前沿速递 | NCS 集萃： 2025-01-24 期

『Abstract』 The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase–wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.

『Abstract』 Incorporation of animal-based foods into early hominin diets has been hypothesized to be a major catalyst of many important evolutionary events, including brain expansion. However, direct evidence of the onset and evolution of animal resource consumption in hominins remains elusive. The nitrogen-15 to nitrogen-14 ratio of collagen provides trophic information about individuals in modern and geologically recent ecosystems (<200,000 years ago), but diagenetic loss of this organic matter precludes studies of greater age. By contrast, nitrogen in tooth enamel is preserved for millions of years. We report enamel-bound organic nitrogen and carbonate carbon isotope measurements of Sterkfontein Member 4 mammalian fauna, including seven Australopithecus specimens. Our results suggest a variable but plant-based diet (largely C 3 ) for these hominins. Therefore, we argue that Australopithecus at Sterkfontein did not engage in regular mammalian meat consumption.

『Abstract』 Soil water sustains terrestrial life, yet its fate is uncertain under a changing climate. We conducted a deuterium labeling experiment to determine whether elevated atmospheric carbon dioxide (CO2 ), warming, and drought impact soil water storage and transport in a temperate grassland. Elevated CO2 created a wetter rootzone compared with ambient conditions, whereas warming decreased soil moisture. Soil water remained well mixed in all global change treatments except for summer drought combined with warming and elevated CO2 . These combined treatments caused the grassland to conserve water and restricted soil water flow to large, rapidly draining pores without mixing with small, slowly draining pores. Our results suggest that drought in a warmer, more CO 2 -rich climate can severely alter grassland ecohydrology by constraining postdrought soil water flow and grassland water use.

『Abstract』 Persistent multiyear drought (MYD) events pose a growing threat to nature and humans in a changing climate. We identified and inventoried global MYDs by detecting spatiotemporally contiguous climatic anomalies, showing that MYDs have become drier, hotter, and led to increasingly diminished vegetation greenness. The global terrestrial land affected by MYDs has increased at a rate of 49,279 ± 14,771 square kilometers per year from 1980 to 2018. Temperate grasslands have exhibited the greatest declines in vegetation greenness during MYDs, whereas boreal and tropical forests have had comparably minor responses. With MYDs becoming more common, this global quantitative inventory of the occurrence, severity, trend, and impact of MYDs provides an important benchmark for facilitating more effective and collaborative preparedness toward mitigation of and adaptation to such extreme events.

『Abstract』 Mechanical bonds arise between molecules that contain interlocked subunits, such as one macrocycle threaded through another. Within polymers, these linkages will confer distinctive mechanical properties and other emergent behaviors, but polymerizations that form mechanical bonds efficiently and use simple monomeric building blocks are rare. In this work, we introduce a solid-state polymerization in which one monomer infiltrates crystals of another to form a macrocycle and mechanical bond at each repeat unit of a two-dimensional (2D) polymer. This mechanically interlocked 2D polymer is formed as a layered solid that is readily exfoliated in common organic solvents, enabling spectroscopic characterization and atomic-resolution imaging using advanced electron microscopy techniques. The 2D mechanically interlocked polymer is easily prepared on multigram scales, which, along with its solution processibility, enables the facile fabrication of composite fibers with Ultem that exhibit enhanced stiffness and strength.

『Abstract』 Climate warming can induce a cost-of-living “squeeze” in ectotherms by increasing energetic expenditures while reducing foraging gains. We used biophysical models (validated by 2685 field observations) to test this hypothesis for 10 ecologically diverse lizards in African and Australian deserts. Historical warming (1950–2020) has been more intense in Africa than in Australia, translating to an energetic squeeze for African diurnal species. Although no net impact on Australian diurnal species was observed, warming generated an energetic “relief” (by increasing foraging time) for nocturnal species. Future warming impacts will be more severe in Africa than in Australia, requiring increased rates of food intake (+10% per hour active for diurnal species). The effects of climate warming on desert lizard energy budgets will thus be species-specific but potentially predictable.

