@article{21485, abstract = {Insulating oxides are among the most abundant solid materials in the universe1,2,3. Of the many ways in which they influence natural phenomena, perhaps the most consequential is their capacity to transfer electrical charge during contact4,5,6,7,8,9,10—which occurs even between samples of the same oxide—yet the symmetry-breaking parameter that causes this remains unidentified11,12. Here we show that adventitious carbonaceous molecules adsorbed from the environment are the symmetry-breaking factor in same-material oxide contact electrification (CE). We use acoustic levitation to measure charge exchange between a sphere and a plate composed of identical amorphous silicon dioxide (SiO2). Although charging polarity is random for co-prepared samples, we control it with baking or plasma treatment. Observing the charge-exchange relaxation afterwards, we see dynamics over a timescale of hours and connect this directly to the presence of adventitious carbon with time-of-flight mass spectrometry, low-energy ion scattering and infrared spectroscopy. Going further, we confirm that adventitious carbon can even determine charge exchange among different oxides. Our results identify the symmetry-breaking parameter that causes insulating oxides to exchange charge in settings ranging from desert sands4 to volcanic plumes5,6, while simultaneously highlighting an overlooked factor in CE more broadly.}, author = {Grosjean, Galien M and Ostermann, Markus and Sauer, Markus and Hahn, Michael and Pichler, Christian M. and Fahrnberger, Florian and Pertl, Felix and Balazs, Daniel and Link, Mason M. and Kim, Seong H. and Schrader, Devin L. and Blanco, Adriana and Gracia, Francisco and Mujica, Nicolás and Waitukaitis, Scott R}, issn = {1476-4687}, journal = {Nature}, number = {8106}, pages = {626--631}, publisher = {Springer Nature}, title = {{Adventitious carbon breaks symmetry in oxide contact electrification}}, doi = {10.1038/s41586-025-10088-w}, volume = {651}, year = {2026}, } @article{21798, abstract = {Phase singularities—points carrying quantized topological charge—are universal features found across diverse wave systems from superfluids and superconductors to acoustic and optical fields1,2,3,4. Ensembles of these singularities exhibit distance correlations resembling particles in liquids5,6,7,8, extensively studied for their role in exotic material phases9,10,11. By contrast, the full correlations in phase space that govern the system evolution have remained unexplored and experimentally inaccessible. Here we directly measure the ultrafast dynamics of optical singularity ensembles, capturing their full phase-space correlations, presenting the joint distance–velocity distribution. Our observations show a breakdown of the particle-singularity analogy12: phase singularities accelerate towards formally divergent velocities in the moment before annihilation7,13,14, indicated by measurements of velocities exceeding the speed of light. These apparent superluminal velocities are paradoxically amplified by the slow group velocity of hyperbolic phonon polaritons in our material platform, hexagonal boron nitride membranes15,16,17,18,19. We demonstrate these phenomena using combined hardware and algorithmic advances in ultrafast electron microscopy18,20,21,22,23,24,25, achieving spatial and temporal resolutions, each an order of magnitude below the polaritonic wavelength and cycle period. Our findings deepen our understanding of phase singularities and their universality, enabling to probe topological defect dynamics at previously unattainable timescales.}, author = {Bucher, T. and Gorlach, A. and Niedermayr, A. and Yan, Q. and Nahari, H. and Wang, K. and Ruimy, R. and Adiv, Y. and Yannai, M. and Abudi, T. L. and Janzen, E. and Spaegele, C. and Roques-Carmes, Charles and Edgar, J. H. and Koppens, F. H. L. and Vanacore, G. M. and H. Sheinfux, H. and Tsesses, S. and Kaminer, I.}, issn = {1476-4687}, journal = {Nature}, number = {8107}, pages = {920--926}, publisher = {Springer Nature}, title = {{Superluminal correlations in ensembles of optical phase singularities}}, doi = {10.1038/s41586-026-10209-z}, volume = {651}, year = {2026}, } @article{22372, abstract = {Neurons acquire polarity by specifying one neurite as the axon, whereas the others become dendrites. But how this fundamental asymmetry is established remains unclear1. Neuronal polarization has been thought to rely primarily on growth cones that sense external cues2. Here we show that growth cones alone do not direct this process and that the soma acts as a central organizer of neuronal polarization. Using live imaging