经典100 | NCS： 2026-01-28 期

『Abstract』Abstract The risks posed by reentering space debris continue to grow as Earth’s orbit becomes more crowded. Currently, responses to uncontrolled reentries are hampered by an inability to reliably track spacecraft once they are burning up within the atmosphere, meaning that debris fallout locations are poorly predicted. We have demonstrated a minimum-gradient fit seismic inversion methodology that allows in-atmosphere debris trajectory, speed, altitude, descent angle, size, and fragmentation pattern to be discerned relatively quickly. We tested this methodology on open-source data from the 2024 reentry of Shenzhou-15, deriving a location significantly south of the predicted track. Observations of cascading, multiplicative fragmentation offer insight into debris disintegration dynamics, with clear implications for space situational awareness and debris hazard mitigation.

『Abstract』Abstract The Main Marmara fault (MMF) in northwestern Turkiye poses the highest seismic risk in broader Europe. The 2025 moment magnitude ( M W ) 6.2 event was the largest earthquake along the MMF in >60 years. We integrated observations from multiple temporal scales including the decade-long evolution of M > 5 earthquakes, their rupture dynamics, and aftershock patterns. We show a series of eastward-propagating M > 5 events and a gradual eastward partial rupture of the MMF over the past ~15 years. The seismically active portion of the fault includes creeping and transitional segments with some of the most recent seismicity located near the presumably locked Princes’ Islands segment south of Istanbul that has the potential to generate a M ~7 earthquake. Our analysis highlights the necessity of real-time monitoring of this part of the MMF.

『Abstract』Abstract Prezygotic interspecific incompatibility prevents hybridization between species, which limits interbreeding strategies for crop improvement using wild relatives. The Brassica rapa female self-incompatibility determinant, S -locus receptor kinase (SRK), recognizes interspecific pollen. Here, we report the discovery of a pan-Brassicaceae SRK-interacting interspecific pollen signal (SIPS). On B. rapa stigmas, SIPSs from Arabidopsis and other Brassicaceae species target Br SRK and recruit the female fertility regulator FERONIA receptor kinase to increase stigmatic reactive oxygen species and reduce interspecific pollen viability. Arabidopsis thaliana sips mutant pollen failed to trigger interspecific incompatibility responses. Unlike self-incompatibility, which is controlled by the polymorphic S locus, different genetic variants of SRK interacted comparably with SIPS. This study establishes SIPS-SRK as a Brassicaceae-specific ligand-receptor pair that broadly maintains the stigmatic interspecific barrier in self-incompatible species.

『Abstract』Abstract The Einstein–de Haas effect is a phenomenon in which angular momentum is transferred from microscopic spins to mechanical rotation of a macroscopic rigid body. We report an observation of the Einstein–de Haas effect in a spinor-dipolar Bose–Einstein condensate, in which the intrinsic magnetic dipole-dipole interaction mediates coherent transfer of angular momentum from atomic spins to collective circulation of a quantum fluid. The depolarized spinor components displayed ring-shaped density distributions that were confirmed as quantized vortices through matter-wave interferometry, revealing a coherent conversion between spin and orbital angular momentum. This observation opens a pathway to exploring ground-state phases with broken chiral symmetry, spin textures, and mass circulation, as well as the Barnett effect in dipolar quantum gases.

『Abstract』Abstract Tectonic events and volcanic pulses forming large igneous provinces (LIPs) have altered Earth’s paleoclimate. Osmium (Os) and strontium (Sr) isotopic ratios are key tracers of past continental weathering and LIP eruptions. However, limited Cretaceous seawater Os and riverine Os–Sr data have hindered quantitative reconstructions. In this study, we present a long-term Os isotopic record from the Cretaceous to the present, revealing ~10– to 20–million-year cycles during the Cretaceous that align with rhythmic LIP eruptions. Seawater Os–Sr isotopic trends indicate transitions in continental weathering patterns during the Late Cretaceous [~90 million years ago (Ma)] and Paleogene (~35 Ma) ascribed to intensified weathering of interior Gondwana during the opening of the Atlantic Ocean and the uplift and glaciation of the Himalaya, respectively. Our Os isotopic record highlights its utility in tracing long-term LIP cycles and identifying major paleogeographic turning points.

『Abstract』Abstract Treponematosis, a bacterial infection caused by Treponema pallidum subspecies and T. carateum (yaws, bejel, syphilis, pinta), has afflicted humans for millennia. Despite paleopathological evidence and emerging genomic data, little is known about the evolutionary history of these pathogens. We report a 5500-year-old Treponema genome (TE1-3) from Middle Holocene hunter-gatherer contexts of the rock shelter Tequendama I in Colombia. Our analyses place TE1-3 as a sister lineage to all known T. pallidum subspecies, positioning this pathogen in the Americas millennia before European contact and before diversification of the subspecies causing syphilis, yaws, and bejel. This discovery broadens the known diversity of T. pallidum while extending the genomic record of treponemal pathogens by millennia, providing molecular support for a deep history of T. pallidum in the Americas.

『Abstract』Abstract Zygotic genome activation (ZGA) failure leads to developmental arrest and poses a clinical challenge to women’s fertility. We observed that human embryos arresting at the eight-cell ZGA stage exhibited specific down-regulation of endogenous retrovirus MLT2A1. Depleting MLT2A1 resulted in a failure in embryo development and a reduction in ZGA gene expression. Mechanistically, MLT2A1s synthesized chimeric transcripts with downstream coding and noncoding sequences, predominantly with heterologous retro–transposable elements. These diverse fusion sequences expanded the genome-targeting spectrum of MLT2A1 RNAs. Nevertheless, the shared MLT2A1 sequences partnered with heterogeneous nuclear ribonucleoprotein U (HNRNPU) to recruit RNA polymerase II, promoting global transcription of ZGA genes and autoamplification of the MLT2A1 subfamily. Thus, MLT2A1 chimeric RNAs formed an interlocking network that acts synergistically to boost human ZGA and early embryogenesis.