『Abstract』 Strigolactones (SLs) are methylbutenolide molecules derived from β-carotene through an intermediate carlactonoic acid (CLA). Canonical SLs act as signals to microbes and plants, whereas noncanonical SLs are primarily plant hormones. The cytochrome P450 CYP722C catalyzes a critical step, converting CLA to canonical SLs in most angiosperms. Using synthetic biology, we investigated the function of CYP722A , an evolutionary predecessor of CYP722C . CYP722A converts CLA into 16-hydroxy-CLA (16-OH-CLA), a noncanonical SL detected exclusively in the shoots of various flowering plants. 16-OH-CLA application restores control of shoot branching to SL-deficient mutants in Arabidopsis thaliana and is perceived by the SL signaling pathway. We hypothesize that biosynthesis of 16-OH-CLA by CYP722A was a metabolic stepping stone in the evolution of canonical SLs that mediate rhizospheric signaling in many flowering plants.

『Abstract』 Formamidinium lead triiodide (FAPbI3 ) is considered the most promising composition for high-performing single-junction solar cells. However, nonalloyed α-FAPbI3 is metastable with respect to the photoinactive δ-phase. We have developed a kinetic modulation strategy to fabricate high-quality and stable nonalloyed α-FAPbI3 films, assisted by cogenetic volatile iodine intercalation and decalation. The intercalation of iodine facilitated the formation of corner-sharing Pb-I framework building blocks and reduced the kinetic barrier for α-FAPbI3 formation, whereas the iodine decalation improved the final perovskite film quality in terms of composition purity and overall homogeneity. Solar cells based on this nonalloyed α-FAPbI3 (free of other extrinsic composition ions) achieved a power conversion efficiency of >24%. The devices also exhibited excellent durability, retaining 99% of their original power conversion efficiency after operating for more than 1100 hours at 85° ± 5°C under illumination.

『Abstract』 Synapses are organized by trans-synaptic adhesion molecules that coordinate assembly of pre- and postsynaptic specializations, which, in turn, are composed of scaffolding proteins forming liquid-liquid phase-separated condensates. Presynaptic teneurins mediate excitatory synapse organization by binding to postsynaptic latrophilins; however, the mechanism of action of teneurins, driven by extracellular domains evolutionarily derived from bacterial toxins, remains unclear. In this work, we show that only the intracellular sequence, a dimerization sequence, and extracellular bacterial toxin–derived latrophilin-binding domains of Teneurin-3 are required for synapse organization, suggesting that teneurin-induced latrophilin clustering mediates synaptogenesis. Intracellular Teneurin-3 sequences capture liquid-liquid phase-separated presynaptic active zone scaffolds, enabling us to reconstitute an entire synaptic junction from purified proteins in which trans-synaptic teneurin-latrophilin complexes recruit phase-separated pre- and postsynaptic specializations.

『Abstract』 Intracortical microstimulation (ICMS) of somatosensory cortex evokes tactile sensations whose properties can be systematically manipulated by varying stimulation parameters. However, ICMS currently provides an imperfect sense of touch, limiting manual dexterity and tactile experience. Leveraging our understanding of how tactile features are encoded in the primary somatosensory cortex (S1), we sought to inform individuals with paralysis about local geometry and apparent motion of objects on their skin. We simultaneously delivered ICMS through electrodes with spatially patterned projected fields (PFs), evoking sensations of edges. We then created complex PFs that encode arbitrary tactile shapes and skin indentation patterns. By delivering spatiotemporally patterned ICMS, we evoked sensation of motion across the skin, the speed and direction of which could be controlled. Thus, we improved individuals’ tactile experience and use of brain-controlled bionic hands.

『Abstract』 Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor–β family, the activins. Our results both challenge activin’s eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.

『Abstract』 Commercial adhesives are petroleum-based thermoset networks or nonbiodegradable thermoplastic hot melts, making them ideal targets for replacement by biodegradable alternatives. Poly(3-hydroxybutyrate) (P3HB) is a biorenewable and biodegradable alternative to conventional plastics, but microbial P3HB, which has a stereoperfect stereomicrostructure, exhibits no adhesion. In this study, by elucidating the fundamental relationship between chemocatalytically engineered P3HB stereomicrostructures and adhesion properties, we found that biodegradable syndio-rich P3HB exhibits high adhesion strength and outperforms common commercial adhesives, whereas syndiotactic, isotactic, or iso-rich P3HB shows no measurable adhesion. The syndio-rich stereomicrostructure brings about desired thermomechanical and viscoelastic properties of P3HB that enable strong adhesion to a range of substrates tested, including aluminum, steel, glass, and wood, and its performance is insensitive to molar mass and reprocessing or reuse.

