经典100 | NCS： 2025-05-05 期

『Abstract』Crop production faces persistent threats from insect-vector-borne viral diseases . Recent advancements have revealed the intricate immune mechanisms that plants deploy against viral pathogens . However, the molecular mechanisms through which plant hosts recognize viral infections and initiate antiviral defence at disease onset have not been elucidated. Here, through the natural infection of rice by inoculation with insect vectors carrying the natural forms of viruses, we show that viral coat proteins are perceived by the RING1–IBR–RING2-type ubiquitin ligase (RBRL), initiating the first step of the natural antiviral response in rice. RBRL subsequently targets an adaptor protein of the transcriptional repression complex of the jasmonate pathway, NOVEL INTERACTOR OF JAZ 3 (NINJA3), for degradation through the ubiquitination system, inducing jasmonate signalling and activating downstream antiviral defence. We further show that this phenomenon is a universal molecular mechanism used by rice plants to perceive viral infections and initiate antiviral signalling cascades. This approach is important not only for obtaining a deeper understanding of virus–host interactions but also for further disease resistance breeding.

『Abstract』Granzymes are a family of serine proteases that are mainly expressed by CD8 T cells, natural killer cells and innate-like lymphocytes . Although their primary function is thought to be the induction of cell death in virally infected cells and tumours, accumulating evidence indicates that some granzymes can elicit inflammation by acting on extracellular substrates . We previously found that most tissue CD8 T cells in rheumatoid arthritis synovium, and in inflamed organs for some other diseases, express granzyme K (GZMK) , a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving the C2 and C4 proteins. The nascent C4b and C2b fragments form a C3 convertase that cleaves C3, enabling the assembly of a C5 convertase that cleaves C5. The resulting convertases generate all the effector molecules of the complement cascade: the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In rheumatoid arthritis synovium, GZMK is enriched in regions with abundant complement activation, and fibroblasts are the main producers of complement proteins that serve as substrates for GZMK-mediated complement activation. Furthermore, Gzmk -deficient mice are significantly protected from inflammatory disease, exhibiting reduced arthritis and dermatitis, with concomitant decreases in complement activation. Our findings describe the discovery of a previously unidentified mechanism of complement activation that is driven entirely by lymphocyte-derived GZMK. Given the widespread abundance of GZMK -expressing T cells in tissues in chronic inflammatory diseases, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.

『Abstract』Abstract Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify formyl peptide receptor 2 (FPR2) as a membrane receptor that specifically binds long-chain ceramides (C14 to C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis through G i cyclic adenosine monophosphate signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo–electron microscopy structures of FPR2 in complex with G i trimers bound to C16:0, C18:0, and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.

『Abstract』Recent breakthroughs in ultrathin, single-crystalline, freestanding complex oxide systems have sparked industry interest in their potential for next-generation commercial devices . However, the mass production of these ultrathin complex oxide membranes has been hindered by the challenging requirement of inserting an artificial release layer between the epilayers and substrates . Here we introduce a technique that achieves atomic precision lift-off of ultrathin membranes without artificial release layers to facilitate the high-throughput production of scalable, ultrathin, freestanding perovskite systems. Leveraging both theoretical insights and empirical evidence, we have identified the pivotal role of lead in weakening the interface. This insight has led to the creation of a universal exfoliation strategy that enables the production of diverse ultrathin perovskite membranes less than 10 nm. Our pyroelectric membranes demonstrate a record-high pyroelectric coefficient of 1.76 × 10 C m K , attributed to their exceptionally low thickness and freestanding nature. Moreover, this method offers an approach to manufacturing cooling-free detectors that can cover the full far-infrared spectrum, marking a notable advancement in detector technology .

