However, it remains debated whether solids first formed at the bottom of the mantle, solidifying upward, or above the melts, solidifying downward. Here we show that gravitational segregation of dense, iron-rich melts from lighter, iron-poor solids drives mantle evolution, regardless of where melting curves and geotherms intersect. This process results in the accumulation of iron-oxide-rich melts above the core, forming a basal magma ocean. We numerically model mantle solidification using a new multiphase fluid dynamics approach that integrates melting phase relations and geochemical models. This enables estimating the compositional signature and spatial distribution of primordial geochemical reservoirs, which may be directly linked to the isotopic anomalies measured in Archean rocks . We find that a substantial amount of solids is produced at the surface of the planet, not at depth, injecting geochemical signatures of shallow silicate fractionation in the deep mantle. This work could serve as a foundation for re-examining the intricate interplay between mantle dynamics, petrology and geochemistry during the first thousand million years of the evolution of rocky planets.

『Abstract』Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent, bioaccumulative and anthropogenic pollutants that have attracted the attention of the public and private sectors because of their adverse impact on human health . Although various technologies have been deployed to degrade PFASs with a focus on non-polymeric functionalized compounds (perfluorooctanoic acid and perfluorooctanesulfonic acid) , a general PFAS destruction method coupled with fluorine recovery for upcycling is highly desirable. Here we disclose a protocol that converts multiple classes of PFAS, including the fluoroplastics polytetrafluoroethylene and polyvinylidene fluoride, into high-value fluorochemicals. To achieve this, PFASs were reacted with potassium phosphate salts under solvent-free mechanochemical conditions, a mineralization process enabling fluorine recovery as KF and K 2 PO 3 F for fluorination chemistry. The phosphate salts can be recovered for reuse, implying no detrimental impact on the phosphorus cycle. Therefore, PFASs are not only destructible but can now contribute to a sustainable circular fluorine economy.

『Abstract』The generation of large-scale entangled states is crucial for quantum technologies, such as quantum computation , communication and metrology . Integrated quantum photonics that enables on-chip encoding, processing and detection of quantum light states offers a promising platform for the generation and manipulation of large-scale entangled states . Generating entanglement between qubits encoded in discrete variables within single photons is challenging, owing to the difficulty of making single photons interact on photonic chips . Devices that operate with continuous variables are more promising, as they enable the deterministic generation and entanglement of qumodes, in which information is encoded in light quadratures. Demonstrations so far have been limited to entanglement between two qumodes . Here we report the deterministic generation of a continuous-variable eight-mode entanglement on an integrated optical chip. The chip delivers a quantum microcomb that produces multimode squeezed-vacuum optical frequency combs below the threshold. We verify the inseparability of our eight-mode state and demonstrate supermode multipartite entanglement over hundreds of megahertz sideband frequencies through violation of the van Loock–Furusawa criteria. By measuring the full matrices of nullifier correlations with sufficiently low off-diagonal noises, we characterize multipartite entanglement structures, which are approximate to the expected cluster-type structures for finite squeezing. This work shows the potential of continuous-variable integrated photonic quantum devices for facilitating quantum computing, networking and sensing.

『Abstract』Many technological breakthroughs in electronics and photonics were made possible by downscaling—the process of making elementary devices smaller in size . The downsizing of light-emitting diodes (LEDs) based on III–V semiconductors led to micro-LEDs , an ‘ultimate technology’ for displays. However, micro-LEDs are costly to produce and they exhibit severe efficiency losses when the pixel sizes are reduced to about 10 μm or less, hindering their potential in commercial applications. Here we show the downscaling of an emerging class of LEDs based on perovskite semiconductors to below the conventional size limits. Micro- and nano-perovskite LEDs (micro-PeLEDs/nano-PeLEDs) with characteristic pixel lengths from hundreds of micrometres down to about 90 nm are demonstrated, through a localized contact fabrication scheme that prevents non-radiative losses at the pixel boundaries. For our near-infrared (NIR) and green micro-PeLEDs, average external quantum efficiencies (EQEs) are maintained at around 20% across a wide range of pixel lengths (650 to 3.5 μm), exhibiting minimum performance reduction on downsizing. Our nano-PeLEDs with characteristic pixel lengths down to about 90 nm represent the smallest LEDs reported, enabling a record-high pixel density of 127,000 pixels per inch (PPI) among all classes of LED arrays. Our demonstration showcases the strength of micro- and nano-PeLEDs as a next-generation light-source technology with unprecedented compactness and scalability.