『Abstract』 The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.

『Abstract』 Architected materials derive their properties from the geometric arrangement of their internal structural elements. Their designs rely on continuous networks of members to control the global mechanical behavior of the bulk. In this study, we introduce a class of materials that consist of discrete concatenated rings or cage particles interlocked in three-dimensional networks, forming polycatenated architected materials (PAMs). We propose a general design framework that translates arbitrary crystalline networks into particle concatenations and geometries. In response to small external loads, PAMs behave like non-Newtonian fluids, showing both shear-thinning and shear-thickening responses, which can be controlled by their catenation topologies. At larger strains, PAMs behave like lattices and foams, with a nonlinear stress-strain relation. At microscale, we demonstrate that PAMs can change their shapes in response to applied electrostatic charges. The distinctive properties of PAMs pave the path for developing stimuli-responsive materials, energy-absorbing systems, and morphing architectures.

『Abstract』 To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling >20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals >3000 different cellular states and >200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts in cellular dynamics during life-span progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our “cell-omics” strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.

『Abstract』The concept of non-Hermiticity has expanded the understanding of band topology, leading to the emergence of counter-intuitive phenomena. An example is the non-Hermitian skin effect (NHSE) , which involves the concentration of eigenstates at the boundary. However, despite the potential insights that can be gained from high-dimensional non-Hermitian quantum systems in areas such as curved space , high-order topological phases and black holes , the realization of this effect in high dimensions remains unexplored. Here we create a two-dimensional (2D) non-Hermitian topological band for ultracold fermions in spin–orbit-coupled optical lattices with tunable dissipation, which exhibits the NHSE. We first experimentally demonstrate pronounced nonzero spectral winding numbers in the complex energy plane with nonzero dissipation, which establishes the existence of 2D skin effect. Furthermore, we observe the real-space dynamical signature of NHSE in real space by monitoring the centre of mass motion of atoms. Finally, we also demonstrate that a pair of exceptional points are created in the momentum space, connected by an open-ended bulk Fermi arc, in contrast to closed loops found in Hermitian systems. The associated exceptional points emerge and shift with increasing dissipation, leading to the formation of the Fermi arc. Our work sets the stage for further investigation into simulating non-Hermitian physics in high dimensions and paves the way for understanding the interplay of quantum statistics with NHSE.

『Abstract』H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models . Arm A of Phase I trial no. NCT04196413 (ref. ) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10 kg ; DL2, 3 × 10 kg ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study ( n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

『Abstract』Animals are often bombarded with visual information and must prioritize specific visual features based on their current needs. The neuronal circuits that detect and relay visual features have been well studied . Much less is known about how an animal adjusts its visual attention as its goals or environmental conditions change. During social behaviours, flies need to focus on nearby flies . Here we study how the flow of visual information is altered when female Drosophila enter an aggressive state. From the connectome, we identify three state-dependent circuit motifs poised to modify the response of an aggressive female to fly-sized visual objects: convergence of excitatory inputs from neurons conveying select visual features and internal state; dendritic disinhibition of select visual feature detectors; and a switch that toggles between two visual feature detectors. Using cell-type-specific genetic tools, together with behavioural and neurophysiological analyses, we show that each of these circuit motifs is used during female aggression. We reveal that features of this same switch operate in male Drosophila during courtship pursuit, suggesting that disparate social behaviours may share circuit mechanisms. Our study provides a compelling example of using the connectome to infer circuit mechanisms that underlie dynamic processing of sensory signals.