『Abstract』To survive in dynamic environments with uncertain resources, animals must adapt their behaviour flexibly, choosing strategies such as persevering with a current choice, exploring alternatives or disengaging altogether. Previous studies have mainly investigated how forebrain regions represent choice costs and values as well as optimal strategies during such decisions . However, the neural mechanisms by which the brain implements alternative behavioural strategies such as persevering, exploring or disengaging remain poorly understood. Here we identify a neural hub that is critical for flexible switching between behavioural strategies, the median raphe nucleus (MRN). Using cell-type-specific optogenetic manipulations, fibre photometry and circuit tracing in mice performing diverse instinctive and learnt behaviours, we found that the main cell types of the MRN—GABAergic (γ-aminobutyric acid-expressing), glutamatergic (VGluT2 ) and serotonergic neurons—have complementary functions and regulate perseverance, exploration and disengagement, respectively. Suppression of MRN GABAergic neurons—for instance, through inhibitory input from lateral hypothalamus, which conveys strong positive valence to the MRN—leads to perseverative behaviour. By contrast, activation of MRN VGluT2 neurons drives exploration. Activity of serotonergic MRN neurons is necessary for general task engagement. Input from the lateral habenula that conveys negative valence suppresses serotonergic MRN neurons, leading to disengagement. These findings establish the MRN as a central behavioural switchboard that is uniquely positioned to flexibly control behavioural strategies. These circuits thus may also have an important role in the aetiology of major mental pathologies such as depressive or obsessive-compulsive disorders.

『Abstract』Although it is one of the most arid regions today, the Sahara Desert was a green savannah during the African Humid Period (AHP) between 14,500 and 5,000 years before present, with water bodies promoting human occupation and the spread of pastoralism in the middle Holocene epoch . DNA rarely preserves well in this region, limiting knowledge of the Sahara’s genetic history and demographic past. Here we report ancient genomic data from the Central Sahara, obtained from two approximately 7,000-year-old Pastoral Neolithic female individuals buried in the Takarkori rock shelter in southwestern Libya. The majority of Takarkori individuals’ ancestry stems from a previously unknown North African genetic lineage that diverged from sub-Saharan African lineages around the same time as present-day humans outside Africa and remained isolated throughout most of its existence. Both Takarkori individuals are closely related to ancestry first documented in 15,000-year-old foragers from Taforalt Cave, Morocco , associated with the Iberomaurusian lithic industry and predating the AHP. Takarkori and Iberomaurusian-associated individuals are equally distantly related to sub-Saharan lineages, suggesting limited gene flow from sub-Saharan to Northern Africa during the AHP. In contrast to Taforalt individuals, who have half the Neanderthal admixture of non-Africans, Takarkori shows ten times less Neanderthal ancestry than Levantine farmers, yet significantly more than contemporary sub-Saharan genomes. Our findings suggest that pastoralism spread through cultural diffusion into a deeply divergent, isolated North African lineage that had probably been widespread in Northern Africa during the late Pleistocene epoch.

『Abstract』The pursuit of non-volatile memory with program speeds below one nanosecond, beyond the capabilities of non-volatile flash and high-speed volatile static random-access memory, remains a longstanding challenge in the field of memory technology . Utilizing fundamental physics innovation enabled by advanced materials, series of emerging memories are being developed to overcome the speed bottleneck of non-volatile memory. As the most extensively applied non-volatile memory, the speed of flash is limited by the low efficiency of the electric-field-assisted program, with reported speeds much slower than sub-one nanosecond. Here we report a two-dimensional Dirac graphene-channel flash memory based on a two-dimensional-enhanced hot-carrier-injection mechanism, supporting both electron and hole injection. The Dirac channel flash shows a program speed of 400 picoseconds, non-volatile storage and robust endurance over 5.5 × 10 cycles. Our results confirm that the thin-body channel can optimize the horizontal electric-field ( E y ) distribution, and the improved E y -assisted program efficiency increases the injection current to 60.4 pA μm at | V DS | = 3.7 V. We also find that the two-dimensional semiconductor tungsten diselenide has two-dimensional-enhanced hot-hole injection, but with different injection behaviour. This work demonstrates that the speed of non-volatile flash memory can exceed that of the fastest volatile static random-access memory with the same channel length.

