Aside from movement initiation and control, the primary motor cortex (M1) has been implicated in pain modulation mechanisms. A large body of clinical data has demonstrated that stimulation and behavioral activation of M1 result in clinically important pain relief in patients with specific chronic pain syndromes. However, despite its clinical importance, the full range of circuits for motor cortex-related analgesia (MCRA) remains an enigma. This review draws on insights from experimental and clinical data and provides an overview of the neurobiological mechanisms of MCRA, with particular emphasis on its neurocircuitry basis. Based on structural and functional connections of the M1 within the pain connectome, neural circuits for MCRA are discussed at different levels of the neuroaxis, specifically, the endogenous pain modulation system, the thalamus, the extrapyramidal system, non-noxious somatosensory systems, and cortico-limbic pain signatures. We believe that novel insights from this review will expedite our understanding of M1-induced pain modulation and offer hope for successful mechanism-based refinements of this interventional approach in chronic pain management.

Ku70 and Ku80 form Ku, a ring-shaped complex that initiates the non-homologous end-joining (NHEJ) DNA repair pathway.1 Ku binds to double-stranded DNA (dsDNA) ends and recruits other NHEJ factors (e.g., LIG4, DNA-PKcs). While Ku can bind to double-stranded RNA (dsRNA)2 and trap mutated-DNA-PKcs on ribosomal RNA (rRNA),3,4 the physiological role on Ku-RNA interaction in otherwise wildtype cells remains unclear. Intriguingly, Ku is dispensable for murine development5,6 but essential in human cells.7 Despite similar genome sizes, human cells express ~100-fold more Ku than mouse cells, implying functions beyond NHEJ - possibly through a dose-sensitive interaction with dsRNA, which binds Ku 10~100 times weaker than dsDNA.2,8 Investigating Ku's essentiality in human cells, we found that Ku-depletion - unlike LIG4 - induces profound interferon (IFN) and NF-kB signaling via dsRNA-sensor MDA5/RIG-I and MAVS. Prolonged Ku-degradation further activates other dsRNA sensors, especially PKR (suppressing translation) and OAS/RNaseL (cleaving rRNA), leading to growth arrest and cell death. MAVS, RIG-I, or MDA5 knockouts suppressed IFN signaling and, like PKR knockouts, all partially rescued Ku-depleted human cells. Ku-irCLIP analyses revealed Ku binding to diverse dsRNA, predominantly stem-loops in primate-specific antisense Alu elements9 in introns and 3'-UTRs. Ku expression rose sharply in higher primates, correlating tightly with Alu-expansion (r = 0.94/0.95). Thus, Ku plays a vital role in accommodating Alu-expansion in primates by limiting dsRNA-induced innate immunity, explaining both Ku's elevated expression and its essentiality in human cells.

In the future, monsoon rainfall over densely populated South Asia is expected to increase, even as monsoon circulation weakens1-3. By contrast, past warm intervals were marked by both increased rainfall and a strengthening of monsoon circulation4-6, posing a challenge to understanding the response of the South Asian summer monsoon to warming. Here we show consistent South Asian summer monsoon changes in the mid-Pliocene, Last Interglacial, mid-Holocene and future scenarios, characterized by an overall increase in monsoon rainfall, a weakening of the monsoon trough-like circulation over the Bay of Bengal and a strengthening of the monsoon circulation over the northern Arabian Sea, as revealed by a compilation of proxy records and climate simulations. Increased monsoon rainfall is thermodynamically dominated by atmospheric moisture following the rich-get-richer paradigm, and dynamically dominated by the monsoon circulation driven by the enhanced land warming in subtropical western Eurasia and northern Africa. The coherent response of monsoon dynamics across warm climates reconciles past strengthening with future weakening, reinforcing confidence in future projections. Further prediction of South Asian summer monsoon circulation and rainfall by physics-based regression models using past information agrees well with climate model projections, with spatial correlation coefficients of approximately 0.8 and 0.7 under the high-emissions scenario. These findings underscore the promising potential of past analogues, bolstered by palaeoclimate reconstruction, in improving future South Asian summer monsoon projections.