『Abstract』Abstract The nearby star Fomalhaut is orbited by a compact source, Fomalhaut b, which has previously been interpreted as either a dust-enshrouded exoplanet or a dust cloud generated by the collision of two planetesimals. Such collisions are rarely observed, but their debris can appear in direct imaging. We report Hubble Space Telescope observations that show the appearance in 2023 of a second point source around Fomalhaut, resembling the appearance of Fomalhaut b 20 years earlier. We interpret this additional source as a dust cloud produced by a recent impact between two planetesimals. The positions and motion of two impact-generated dust clouds over 20 years provide constraints on the collisional dynamics in the debris belt.

『Abstract』Abstract Oligodendrocytes form myelin sheaths around axons to enable rapid signaling within neural circuits. The generation of new oligodendrocytes through differentiation of oligodendrocyte precursor cells (OPCs) promotes myelin plasticity and repair in the adult brain. Here, we performed genetic interrogation and in vivo analysis of OPCs in the mouse brain to determine their differentiation dynamics. Our results show that OPCs attempt to differentiate throughout the adult central nervous system with spatial and temporal regularity. The differentiation rate was not influenced by myelin demand or oligodendrocyte loss and declined with age and in response to acute inflammation. The results suggest that OPC differentiation is governed primarily by constitutive processes and might be negatively influenced by aging and inflammation.

『Abstract』Abstract Platelet integrin αIIbβ3 is essential for hemostasis, thrombosis, and inflammation. We found that ligation of αIIbβ3 by von Willebrand factor or fibrin under flow triggered its accumulation in plasma membrane extensions or “platelet-derived integrin- and tetraspanin-enriched tethers” (PITTs). PITTs remained anchored to leukocytes or endothelial cells, whereas the partially αIIbβ3-deficient platelet body detached. Although still responsive to stimuli, αIIbβ3-deficient platelets did not support thrombus formation. PITTs promoted leukocyte activation and vascular inflammation in mouse models of infection and endotoxemia, and αIIbβ3 blockade reduced immune-mediated tissue damage. In patients with sepsis, COVID-19, or severe infections, PITT formation and platelet αIIbβ3 loss correlated with disease severity and adverse outcomes. We propose that PITTs are proinflammatory structures that amplify immune responses while contributing to platelet dysfunction in thrombo-inflammatory disease.

『Abstract』Abstract In quantum metrology, entangled states of many-particle systems are investigated to enhance measurement precision of the most precise clocks and field sensors. Whereas single-parameter quantum metrology is well established, joint multiparameter estimation poses conceptual challenges and has been explored only theoretically. We experimentally demonstrated multiparameter quantum metrology with an array of entangled atomic ensembles. By splitting a spin-squeezed ensemble, we created an atomic sensor array featuring intersensor entanglement that can be flexibly configured to enhance measurement precision of multiple parameters jointly. Using an optimal estimation protocol, we achieved substantial gains over the standard quantum limit in key multiparameter estimation tasks, thus grounding the concept of quantum enhancement of field sensor arrays and imaging devices.

『Abstract』Abstract Bose-Fermi mixtures can be realized in semiconductor heterostructures, with bosons as excitons and fermions as dopant charges. However, the complexity of these hybrid systems challenges understanding of the mechanisms that determine properties such as mobility. We investigated interlayer exciton diffusion in tungsten diselenide–tungsten disulfide heterobilayers at ultralow exciton density and low temperatures to examine how charges affect exciton mobility. Near the electronic Mott insulator phase, we observed a giant thousand-fold enhancement of exciton diffusion relative to charge neutrality. We attribute this to mobile valence holes, which experienced a suppressed moire potential due to charge order and recombined nonmonogamously with conduction electrons. Our results show exciton diffusion as a probe of correlated electron states and Bose-Fermi interplay.

『Abstract』Optical tweezer arrays have emerged as a key experimental platform for quantum computation , quantum simulation and quantum metrology , enabling unprecedented levels of control over single atoms and molecules. The ability to scale such arrays has become a defining challenge. Typically, optical tweezer arrays are generated using acousto-optic deflectors or liquid-crystal spatial light modulators. Fundamental limitations in optical resolution have constrained array sizes to about 10,000 traps . Metasurfaces , planar photonic devices comprising millions of subwavelength pixels, provide an intriguing alternative for the generation of optical tweezer arrays . Here we demonstrate the trapping of single strontium atoms in optical tweezer arrays generated via holographic metasurfaces. We realize two-dimensional arrays with more than 100 single atoms, arranged in arbitrary geometries with trap spacings as small as 1.5 μm. The arrays have a high uniformity in terms of trap depth, trap frequency and positional accuracy, rivalling or surpassing existing approaches. This is enabled by highly efficient holographic metasurfaces fabricated from high-refractive-index materials, silicon-rich silicon nitride and titanium dioxide. Through analytical and numerical methods, we find that the subwavelength pixel sizes of these metasurfaces allow scaling of tweezer arrays far beyond current capabilities. As a demonstration, we realize an optical tweezer array with 360,000 traps. These advances overcome a critical barrier to realizing scalable neutral-atom quantum technologies.

『Abstract』Recently, the Ruddlesden–Popper bilayer nickelate La 3 Ni 2 O 7 has emerged as a superconductor with a transition temperature ( T c ) of approximately 80 K above 14 GPa (refs. ). Achieving a higher T c in nickelate superconductors, along with the synthesis of reproducible high-quality single crystals without relying on high-oxygen-pressure growth conditions, remains a significant challenge . Here we report superconductivity up to 96 K under high pressure in bilayer nickelate single crystals synthesized at ambient pressure. Energy-dispersive spectroscopy, single-crystal X-ray diffraction, nuclear quadrupole resonance and scanning transmission electron microscopy evidenced high crystal quality of the flux-grown La 2 SmNi 2 O 7− δ single crystals. La 2 SmNi 2 O 7 exhibits clear bulk superconductivity, including zero resistivity ( \({T}_{{\rm{c}},\max }^{{\rm{onset}}}\) = 92 K and \({T}_{{\rm{c}},\max }^{{\rm{zero}}}\) = 73 K at 21.6 GPa) and the Meissner effect ( T c = 60 K at 20.6 GPa). A low-temperature high-pressure structural study indicates that both monoclinic and tetragonal structures can support superconductivity in this bilayer nickelate. Furthermore, we established a correlation between higher T c under high pressures and larger in-plane lattice distortion under ambient conditions, corroborated by observing even higher \({T}_{{\rm{c}}}^{{\rm{onset}}}\) of 96 K in La 1.57 Sm 1.43 Ni 2 O 7− δ . This study overcomes key limitations in growing nickelate superconductor crystals, resolves the crystal structure in the superconducting state and demonstrates an effective pathway towards achieving higher T c .