『Abstract』Revealing the connectivity of functionally identified individual neurons is necessary to understand how activity patterns emerge and support behaviour. Yet the brain-wide presynaptic wiring rules that lay the foundation for the functional selectivity of individual neurons remain largely unexplored. Cortical neurons, even in primary sensory cortex, are heterogeneous in their selectivity, not only to sensory stimuli but also to multiple aspects of behaviour. Here, to investigate presynaptic connectivity rules underlying the selectivity of pyramidal neurons to behavioural state in primary somatosensory cortex (S1), we used two-photon calcium imaging, neuropharmacology, single-cell-based monosynaptic input tracing and optogenetics. We show that behavioural state-dependent activity patterns are stable over time. These are minimally affected by direct neuromodulatory inputs and are driven primarily by glutamatergic inputs. Analysis of brain-wide presynaptic networks of individual neurons with distinct behavioural state-dependent activity profiles revealed that although behavioural state-related and behavioural state-unrelated neurons shared a similar pattern of local inputs within S1, their long-range glutamatergic inputs differed. Individual cortical neurons, irrespective of their functional properties, received converging inputs from the main S1-projecting areas. Yet neurons that tracked behavioural state received a smaller proportion of motor cortical inputs and a larger proportion of thalamic inputs. Optogenetic suppression of thalamic inputs reduced behavioural state-dependent activity in S1, but this activity was not externally driven. Our results reveal distinct long-range glutamatergic inputs as a substrate for preconfigured network dynamics associated with behavioural state.

『Abstract』The axion is a hypothetical fundamental particle that is conjectured to correspond to the coherent oscillation of the θ field in quantum chromodynamics . Its existence would solve multiple fundamental questions, including the strong CP problem of quantum chromodynamics and dark matter, but the axion has never been detected. Electrodynamics of condensed-matter systems can also give rise to a similar θ , so far studied as a static, quantized value to characterize the topology of materials . Coherent oscillation of θ in condensed matter has been proposed to lead to physics directly analogous to the high-energy axion particle—the dynamical axion quasiparticle (DAQ) . Here we report the observation of the DAQ in MnBi 2 Te 4 . By combining a two-dimensional electronic device with ultrafast pump–probe optics, we observe a coherent oscillation of θ at about 44 gigahertz, which is uniquely induced by its out-of-phase antiferromagnetic magnon. This represents direct evidence for the presence of the DAQ, which in two-dimensional MnBi 2 Te 4 is found to arise from the magnon-induced coherent modulation of the Berry curvature. The DAQ also has implications in light–matter interaction and coherent antiferromagnetic spintronics , as it might lead to axion polaritons and electric control of ultrafast spin polarization . Finally, the DAQ could be used to detect axion particles . We estimate the detection frequency range and sensitivity in the millielectronvolt regime, which has so far been poorly explored.

『Abstract』Hexameric helicases are nucleotide-driven molecular machines that unwind DNA to initiate replication across all domains of life. Despite decades of intensive study, several critical aspects of their function remain unresolved : the site and mechanism of DNA strand separation, the mechanics of unwinding propagation, and the dynamic relationship between nucleotide hydrolysis and DNA movement. Here, using cryo-electron microscopy (cryo-EM), we show that the simian virus 40 large tumour antigen (LTag) helicase assembles in the form of head-to-head hexamers at replication origins, melting DNA at two symmetrically positioned sites to establish bidirectional replication forks. Through continuous heterogeneity analysis , we characterize the conformational landscape of LTag on forked DNA under catalytic conditions, demonstrating coordinated motions that drive DNA translocation and unwinding. We show that the helicase pulls the tracking strand through DNA-binding loops lining the central channel, while directing the non-tracking strand out of the rear, in a cyclic process. ATP hydrolysis functions as an ‘entropy switch’, removing blocks to translocation rather than directly powering DNA movement. Our structures show the allosteric couplings between nucleotide turnover and subunit motions that enable DNA unwinding while maintaining dedicated exit paths for the separated strands. These findings provide a comprehensive model for replication fork establishment and progression that extends from viral to eukaryotic systems. More broadly, they introduce fundamental principles of the mechanism by which ATP-dependent enzymes achieve efficient mechanical work through entropy-driven allostery.