『Abstract』Online platforms are rife with racial discrimination , but current interventions focus on employers rather than customers. We propose a customer-facing solution: changing to a two-point rating scale (dichotomization). Compared with the ubiquitous five-star scale, we argue that dichotomization reduces modern racial discrimination by focusing evaluators on the distinction between ‘good’ and ‘bad’ performance, thereby reducing how personal beliefs shape customer assessments. Study 1 is a quasi-natural experiment on a home-services labour platform ( n = 69,971) in which the company exogenously changed from a five-star scale to a dichotomous scale (thumbs up or thumbs down). Dichotomization eliminated customers’ racial discrimination whereby non-white workers received lower ratings and earned 91 cents for each US dollar paid to white workers for the same work. A pre-registered experiment (study 2, n = 652) found that the equalizing effect of dichotomization is most prevalent among evaluators holding modern racist beliefs. Further experiments (study 3, n = 1,435; study 4, n = 528) provide evidence of the proposed mechanism, and eight supplementary studies support measurement and design choices. Our research offers a promising intervention for reducing customers’ subtle racial discrimination in a large section of the economy and contributes to the interdisciplinary literature on evaluation processes and racial inequality.

『Abstract』Greenlandic Inuit and other indigenous populations are underrepresented in genetic research , leading to inequity in healthcare opportunities. To address this, we performed analyses of sequenced or imputed genomes of 5,996 Greenlanders with extensive phenotypes. We quantified their historical population bottleneck and how it has shaped their genetic architecture to have fewer, but more common, variable sites. Consequently, we find twice as many high-impact genome-wide associations to metabolic traits in Greenland compared with Europe. We infer that the high-impact variants arose after the population split from Native Americans and thus are Arctic-specific, and show that some of them are common due to not only genetic drift but also selection. We also find that European-derived polygenic scores for metabolic traits are only half as accurate in Greenlanders as in Europeans, and that adding Arctic-specific variants improves the overall accuracy to the same level as in Europeans. Similarly, lack of representation in public genetic databases makes genetic clinical screening harder in Greenlandic Inuit, but inclusion of Greenlandic data remedies this by reducing the number of non-causal candidate variants by sixfold. Finally, we identify pronounced genetic fine structure that explains differences in prevalence of monogenic diseases in Greenland and, together with recent changes in mobility, leads to a predicted future reduction in risk for certain recessive diseases. These results illustrate how including data from Greenlanders can greatly reduce inequity in genomic-based healthcare.

『Abstract』Duchenne muscular dystrophy (DMD) is a muscle-degenerating disease caused by mutations in the DMD gene, which encodes the dystrophin protein . Utrophin ( UTRN ), the genetic and functional paralogue of DMD , is upregulated in some DMD patients . To further investigate this UTRN upregulation, we first developed an inducible messenger RNA (mRNA) degradation system for DMD by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers DMD mutant mRNA decay and UTRN upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of UTRN upregulation, whereas overexpressing DMD does not. Furthermore, overexpressing DMD minigenes in wild-type cells causes UTRN upregulation, as does a wild-type DMD minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of DMD , aiming to introduce PTCs. We found that these ASOs cause UTRN upregulation. In addition, when using an ASO to restore the DMD reading frame in myotubes derived from a DMD patient, an actual DMD treatment, UTRN upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation plays a key role in UTRN upregulation in DMD patients, and they highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via transcriptional adaptation.

『Abstract』Nucleotide-binding leucine-rich repeat (NLR) receptors play crucial roles in plant immunity by sensing pathogen effectors . In Arabidopsis , certain sensor NLRs function as NADases to catalyse the production of second messengers , which can be recognized by enhanced disease susceptibility 1 (EDS1) with its partner senescence-associated gene 101 (SAG101), to activate helper NLR N requirement gene 1 (NRG1) . A cryoelectron microscopy structure shows that second-messenger-activated EDS1–SAG101 mainly contacts the leucine-rich repeat domain of NRG1A to mediate the formation of an induced EDS1–SAG101–NRG1A complex. Structural comparisons show that binding of a second messenger induces conformational changes in EDS1–SAG101, which are recognized by NRG1A, leading to its allosteric activation. We further show that an inhibitory NRG1 family member, NRG1C, efficiently outcompetes NRG1A for binding to second-messenger-activated EDS1–SAG101. These findings uncover mechanisms for NRG1A activation through its recognition of a modified host EDS1–SAG101 complex, and NRG1A inhibition by NRG1C through sequestration of the activated EDS1–SAG101, thus shedding light on the activation and constraint of a central plant immune response system.