『Abstract』Topological design of π electrons in zigzag-edged graphene nanoribbons (ZGNRs) leads to a wealth of magnetic quantum phenomena and exotic quantum phases . Symmetric ZGNRs typically show antiferromagnetically coupled spin-ordered edge states . Eliminating cross-edge magnetic coupling in ZGNRs not only enables the realization of a class of ferromagnetic quantum spin chains , enabling the exploration of quantum spin physics and entanglement of multiple qubits in the one-dimensional limit , but also establishes a long-sought-after carbon-based ferromagnetic transport channel, pivotal for ultimate scaling of GNR-based quantum electronics . Here we report a general approach for designing and fabricating such ferromagnetic GNRs in the form of Janus GNRs (JGNRs) with two distinct edge configurations. Guided by Lieb’s theorem and topological classification theory , we devised two JGNRs by asymmetrically introducing a topological defect array of benzene motifs to one zigzag edge, while keeping the opposing zigzag edge unchanged. This breaks the structural symmetry and creates a sublattice imbalance within each unit cell, initiating a spin-symmetry breaking. Three Z-shaped precursors are designed to fabricate one parent ZGNR and two JGNRs with an optimal lattice spacing of the defect array for a complete quench of the magnetic edge states at the ‘defective’ edge. Characterization by scanning probe microscopy and spectroscopy and first-principles density functional theory confirms the successful fabrication of JGNRs with a ferromagnetic ground-state localized along the pristine zigzag edge.

『Abstract』Organic halides are highly useful compounds in chemical synthesis, in which the halide serves as a versatile functional group for elimination, substitution and cross-coupling reactions with transition metals or photocatalysis . However, the activation of carbon–fluorine (C–F) bonds—the most commercially abundant organohalide and found in polyfluoroalkyl substances (PFAS), or ‘forever chemicals’—is much rarer. Current approaches based on photoredox chemistry for the activation of small-molecule C–F bonds are limited by the substrates and transition metal catalysts needed . A general method for the direct activation of organofluorines would have considerable value in organic and environmental chemistry. Here we report an organic photoredox catalyst system that can efficiently reduce C–F bonds to generate carbon-centred radicals, which can then be intercepted for hydrodefluorination (swapping F for H) and cross-coupling reactions. This system enables the general use of organofluorines as synthons under mild reaction conditions. We extend this method to the defluorination of PFAS and fluorinated polymers, a critical challenge in the breakdown of persistent and environmentally damaging forever chemicals.

『Abstract』The stretch reflex is a fundamental component of the motor system that orchestrates the coordinated muscle contractions underlying movement. At the heart of this process lie the muscle spindles (MS), specialized receptors finely attuned to fluctuations in tension within intrafusal muscle fibres. The tension variation in the MS triggers a series of neuronal events including an initial depolarization of sensory type Ia afferents that subsequently causes the activation of motoneurons within the spinal cord . This neuronal cascade culminates in the execution of muscle contraction, underscoring a presumed closed-loop mechanism between the musculoskeletal and nervous systems. By contrast, here we report the discovery of a new population of macrophages with exclusive molecular and functional signatures within the MS that express the machinery for synthesizing and releasing glutamate. Using mouse intersectional genetics with optogenetics and electrophysiology, we show that activation of MS macrophages (MSMP) drives proprioceptive sensory neuron firing on a millisecond timescale. MSMP activate spinal circuits, motor neurons and muscles by means of a glutamate-dependent mechanism that excites the MS. Furthermore, MSMP respond to neural and muscle activation by increasing the expression of glutaminase, enabling them to convert the uptaken glutamine released by myocytes during muscle contraction into glutamate. Selective silencing or depletion of MSMP in hindlimb muscles disrupted the modulation of the stretch reflex for force generation and sensory feedback correction, impairing locomotor strategies in mice. Our results have identified a new cellular component, the MSMP, that directly regulates neural activity and muscle contraction. The glutamate-mediated signalling of MSMP and their dynamic response to sensory cues introduce a new dimension to our understanding of sensation and motor action, potentially offering innovative therapeutic approaches in conditions that affect sensorimotor function.

『Abstract』Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis . Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR–PTPN11–FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.