『Abstract』We investigate the impact of germline variants on cancer patients’ proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, “precision peptidomics,” mapping 337,469 coding germline variants onto peptides from patients’ mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases ( ERBB2 and MAP2K2 ) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial fibrillary acid protein (GFAP), relevant to immunomodulation and glioblastoma diagnostics, respectively. Genome-wide association studies identified quantitative trait loci for gene expression and protein levels, spanning millions of SNPs and thousands of proteins. Polygenic risk scores correlated with distal effects from risk variants. Our findings emphasize the contribution of germline genetics to cancer heterogeneity and high-throughput precision peptidomics.

『Abstract』The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate—a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation—into the mitochondrial matrix . It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases . However, despite MPC’s critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC’s function and pave the way for the development of more-effective therapeutic reagents that target MPC.

『Abstract』The interplay between nontrivial band topology and layered antiferromagnetism in MnBi 2 Te 4 has opened a new avenue for exploring topological phases of matter . The quantum anomalous Hall effect and axion insulator state have been observed in odd and even number layers of MnBi 2 Te 4 , and the quantum metric nonlinear Hall effect has been shown to exist in this topological antiferromagnet. The rich and complex antiferromagnetic spin dynamics in MnBi 2 Te 4 is expected to generate new quantum anomalous Hall phenomena that are absent in conventional ferromagnetic topological insulators, but experimental observations are still unknown. Here we fabricate a device of 7-septuple-layer MnBi 2 Te 4 covered with an AlO x capping layer, which enables the investigation of antiferromagnetic quantum anomalous Hall effect over wide parameter spaces. By tuning the gate voltage and perpendicular magnetic field, we uncover a cascade of quantum phase transitions that can be attributed to the influence of complex spin configurations on edge state transport. Furthermore, we find that an in-plane magnetic field enhances both the coercive field and the exchange gap of the surface state, in contrast to that in the ferromagnetic quantum anomalous Hall state. Combined with numerical simulations, we propose that these peculiar features arise from the spin flip and flop transitions that are inherent to a van der Waals antiferromagnet. The versatile tunability of the quantum anomalous Hall effect in MnBi 2 Te 4 paves the way for potential applications in topological antiferromagnetic spintronics .

『Abstract』Tropical forest canopies are the biosphere’s most concentrated atmospheric interface for carbon, water and energy . However, in most Earth System Models, the diverse and heterogeneous tropical forest biome is represented as a largely uniform ecosystem with either a singular or a small number of fixed canopy ecophysiological properties . This situation arises, in part, from a lack of understanding about how and why the functional properties of tropical forest canopies vary geographically . Here, by combining field-collected data from more than 1,800 vegetation plots and tree traits with satellite remote-sensing, terrain, climate and soil data, we predict variation across 13 morphological, structural and chemical functional traits of trees, and use this to compute and map the functional diversity of tropical forests. Our findings reveal that the tropical Americas, Africa and Asia tend to occupy different portions of the total functional trait space available across tropical forests. Tropical American forests are predicted to have 40% greater functional richness than tropical African and Asian forests. Meanwhile, African forests have the highest functional divergence—32% and 7% higher than that of tropical American and Asian forests, respectively. An uncertainty analysis highlights priority regions for further data collection, which would refine and improve these maps. Our predictions represent a ground-based and remotely enabled global analysis of how and why the functional traits of tropical forest canopies vary across space.

『Abstract』Voltage-gated potassium (K V ) channels contain cytoplasmically exposed β-subunits whose aldo-keto reductase activity is required for the homeostatic regulation of sleep . Here we show that Hyperkinetic, the β-subunit of the K V 1 channel Shaker in Drosophila , forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetic’s nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls , such as 4-oxo-2-nonenal or an endogenous analogue generated by illuminating a membrane-bound photosensitizer , abstract an electron pair. NADP remains locked in the active site of K V β until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their K V β subunits; this biochemical memory influences—and is erased by—spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.

『Abstract』Abstract The gut microbiota is known to be associated with a variety of human metabolic diseases, including metabolic dysfunction–associated steatohepatitis (MASH). Fungi are increasingly recognized as important members of this community; however, the role of fungal symbionts in metabolic diseases is unknown. We have systematically isolated and characterized gut fungi, identifying Fusarium foetens as an intestinal symbiotic filamentous fungus in mice. F. foetens reverses MASH progression in mouse models through an intestinal ceramide synthetase 6 (CerS6)–ceramide axis. Moreover, we identified FF-C1, a secondary metabolite from F. foetens , as a CerS6 inhibitor that has an endogenous protective effect on MASH progression.