『Abstract』Plant nucleotide-binding leucine-rich repeat (NLR) receptors sense pathogen effectors and form resistosomes to confer immunity . Some sensor NLR resistosomes produce small molecules to induce formation of a heterotrimer complex with two lipase-like proteins, EDS1 and SAG101, and a helper NLR called NRG1 (refs. ). Activation of sensor NLR resistosomes also triggers NRG1 oligomerization and resistosome formation at the plasma membrane . We demonstrate that the Arabidopsis AtEDS1–AtSAG101–AtNRG1A heterotrimer formation is stabilized by the AtNRG1A loss-of-oligomerization mutant L134E . We report structures of AtEDS1–AtSAG101–AtNRG1A L134E and AtEDS1–AtSAG101–AtNRG1C heterotrimers with similar assembly mechanisms. AtNRG1A signalling is activated by the interaction with the AtEDS1–AtSAG101 heterodimer in complex with their small-molecule ligand. The truncated AtNRG1C maintains core interacting domains of AtNRG1A but develops further interactions with AtEDS1–AtSAG101 to outcompete AtNRG1A. Moreover, AtNRG1C lacks an N-terminal signalling domain and shows nucleocytoplasmic localization, facilitating its sequestration of AtEDS1–AtSAG101, which is also nucleocytoplasmic. Our study shows the activation and inhibition mechanisms of a plant helper NLR.

『Abstract』The recognition of ligands by transmembrane proteins is essential for the exchange of materials, energy and information across biological membranes. Progress has been made in the de novo design of transmembrane proteins , as well as in designing water-soluble proteins to bind small molecules , but de novo design of transmembrane proteins that tightly and specifically bind to small molecules remains an outstanding challenge . Here we present the accurate design of ligand-binding transmembrane proteins by integrating deep learning and energy-based methods. We designed pre-organized ligand-binding pockets in high-quality four-helix backbones for a fluorogenic ligand, and generated a transmembrane span using gradient-guided hallucination. The designer transmembrane proteins specifically activated fluorescence of the target fluorophore with mid-nanomolar affinity, exhibiting higher brightness and quantum yield compared to those of enhanced green fluorescent protein. These proteins were highly active in the membrane fraction of live bacterial and eukaryotic cells following expression. The crystal and cryogenic electron microscopy structures of the designer protein–ligand complexes were very close to the structures of the design models. We showed that the interactions between ligands and transmembrane proteins within the membrane can be accurately designed. Our work paves the way for the creation of new functional transmembrane proteins, with a wide range of applications including imaging, ligand sensing and membrane transport.

『Abstract』Human treponemal infections are caused by a family of closely related Treponema pallidum that give rise to the diseases yaws, bejel, pinta and, most notably, syphilis . Debates on a common origin for these pathogens and the history of syphilis itself have weighed evidence for the ‘Columbian hypothesis’ , which argues for an American origin, against that for the ‘pre-Columbian hypothesis’ , which argues for the presence of the disease in Eurasia in the Medieval period and possibly earlier. Although molecular data has provided a genetic basis for distinction of the typed subspecies , deep evolution of the complex has remained unresolved owing to limitations in the conclusions that can be drawn from the sparse palaeogenomic data that are currently available. Here we explore this evolutionary history through analyses of five pre- and peri-contact ancient treponemal genomes from the Americas that represent ancient relatives of the T. pallidum subsp. pallidum (syphilis), T. pallidum subsp. pertenue (yaws) and T. pallidum subsp. endemicum (bejel) lineages. Our data indicate unexplored diversity and an emergence of T. pallidum that post-dates human occupation in the Americas. Together, these results support an American origin for all T. pallidum characterized at the genomic level, both modern and ancient.

『Abstract』Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens . However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient’s tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL , PBRM1 , BAP1 , KDM5C and PIK3CA . Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.

『Abstract』The genetic code is conserved across all domains of life, yet exceptions have revealed variations in codon assignments and associated translation factors . Inspired by this natural malleability, synthetic approaches have demonstrated whole-genome replacement of synonymous codons to construct genomically recoded organisms (GROs) with alternative genetic codes. However, no efforts have fully leveraged translation factor plasticity and codon degeneracy to compress translation function to a single codon and assess the possibility of a non-degenerate code. Here we describe construction and characterization of Ochre, a GRO that fully compresses a translational function into a single codon. We replaced 1,195 TGA stop codons with the synonymous TAA in ∆TAG Escherichia coli C321.∆A . We then engineered release factor 2 (RF2) and tRNA to mitigate native UGA recognition, translationally isolating four codons for non-degenerate functions. Ochre thus utilizes UAA as the sole stop codon, with UGG encoding tryptophan and UAG and UGA reassigned for multi-site incorporation of two distinct non-standard amino acids into single proteins with more than 99% accuracy. Ochre fully compresses degenerate stop codons into a single codon and represents an important step toward a 64-codon non-degenerate code that will enable precise production of multi-functional synthetic proteins with unnatural encoded chemistries and broad utility in biotechnology and biotherapeutics.

『Abstract』Tissue-resident memory CD8 T (T RM ) cells provide protection from infection at barrier sites. In the small intestine, T RM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential . However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the phenotypic heterogeneity of T RM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific T RM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct T RM cell states: differentiated T RM cells and progenitor-like T RM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand–receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.