and genetic loss-of-function approaches in vivo, combined with optogenetic control and local cytoskeletal perturbations in cultured neurons, we uncover a soma-initiated oscillatory program that primes axon selection. Periodic actin branching that depends on the actin-related protein 2/3 (ARP2/3) complex at the soma remodels a global actomyosin network, thereby generating an actin wave that retracts neurites before propagating into a single neurite tip. Exposure to this wave relaxes local actomyosin contractility, which drives a transient microtubule-based protrusion and biases this neurite towards axon fate. As the cell exits this oscillatory stage, this neurite can overcome global inhibition and extend independently of ARP2/3, whereas actomyosin activity suppresses axon formation in the remaining neurites so that they subsequently become dendrites. This soma-driven mechanism ensures the emergence of a single axon independent of environmental cues and underpins the unidirectional information flow in neuronal circuits.}, author = {Lin, Tien Chen and Coles, Charlotte H. and Alfadil, Eissa and Fäßler, Florian and Husch, Andreas and Dupraz, Sebastian and Pietralla, Thorben and Narita, Akihiro and Schelski, Max and Flynn, Kevin C. and Stern, Sina and Möhl, Christoph and Hilton, Brett J. and Vauti, Franz and Arnold, Hans Henning and Schur, Florian Km and Bradke, Frank}, issn = {1476-4687}, journal = {Nature}, publisher = {Springer Nature}, title = {{An intrinsic cytoskeletal oscillator establishes neuronal polarity}}, doi = {10.1038/s41586-026-10755-6}, year = {2026}, } @article{20963, abstract = {In all domains of life, tRNAs mediate the transfer of genetic information from mRNAs to proteins. As their depletion suppresses translation and, consequently, viral replication, tRNAs represent long-standing and increasingly recognized targets of innate immunity1,2,3,4,5. Here we report Cas12a3 effector nucleases from type V CRISPR–Cas adaptive immune systems in bacteria that preferentially cleave tRNAs after recognition of target RNA. Cas12a3 orthologues belong to one of two previously unreported nuclease clades that exhibit RNA-mediated cleavage of non-target RNA, and are distinct from all other known type V systems. Through cell-based and biochemical assays and direct RNA sequencing, we demonstrate that recognition of a complementary target RNA by the CRISPR RNA triggers Cas12a3 to cleave the conserved 5′-CCA-3′ tail of diverse tRNAs to drive growth arrest and anti-phage defence. Cryogenic electron microscopy structures further revealed a distinct tRNA-loading domain that positions the tRNA tail in the RuvC active site of the nuclease. By designing synthetic reporters that mimic the tRNA acceptor stem and tail, we expanded the capacity of current CRISPR-based diagnostics for multiplexed RNA detection. Overall, these findings reveal widespread tRNA inactivation as a previously unrecognized CRISPR-based immune strategy that broadens the application space of the existing CRISPR toolbox.}, author = {Dmytrenko, Oleg and Yuan, Biao and Crosby, Kadin T. and Krebel, Max and Chen, Xiye and Nowak, Jakub S. and Chramiec-Głąbik, Andrzej and Filani, Bamidele and Gribling-Burrer, Anne-Sophie and van der Toorn, Wiep and von Kleist, Max and Achmedov, Tatjana and Smyth, Redmond P. and Glatt, Sebastian and Bravo, Jack Peter Kelly and Heinz, Dirk W. and Jackson, Ryan N. and Beisel, Chase L.}, issn = {1476-4687}, journal = {Nature}, pages = {1312--1321}, publisher = {Springer Nature}, title = {{RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity}}, doi = {10.1038/s41586-025-09852-9}, volume = {649}, year = {2026}, } @article{22295, abstract = {Despite the functional diversity of over 100 causal genes1,2,3, phenotypic convergence across models may reveal common neurobiological processes in autism spectrum disorder (ASD). Here we profiled 251 samples from 11 monogenic mouse models of ASD using single-nucleus multi-omic sequencing across three developmental stages, both sexes and two brain regions. Despite genetic heterogeneity, ASD-linked mutations converged on perturbations of the radial glial cell lineage. These alterations reflect a transient developmental delay rather than lasting lineage misspecification and resolve by postnatal stages. Molecularly, the largest transcriptional differences emerged in neurons at early postnatal stages. These changes included downregulation of synaptic and ion channel-related genes, consistent with homeostatic adaptation or delayed maturation. Network analysis showed molecular convergence across models within each developmental stage, suggesting that diverse mutations linked to ASD impinge on common, stage-specific processes. Convergence becomes less pronounced by postnatal day 14, highlighting the dynamic nature of ASD-associated changes. Cross-genotype heterogeneity is superimposed on stage-specific effects. Electrophysiology corroborated this pattern: mutants generally showed altered neuronal excitability and synaptic properties with model-specific nuances. Our study also highlighted sex-specific gene expression alterations, with female mice often displaying larger effect sizes than male mice. Together, our findings provide a comprehensive view of developmental cellular and molecular dynamics across models of ASD.