『Abstract』The cratonic crust contains abundant mineral deposits of metals such as gold, copper and rare earths and is underlain by a thick mantle lithosphere rich in the volatiles carbon, sulfur and water. Although volatiles are known to be key components in metallogenesis , how and where they are distributed in the cratonic lithosphere mantle and their role in the initial enrichment of metals have not been sufficiently explored. Here we compile sulfur and copper contents of global cratonic peridotites, identifying sulfide-rich and copper-rich continental roots at depths of 160–190 km at cratonic margins. Our new high-pressure experiments show that carbonated silicate melts originating from the asthenosphere lose silicate components during reaction with lithospheric peridotite, evolving to carbonatite melts that become concentrated at cratonic margins. Sulfur solubility in melts substantially decreases as the SiO2 content of melts decreases during this process, forcing sulfide precipitation and the formation of sulfide-rich continental roots at the base of the mantle lithosphere. The migration of carbonated melts towards cratonic margins replenishes the continental roots there with sulfur, explaining the co-location of magmatic metal deposits with carbonatites close to cratonic margins. These findings highlight the notable role of carbonated melts in metallogenesis and provide a potential platform for metal ore exploration.

『Abstract』The rapid melting of mountain glaciers and the vanishing of their streams is emblematic of climate change . Glacier-fed streams (GFSs) are cold, oligotrophic and unstable ecosystems in which life is dominated by microbial biofilms . However, current knowledge on the GFS microbiome is scarce , precluding an understanding of its response to glacier shrinkage. Here, by leveraging metabarcoding and metagenomics, we provide a comprehensive survey of bacteria in the benthic microbiome across 152 GFSs draining the Earth’s major mountain ranges. We find that the GFS bacterial microbiome is taxonomically and functionally distinct from other cryospheric microbiomes. GFS bacteria are diverse, with more than half being specific to a given mountain range, some unique to single GFSs and a few cosmopolitan and abundant. We show how geographic isolation and environmental selection shape their biogeography, which is characterized by distinct compositional patterns between mountain ranges and hemispheres. Phylogenetic analyses furthermore uncovered microdiverse clades resulting from environmental selection, probably promoting functional resilience and contributing to GFS bacterial biodiversity and biogeography. Climate-induced glacier shrinkage puts this unique microbiome at risk. Our study provides a global reference for future climate-change microbiology studies on the vanishing GFS ecosystem.

『Abstract』In organisms ranging from vertebrates to plants, major components of centromeres are rapidly evolving repeat sequences, such as tandem repeats (TRs) and transposable elements (TEs), which harbour centromere-specific histone H3 (CENH3) . Complete centromere structures recently determined in human and Arabidopsis suggest frequent integration and purging of retrotransposons within the TR regions of centromeres . Despite the high impact of ‘centrophilic’ retrotransposons on the paradox of rapid centromere evolution, the mechanisms involved in centromere targeting remain poorly understood in any organism. Here we show that both Ty3 and Ty1 long terminal repeat retrotransposons rapidly turnover within the centromeric TRs of Arabidopsis species. We demonstrate that the Ty1/Copia element Tal1 ( Transposon of Arabidopsis lyrata 1 ) integrates de novo into regions occupied by CENH3 in Arabidopsis thaliana , and that ectopic expansion of the CENH3 region results in spread of Tal1 integration regions. The integration spectra of chimeric TEs reveal the key structural variations responsible for contrasting chromatin-targeting specificities to centromeres versus gene-rich regions, which have recurrently converted during the evolution of these TEs. Our findings show the impact of centromeric chromatin on TE-mediated rapid centromere evolution, with relevance across eukaryotic genomes.

『Abstract』C–H activation is the most direct way of functionalizing organic molecules. Many advances in this field still require specific directing groups to achieve the necessary activity and selectivity. Developing C–H activation reactions directed by native functional groups is essential for their broad application in synthesis . Over the past decade, several generations of bifunctional ligands developed have enabled C( sp )–H activation reactions of free carboxylic acids , free aliphatic amines , native amides and alcohols . However, an effective catalyst for ketones and carboxylic esters remains to be realized. Here we report diverse methyl β-C−H functionalizations, including intermolecular arylation, hydroxylation and intramolecular C( sp )–H/C( sp )–H coupling of ketones and carboxylic esters with a monoprotected amino neutral amide (MPANA) ligand. The in situ generation of cationic Pd(II) complexes by the combination MPANA ligand and HBF 4 is crucial for achieving the reactivity. The compatibility of these reactions with cyclic ketones and lactams provides a method to access spirocyclic and fused ring systems. Mechanistic experiments and density functional theory studies support the role of cationic Pd complexes with MPANA ligands in enhancing catalyst–substrate affinity and facilitating the C−H cleavage step.