『Abstract』Cardiomyocytes can be implanted to remuscularize the failing heart . Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques. After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation , long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed. The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.

『Abstract』Numerous studies support the role of dopamine in modulating aggression , but the exact neural mechanisms remain elusive. Here we show that dopaminergic cells in the ventral tegmental area (VTA) can bidirectionally modulate aggression in male mice in an experience-dependent manner. Although VTA dopaminergic cells strongly influence aggression in novice aggressors, they become ineffective in expert aggressors. Furthermore, eliminating dopamine synthesis in the VTA prevents the emergence of aggression in naive mice but leaves aggression intact in expert aggressors. VTA dopamine modulates aggression through the dorsal lateral septum (dLS), a region known for aggression control. Dopamine enables the flow of information from the hippocampus to the dLS by weakening local inhibition in novice aggressors. In expert aggressors, dLS local inhibition naturally weakens, and the ability of dopamine to modulate dLS cells diminishes. Overall, these results reveal a sophisticated role of dopamine in the rise of aggression in adult male mice.

『Abstract』Molecular recognition events between proteins drive biological processes in living systems . However, higher levels of mechanistic regulation have emerged, in which protein–protein interactions are conditioned to small molecules . Despite recent advances, computational tools for the design of new chemically induced protein interactions have remained a challenging task for the field . Here we present a computational strategy for the design of proteins that target neosurfaces, that is, surfaces arising from protein–ligand complexes. To develop this strategy, we leveraged a geometric deep learning approach based on learned molecular surface representations and experimentally validated binders against three drug-bound protein complexes: Bcl2–venetoclax, DB3–progesterone and PDF1–actinonin. All binders demonstrated high affinities and accurate specificities, as assessed by mutational and structural characterization. Remarkably, surface fingerprints previously trained only on proteins could be applied to neosurfaces induced by interactions with small molecules, providing a powerful demonstration of generalizability that is uncommon in other deep learning approaches. We anticipate that such designed chemically induced protein interactions will have the potential to expand the sensing repertoire and the assembly of new synthetic pathways in engineered cells for innovative drug-controlled cell-based therapies .

『Abstract』The ability to flexibly switch our responses to external stimuli according to contextual information is critical for successful interactions with a complex world. Context-dependent computations are necessary across many domains , yet their neural implementations remain poorly understood. Here we developed a novel behavioural task in rats to study context-dependent selection and accumulation of evidence for decision-making . Under assumptions supported by both monkey and rat data, we first show mathematically that this computation can be supported by three dynamical solutions and that all networks performing the task implement a combination of these solutions. These solutions can be identified and tested directly with experimental data. We further show that existing electrophysiological and modelling data are compatible with the full variety of possible combinations of these solutions, suggesting that different individuals could use different combinations. To study variability across individual subjects, we developed automated, high-throughput methods to train rats on our task and trained many subjects using these methods. Consistent with theoretical predictions, neural and behavioural analyses revealed substantial heterogeneity across rats, despite uniformly good task performance. Our theory further predicts a specific link between behavioural and neural signatures, which was robustly supported in the data. In summary, our results provide an experimentally supported theoretical framework to analyse individual variability in biological and artificial systems that perform flexible decision-making tasks, open the door to cellular-resolution studies of individual variability in higher cognition, and provide insights into neural mechanisms of context-dependent computation more generally.

『Abstract』The human genome contains millions of candidate cis -regulatory elements (cCREs) with cell-type-specific activities that shape both health and many disease states . However, we lack a functional understanding of the sequence features that control the activity and cell-type-specific features of these cCREs. Here we used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test the regulatory activity of more than 680,000 sequences, representing an extensive set of annotated cCREs among three cell types (HepG2, K562 and WTC11), and found that 41.7% of these sequences were active. By testing sequences in both orientations, we find promoters to have strand-orientation biases and their 200-nucleotide cores to function as non-cell-type-specific ‘on switches’ that provide similar expression levels to their associated gene. By contrast, enhancers have weaker orientation biases, but increased tissue-specific characteristics. Utilizing our lentiMPRA data, we develop sequence-based models to predict cCRE function and variant effects with high accuracy, delineate regulatory motifs and model their combinatorial effects. Testing a lentiMPRA library encompassing 60,000 cCREs in all three cell types further identified factors that determine cell-type specificity. Collectively, our work provides an extensive catalogue of functional CREs in three widely used cell lines and showcases how large-scale functional measurements can be used to dissect regulatory grammar.