『Abstract』Elastocaloric cooling using shape-memory alloys (SMAs) is a promising greenhouse gas (GHG)-free alternative to conventional vapour-compression refrigeration that relies on high global warming potential (GWP) gas refrigerants . However, existing elastocaloric systems have not yet reached sub-zero Celsius temperatures, which restricts their application in various freezing scenarios . Here we constructed a compression-based, regenerative elastocaloric cooling device using low-transition-temperature tubular NiTi units in a cascaded configuration. The selected NiTi alloy exhibited superelasticity and substantial entropy changes down to −20 °C. Moreover, low-freezing-point aqueous calcium chloride solution was used as the heat-transfer fluid, ensuring effective flow at low operational temperatures. Our desktop device achieved a heat-source temperature of −12 °C from a room-temperature heat sink, paving the way for next-generation green elastocaloric freezing technologies.

『Abstract』Micrometre-sized, densely packed natural cilia that perform non-reciprocal 3D motions with dynamically tunable collective patterns are crucial for biological processes such as microscale locomotion , nutrient acquisition , cell trafficking and embryonic and neurological development . However, replicating these motions in artificial systems remains challenging given the limits of scalable, locally controllable soft-bodied actuation at the micrometre scale. Overcoming this challenge would enhance our understanding of ciliary dynamics, clarify their biological importance and enable new microscale devices and bioinspired technologies. Here we show a previously unrecognized fast electrical response of micrometre-scale hydrogels, induced by voltages down to 1.5 V without hydrolysis, with bending motions driven by ion migration across a nanometre-scale hydrogel network 3D-printed by two-photon polymerization, occurring within milliseconds. On the basis of these findings, we print gel microcilia arrays composed of a soft acrylic acid-co-acrylamide (AAc-co-AAm) hydrogel (modulus of approximately 1,000 Pa) that respond to electrical stimuli within milliseconds. Each microcilium measures 2–10 µm in diameter and 18–90 µm in height, achieving 3D rotational bending motion at up to 40 Hz, mirroring the geometry and dynamics of natural cilia. These gel microcilia maintain functionality after 330,000 continuous actuation cycles with less than 30% performance degradation. The gel microcilia arrays can be integrated on flexible polyimide substrates and fabricated at large scale using conventional lithography techniques. They also offer individual dynamic control by means of microelectrode arrays and enable fluid manipulation and particle transport at the micrometre scale.

『Abstract』Crystalline silicates form at high temperatures (>900 K) (refs. ). Their presence in comets suggests that high-temperature dust processing occurred in the early Solar System and was subsequently transported outwards to comet-forming regions. However, direct evidence for this crystallization and redistribution in Sun-like protostars has remained unknown. By comparing James Webb Space Telescope mid-infrared spectra of the periodically bursting protostar EC 53 (ref. ), we detect crystalline silicate (forsterite and enstatite) emission features that appear only during the burst. The emergence of these features indicates active crystal formation by thermal annealing in the hot inner disk during the accretion burst. We also detect a nested outflow—a collimated atomic jet enclosed by slower molecular outflows, consistent with magnetohydrodynamic wind models . This configuration provides a mechanism for the outward transport of freshly crystallized silicates . To our knowledge, our results provide the first direct observational evidence of in situ silicate crystallization during episodic accretion bursts in a very young star still embedded in its dense envelope. Although we do not directly detect grains transported to the outer disk, the observed trends are consistent with outward redistribution, indicating that both dust processing and transport occur during the earliest and most dynamic stages of star formation.

『Abstract』River deltas sustain dense human populations, major economic centres and vital ecosystems worldwide . Rising sea levels and subsiding land threaten the sustainability of these valuable landscapes with relative sea-level rise and associated flood, land loss and salinization hazards . Despite these risks, vulnerability assessments are impeded by the lack of contemporary, high-resolution, delta-wide subsidence observations . Here we present spatially variable surface-elevation changes across 40 global deltas using interferometric synthetic aperture radar. Using this dataset, we quantify delta surface-elevation loss and show the prevalence and severity of subsidence in river deltas worldwide. Our analysis of three key anthropogenic drivers of delta elevation changes shows that groundwater storage has the strongest relative influence on vertical land motion in 10 of the 40 deltas. The other deltas are either influenced by multiple drivers or dominated by sediment flux or urban expansion. Furthermore, we find that contemporary subsidence surpasses absolute (geocentric) sea-level rise as the dominant driver of relative sea-level rise for most deltas over the twenty-first century. These findings suggest the need for targeted interventions addressing subsidence as an immediate and localized challenge, in parallel with broader efforts to mitigate and adapt to climate change-driven global sea-level rise.

『Abstract』The quantum superposition principle is a fundamental concept of physics and the basis of numerous quantum technologies . Yet, it is still often regarded counterintuitive because we do not observe its key features on the macroscopic scales of our daily lives. It is, therefore, interesting to ask how quantum properties persist or change as we increase the size and complexity of objects . A model test for this question can be realized by matter-wave interferometry, in which the motion of individual massive particles becomes delocalized and needs to be described by a wave function that spans regions far larger than the particle itself . Over the years, this has been explored with a series of objects of increasing mass and complexity and a growing community aims at pushing this to ever larger limits. Here we present an experimental platform that extends matter-wave interference to large metal clusters, a qualitatively new material class for quantum experiments. We specifically demonstrate quantum interference of sodium nanoparticles, which can each contain more than 7,000 atoms at masses greater than 170,000 Da. They propagate in a Schrodinger cat state with a macroscopicity of μ = 15.5, surpassing previous experiments by an order of magnitude.