『Abstract』Understanding the relationship between antibiotic use and the evolution of antimicrobial resistance is vital for effective antibiotic stewardship. Yet, animal models and in vitro experiments poorly replicate real-world conditions . To explain how resistance evolves in vivo, we exposed 60 human participants to ciprofloxacin and used longitudinal stool samples and a new computational method to assemble the genomes of 5,665 populations of commensal bacterial species within participants. Analysis of 2.3 million polymorphic sequence variants revealed 513 populations that underwent selective sweeps. We found convergent evolution focused on DNA gyrase and evidence of dispersed selective pressure at other genomic loci. Roughly 10% of susceptible bacterial populations evolved towards resistance through sweeps that involved substitutions at a specific amino acid in gyrase. The evolution of gyrase was associated with large populations that decreased in relative abundance during exposure. Sweeps persisted for more than 10 weeks in most cases and were not projected to revert within a year. Targeted amplification showed that gyrase mutations arose de novo within the participants and exhibited no measurable fitness cost. These findings revealed that brief ciprofloxacin exposure drives the evolution of resistance in gut commensals, with mutations persisting long after exposure. This study underscores the capacity of the human gut to promote the evolution of resistance and identifies key genomic and ecological factors that shape bacterial adaptation in vivo.

『Abstract』Wurtzite ferroelectrics have transformative potential for next-generation microelectronics. A comprehensive understanding of their ferroelectric properties and domain energetics is crucial for tailoring their ferroelectric characteristics and exploiting their functional properties in practical devices. Despite burgeoning interest, the exact configurations and electronic structures of domain walls in wurtzite ferroelectrics remain elusive. Here we explain the atomic configurations and electronic properties of electric-field-induced domain walls in ferroelectric ScGaN. By combining transmission electron microscopy and theoretical calculations, a charged domain wall with a buckled two-dimensional hexagonal phase is revealed. Density functional theory calculations confirm that such domain-wall structures further give rise to unprecedented mid-gap states within the forbidden band. Quantitative analysis unveils a universal charge-compensation mechanism stabilizing antipolar domain walls in ferroelectric materials, in which the polarization discontinuity at the 180° domain wall is compensated by the unbonded valence electrons. Furthermore, the reconfigurable conductivity of these domain walls is experimentally demonstrated, showcasing their potential for ultrascaled device applications.

『Abstract』The discovery of ferrocene heralded the advent of modern organometallic chemistry. Characterized by the π -coordination of a metal by one or two planar annulene anions, ferrocenes and their analogues exemplify the archetype of out-of-plane annulene metal complexes. By contrast, the integration of metal within the annulene core to form in-plane annulene metal complexes featuring metal–carbon σ bonds has been obstructed not only by the synthetic difficulty and the non-planarity of annulenes with appropriate internal dimensions, but also by the difficulty of embedding the metal. These challenges have prevented the isolation of such in-plane annulene metal complexes. Here we report the preparation of three metal-centred planar [15]annulene frameworks. The most symmetrical fragment has D 5 h symmetry, with the metal centre shared by five identical five-membered rings. Density functional theory calculations demonstrate that metal d orbitals participate in conjugation with these five-membered rings, rendering all of them aromatic. The overall framework bears a loose structural and spectroscopic analogy to metallo-expanded porphyrins with multiple aza donors , which thus provides a nexus between annulene chemistry and classic heteroatom-based coordination chemistry. The present systems display high stability and are easily functionalized. We thus suggest that metal-centred planar annulenes could emerge as promising building blocks for materials science.