『Abstract』Peripheral neuropathy is a common complication of type 2 diabetes, which is strongly associated with obesity , causing sensory loss and, in some patients, neuropathic pain . Although the onset and progression of diabetic peripheral neuropathy is linked with dyslipidaemia and hyperglycaemia , the contribution of inflammation to peripheral neuropathy pathogenesis has not been investigated. Here we used a high-fat, high-fructose diet (HFHFD), which induces obesity and prediabetic metabolic changes, to study the onset of peripheral neuropathy. Mice fed the HFHFD developed persistent heat hypoalgesia after 3 months, but a reduction in epidermal skin nerve fibre density manifested only at 6 months. Using single-cell sequencing, we found that CCR2 macrophages infiltrate the sciatic nerves of HFHFD-fed mice well before axonal degeneration is detectable. These infiltrating macrophages share gene expression similarities with nerve-crush-induced macrophages and express neurodegeneration-associated microglial marker genes , although there is no axon loss or demyelination. Inhibiting the macrophage recruitment by genetically or pharmacologically blocking CCR2 signalling resulted in more severe heat hypoalgesia and accelerated skin denervation, as did deletion of Lgals3 , a gene expressed in recruited macrophages. Recruitment of macrophages into the peripheral nerves of obese prediabetic mice is, therefore, neuroprotective, delaying terminal sensory axon degeneration by means of galectin 3. Potentiating and sustaining early neuroprotective immune responses in patients could slow or prevent peripheral neuropathy.

『Abstract』Nanoribbons, nanometre-wide strips of a two-dimensional material, are a unique system in condensed matter. They combine the exotic electronic structures of low-dimensional materials with an enhanced number of exposed edges, where phenomena including ultralong spin coherence times , quantum confinement and topologically protected states can emerge. An exciting prospect for this material concept is the potential for both a tunable semiconducting electronic structure and magnetism along the nanoribbon edge, a key property for spin-based electronics such as (low-energy) non-volatile transistors . Here we report the magnetic and semiconducting properties of phosphorene nanoribbons (PNRs). We demonstrate that at room temperature, films of PNRs show macroscopic magnetic properties arising from their edge, with internal fields of roughly 240 to 850 mT. In solution, a giant magnetic anisotropy enables the alignment of PNRs at sub-1-T fields. By leveraging this alignment effect, we discover that on photoexcitation, energy is rapidly funnelled to a state that is localized to the magnetic edge and coupled to a symmetry-forbidden edge phonon mode. Our results establish PNRs as a fascinating system for studying the interplay between magnetism and semiconducting ground states at room temperature and provide a stepping-stone towards using low-dimensional nanomaterials in quantum electronics.

『Abstract』The biogenic structures produced by termites, ants and earthworms provide key functions across global ecosystems . However, little is known about the drivers of the soil engineering effects caused by these small but important invertebrates at the global scale. Here we show, on the basis of a meta-analysis of 12,975 observations from 1,047 studies on six continents, that all three taxa increase soil macronutrient content, soil respiration and soil microbial and plant biomass compared with reference soils. The effect of termites on soil respiration and plant biomass, and the effect of earthworms on soil nitrogen and phosphorus content, increase with mean annual temperature and peak in the tropics. By contrast, the effects of ants on soil nitrogen, soil phosphorus, plant biomass and survival rate peak at mid-latitude ecosystems that have the lowest primary productivity. Notably, termites and ants increase plant growth by alleviating plant phosphorus limitation in the tropics and nitrogen limitation in temperate regions, respectively. Our study highlights the important roles of these invertebrate taxa in global biogeochemical cycles and ecosystem functions. Given the importance of these soil-engineering invertebrates, biogeochemical models should better integrate their effects, especially on carbon fluxes and nutrient cycles.

『Abstract』DNA damage promotes mutations that fuel cancer, ageing and neurodegenerative diseases , but surprisingly, the causes and types of damage remain largely unknown. There are three identified mechanisms that damage DNA during transcription: collision of RNA polymerase (RNAP) with the DNA-replication machinery head-on and co-directionally , and R-loop-induced DNA breakage . Here we identify novel DNA damage reaction intermediates and uncover a fourth transcription-related source of DNA damage: endogenous DNA damage at sites of terminated transcripts. We engineered proteins to capture single-stranded DNA (ssDNA) ends with 3′ polarity in bacterial and human cells. In Escherichia coli , spontaneous 3′-ssDNA-end foci were unexpectedly frequent, at one or more per cell division, and arose via two identifiable pathways, both of which were dependent on DNA replication. A pathway associated with double-strand breaks was suppressed by overexpression of replicative DNA polymerase (pol) III, suggesting competition between pol III and DNA damage-promoting proteins. Mapping of recurrent 3′-ssDNA-ends identified distinct 3′-ssDNA-end-hotspots, mostly unrelated to double-strand breaks, next to the 5′-CCTTTTTT transcription-terminator-like sequence. These 3′-ssDNA-termini coincide with RNA 3′-termini identified by DirectRNA sequencing or simultaneous 5′ and 3′ end RNA sequencing (SEnd-seq) and were prevented by a mutant RNAP that reads through terminators. Our findings reveal that transcription termination or pausing can promote DNA damage and subsequent genomic instability.