}, author = {Schwarz, Lena A and Dotter, Christoph and Isaev, Sergey and Lisi, Michela and Malzl, Daniel and Büschl, Christoph and Ladstätter, Sabrina and Oliveira, Bárbara and Barel, Matteo and Basilico, Bernadette and Chintaluri, Chaitanya and Gorkiewicz, Sarah and Goudarzi, Mohammad and Belinova, Tereza and Reichl, Stephan and Sendžikaitė, Gintarė and Arcot Jayaram, Satish and Koppensteiner, Peter and Sommer, Christoph M and Vogels, Tim P and Menche, Jörg and Adameyko, Igor and Kharchenko, Peter Vasili and Bock, Christoph and Novarino, Gaia}, issn = {1476-4687}, journal = {Nature}, publisher = {Springer Nature}, title = {{Cortical development dynamics across autism spectrum disorder mouse models}}, doi = {10.1038/s41586-026-10679-1}, year = {2026}, } @article{22751, abstract = {The physical processes that led to the formation of billion-solar-mass black holes within the first 700 million years of cosmic time, a period known as cosmic dawn, remain a puzzle1. Several theoretical scenarios have been proposed to seed and rapidly grow black holes2,3,4, but direct observations of these mechanisms remain elusive. Here we present a source 660 million years after the Big Bang that exhibits singular properties: among the largest hydrogen Balmer breaks reported at any redshift, broad multi-peaked Hβ emission, and Balmer line absorption in several transitions. We model this source as an enshrouded black hole in which the Balmer break and absorption features are a result of extremely dense, turbulent gas forming a dust-free envelope around a supermassive black hole5,6. This source may provide evidence of an early black hole embedded in dense gas—a theoretical configuration proposed to rapidly grow black holes by super-Eddington accretion7,8. Radiation from the black hole seems to dominate almost all observed light, leaving limited room for contribution from its host galaxy. If the source merged with its brighter neighbour, it would resemble the recently discovered ‘little red dots’ with perplexing spectral energy distributions9,10,11. The redness of the black hole is due to gas, not dust12,13, and scattering, not kinematics, gives rise to the complex line shapes and luminosities—black hole masses of these sources may therefore be overestimated by orders of magnitude.}, author = {Naidu, Rohan P. and Matthee, Jorryt J and Katz, Harley and De Graaff, Anna and Oesch, Pascal A. and Smith, Aaron and Greene, Jenny E. and Brammer, Gabriel and Weibel, Andrea and Hviding, Raphael and Chisholm, John and Labbé, Ivo and Simcoe, Robert A. and Witten, Callum and Sun, Wendy Q. and Atek, Hakim and Baggen, Josephine F.W. and Belli, Sirio and Bezanson, Rachel and Boogaard, Leindert A. and Bose, Sownak and Bouwens, Rychard J. and Covelo-Paz, Alba and Dayal, Pratika and Fudamoto, Yoshinobu and Furtak, Lukas J. and Giovinazzo, Emma and Goulding, Andy and Gronke, Max and Heintz, Kasper E. and Hirschmann, Michaela and Illingworth, Garth and Inoue, Akio K. and Johnson, Benjamin D. and Leja, Joel and Leonova, Ecaterina and Mcconachie, Ian and Maseda, Michael V. and Natarajan, Priyamvada and Nelson, Erica and Setton, David J. and Shivaei, Irene and Sobral, David and Stefanon, Mauro and Tacchella, Sandro and Toft, Sune and Torralba Torregrosa, Alberto and Van Dokkum, Pieter and Van Der Wel, Arjen and Volonteri, Marta and Walter, Fabian and Wang, Bingjie and Watson, Darach and Whitaker, Katherine}, issn = {1476-4687}, journal = {Nature}, number = {8127}, pages = {329--333}, publisher = {Springer Nature}, title = {{A gas-enshrouded and gas-reddened black hole at cosmic dawn}}, doi = {10.1038/s41586-026-10846-4}, volume = {656}, year = {2026}, } @article{22753, abstract = {Radial glial progenitors (RGPs) produce all excitatory neurons in the developing cerebral cortex. Mosaic analysis with double markers (MADM)-based lineage tracing in vivo has revealed a quantitative framework of RGP lineage progression1. Here we established MADM technology2,3 in mouse