Hilbert space dimension is a key resource for quantum information processing1,2. Not only is a large overall Hilbert space an essential requirement for quantum error correction, but a large local Hilbert space can also be advantageous for realizing gates and algorithms more efficiently3-7. As a result, there has been considerable experimental effort in recent years to develop quantum computing platforms using qudits (d-dimensional quantum systems with d > 2) as the fundamental unit of quantum information8-19. Just as with qubits, quantum error correction of these qudits will be necessary in the long run, but so far, error correction of logical qudits has not been demonstrated experimentally. Here we report the experimental realization of an error-corrected logical qutrit (d = 3) and ququart (d = 4), which was achieved with the Gottesman-Kitaev-Preskill bosonic code20. Using a reinforcement learning agent21,22, we optimized the Gottesman-Kitaev-Preskill qutrit (ququart) as a ternary (quaternary) quantum memory and achieved beyond break-even error correction with a gain of 1.82 ± 0.03 (1.87 ± 0.03). This work represents a novel way of leveraging the large Hilbert space of a harmonic oscillator to realize hardware-efficient quantum error correction.

When two massive objects (black holes, neutron stars or stars) in our universe fly past each other, their gravitational interactions deflect their trajectories1,2. The gravitational waves emitted in the related bound-orbit system-the binary inspiral-are now routinely detected by gravitational-wave observatories3. Theoretical physics needs to provide high-precision templates to make use of unprecedented sensitivity and precision of the data from upcoming gravitational-wave observatories4. Motivated by this challenge, several analytical and numerical techniques have been developed to approximately solve this gravitational two-body problem. Although numerical relativity is accurate5-7, it is too time-consuming to rapidly produce large numbers of gravitational-wave templates. For this, approximate analytical results are also required8-15. Here we report on a new, highest-precision analytical result for the scattering angle, radiated energy and recoil of a black hole or neutron star scattering encounter at the fifth order in Newton's gravitational coupling G, assuming a hierarchy in the two masses. This is achieved by modifying state-of-the-art techniques for the scattering of elementary particles in colliders to this classical physics problem in our universe. Our results show that mathematical functions related to Calabi-Yau (CY) manifolds, 2n-dimensional generalizations of tori, appear in the solution to the radiated energy in these scatterings. We anticipate that our analytical results will allow the development of a new generation of gravitational-wave models, for which the transition to the bound-state problem through analytic continuation and strong-field resummation will need to be performed.

Debris disks are exoplanetary systems that contain planets, minor bodies (asteroids, Kuiper belt objects, comets and so on) and micrometre-sized debris dust1. Because water ice is the most common frozen volatile, it plays an essential role in the formation of planets2,3 and minor bodies. Although water ice has been commonly found in Kuiper belt objects and comets in the Solar System4, no definitive evidence for water ice in debris disks has been obtained to date1. Here we report the discovery of water ice in the HD 181327 debris disk using the near-infrared spectrograph onboard the James Webb Space Telescope. We detected the solid-state broad absorption feature of water ice at 3 µm including a distinct Fresnel peak at 3.1 µm, which is indicative of large, crystalline water-ice particles. Gradients in the water-ice feature as a function of stellocentric distance reveal a dynamic environment in which water ice is destroyed and replenished. We estimated the water-ice mass fractions as ranging from 0.1% at approximately 85 au to 21% at approximately 113 au, indicating the presence of a water-ice reservoir in the HD 181327 disk beyond the snow line. The icy bodies that release water ice in HD 181327 are probably the extra-solar counterparts of water-ice-rich Kuiper belt objects in our Solar System.

High-capacity lithium-ion batteries (LIBs) play a critical role as power sources across diverse applications, including portable electronics, electric vehicles (EVs) and renewable-energy-storage systems1. However, there is growing concern about the safety of integrated LIB systems, with reports of up to 9,486 incidents between 2020 and 2024 (ref. 2). To ensure the safe application of commercial LIBs, it is essential to capture internal signals that enable early failure diagnosis and warning. Monitoring non-uniform temperature and strain distributions within the jelly-roll structures of the battery provides a promising approach to achieving this goal3,4. Here we propose a miniaturized and low-power-consumption system capable of accurate sensing and wireless transmission of internal temperature and strain signals inside LIBs, with negligible influence on its performance. The acquisition of internal temperature signals and the area ratio between initial internal-short-circuited regions and battery electrodes enables quantitative analysis of thermal fusing and thermal runaway phenomena, leading to the evaluation of the intensity of battery thermal runaway and recognition of thermal abuse behaviours. This work provides a foundation for designing next-generation smart LIBs with safety warning and failure positioning capabilities.