『Abstract』Motor skill repertoire can be stably retained over long periods, but the neural mechanism that underlies stable memory storage remains poorly understood . Moreover, it is unknown how existing motor memories are maintained as new motor skills are continuously acquired. Here we tracked neural representation of learned actions throughout a significant portion of the lifespan of a mouse and show that learned actions are stably retained in combination with context, which protects existing memories from erasure during new motor learning. We established a continual learning paradigm in which mice learned to perform directional licking in different task contexts while we tracked motor cortex activity for up to six months using two-photon imaging. Within the same task context, activity driving directional licking was stable over time with little representational drift. When learning new task contexts, new preparatory activity emerged to drive the same licking actions. Learning created parallel new motor memories instead of modifying existing representations. Re-learning to make the same actions in the previous task context re-activated the previous preparatory activity, even months later. Continual learning of new task contexts kept creating new preparatory activity patterns. Context-specific memories, as we observed in the motor system, may provide a solution for stable memory storage throughout continual learning.

『Abstract』The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses . Within the tumour microenvironment, CD8 T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches . Although interactions with type 1 conventional dendritic cells have been implicated in this process , the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9 , Cxcl10 and Il15 , but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E 2 (PGE 2 ), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE 2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE 2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

『Abstract』Proximity ferroelectricity is an interface-associated phenomenon in electric-field-driven polarization reversal in a non-ferroelectric polar material induced by one or more adjacent ferroelectric materials. Here we report proximity ferroelectricity in wurtzite ferroelectric heterostructures. In the present case, the non-ferroelectric layers are AlN and ZnO, whereas the ferroelectric layers are Al 1 − x B x N, Al 1 − x Sc x N and Zn 1 − x Mg x O. The layered structures include nitride–nitride, oxide–oxide and nitride–oxide stacks that feature two-layer (asymmetric) and three-layer (symmetric) configurations . Ferroelectric switching in both layers is validated by multimodal characterization methods, including polarization hysteresis, anisotropic chemical etching, second harmonic generation, piezo response force microscopy, electromechanical testing and atomic resolution polarization orientation imaging in real space by scanning transmission electron microscopy. We present a physical switching model in which antipolar nuclei originate in the ferroelectric layer and propagate towards the internal non-ferroelectric interface. The domain wall leading edge produces elastic and electric fields that extend beyond the interface at close proximity, reducing the switching barrier in the non-ferroelectric layer, and allowing complete domain propagation without breakdown. Density functional theory calculations of polymorph energies, reversal barriers and domain wall energies support this model. Proximity ferroelectricity enables polarization reversal in wurtzites without the chemical or structural disorder that accompanies elemental substitution, opening new questions and opportunities regarding interface-based ferroelectricity.

『Abstract』The dynamics of the genetic diversity of pathogens, including the emergence of lineages with increased fitness, is a foundational concept of disease ecology with key public-health implications. However, the identification of such lineages and estimation of associated fitness remain challenging, and is rarely done outside densely sampled systems . Here we present phylowave, a scalable approach that summarizes changes in population composition in phylogenetic trees, enabling the automatic detection of lineages based on shared fitness and evolutionary relationships. We use our approach on a broad set of viruses and bacteria (SARS-CoV-2, influenza A subtype H3N2, Bordetella pertussis and Mycobacterium tuberculosis ), which include both well-studied and understudied threats to human health. We show that phylowave recovers the main known circulating lineages for each pathogen and that it can detect specific amino acid changes linked to fitness changes. Furthermore, phylowave identifies previously undetected lineages with increased fitness, including three co-circulating B. pertussis lineages. Inference using phylowave is robust to uneven and limited observations. This widely applicable approach provides an avenue to monitor evolution in real time to support public-health action and explore fundamental drivers of pathogen fitness.