embryonic stem cells to probe RGP lineage progression in a self-organizing cortical organoid system. We found that RGPs exhibit a high level of plasticity in proliferative potential in organoids rather than strict temporally stereotyped lineage progression as observed in vivo. RGPs in organoids showed increased lineage restriction, diminishing cell-type diversity in clones of cortical projection neurons, despite uniform single-cell transcriptional signatures of RGPs and a unitary lineage trajectory. Thus, critical non-cell-autonomous cues that are absent in self-organizing systems and/or the genuine stem cell niche are essential for faithful temporal control of RGP lineage progression and the generation of clonal cortical cell-type diversity.}, author = {Stouffer, Melissa A and Miranda, Osvaldo and Pauler, Florian and Pipicelli, Fabrizia and Streicher, Carmen and Cheung, Giselle T and Hippenmeyer, Simon}, issn = {1476-4687}, journal = {Nature}, publisher = {Springer Nature}, title = {{Temporal uncoupling of radial glia lineage progression in cortical organoids}}, doi = {10.1038/s41586-026-10916-7}, year = {2026}, } @article{21548, abstract = {Non-Abelian gauge fields provide a conceptual framework to describe particles having spins, underlying many phenomena in electrodynamics, condensed-matter physics and particle physics. Lattice models of non-Abelian gauge fields allow us to understand their physical implications in extended systems. The theoretical importance of non-Abelian lattice gauge fields motivates their experimental synthesis and explorations. Photons are fundamental particles for which artificial gauge fields can be synthesized, yet the demonstration of non-Abelian lattice gauge fields for photons has not been achieved. Here we demonstrate SU(2) lattice gauge fields for photons in the synthetic frequency dimensions, a playground to study lattice physics in a scalable and programmable way. In our lattice model, we theoretically observe that homogeneous non-Abelian lattice gauge potentials induce Dirac cones at time-reversal-invariant momenta in the Brillouin zone. We experimentally confirm the presence of non-Abelian lattice gauge fields by two signatures: linear band crossings at the Dirac cones, and the associated direction reversal of eigenstate trajectories. We further demonstrate a non-Abelian scalar lattice gauge potential that lifts the degeneracies of the Dirac cones. Our results highlight the implications of non-Abelian lattice gauge fields in topological physics, and provide a starting point for demonstrations of emerging non-Abelian physics in the photonic synthetic dimensions. Our results may also benefit photonic technologies by providing controls of photon spins and pseudo-spins in topologically non-trivial ways.}, author = {Cheng, Dali and Wang, Kai and Roques-Carmes, Charles and Lustig, Eran and Long, Olivia Y. and Wang, Heming and Fan, Shanhui}, issn = {1476-4687}, journal = {Nature}, number = {8044}, pages = {52--56}, publisher = {Springer Nature}, title = {{Non-Abelian lattice gauge fields in photonic synthetic frequency dimensions}}, doi = {10.1038/s41586-024-08259-2}, volume = {637}, year = {2025}, } @article{21549, abstract = {Integrated photonics, particularly silicon photonics, have emerged as cutting-edge technology driven by promising applications such as short-reach communications, autonomous driving, biosensing and photonic computing1,2,3,4. As advances in AI lead to growing computing demands, photonic computing has gained considerable attention as an appealing candidate. Nonetheless, there are substantial technical challenges in the scaling up of integrated photonics systems to realize these advantages, such as ensuring consistent performance gains in upscaled integrated device clusters, establishing standard designs and verification processes for complex circuits, as well as packaging large-scale systems. These obstacles arise primarily because of the relative immaturity of integrated photonics manufacturing and the scarcity of advanced packaging solutions involving photonics. Here we report a large-scale integrated photonic accelerator comprising more than 16,000 photonic components. The accelerator is designed to deliver standard linear matrix multiply–accumulate (MAC) functions, enabling computing with high speed up to 1 GHz frequency and low latency as small as 3 ns per cycle. Logic, memory and control functions that support photonic matrix MAC operations were designed into a cointegrated electronics chip. To seamlessly integrate the electronics and photonics chips at the commercial scale, we have made use of an innovative 2.5D hybrid advanced packaging approach. Through the development of this accelerator system, we demonstrate an ultralow computation latency for heuristic solvers of computationally hard Ising problems whose performance greatly relies on the computing latency.