『Abstract』The Maltese archipelago is a small island chain that is among the most remote in the Mediterranean. Humans were not thought to have reached and inhabited such small and isolated islands until the regional shift to Neolithic lifeways, around 7.5 thousand years ago (ka) . In the standard view, the limited resources and ecological vulnerabilities of small islands, coupled with the technological challenges of long-distance seafaring, meant that hunter-gatherers were either unable or unwilling to make these journeys . Here we describe chronological, archaeological, faunal and botanical data that support the presence of Holocene hunter-gatherers on the Maltese islands. At this time, Malta’s geographical configuration and sea levels approximated those of the present day, necessitating seafaring distances of around 100 km from Sicily, the closest landmass. Occupations began at around 8.5 ka and are likely to have lasted until around 7.5 ka. These hunter-gatherers exploited land animals, but were also able to take advantage of marine resources and avifauna, helping to sustain these groups on a small island. Our discoveries document the longest yet-known hunter-gatherer sea crossings in the Mediterranean, raising the possibility of unknown, precocious connections across the wider region.

『Abstract』Glacial cycles significantly influenced Earth’s surface processes throughout the Quaternary, impacting the climate, sea level, and seismic and magmatic activity . However, the effects of glaciation and deglaciation (that is, glacial forcing) on lithospheric motion are unknown. To study these effects, we formulated high-resolution numerical models with realistic lithospheric structures, including weak plate margins, lithospheric thickness variations and crustal structure. Our results show that glacial forcing significantly altered lithospheric motion and the spreading rates of mid-ocean ridges situated near major ice sheets in the last glacial cycle. For example, deglaciation-induced motion in the North American plate had a rotational part that was up to around 25% of its tectonic plate motion over 10,000-year timescales. The deglaciation in Greenland and Fennoscandia caused up to 40% fluctuations in the spreading rates of the Iceland Ridge between 12,000 and 6,000 years ago, which may explain the Holocene volcanism in Iceland. Our modelling also indicates increased (decreased) rates of global sea-floor production during the deglaciation (glaciation) periods with implications for mantle degassing rates. These results underscore the critical dynamic interplay between glacial cycles, lithospheric motion, ridge spreading and climate during ice ages.

『Abstract』The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a notable challenge in drug optimization campaigns . The late-stage introduction of alkyl fragments is especially desirable due to the high sp character and structural versatility of these motifs . Given their prevalence in molecular frameworks, C( sp )–H bonds serve as attractive targets for diversification, although this process often requires difficult prefunctionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by using Friedel–Crafts reaction conditions with strong Bronsted or Lewis acids . However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Here we report the application of a new strategy for the selective coupling of differently hybridized radical species, which we term ‘dynamic orbital selection’. This mechanistic model overcomes common limitations of Friedel–Crafts alkylations via the in situ formation of two distinct radical species, which are subsequently differentiated by a copper-based catalyst on the basis of their respective binding properties. As a result, we demonstrate here a general and highly modular reaction for the direct alkylation of native arene C–H bonds using abundant and benign alcohols and carboxylic acids as the alkylating agents. Ultimately, this solution overcomes the synthetic challenges associated with the introduction of complex alkyl groups into highly sophisticated drug scaffolds in a late-stage fashion, thereby granting access to vast new chemical space. Based on the generality of the underlying coupling mechanism, ‘dynamic orbital selection’ is expected to be a broadly applicable coupling platform for further challenging transformations involving two distinct radical species.

『Abstract』CD8 T cell immune responses are critical for combating infectious diseases and tumours . Antigen cross-presentation, primarily occurring at the endoplasmic reticulum (ER) of dendritic cells, is essential for protein-based vaccines to induce CD8 T cell responses . Current efforts have focused on antigen delivery at the tissue and cellular levels, whereas subcellular delivery has been limited to facilitating antigen escape from lysosomes into the cytosol. In the absence of a small-sized high-affinity ER-targeting molecule, the importance of the ‘last mile’ from the cytosol to the ER remains elusive. Here we developed stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), which effectively deliver antigens to the ER and cluster key machinery in cross-presentation to form microreactors by folding the ER membrane. Conjugation of SABER to various antigens substantially enhances the induction of CD8 T cell immune responses to tumour neoantigens and conserved viral epitopes, far exceeding that achieved by mixtures of antigens with STING agonists or conventional adjuvants. SABER also retains a potent adjuvant effect, effectively enhancing the ability of a SARS-CoV-2 subunit vaccine to induce broadly neutralizing antibodies. This study provides a high-affinity ER-targeting delivery system and vaccine adjuvant, demonstrating that precise subcellular delivery targeting the last mile of cross-presentation can lead to a qualitative leap.