『Abstract』Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder . The neural underpinnings of anhedonia and how this emotional state drives behaviour remain unclear. Here we investigated the neural code of anhedonia by taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient. By performing high-density electrophysiology to record neural activity patterns in the basolateral amygdala (BLA) and ventral CA1 (vCA1), we identified neural signatures of susceptibility and resilience. When mice actively sought rewards, BLA activity in resilient mice showed robust discrimination between reward choices. By contrast, susceptible mice exhibited a rumination-like signature, in which BLA neurons encoded the intention to switch or stay on a previously chosen reward. Manipulation of vCA1 inputs to the BLA in susceptible mice rescued dysfunctional neural dynamics, amplified dynamics associated with resilience, and reversed anhedonic behaviour. Finally, when animals were at rest, the spontaneous BLA activity of susceptible mice showed a greater number of distinct neural population states. This spontaneous activity allowed us to decode group identity and to infer whether a mouse had a history of stress better than behavioural outcomes alone. This work reveals population-level neural dynamics that explain individual differences in responses to traumatic stress, and suggests that modulating vCA1–BLA inputs can enhance resilience by regulating these dynamics.

『Abstract』Aquatic life is strongly structured by the distribution of light, which, besides attenuation in intensity, exhibits a continuous change in the spectrum with depth . The extent to which these light changes are perceived by phytoplankton through photoreceptors is still inadequately known. We addressed this issue by integrating functional studies of diatom phytochrome (DPH) photoreceptors in model species with environmental surveys of their distribution and activity. Here, by developing an in vivo dose–response assay to light spectral variations mediated by DPH, we show that DPH can trigger photoreversible responses across the entire light spectrum, resulting in a change in DPH photoequilibrium with depth. By generating dph mutants in the diatom Thalassiosira pseudonana , we also demonstrate that under simulated low-blue-light conditions of ocean depth, DPH regulates photosynthesis acclimation, thus linking optical depth detection with a functional response. The latitudinal distribution of DPH -containing diatoms from permanently stratified regions to seasonally mixed regions suggests an adaptive value of DPH functions in coping with vertical displacements in the water column. By establishing DPH as a detector of optical depth, this study provides a new view of how information embedded in the underwater light field can be exploited by diatoms to modulate their physiology throughout the photic zone.

『Abstract』The formation of the vertebrate body involves the coordinated production of trunk tissues from progenitors located in the posterior of the embryo. Although in vitro models using pluripotent stem cells replicate aspects of this process , they lack crucial components, most notably the notochord—a defining feature of chordates that patterns surrounding tissues . Consequently, cell types dependent on notochord signals are absent from current models of human trunk formation. Here we performed single-cell transcriptomic analysis of chick embryos to map molecularly distinct progenitor populations and their spatial organization. Guided by this map, we investigated how differentiating human pluripotent stem cells develop a stereotypical spatial organization of trunk cell types. We found that YAP inactivation in conjunction with FGF-mediated MAPK signalling facilitated WNT pathway activation and induced expression of TBXT (also known as BRA). In addition, timely inhibition of WNT-induced NODAL and BMP signalling regulated the proportions of different tissue types, including notochordal cells. This enabled us to create a three-dimensional model of human trunk development that undergoes morphogenetic movements, producing elongated structures with a notochord and ventral neural and mesodermal tissues. Our findings provide insights into the mechanisms underlying vertebrate notochord formation and establish a more comprehensive in vitro model of human trunk development. This paves the way for future studies of tissue patterning in a physiologically relevant environment.

『Abstract』Cells display a range of mechanical activities generated by motor proteins powered through catalysis . This raises the fundamental question of how the acceleration of a chemical reaction can enable the energy released from that reaction to be transduced (and, consequently, work to be done) by a molecular catalyst . Here we demonstrate the molecular-level transduction of chemical energy to mechanical force in the form of the powered contraction and powered re-expansion of a cross-linked polymer gel driven by the directional rotation of artificial catalysis-driven molecular motors. Continuous 360° rotation of the rotor about the stator of the catalysis-driven motor-molecules incorporated in the polymeric framework of the gel twists the polymer chains of the cross-linked network around one another. This progressively increases writhe and tightens entanglements, causing a macroscopic contraction of the gel to approximately 70% of its original volume. The subsequent addition of the opposite enantiomer fuelling system powers the rotation of the motor-molecules in the reverse direction, unwinding the entanglements and causing the gel to re-expand. Continued powered twisting of the strands in the new direction causes the gel to re-contract. In addition to actuation, motor-molecule rotation in the gel produces other chemical and physical outcomes, including changes in the Young modulus and storage modulus—the latter is proportional to the increase in strand crossings resulting from motor rotation. The experimental demonstration of work against a load by a synthetic organocatalyst, and its mechanism of energy transduction , informs both the debate surrounding the mechanism of force generation by biological motors and the design principles for artificial molecular nanotechnology.