『Abstract』Palaeogenetic evidence suggests that the last common ancestor of present-day humans, Neanderthals and Denisovans lived around 765–550 thousand years ago (ka) . However, both the geographical distribution and the morphology of these ancestral humans remain uncertain. The Homo antecessor fossils from the TD6 layer of Gran Dolina at Atapuerca, Spain, dated between 950 ka and 770 ka (ref. ), have been proposed as potential candidates for this ancestral population . However, all securely dated Homo sapiens fossils before 90 ka were found either in Africa or at the gateway to Asia, strongly suggesting an African rather than a Eurasian origin of our species. Here we describe new hominin fossils from the Grotte a Hominides at Thomas Quarry I (ThI-GH) in Casablanca, Morocco, dated to around 773 ka. These fossils are similar in age to H. antecessor , yet are morphologically distinct, displaying a combination of primitive traits and of derived features reminiscent of later H. sapiens and Eurasian archaic hominins. The ThI-GH hominins provide insights into African populations predating the earliest H. sapiens individuals discovered at Jebel Irhoud in Morocco and provide strong evidence for an African lineage ancestral to our species. These fossils offer clues about the last common ancestor shared with Neanderthals and Denisovans.

『Abstract』At every scale they occupy, magnetic fields affect various phenomena, including star formation, cosmic-ray transport, charged-particle acceleration, space weather, transport in planetary atmospheres and laboratory plasmas. These fields are often generated and sustained by turbulent flows in a process called the dynamo. In 1955, E. N. Parker parameterized the effects of small-scale turbulence to propose a mean-field dynamo theory . The widely used theory reproduces observed large-scale fields but suffers from difficulty in tuning parameters as they are not justified from first principles: studies of turbulent flows show tangled magnetic fields, which are folded and fragmented into small-scale structures owing to shear-flow straining . Here, considering a shear flow that is unstable and driven, we develop analytic theory and perform three-dimensional, advanced computer simulations of turbulence with up to 4,096 × 4,096 × 8,192 grid points, showing ab initio generation of quasi-periodic, large-scale magnetic fields. The generation occurs via the mean-vorticity effect—an additional mean-field dynamo process postulated in 1990. Crucial to this dynamo is the prior generation of large-scale three-dimensional jets, robustly produced as topologically protected and exact nonlinear solutions of the magnetohydrodynamic equations. The jet-driven dynamo applies to shear-driven laboratory and astrophysical systems. These include binary neutron star mergers , where the reported dynamo probably operates on microsecond timescales to produce in milliseconds some of the strongest magnetic fields in the Universe , providing signals for multi-messenger astronomy .

『Abstract』The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, but how opioid analgesics modulate this cortical circuit remains unclear . Uncovering how opioids alter nociceptive neural dynamics to produce pain relief is essential for developing safer and more targeted treatments for chronic pain. Here we show that a population of cingulate neurons encodes spontaneous pain-related behaviours and is selectively modulated by morphine. Using deep learning behavioural analyses combined with longitudinal neural recordings in mice, we identified a persistent shift in cortical activity patterns following nerve injury that reflects the emergence of an unpleasant, affective chronic pain state. Morphine reversed these neuropathic neural dynamics and reduced affective–motivational behaviours without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired chemogenetic gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic μ-opioid receptor promoter to drive inhibition . This opioid-mimetic chemogenetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management that targets a key nociceptive cortical opioid circuit with safe, on-demand analgesia.

『Abstract』Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation . Lesion-remote astrocytes (LRAs), which interact with viable neurons and glia, undergo reactive transformations whose molecular and functional properties are poorly understood . Here, using multiple transcriptional profiling methods, we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury. We show that LRAs acquire a spectrum of molecularly distinct, neuroanatomically restricted reactivity states that evolve after spinal cord injury. We identify transcriptionally unique reactive LRAs in degenerating white matter that direct the specification and function of local microglia that clear lipid-rich myelin debris to promote tissue repair. Fuelling this LRA functional adaptation is the secreted matricellular protein CCN1. Loss of astrocyte-derived CCN1 results in excessive, aberrant activation of local microglia, characterized by abnormal molecular specification, impaired debris processing reflected by the intracellular accumulation of myelin and axon debris, and dysregulated lipid metabolism with distinctive attenuation in lipid droplet accumulation. Mechanistically, we find that CCN1 binds microglial SDC4 to augment lipid storage, linking this signalling axis to a vital repair-associated lipid buffering response in debris-clearing microglia. Accordingly, microglial deficits resulting from astrocyte CCN1 depletion culminate in blunted clearance of white matter debris and impaired neurological recovery from spinal cord injury. Ccn1 -expressing white matter astrocytes are induced by local myelin damage and are generated in diverse demyelinating disorders in mice and humans, pointing to their fundamental, evolutionarily conserved role in white matter repair. Our findings show that context-specific cues shape regionally distinct LRA reactivity states with functional adaptations that orchestrate multicellular processes underlying neural repair and influence disease outcome.

『Abstract』The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients . However, resistance is common and tumours often progress after years of endocrine suppression . Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear . Here we show that fasting induces extensive epigenetic reprogramming in ERα-positive breast cancer xenografts when combined with endocrine therapy, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor signalling and concomitant reduction in the activity of activator protein-1 (AP-1) family members. GR-driven gene programmes are selectively activated in in vivo models of ERα-positive breast cancer during fasting, and GR knockout hinders the anti-tumour effects of fasting combined with tamoxifen. Exogenous administration of GR ligands recapitulates fasting-enhanced anti-oestrogen action, thus promoting tumour regression. Patients undergoing a cyclic fasting-mimicking diet exhibited increased blood progesterone and cortisol concentrations. Additionally, tumours collected after the fasting-mimicking diet showed an inverse correlation of GR activation with proliferation markers, providing clinical confirmation of our observations in animal models. Our results indicate that GR activation has a pivotal role in the ability of fasting to enhance endocrine therapy activity in breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this setting.