}, author = {Hua, Shiyue and Divita, Erwan and Yu, Shanshan and Peng, Bo and Roques-Carmes, Charles and Su, Zhan and Chen, Zhang and Bai, Yanfei and Zou, Jinghui and Zhu, Yunpeng and Xu, Yelong and Lu, Cheng-kuan and Di, Yuemiao and Chen, Hui and Jiang, Lushan and Wang, Lijie and Ou, Longwu and Zhang, Chaohong and Chen, Junjie and Zhang, Wen and Zhu, Hongyan and Kuang, Weijun and Wang, Long and Meng, Huaiyu and Steinman, Maurice and Shen, Yichen}, issn = {1476-4687}, journal = {Nature}, pages = {361--367}, publisher = {Springer Nature}, title = {{An integrated large-scale photonic accelerator with ultralow latency}}, doi = {10.1038/s41586-025-08786-6}, volume = {640}, year = {2025}, } @article{21912, abstract = {The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis1. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections2,3. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP+ plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP–DH and ACP–ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.}, author = {Schultz, Kollin and Costa-Pinheiro, Pedro and Gardner, Lauren and Pinheiro, Laura V. and Ramirez-Solis, Julio and Gardner, Sarah M. and Wellen, Kathryn E. and Marmorstein, Ronen}, issn = {1476-4687}, journal = {Nature}, number = {8062}, pages = {520--528}, publisher = {Springer Nature}, title = {{Snapshots of acyl carrier protein shuttling in human fatty acid synthase}}, doi = {10.1038/s41586-025-08587-x}, volume = {641}, year = {2025}, } @article{19421, abstract = {The phytohormone auxin (Aux) is a principal endogenous developmental signal in plants. It mediates transcriptional reprogramming by a well-established canonical signalling mechanism. TIR1/AFB auxin receptors are F-box subunits of an ubiquitin ligase complex; after auxin perception, they associate with Aux/IAA transcriptional repressors and ubiquitinate them for degradation, thus enabling the activation of auxin response factor (ARF) transcription factors1,2,3. Here we revise this paradigm by showing that without TIR1 adenylate cyclase (AC) activity4, auxin-induced degradation of Aux/IAAs is not sufficient to mediate the transcriptional auxin response. Abolishing the TIR1 AC activity does not affect auxin-induced degradation of Aux/IAAs but renders TIR1 non-functional in mediating transcriptional reprogramming and auxin-regulated development, including shoot, root, root hair growth and lateral root formation. Transgenic plants show that local cAMP production in the vicinity of the Aux/IAA–ARF complex by unrelated AC enzymes bypasses the need for auxin perception and is sufficient to induce ARF-mediated transcription. These discoveries revise the canonical model of auxin signalling and establish TIR1/AFB-produced cAMP as a second messenger essential for transcriptional reprograming.}, author = {Chen, Huihuang and Qi, Linlin and Zou, Minxia and Lu, Mengting and Kwiatkowski, M and Pei, Yuanrong and Jaworski, K and Friml, Jiří}, issn = {1476-4687}, journal = {Nature}, pages = {1011--1016}, publisher = {Springer Nature}, title = {{TIR1-produced cAMP as a second messenger in transcriptional auxin signalling}}, doi = {10.1038/s41586-025-08669-w}, volume = {640}, year = {2025}, } @article{19444, abstract = {As the field of neural organoids and assembloids expands, there is an emergent need for guidance and advice on designing, conducting and reporting experiments to increase the reproducibility and utility of these models. In this Perspective, we present a framework for the experimental process that encompasses ensuring the quality and integrity of human pluripotent stem cells, characterizing and manipulating neural cells in vitro, transplantation techniques and considerations for modelling human development, evolution and disease. As with all scientific endeavours, we advocate for rigorous experimental designs tailored to explicit scientific questions as well as transparent methodologies and data sharing to provide useful knowledge for current research practices and for developing regulatory standards.