『Abstract』Creating the Babel Fish, a tool that helps individuals translate speech between any two languages, requires advanced technological innovation and linguistic expertise. Although conventional speech-to-speech translation systems composed of multiple subsystems performing translation in a cascaded fashion exist , scalable and high-performing unified systems remain underexplored. To address this gap, here we introduce SEAMLESSM4T–Massively Multilingual and Multimodal Machine Translation–a single model that supports speech-to-speech translation (101 to 36 languages), speech-to-text translation (from 101 to 96 languages), text-to-speech translation (from 96 to 36 languages), text-to-text translation (96 languages) and automatic speech recognition (96 languages). Built using a new multimodal corpus of automatically aligned speech translations and other publicly available data, SEAMLESSM4T is one of the first multilingual systems that can translate from and into English for both speech and text. Moreover, it outperforms the existing state-of-the-art cascaded systems, achieving up to 8% and 23% higher BLEU (Bilingual Evaluation Understudy) scores in speech-to-text and speech-to-speech tasks, respectively. Beyond quality, when tested for robustness, our system is, on average, approximately 50% more resilient against background noise and speaker variations in speech-to-text tasks than the previous state-of-the-art systems. We evaluated SEAMLESSM4T on added toxicity and gender bias to assess translation safety. For the former, we included two strategies for added toxicity mitigation working at either training or inference time. Finally, all contributions in this work are publicly available for non-commercial use to propel further research on inclusive speech translation technologies.

『Abstract』During translation initiation, mRNA molecules must be identified and activated for loading into a ribosome . In this rate-limiting step, the heterotrimeric protein eukaryotic initiation factor eIF4F must recognize and productively interact with the 7-methylguanosine cap at the 5′ end of the mRNA and subsequently activate the message . Despite its fundamental, regulatory role in gene expression, the molecular events underlying cap recognition and mRNA activation remain unclear . Here we generate a single-molecule fluorescence imaging system to examine the dynamics with which eIF4F discriminates productive and non-productive locations on full-length, native mRNA molecules. At the single-molecule level, we observe stochastic sampling of eIF4F along the length of the mRNA and identify allosteric communication between the eIF4F subunits that ultimately drive cap-recognition and subsequent activation of the message. Our experiments uncover functions for each subunit of eIF4F and we conclude by presenting a model for mRNA activation that precisely defines the composition of the activated message. This model provides a general framework for understanding how mRNA molecules may be discriminated from one another and how other RNA-binding proteins may control the efficiency of translation initiation.

『Abstract』Mollusca is the second most species-rich animal phylum, but the pathways of early molluscan evolution have long been controversial . Modern faunas retain only a fraction of the past forms in this hyperdiverse and long-lived group. Recent analyses have consistently recovered a fundamental split into two sister clades, Conchifera (including gastropods, bivalves and cephalopods) and Aculifera , comprising Polyplacophora (‘chitons’) and Aplacophora. Molluscan evolution in toto is characterized by plasticity in body-plan characters , but historically aculiferans have been interpreted as more conservative . The few completely preserved aculiferan or aculiferan-like fossils from the early Palaeozoic have been largely regarded as transitional forms that inform questions of character polarity between the extant polyplacophoran and aplacophoran body forms . The history of early aculiferans, and the morphological and ecological range that they occupied, remain inadequately sampled. Here we describe two new three-dimensionally preserved aculiferan species from the Silurian Herefordshire Lagerstatte , which substantially extend the morphological and ecological range of the clade. Phylogenetic analyses indicate positions within a complex nexus of taxa and suggest reversals in the states of fundamental characters such as the presence of valves and the nature of the foot. In contrast to previous hypotheses of morphological conservatism, evolution in early aculiferans generated a profusion of unusual forms comparable to the diversification of other crown-group molluscs.