『Abstract』The nuclear export of mRNA is an important step in eukaryotic gene expression . Despite recent molecular insights into how newly transcribed mRNAs are packaged into ribonucleoprotein complexes (mRNPs) , the subsequent events that govern mRNA export are poorly understood. Here we uncover the molecular basis underlying key events of human mRNA export, including the remodelling of mRNP-bound transcription–export complexes (TREX), the formation of export-competent mRNPs, the docking of mRNPs at the nuclear pore complex (NPC), and the release of mRNPs at the NPC to initiate their export. Our biochemical and structural data show that the ATPase UAP56 (also known as DDX39) acts as a central molecular switch that directs nucleoplasmic mRNPs from TREX to NPC-anchored TREX-2 complexes through its ATP-gated mRNA-binding cycle. Collectively, these findings establish a mechanistic framework for a general and evolutionarily conserved mRNA export pathway.

『Abstract』Neutrophils exhibit remarkable phenotypic and functional diversity across tissues and diseases , yet the lack of understanding of how this immune compartment is globally organized challenges translation to the clinic. Here we performed single-cell transcriptional profiling of neutrophils spanning 47 anatomical, physiological and pathological scenarios to generate an integrated map of the global neutrophil compartment in mice, which we refer to as NeuMap. NeuMap integrates and expands existing models to generate fundamental new insights; it reveals that neutrophils organize in a finite number of functional hubs that distribute sequentially during maturation to then branch out into interferon-responsive and immunosuppressive states, as well as a functionally silent state that dominates in the healthy circulation. Computational modelling and timestamp analyses identify prototypical trajectories that connect these hubs, and reveal that the dynamics and preferred paths vary during health, inflammation and cancer. We show that TGFβ, IFNβ and GM-CSF push neutrophils along the different trajectories, and projection of chromatin accessibility sites onto NeuMap reveals that the transcription factor JUNB controls angiogenic and immunosuppressive states and promotes tissue revascularization. The architecture of NeuMap appears to be conserved across sex, environmental and genetic backgrounds, as well as in humans. Finally, we show that NeuMap enables inference of the pathophysiological state of the host by profiling blood neutrophils. Our study delineates the global architecture of the neutrophil compartment and establishes a framework for exploration and exploitation of neutrophil biology.

『Abstract』Upon viral infection, the current paradigm of humoral immunity posits that germinal centre reactions occurring within secondary lymphoid organs (SLOs) yield effector plasma cells that subsequently traffic to infected organs or the bone marrow . However, it is not well understood how viral tissue tropism may govern the spatiotemporal dynamics of such responses. Here we demonstrate that infection with a prototypical systemic virus indeed induces liver-trafficking plasma cells generated in SLOs, whereas strictly hepatotropic hepaciviral infection elicits locally primed, virus-specific plasma cells in the liver independently of SLO contribution. Such locally derived progenies emerged from inducible hepatic-associated lymphoid tissue (iHALT) structures containing generative foci of T follicular helper cells, myeloid cells and germinal centre-like B cells, often arising from single founder clones unique to individual periportal structures and locally supporting somatic hypermutation. Critically, the cellular composition, cell–cell contact partners and microarchitecture of such iHALT structures in mice were closely mirrored upon hepaciviral infection in humans. Functionally dependent upon CD40L signalling and cognate B cell receptor specificity, emerging CXCR4 VLA-4 LFA-1 CD44 CD138 plasma cells were immediately retained along CXCL12 fibronectin ICAM2 osteopontin type I collagen periportal fibroblast tracts, acting as cognate anchoring pairs that were critical to their maintenance therein. In summary, we characterize humoral immunity exclusively generated and maintained within its extralymphoid site of viral infection in the liver amidst SLO dormancy, in which functional iHALT successfully compensates for strictly hepatotropic virus-induced SLO-evasion strategies to prevent persistent infection.

『Abstract』Exposure to economic inequality is widely thought to erode subjective well-being and mental health , which carries important societal implications . However, existing studies face reproducibility issues , and theory suggests that inequality only affects individuals in disadvantaged contexts . Here we present a meta-analysis of 168 studies using multilevel data (11,389,871 participants from 38,335 geographical units) identified across 10 bibliographical databases (2000–2022). Contrary to popular narratives, random-effects models showed that individuals in more unequal areas do not report lower subjective well-being (standardized odds ratio (OR +0.05 ) = 0.979, 95% confidence interval = 0.951–1.008). Moreover, although inequality initially seemed to undermine mental health, the publication-bias-corrected association was null (OR +0.05 = 1.019; 0.990–1.049) . Meta-analytical effects were smaller than the smallest effect of interest, and specification curve analyses confirmed these results across ≈95% of 768 alternative models . When assessing study quality and certainty of evidence using ROBINS-E and GRADE criteria, ROBINS-E rated 80% of studies at high risk of bias, and GRADE assigned greater certainty to the null effects than to the negative effects. Meta-regressions revealed that the adverse association between inequality and mental health was confined to low-income samples. Moreover, machine-learning analyses indicated that the association with well-being was negative in high-inflation contexts but positive in low-inflation contexts. These moderation effects were replicated using Gallup World Poll data (up to 2 million participants). These findings challenge the view that economic inequality universally harms psychological health and can inform public health policy.