『Abstract』Globalization increasingly allows countries to externalize the environmental costs of land use, including biodiversity loss . So far, we have a very incomplete understanding of how countries cause biodiversity loss outside their own borders through their demand for agricultural and forestry products grown in other countries . Here we quantify the global range losses to forest vertebrates from 2001 to 2015 caused by deforestation attributable to 24 developed countries by means of their consumption of products obtained through global supply chains. We show that these driver countries are responsible for much greater cumulative range loss to species outside their own borders than within them. These international impacts were concentrated geographically, allowing us to map global hotspots of outsourced losses of biodiversity. Countries had the greatest external impacts on species occurring in nearby regions. However, in a few cases, developed countries also inflicted disproportionate harm on vertebrates in distant countries.

『Abstract』Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence . Mutation of Apc , the most common initiating event in conventional adenomas , activates Wnt signalling, thus conferring fitness on mutant intestinal stem cells (ISCs) . Apc mutations may occur in ISCs that arise by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar , it is unclear whether both generate tumours equally well in uninjured intestines. It is also unknown whether cis -regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source, but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc -null ISCs that are not associated with adenomas. These cis elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumorigenesis.

『Abstract』T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens . However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity . Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22 . In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cells under physiologic conditions and are sufficient to trigger cancer cell eradication by neoantigen-specific CD8 T cells. Moreover, our study highlights a role for dysregulated splicing factor expression in specific cancer types, leading to recurrent patterns of neojunction upregulation. These findings establish a molecular basis for T cell-based immunotherapies addressing the challenges of intratumoural heterogeneity.

『Abstract』Cognitive maps confer animals with flexible intelligence by representing spatial, temporal and relationships that can be used to shape thought, planning and behaviour. Cognitive maps have been observed in the hippocampus , but their algorithmic form and learning mechanisms remain obscure. Here we used large-scale, longitudinal two-photon calcium imaging to record activity from thousands of neurons in the CA1 region of the hippocampus while mice learned to efficiently collect rewards from two subtly different linear tracks in virtual reality. Throughout learning, both animal behaviour and hippocampal neural activity progressed through multiple stages, gradually revealing improved task representation that mirrored improved behavioural efficiency. The learning process involved progressive decorrelations in initially similar hippocampal neural activity within and across tracks, ultimately resulting in orthogonalized representations resembling a state machine capturing the inherent structure of the task. This decorrelation process was driven by individual neurons acquiring task-state-specific responses (that is, ‘state cells’). Although various standard artificial neural networks did not naturally capture these dynamics, the clone-structured causal graph, a hidden Markov model variant, uniquely reproduced both the final orthogonalized states and the learning trajectory seen in animals. The observed cellular and population dynamics constrain the mechanisms underlying cognitive map formation in the hippocampus, pointing to hidden state inference as a fundamental computational principle, with implications for both biological and artificial intelligence.

『Abstract』Bacteriophages use diverse mechanisms to evade antiphage defence systems. ΦKZ-like jumbo phages assemble a proteinaceous, nucleus-like compartment that excludes antagonistic host nucleases and also internalizes DNA replication and transcription machinery . The phage factors required for protein import and the mechanisms of selectivity remain unknown, however. Here we uncover an import system comprising proteins highly conserved across nucleus-forming phages, together with additional cargo-specific contributors. Using a genetic selection that forces the phage to decrease or abolish the import of specific proteins, we determine that the importation of five different phage nuclear-localized proteins requires distinct interfaces of the same factor, Imp1 (gp69). Imp1 localizes early to the nascent phage nucleus and forms discrete puncta in the mature phage nuclear periphery, probably in complex with direct interactor Imp6 (gp67), a conserved protein encoded in the same locus. The import of certain proteins, including a host topoisomerase, additionally requires Imp3 (gp59), a conserved factor necessary for proper Imp1 function. Three additional non-conserved phage proteins (Imp2 and Imp4/Imp5) are required for the import of two queried nuclear cargos (nuclear-localized protein 1 and host topoisomerase, respectively), perhaps acting as specific adaptors. We therefore propose a core import system that includes Imp1, Imp3 and Imp6, with multiple interfaces of Imp1 licensing transport through a protein lattice.