Photonic double-zero-index media, distinguished by concurrently zero-valued permittivity and permeability, exhibit extraordinary properties not found in nature1-8. Notably, the notion of zero index can be substantially expanded by generalizing the constitutive parameters from null scalars to non-reciprocal tensors with non-zero matrix elements but zero determinants9,10. Here we experimentally realize this class of gyromagnetic double-zero-index metamaterials possessing both double-zero-index features and non-reciprocal hallmarks. As an intrinsic property, this metamaterial always emerges at a spin-1/2 Dirac point of a topological phase transition. We discover and demonstrate that a spatiotemporal reflection vortex singularity is always anchored to the Dirac point of the metamaterial, with the vortex charge being determined by the topological invariant leap across the phase transition. This establishes a unique bulk-spatiotemporal vortex correspondence that extends the protected boundary effects into the time domain and characterizes topological phase-transition points, setting it apart from any pre-existing bulk-boundary correspondence. Based on this correspondence, we propose and experimentally demonstrate a mechanism to deterministically generate optical spatiotemporal vortex pulses11,12 with firmly fixed central frequency and momentum, hence showing ultrarobustness. Our findings uncover connections between zero-refractive-index photonics, topological photonics and singular optics, which might enable the manipulation of space-time topological light fields using the inherent topology of extreme-parameter metamaterials.

The pressures humanity has been placing on the environment have put Earth's stability at risk. The planetary boundaries framework serves as a method to define a 'safe operating space for humanity'1,2 and has so far been applied mostly to highlight the currently prevailing unsustainable environmental conditions. The ability to evaluate trends over time, however, can help us explore the consequences of alternative policy decisions and identify pathways for living within planetary boundaries3. Here we use the Integrated Model to Assess the Global Environment4 to project control variables for eight out of nine planetary boundaries under alternative scenarios to 2050, both with and without strong environmental policy measures. The results show that, with current trends and policies, the situation is projected to worsen to 2050 for all planetary boundaries, except for ozone depletion. Targeted interventions, such as implementing the Paris climate agreement, a shift to a healthier diet, improved food, and water- and nutrient-use efficiency, can effectively reduce the degree of transgression of the planetary boundaries, steering humanity towards a more sustainable trajectory (that is, if they can be implemented based on social and institutional feasibility considerations). However, even in this scenario, several planetary boundaries, including climate change, biogeochemical flows and biodiversity, will remain transgressed in 2050, partly as result of inertia. This means that more-effective policy measures will be needed to ensure we are living well within the planetary boundaries.

Based on seminal work in placental species (eutherians)1-10, a paradigm of mammalian development has emerged wherein the genome-wide erasure of parental DNA methylation is required for embryogenesis. Whether such DNA methylation reprogramming is, in fact, conserved in other mammals is unknown. Here, to resolve this point, we generated base-resolution DNA methylation maps in gametes, embryos and adult tissues of a marsupial, the opossum Monodelphis domestica, revealing variations from the eutherian-derived model. The difference in DNA methylation level between oocytes and sperm is less pronounced than that in eutherians. Furthermore, unlike the genome of eutherians, that of the opossum remains hypermethylated during the cleavage stages. In the blastocyst, DNA demethylation is transient and modest in the epiblast. However, it is sustained in the trophectoderm, suggesting an evolutionarily conserved function for DNA hypomethylation in the mammalian placenta. Furthermore, unlike that in eutherians, the inactive X chromosome becomes globally DNA hypomethylated during embryogenesis. We identify gamete differentially methylated regions that exhibit distinct fates in the embryo, with some transient, and others retained and that represent candidate imprinted loci. We also reveal a possible mechanism for imprinted X inactivation, through maternal DNA methylation of the Xist-like noncoding RNA RSX11. We conclude that the evolutionarily divergent eutherians and marsupials use DNA demethylation differently during embryogenesis.

Evidence indicates that supermassive black holes (SMBHs) exist at the centres of most galaxies. Their mass correlates with the galactic bulge mass1, suggesting a coevolution with their host galaxies2, most likely through powerful winds3. X-ray observations have detected highly ionized winds outflowing at sub-relativistic speeds from the accretion disks around SMBHs4,5. However, the limited spectral resolution of present X-ray instruments has left the physical structure and location of the winds poorly understood, hindering accurate estimates of their kinetic power6,7. Here the first X-Ray Imaging and Spectroscopy Mission (XRISM) observation of the luminous quasar PDS 456 is reported. The high-resolution spectrometer Resolve aboard XRISM enabled the discovery of five discrete velocity components outflowing at 20-30% of the speed of light. This demonstrates that the wind structure is highly inhomogeneous, which probably consists of up to a million clumps. The mass outflow rate is estimated to be 60-300 solar masses per year, with the wind kinetic power exceeding the Eddington luminosity limit. Compared with the galaxy-scale outflows, the kinetic power is more than three orders of magnitude larger, whereas the momentum flux is ten times larger. These estimates disfavour both energy-driven and momentum-driven outflow models. This suggests that such wind activity occurs in less than 10% of the quasar phase and/or that its energy/momentum is not efficiently transferred to the galaxy-scale outflows owing to the clumpiness of the wind and the interstellar medium.