『Abstract』Over the past 20 years, there have been considerable advances in revealing the microbiomes that underpin processes in natural and human-associated environments. Recent large-scale metagenome surveys have recorded the variety of microbial life in the oceans , in the human gut and on Earth , with compilations encompassing thousands of public datasets . However, despite their broad scope, these studies often lack functional information, and their sample locations are frequently sparsely distributed, limited in resolution or lacking metadata. Here we present Microflora Danica—an atlas of Danish environmental microbiomes encompassing 10,683 shotgun metagenomes and 450 nearly full-length 16S and 18S rRNA datasets, linked to a five-level habitat classification scheme. We show that although human-disturbed habitats have high alpha diversity, species reoccur, revealing hidden homogeneity. This underlines the role of natural systems in maintaining total species (gamma) diversity and emphasizes the need for national baselines for tracking microbial responses to land-use and climate change. Consequently, we focused our dataset exploration on nitrifiers, a functional group closely linked to climate change and of major importance for Denmark’s primary land use: agriculture. We identify several lineages encoding nitrifier key genes and reveal the effects of land disturbance on the abundance of well-studied, as well as uncharacterized, nitrifier groups, with potential implications for N 2 O emissions. Microflora Danica offers an unparalleled resource for addressing fundamental questions in microbial ecology about what drives microbial diversity, distribution and function.

『Abstract』Gut bacteriophages profoundly impact microbial ecology and health ; yet, they are understudied. Using deep long-read bulk metagenomic sequencing, we tracked prophage integration dynamics in stool samples from six healthy individuals, spanning a 2-year timescale. Although most prophages remained stably integrated into their hosts, approximately 5% of phages were dynamically gained or lost from persistent bacterial hosts. Within a sample, we found that bacterial hosts with and without a given prophage coexisted simultaneously. Furthermore, phage induction, when detected, occurred predominantly at low levels (1–3× coverage compared to the host region), in line with theoretical expectations . We identified multiple instances of integration of the same phage into bacteria of different taxonomic families, challenging the dogma that phages are specific to a host of a given species or strain . Finally, we describe a new class of ‘IScream phages’, which co-opt bacterial IS30 transposases to mediate their mobilization, representing a previously unrecognized form of phage domestication of selfish bacterial elements. Taken together, these findings illuminate fundamental aspects of phage–bacterial dynamics in the human gut microbiome and expand our understanding of the evolutionary mechanisms that drive horizontal gene transfer and microbial genome plasticity.

『Abstract』Ribosome collisions activate the ribotoxic stress response mediated by the MAP3K ZAK, which in turn regulates cell-fate consequences through downstream phosphorylation of the MAPKs p38 and JNK . Despite the critical role of ZAK during cellular stress, a mechanistic and structural understanding of ZAK–ribosome interactions and how these lead to activation remain elusive. Here we combine biochemistry and cryo-electron microscopy to discover distinct ZAK–ribosome interactions required for constitutive recruitment and for activation. We find that upon induction of ribosome collisions, interactions between ZAK and the ribosomal protein RACK1 enable its activation by dimerization of its SAM domains at the collision interface. Furthermore, we discover how this process is negatively regulated by the ribosome-binding protein SERBP1 to prevent constitutive ZAK activation. Characterization of novel SAM variants as well as a known pathogenic variant of the SAM domain of ZAK supports a key role of the SAM domain in regulating kinase activity on and off the ribosome, with some mutants bypassing the ribosome requirement for ZAK activation. Collectively, our data provide a mechanistic blueprint of the kinase activity of ZAK at the collided ribosome interface.

『Abstract』Neural circuits in many brain regions are refined by experience. Sensory circuits support higher plasticity at younger ages during critical periods—times of circuit refinement and maturation—and limit plasticity in adulthood for circuit stability . How astrocytes, a glial subtype, maintain these differing plasticity levels, and whether they stabilize the properties of sensory circuits in adulthood, remain largely unclear. Here we take a comprehensive approach to address these questions and establish astrocytes as key orchestrators of circuit stability. Combining a transcriptomic approach with ex vivo electrophysiology and in vivo imaging, we identify that astrocytes release CCN1 (refs. ) to maintain synapse and circuit stability in the adult visual cortex. Overexpressing CCN1 in astrocytes during the critical period promotes the maturation of inhibitory neurons, limits ocular dominance plasticity and promotes oligodendrocyte differentiation and maturation. Conversely, knocking out astrocyte CCN1 in adults destabilizes binocular circuits and reduces myelination. This establishes CCN1 as an astrocyte-secreted factor that stabilizes neuronal circuits by coordinating the maturation state of multiple cell types, and demonstrates that the composition and properties of sensory circuits require ongoing maintenance in adulthood, and that these maintenance cues are provided by astrocytes.

『Abstract』Targeted protein degradation is a pharmacological strategy that relies on small molecules such as proteolysis-targeting chimeras (PROTACs) or molecular glues, which induce proximity between a target protein and an E3 ubiquitin ligase to prompt target ubiquitination and proteasomal degradation . Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization . Among others, this has repeatedly been observed for kinase inhibitors . However, we lack an understanding of the frequency, generalizability and mechanistic underpinnings of these phenomena. Here, to address this knowledge gap, we generated dynamic abundance profiles of 98 kinases after cellular perturbations with 1,570 kinase inhibitors, revealing 160 selective instances of inhibitor-induced kinase destabilization. Kinases prone to degradation are frequently annotated as HSP90 clients, therefore affirming chaperone deprivation as an important route of destabilization. However, detailed investigation of inhibitor-induced degradation of LYN, BLK and RIPK2 revealed a differentiated, common mechanistic logic whereby inhibitors function by inducing a kinase state that is more efficiently cleared by endogenous degradation mechanisms. Mechanistically, effects can manifest by ligand-induced changes in cellular activity, localization or higher-order assemblies, which may be triggered by direct target engagement or network effects. Collectively, our data suggest that inhibitor-induced kinase degradation is a common event and positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

『Abstract』Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle , which is dynamically regulated by nutritional status, such as fasting . Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY ), mitochondrial citrate/malate antiporter (encoded by SLC25A1 ) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2 ), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA–NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.