『Abstract』Glaciers are indicators of ongoing anthropogenic climate change . Their melting leads to increased local geohazards , and impacts marine and terrestrial ecosystems, regional freshwater resources , and both global water and energy cycles . Together with the Greenland and Antarctic ice sheets, glaciers are essential drivers of present and future sea-level rise. Previous assessments of global glacier mass changes have been hampered by spatial and temporal limitations and the heterogeneity of existing data series . Here we show in an intercomparison exercise that glaciers worldwide lost 273 ± 16 gigatonnes in mass annually from 2000 to 2023, with an increase of 36 ± 10% from the first (2000–2011) to the second (2012–2023) half of the period. Since 2000, glaciers have lost between 2% and 39% of their ice regionally and about 5% globally. Glacier mass loss is about 18% larger than the loss from the Greenland Ice Sheet and more than twice that from the Antarctic Ice Sheet . Our results arise from a scientific community effort to collect, homogenize, combine and analyse glacier mass changes from in situ and remote-sensing observations. Although our estimates are in agreement with findings from previous assessments at a global scale, we found some large regional deviations owing to systematic differences among observation methods. Our results provide a refined baseline for better understanding observational differences and for calibrating model ensembles , which will help to narrow projection uncertainty for the twenty-first century .

『Abstract』A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix . Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR fibroblasts that arise during alveologenesis include SCUBE2 alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1 POSTN pathological fibroblasts. Genetic ablation of POSTN pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with Lepr or Scube2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR cells that include SCUBE2 alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.

『Abstract』Modular structure and function are ubiquitous in biology, from the organization of animal brains and bodies to the scale of ecosystems. However, the mechanisms of modularity emergence from non-modular precursors remain unclear. Here we introduce the principle of peak selection, a process by which purely local interactions and smooth gradients can drive the self-organization of discrete global modules. The process combines strengths of the positional and Turing pattern-formation mechanisms into a model for morphogenesis. Applied to the grid-cell system of the brain, peak selection results in the self-organization of functionally distinct modules with discretely spaced spatial periods. Applied to ecological systems, it results in discrete multispecies niches and synchronous spawning across geographically distributed coral colonies. The process exhibits self-scaling with system size and ‘topological robustness’ , which renders module emergence and module properties insensitive to most parameters. Peak selection ameliorates the fine-tuning requirement for continuous attractor dynamics in single grid-cell modules and it makes a detail-independent prediction that grid module period ratios should approximate adjacent integer ratios, providing a highly accurate match to the available data. Predictions for grid cells at the transcriptional, connectomic and physiological levels promise to elucidate the interplay of molecules, connectivity and function emergence in brains.

『Abstract』The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA-binding proteins (RBPs) is present on the surface of living cells. These cell-surface RBPs (csRBPs) precisely organize into well-defined nanoclusters enriched for multiple RBPs and glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell-surface interaction for the cell-penetrating peptide trans -activator of transcription (TAT). Removal of RNA from the cell surface, or loss of RNA-binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.

『Abstract』Coenzyme Q (CoQ) is essential for energy production by mitochondrial respiration, and it is a supplement most often used to promote cardiovascular health. Humans make CoQ 10 , but cereals and some vegetable/fruit crops synthesize CoQ 9 with a side chain of nine isoprene units. Engineering CoQ 10 production in crops would benefit human health, but this is hindered by the fact that the specific residues of the enzyme Coq1 that control chain length are unknown. Based on an extensive investigation of the distribution of CoQ 9 and CoQ 10 in land plants and the associated Coq1 sequence variation, we identified key amino acid changes at the base of the Coq1 catalytic pocket that occurred independently in multiple angiosperm lineages and repeatedly drove CoQ 9 formation. Guided by this knowledge, we used gene editing to modify the native Coq1 genes of rice and wheat to produce CoQ 10 , paving the way for developing additional dietary sources of CoQ 10 .

『Abstract』Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (m A) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the cancer genome with the potential to perturb m A modification patterns, which we refer to as “m A disruption mutations (m A-DMs).” These are either synonymous m A-DMs (sm A-DMs) or missense m A-DMs (mm A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m A levels at specific sm A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm A-DMs into cancer cells promotes tumor growth while BRCA2 sm A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.

『Abstract』Despite ongoing efforts to study CRISPR systems, the evolutionary origins giving rise to reprogrammable RNA-guided mechanisms remain poorly understood. Here, we describe an integrated sequence/structure evolutionary tracing approach to identify the ancestors of the RNA-targeting CRISPR-Cas13 system. We find that Cas13 likely evolved from AbiF, which is encoded by an abortive infection-linked gene that is stably associated with a conserved non-coding RNA (ncRNA). We further characterize a miniature Cas13, classified here as Cas13e, which serves as an evolutionary intermediate between AbiF and other known Cas13s. Despite this relationship, we show that their functions substantially differ. Whereas Cas13e is an RNA-guided RNA-targeting system, AbiF is a toxin-antitoxin (TA) system with an RNA antitoxin. We solve the structure of AbiF using cryoelectron microscopy (cryo-EM), revealing basic structural alterations that set Cas13s apart from AbiF. Finally, we map the key structural changes that enabled a non-guided TA system to evolve into an RNA-guided CRISPR system.