『Abstract』Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumour progression . Synaptic inputs onto GBM cells identified so far are largely short range and glutamatergic . The extent of GBM integration into the brain-wide neuronal circuitry remains unclear. Here we applied rabies virus-mediated and herpes simplex virus-mediated trans-monosynaptic tracing to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrate into diverse local and long-range neural circuits across the brain. Beyond glutamatergic inputs, we identified various neuromodulatory inputs, including synapses between basal forebrain cholinergic neurons and GBM cells. Acute acetylcholine stimulation induces long-lasting elevation of calcium oscillations and transcriptional reprogramming of GBM cells into a more motile state via the metabotropic CHRM3 receptor. CHRM3 activation promotes GBM cell motility, whereas its downregulation suppresses GBM cell motility and prolongs mouse survival. Together, these results reveal the striking capacity for human GBM cells to rapidly and robustly integrate into anatomically diverse neuronal networks of different neurotransmitter systems. Our findings further support a model in which rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumour fitness.

『Abstract』The mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex that is essential for the uptake of pyruvate into the mitochondrial matrix as the primary carbon source for the tricarboxylic acid cycle . Here we present six cryo-electron microscopy structures of human MPC in three states: three structures in the intermembrane space (IMS)-open state, obtained in different conditions; a structure of pyruvate-treated MPC in the occluded state; and two structures in the matrix-facing state, bound with the inhibitor UK5099 or with an inhibitory nanobody on the matrix side. MPC is a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo- C 2 symmetry. Approximate rigid-body movements occur between the IMS-open state and the occluded state, whereas structural changes, mainly on the matrix side, facilitate the transition between the occluded state and the matrix-facing state, revealing an alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide key insights into the mechanisms that underlie MPC-mediated substrate transport, and shed light on the recognition and inhibition of MPC by UK5099, which will facilitate the future development of drugs that target MPC.

『Abstract』Despite the continuing progress in integrated optical frequency comb technology , compact sources of short, bright pulses in the mid-infrared wavelength range from 3 to 12 μm so far remain beyond reach. The state-of-the-art ultrafast pulse emitters in the mid-infrared are complex, bulky and inefficient systems based on the downconversion of near-infrared or visible pulsed laser sources. Here we show a purely DC-driven semiconductor laser chip that generates 1-ps solitons at the centre wavelength of 8.3 μm at GHz repetition rates. The soliton generation scheme is akin to that of passive nonlinear Kerr resonators . It relies on a fast bistability in active nonlinear laser resonators, unlike traditional passive mode-locking, which relies on saturable absorbers , or active mode-locking by gain modulation in semiconductor lasers . Monolithic integration of all components—drive laser, active ring resonator, coupler and pump filter—enables turnkey generation of bright solitons that remain robust for hours of continuous operation without active stabilization. Such devices can be readily produced at industrial laser foundries using standard fabrication protocols. Our work unifies the physics of active and passive microresonator frequency combs while simultaneously establishing a technology for nonlinear integrated photonics in the mid-infrared .

『Abstract』Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1) . However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight.

『Abstract』Microbiota-derived bile acids (BAs) are associated with host biology/disease, yet their causal effects remain largely undefined. Herein, we speculate that characterizing previously undefined microbiota-derived BAs would uncover previously unknown BA-sensing receptors and their biological functions. We integrated BA metabolomics and microbial genetics to functionally profile >200 putative microbiota BA metabolic genes. We identified 56 less-characterized BAs, many of which are detected in humans/mammals. Notably, a subset of these BAs are potent antagonists of the human androgen receptor (hAR). They inhibit AR-related gene expression and are human-relevant. As a proof-of-principle, we demonstrate that one of these BAs suppresses tumor progression and potentiates the efficacy of anti-PD-1 treatment in an AR-dependent manner. Our findings show that an approach combining bioinformatics, BA metabolomics, and microbial genetics can expand our knowledge of the microbiota metabolic potential and reveal an unexpected microbiota BA-AR interaction and its role in regulating host biology.