『Abstract』Standard genome-wide association studies (GWAS) and rare variant burden tests are essential tools for identifying trait-relevant genes . Although these methods are conceptually similar, by analysing association studies of 209 quantitative traits in the UK Biobank , we show that they systematically prioritize different genes. This raises the question of how genes should ideally be prioritized. We propose two prioritization criteria: (1) trait importance — how much a gene quantitatively affects a trait; and (2) trait specificity — the importance of a gene for the trait under study relative to its importance across all traits. We find that GWAS prioritize genes near trait-specific variants, whereas burden tests prioritize trait-specific genes. Because non-coding variants can be context specific, GWAS can prioritize highly pleiotropic genes, whereas burden tests generally cannot. Both study designs are also affected by distinct trait-irrelevant factors, complicating their interpretation. Our results illustrate that burden tests and GWAS reveal different aspects of trait biology and suggest ways to improve their interpretation and usage.

『Abstract』Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component . It affects around 5% of children and 2.5% of adults , and is associated with several severe outcomes . Common genetic variants associated with the disorder have been identified , but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes ( MAP1A , ANO8 and ANK2 ; P < 3.07 × 10 ; odds ratios 5.55–15.13) that are implicated in ADHD. The protein–protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neuronal cell types, including GABAergic (γ-aminobutyric-acid-producing) and dopaminergic neurons. Deleterious variants were associated with lower socioeconomic status and lower levels of education in individuals with ADHD, and a decrease of 2.25 intelligence quotient (IQ) points per rare deleterious variant in a sample of adults with ADHD ( n = 962). Individuals with ADHD and intellectual disability showed an increased load of rare variants overall, whereas other psychiatric comorbidities had an increased load only for specific gene sets associated with those comorbidities. This suggests that psychiatric comorbidity in ADHD is driven mainly by rare variants in specific genes, rather than by a general increased load across constrained genes.

『Abstract』Epstein-Barr virus (EBV) is involved in causing and probably also in perpetuating multiple sclerosis (MS). Among several mechanisms of how EBV may contribute are transcriptome alterations, including changes of antigen processing and preferential presentation of both viral and self-antigens. Here, we report that EBV reprograms the transcriptome and immunopeptidome presented on the MS-associated human leukocyte antigen (HLA)-DR15 molecules of infected B cells. Identical myelin basic protein (MBP) peptides were found to be presented on both EBV-infected B cells and MS brain tissue but not primary B cells and thymic tissue. Peripheral memory and cerebrospinal fluid (CSF)-derived CD4 T cells of HLA-DR15 MS patients responded to MBP peptides, MBP (78–90) and/or MBP (83–90) , and T cell clones raised with these peptides recognized all MBP peptides ending at amino acid MBP 90 in MS brain tissue. Our study provides a new mechanistic link for how the environmental and genetic risk factors, EBV infection and HLA-DR15 haplotype, may contribute jointly to MS.

『Abstract』Epstein-Barr virus (EBV) infection constitutes a prerequisite for multiple sclerosis (MS) development, and cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies was previously demonstrated in persons with MS (pwMS). Here, we show that ANO2-specific CD4 T cells are more frequent in pwMS. Immunization of SJL/J mice with ANO2 or EBNA1 led to cross-reactive CD4 T cell and antibody responses. ANO2 pre-immunization led to exacerbated experimental autoimmune encephalomyelitis (EAE), an effect mediated by CD4 T cells, as confirmed by adoptive transfer experiments. T cell clones with cross-reactivity to EBNA1 and ANO2 could be isolated from natalizumab-treated pwMS, and sequencing of EBNA1- and ANO2-specific T cell receptors (TCRs) revealed a significant repertoire overlap. We thus report the first mechanistic evidence that EBNA1 CD4 T cells can target the MS autoantigen ANO2, thereby establishing a link between EBV infection and neuroinflammation.

『Abstract』The efficacy of B cell depletion therapies, and their association with Epstein-Barr virus (EBV), implicate B cells in the pathogenesis of multiple sclerosis (MS). In mice, we observed that viral infections induce infiltration of B cells into the brain, independent of phenotype and specificity, and that myelin-reactive B cells then capture antigens directly from parenchyma. Trafficking of these antigen-loaded B cells to draining lymph nodes was not observed, and without T cell help, antigen-capturing B cells die rapidly. CD40L signaling or EBV latent membrane protein 1 (LMP1) can override this checkpoint, leading to B cell-receptor- and/or antibody-dependent inflammatory demyelination. Myelin-reactive B cells were identified in the healthy human B cell repertoire, and expression of LMP1 was observed in the brains of a subset of MS patients. These observations can explain the dependency of disease incidence on prior EBV infection, and the increased risk associated with brain infections, and suggest possible treatment strategies.

『Abstract』Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.

『Abstract』Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris , a notorious global threat, is also increasingly resistant. We performed a natural product screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris . Mode-of-action studies reveal that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.

『Abstract』Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8 and CD4 effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.

『Abstract』During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress’ functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells’ early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.

『Abstract』Lymph nodes (LNs) enable innate defense to limit pathogen dissemination while also driving adaptive immunity. Yet, certain innate responses can restrict adaptive processes, suggesting that these must be tightly regulated. Here, we report that after infection or immunization, LN architecture is rapidly altered, with large-scale, polarized recruitment of neutrophils and monocytes from inflamed blood vessels and intranodal repositioning of natural killer (NK) cells. Mechanistically, dendritic cells (DCs) promote this through expression of inflammatory chemokines and integrin ligands. While these DC-driven innate responses are necessary for efficient pathogen containment, they paradoxically limit early adaptive immunity, with infiltrating neutrophils displacing lymphocytes and reducing the LN area available for T cell priming. Upon threat cessation, however, DCs and DC-recruited monocytes phagocytose the neutrophils, restoring tissue architecture and generating polarized domains for downstream adaptive immune cell activation. Thus, DCs orchestrate innate cell organization during inflammation, serving as rheostats of innate versus adaptive functions of the LN.