『Abstract』The Sec translocon is vital for guiding membrane protein insertion into lipid bilayers. The insertion and folding processes of membrane proteins are poorly understood. Here, we report cryo-electron microscopy structures of multi-spanning membrane proteins inserting through the SecY channel, the Sec translocon in prokaryotes. The high-resolution structures illustrate how bulky amino acids pass the narrow channel restriction. Comparison of different translocation states reveals that the cytoplasmic and extracellular cavities of the channel create distinct environments for promoting the unfolding and folding of transmembrane segments (TMs), respectively. Released substrate TMs are either flexible or stabilized by an unexpected hydrophilic groove between TM3 and TM4 of SecY. Disruption of the groove causes global defects in the folding of the membrane proteome. These findings demonstrate that beyond its role as a passive protein-conducting channel, the SecY translocon actively serves as a chaperone, employing multiple mechanisms to promote membrane protein insertion and folding.

『Abstract』Space habitation provides unique challenges in built environments isolated from Earth. We produced a 3D map of the microbes and metabolites throughout the United States Orbital Segment (USOS) of the International Space Station (ISS) with 803 samples collected during space flight, including controls. We find that the use of each of the nine sampled modules within the ISS strongly drives the microbiology and chemistry of the habitat. Relating the microbiology to other Earth habitats, we find that, as with human microbiota, built environment microbiota also align naturally along an axis of industrialization, with the ISS providing an extreme example of an industrialized environment. We demonstrate the utility of culture-independent sequencing for microbial risk monitoring, especially as the location of sequencing moves to space. The resulting resource of chemistry and microbiology in the space-built environment will guide long-term efforts to maintain human health in space for longer durations.

『Abstract』Parasitism with Striga poses a major threat to global food production. Striga germination and growth rely on strigolactones (SLs) exuded by crop roots under phosphate (Pi)-deficient conditions, although the mechanism of this host-parasite interaction remains elusive. In this study, transcriptomic and functional analyses of sorghum treated with Pi deficiency or the SL GR24 identify two ABC transporter G (ABCG) transporters of SL, Sorghum biocolor strigolactones transporter 1 (SbSLT1) and SbSLT2. Using AlphaFold2 and amino acid conversion mutants, we identify highly conserved amino acids in SL transport channels essential for transport function. Sorghum lines with single or double knockouts of these transporters exhibit significantly reduced SL secretion from roots, leading to decreased Striga germination and parasitism in field experiments and consequently reducing the grain loss under Striga infestation. This study thus describes the mechanism of SL exudation in monocots and defines conserved residues essential for SL transporter function, offering a potential strategy for enhancing crop resistance to Striga parasitism.

『Abstract』Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form “vitcyl-lysine”—a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo . The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC’s cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.

『Abstract』Plants are composed of diverse secondary metabolites (PSMs), which are widely associated with human health. Whether and how the gut microbiome mediates such impacts of PSMs is poorly understood. Here, we show that discrete dietary and medicinal phenolic glycosides, abundant health-associated PSMs, are utilized by distinct members of the human gut microbiome. Within the Bacteroides , the predominant gram-negative bacteria of the Western human gut, we reveal a specialized multi-enzyme system dedicated to the processing of distinct glycosides based on structural differences in phenolic moieties. This Bacteroides metabolic system liberates chemically distinct aglycones with diverse biological functions, such as colonization resistance against the gut pathogen Clostridioides difficile via anti-microbial activation of polydatin to the stilbene resveratrol and intestinal homeostasis via activation of salicin to the immunoregulatory aglycone saligenin. Together, our results demonstrate generation of biological diversity of phenolic aglycone “effector” functions by a distinct gut-microbiome-encoded PSM-processing system.

『Abstract』Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.

『Abstract』Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10R state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8 T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10R state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy’s dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.

『Abstract』Coronary arteries have a specific branching pattern crucial for oxygenating heart muscle. Among humans, there is natural variation in coronary anatomy with respect to perfusion of the inferior/posterior left heart, which can branch from either the right arterial tree, the left, or both—a phenotype known as coronary dominance. Using angiographic data for >60,000 US veterans of diverse ancestry, we conducted a genome-wide association study of coronary dominance, revealing moderate heritability and identifying ten significant loci. The strongest association occurred near CXCL12 in both European- and African-ancestry cohorts, with downstream analyses implicating effects on CXCL12 expression. We show that CXCL12 is expressed in human fetal hearts at the time dominance is established. Reducing Cxcl12 in mice altered coronary dominance and caused septal arteries to develop away from Cxcl12 expression domains. These findings indicate that CXCL12 patterns human coronary arteries, paving the way for “medical revascularization” through targeting developmental pathways.