The structural evolution of molecular hydrogen H2 under multi-megabar compression and its relation to atomic metallic hydrogen is a key unsolved problem in condensed-matter physics. Although dozens of crystal structures have been proposed by theory1-4, only one, the simple hexagonal-close-packed (hcp) structure of only spherical disordered H2, has been previously confirmed in experiments5. Through advancing nano-focused synchrotron X-ray probes, here we report the observation of the transition from hcp H2 to a post-hcp structure with a six-fold larger supercell at pressures above 212 GPa, indicating the change of spherical H2 to various ordered configurations. Theoretical calculations based on our XRD results found a time-averaged structure model in the space group P6¯2c with alternating layers of spherically disordered H2 and new graphene-like layers consisting of H2 trimers (H6) formed by the association of three H2 molecules. This supercell has not been reported by any previous theoretical study for the post-hcp phase, but is close to a number of theoretical models with mixed-layer structures. The evidence of a structural transition beyond hcp establishes the trend of H2 molecular association towards polymerization at extreme pressures, giving clues about the nature of the molecular-to-atomic transition of metallic hydrogen. Considering the spectroscopic behaviours that show strong vibrational and bending peaks of H2 up to 400 GPa, it would be prudent to speculate the continuation of hydrogen molecular polymerization up to its metallization.

A key function of brain systems mediating emotion is to learn to anticipate unpleasant experiences. Although organisms readily associate sensory stimuli with aversive outcomes, higher-order forms of emotional learning and memory require inference to extrapolate the circumstances surrounding directly experienced aversive events to other indirectly related sensory patterns that were not part of the original experience. This type of learning requires internal models of emotion, which flexibly track directly experienced and inferred aversive associations. Although the brain mechanisms of simple forms of aversive learning have been well studied in areas such as the amygdala1-4, whether and how the brain forms and represents internal models of emotionally relevant associations are not known5. Here we report that neurons in the rodent dorsomedial prefrontal cortex (dmPFC) encode a flexible internal model of emotion by linking sensory stimuli in the environment with aversive events, whether they were directly or indirectly associated with that experience. These representations form through a multi-step encoding mechanism involving recruitment and stabilization of dmPFC cells that support inference. Although dmPFC population activity encodes all salient associations, dmPFC neurons projecting to the amygdala specifically represent and are required to express inferred associations. Together, these findings reveal how internal models of emotion are encoded in the dmPFC to regulate subcortical systems for recall of inferred emotional memories.

Humans have evolved an extraordinarily expanded and complex cerebral cortex associated with developmental and gene regulatory modifications1-3. Human accelerated regions (HARs) are highly conserved DNA sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to species-specific cortical development remains largely unknown4,5. HARE5 is a HAR transcriptional enhancer of the WNT signalling receptor Frizzled8 that is active during brain development6. Here, using genome-edited mouse (Mus musculus, Mm) and primate models, we demonstrated that human (Homo sapiens, Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacities of neural progenitor cells. Hs-HARE5 knock-in mice have significantly enlarged neocortices, containing more excitatory neurons. By measuring neural dynamics in vivo, we showed that these anatomical features result in increased functional independence between cortical regions. We assessed underlying developmental mechanisms using fixed and live imaging, lineage analysis and single-cell RNA sequencing. We discovered that Hs-HARE5 modifies radial glial cell behaviour, with increased self-renewal at early developmental stages, followed by expanded neurogenic potential. Using genome-edited human and chimpanzee (Pan troglodytes, Pt) neural progenitor cells and cortical organoids, we showed that four human-specific variants of Hs-HARE5 drive increased enhancer activity that promotes progenitor proliferation. Finally, we showed that Hs-HARE5 increased progenitor proliferation by amplifying canonical WNT signalling. These findings illustrate how small changes in regulatory DNA can directly affect critical signalling pathways to modulate brain development. Our study uncovered new functions of HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1-5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC-niche interactions that are essential for leukaemogenesis. These analyses identify the taurine-taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.

Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a brain cancer of unknown cellular origin and challenging to treat, is associated with diverse in-frame gene fusions, including MN1-BEND2 and MN1-CXXC5 (refs. 1,2). However, it remains unclear whether these gene fusions contribute to tumorigenesis. Here we show in mice that these two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognize similar DNA motifs, which indicates a convergence on downstream gene regulation. Expression of MN1-BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM and acquisition of an ABM-associated transcriptional signature. By contrast, MN1-BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type-specific malignancy depends on OLIG2 expression. Mechanistically, both ABM-associated fusion proteins (MN1-BEND2 and MN1-CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggest that distinct ABM-associated fusions upregulate shared transcriptional networks to disrupt the normal development of ventral telencephalon neural progenitors, which leads to oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.

Episodic memories-high-fidelity memories for events that depend initially on the hippocampus-do not maintain their precision in perpetuity. One benefit of this time-dependent loss of precision is the emergence of event-linked gist memories that may be used to guide future behaviour in new but related situations (that is, generalization)1-3. Models of systems consolidation propose that memory reorganization accompanies this loss of memory precision1,4; however, the locus of this reorganization is unclear. Here we report that time-dependent reorganization of hippocampal engram circuitry is sufficient to explain shifts in memory precision associated with systems consolidation. Using engram labelling tools in mice, we demonstrate that the passage of time rewires hippocampal engram circuits, enabling hippocampal engram neurons to be promiscuously active and guide behaviour in related situations that do not match the original training conditions. Reorganization depends on hippocampal neurogenesis; eliminating hippocampal neurogenesis prevents reorganization and maintains precise, event memories. Conversely, promoting hippocampal neurogenesis accelerates memory reorganization and the emergence of event-linked gist memories in the hippocampus. Our results indicate that systems consolidation models require updating to account for within-hippocampus reorganization that leads to qualitative shifts in memory precision.

Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNγ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lung cancer, breast cancer and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNγ or its receptor fail to control the growth of leptomeningeal metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNγ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNγ signalling and suggests an immune-therapeutic approach against tumours within this space.

Here we report on the nearly complete and uncrushed 14th specimen of Archaeopteryx. Exceptional preservation and preparation guided by micro-computed tomographic data make this one of the best exemplars of this iconic taxon, preserving important data regarding skeletal transformation and plumage evolution in relation to the acquisition of flight during early avian evolution. The ventrolaterally exposed skull reveals a palatal morphology intermediate between troodontids1 and crownward Cretaceous birds2,3. Modifications of the skull reflect the shift towards a less rigid cranial architecture in archaeopterygids from non-avian theropods. The complete vertebral column reveals paired proatlases and a tail longer than previously recognized. Skin traces on the right major digit of the hand suggest that the minor digit was free and mobile distally, contrary to previous interpretations4. The morphology of the foot pads indicates that they were adapted for non-raptorial terrestrial locomotion. Specialized inner secondary feathers called tertials5,6 are observed on both wings. Humeral tertials are absent in non-avian dinosaurs closely related to birds, suggesting that these feathers evolved for flight, creating a continuous aerodynamic surface. These new findings clarify the mosaic of traits present in Archaeopteryx, refine ecological predictions and elucidate the unique evolutionary history of the Archaeopterygidae, providing clues regarding the ancestral avian condition.

The human cerebral cortex is composed of six layers and dozens of areas that are molecularly and structurally distinct1-4. Although single-cell transcriptomic studies have advanced the molecular characterization of human cortical development, a substantial gap exists owing to the loss of spatial context during cell dissociation5-8. Here we used multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based nucleus segmentation, to examine the molecular, cellular and cytoarchitectural development of the human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing more than 18 million single cells, spans eight cortical areas across seven developmental time points. We uncovered the early establishment of the six-layer structure, identifiable by the laminar distribution of excitatory neuron subtypes, 3 months before the emergence of cytoarchitectural layers. Notably, we discovered two distinct modes of cortical areal specification during mid-gestation: (1) a continuous, gradual transition observed across most cortical areas along the anterior-posterior axis and (2) a discrete, abrupt boundary specifically identified between the primary (V1) and secondary (V2) visual cortices as early as gestational week 20. This sharp binary transition in V1-V2 neuronal subtypes challenges the notion that mid-gestation cortical arealization involves only gradient-like transitions6,10. Furthermore, integrating single-nucleus RNA sequencing with MERFISH revealed an early upregulation of synaptogenesis in V1-specific layer 4 neurons. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This study establishes a spatially resolved single-cell analysis paradigm and paves the way for the construction of a comprehensive developmental atlas of the human brain.