『Abstract』The mammalian brain contains diverse neuronal and immune cell types that exhibit dynamic motions in response to distinct extracellular environments. However, technical limitations make it difficult to investigate complex cellular motions in the developing brain in vivo . Here, we establish the intravital imaging of externally immobilized embryos (IMEE) method for long-term, large-field, and deep-depth imaging of mouse embryos, excelling in viewing angle flexibility, procedural simplicity, and functional applicability. Through combining IMEE with in utero retro-orbital injection and topological analysis of vector fields, we characterize distinct neuronal migration patterns and illustrate interactions among neurons, immune cells, and vasculature under physiological conditions and environmental stress during brain development. Our results suggest that neuronal migration guidance and immune surveillance depend on cellular adaptation to the local environment through distinct motion patterns of somata or processes. Our findings provide critical insight into the environmentally adaptive nature of neural cells in the developmental landscape.

『Abstract』The tumor immune microenvironment (TIME) critically impacts cancer progression and immunotherapy response. Multiplex immunofluorescence (mIF) is a powerful imaging modality for deciphering TIME, but its applicability is limited by high cost and low throughput. We propose GigaTIME , a multimodal AI framework for population-scale TIME modeling by bridging cell morphology and states. GigaTIME learns a cross-modal translator to generate virtual mIF images from hematoxylin and eosin (H&E) slides by training on 40 million cells with paired H&E and mIF data across 21 proteins. We applied GigaTIME to 14,256 patients from 51 hospitals and over 1,000 clinics across seven US states in Providence Health, generating 299,376 virtual mIF slides spanning 24 cancer types and 306 subtypes. This virtual population uncovered 1,234 statistically significant associations linking proteins, biomarkers, staging, and survival. Such analyses were previously infeasible due to the scarcity of mIF data. Independent validation on 10,200 TCGA patients further corroborated our findings.

『Abstract』Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.

『Abstract』Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin’s effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.

『Abstract』Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the β-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTα chain. CARs harboring the pTα 1A domain imparted greater expansion, cytokine production, and in vivo persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.

『Abstract』Bacteria exist in competitive and rapidly changing environments in which the nature of future threats cannot be easily predicted. Streptomyces coelicolor produces three antibacterial umbrella particles that harbor distinct polymorphic toxin domains and an overlapping set of six diversified lectins. Here, we show that the exquisite specificity of umbrella particles derives from lectin-mediated species-specific binding to previously undescribed hypervariable surface glycoconjugates. A cryo-electron microscopy (cryo-EM) structure of one such lectin in complex with its oligosaccharide substrate defines the molecular basis for targeting through the coordinated recognition of multiple glycan features. Biochemical and genetic studies of several target species, in conjunction with lectin-swapping experiments, support a model whereby S. coelicolor umbrella toxin diversification at the levels of lectin composition and toxin polymorphism represents a unique, two-tiered bet-hedging strategy. Bioinformatic analyses support this as a means by which the unusual architecture of umbrella toxins offers Streptomyces a generalizable strategy to antagonize an unpredictable array of competitors.

『Abstract』Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer’s disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein subtypes revealed that distinct receptor conformations contribute to selective G protein bias. Leveraging these structural insights, we rationally develop synthetic CCKBR agonists, including a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). Notably, 3r1 demonstrates therapeutic potential by ameliorating cognitive decline in 5×FAD mice, reducing the number of amyloid-β plaques, and promoting long-term potentiation (LTP) via upregulation of the α-secretase (ADAM10) and the calcium signaling molecule PLCB4. Our findings suggest that synthetic biased agonists targeting CCKBR-Gq signaling have therapeutic potential for AD.

『Abstract』Cellular senescence and brain atrophy are both associated with brain aging, suggesting these processes may share underlying biological mechanisms. This study investigated these mechanisms by integrating structural neuroimaging with gene and protein expression data from prefrontal cortex tissue collected from individuals who underwent neurosurgery. Cell-type-specific gene expression signatures associated with neuroimaging features and cellular senescence were identified and replicated in several independent datasets. Significant correlations between these signatures were observed in excitatory neurons and microglia, especially for volume-related features. These associations were also observed for excitatory neurons in an independent brain gene expression dataset from individuals below 5 years of age, implying a role for senescence during brain development. Together, this study provides a deep characterization of molecular signatures linking brain structure and cellular senescence across different life stages and suggests mechanisms supporting brain development may also contribute to volume reduction observed during aging.

『Abstract』Abstract Couple-close as a synthetic paradigm has the potential to change the way that synthetic organic chemists approach cyclic scaffold construction. One class of cyclic molecules that has been increasingly sought after is semisaturated cyclic scaffolds, whose specific blend of Csp - and Csp -hybridized components confers distinct properties to these species. However, existing methods to construct these scaffolds are limited, often relying on arene saturation or annulations that require lengthy de novo syntheses. Herein, we describe a unified and highly modular couple-close strategy for the synthesis of semisaturated scaffolds. This approach installs bifunctional linkers onto aromatic rings through a range of bond-forming reactions, and subsequent cyclization furnishes semisaturated bicyclic adducts. Key to this approach is a mechanistically distinct cobalt-catalyzed dehydrogenative radical cyclization that proceeds efficiently even on electronically unbiased arenes, enabling a broad substrate scope under mild reaction conditions.

『Abstract』Abstract Ferroelectric charged domain walls (CDWs) with nanoscale thickness and bound charges are typically viewed as ultrathin, reconfigurable, and highly conductive two-dimensional components for domain wall nanoelectronics. Dimensional confinement of such polar topological structures has the potential to increase device density and unlock novel functionalities. We report 180° head-to-head and tail-to-tail CDWs exhibiting one-dimensional (1D) characteristics. These 1D CDWs are confined within the polar layers of ferroelectric ZrO 2 and have atomic-scale dimensions in both width and thickness. Quantitative analysis unveils a distinct screening mechanism of these walls whereby bound polarization charges are compensated by self-balancing oxygen occupancy. We demonstrate electric field–driven manipulation of these 1D CDWs, revealing the microscopic coupling between polarization switching and oxygen-ion transport.