}, author = {Pașca, Sergiu P. and Arlotta, Paola and Bateup, Helen S. and Camp, J. Gray and Cappello, Silvia and Gage, Fred H. and Knoblich, Jürgen A. and Kriegstein, Arnold R. and Lancaster, Madeline A. and Ming, Guo Li and Novarino, Gaia and Okano, Hideyuki and Parmar, Malin and Park, In Hyun and Reiner, Orly and Song, Hongjun and Studer, Lorenz and Takahashi, Jun and Temple, Sally and Testa, Giuseppe and Treutlein, Barbara and Vaccarino, Flora M. and Vanderhaeghen, Pierre and Young-Pearse, Tracy}, issn = {1476-4687}, journal = {Nature}, number = {8054}, pages = {315--320}, publisher = {Springer Nature}, title = {{A framework for neural organoids, assembloids and transplantation studies}}, doi = {10.1038/s41586-024-08487-6}, volume = {639}, year = {2025}, } @article{19704, abstract = {The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution1,2 with dense cellular labelling. Light microscopy is uniquely positioned to visualize specific molecules, but dense, synapse-level circuit reconstruction by light microscopy has been out of reach, owing to limitations in resolution, contrast and volumetric imaging capability. Here we describe light-microscopy-based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning-based segmentation and analysis of connectivity, thereby directly incorporating molecular information into synapse-level reconstructions of brain tissue. LICONN will allow synapse-level phenotyping of brain tissue in biological experiments in a readily adoptable manner.}, author = {Tavakoli, Mojtaba and Lyudchik, Julia and Januszewski, Michał and Vistunou, Vitali and Agudelo Duenas, Nathalie and Vorlaufer, Jakob and Sommer, Christoph M and Kreuzinger, Caroline and Oliveira, Bárbara and Cenameri, Alban and Novarino, Gaia and Jain, Viren and Danzl, Johann G}, issn = {1476-4687}, journal = {Nature}, pages = {398--410}, publisher = {Springer Nature}, title = {{Light-microscopy-based connectomic reconstruction of mammalian brain tissue}}, doi = {10.1038/s41586-025-08985-1}, volume = {642}, year = {2025}, } @article{20430, abstract = {Protein design has focused on the design of ground states, ensuring that they are sufficiently low energy to be highly populated1. Designing the kinetics and dynamics of a system requires, in addition, the design of excited states that are traversed in transitions from one low-lying state to another2,3. This is a challenging task because such states must be sufficiently strained to be poorly populated, but not so strained that they are not populated at all, and because protein design methods have focused on generating near-ideal structures4,5,6,7. Here we describe a general approach for designing systems that use an induced-fit power stroke8 to generate a structurally frustrated9 and strained excited state, allosterically driving protein complex dissociation. X-ray crystallography, double electron–electron resonance spectroscopy and kinetic binding measurements show that incorporating excited states enables the design of effector-induced increases in dissociation rates as high as 5,700-fold. We highlight the power of this approach by designing rapid biosensors, kinetically controlled circuits and cytokine mimics that can be dissociated from their receptors within seconds, enabling dissection of the temporal dynamics of interleukin-2 signalling.}, author = {Broerman, Adam J. and Pollmann, Christoph and Zhao, Yang and Lichtenstein, Mauriz A. and Jackson, Mark D. and Tessmer, Maxx H. and Ryu, Won Hee and Ogishi, Masato and Abedi, Mohamad H. and Sahtoe, Danny D. and Allen, Aza and Kang, Alex and De La Cruz, Joshmyn and Brackenbrough, Evans and Sankaran, Banumathi and Bera, Asim K. and Zuckerman, Daniel M. and Stoll, Stefan and Garcia, K. Christopher and Praetorius, Florian M and Piehler, Jacob and Baker, David}, issn = {1476-4687}, journal = {Nature}, pages = {528--535}, publisher = {Springer Nature}, title = {{Design of facilitated dissociation enables timing of cytokine signalling}}, doi = {10.1038/s41586-025-09549-z}, volume = {647}, year = {2025}, } @article{20101, abstract = {Evading imminent threat from predators is critical for animal survival. Effective defensive strategies can vary, even between closely related species. However, the neural basis of such species-specific behaviours remains poorly understood1,2,3,4. Here we find that two sister species of deer mice (genus Peromyscus)5 show different responses to the same looming stimulus: Peromyscus maniculatus, which occupies densely vegetated habitats, predominantly escapes, whereas the open field specialist, Peromyscus polionotus, briefly freezes. This difference arises from species-specific escape thresholds, is largely context-independent, and can be triggered by both visual and auditory threat stimuli. Using immunohistochemistry and electrophysiological recordings, we find that although visual threat activates the superior colliculus in both species, the role of the dorsal periaqueductal grey (dPAG) in driving behaviour differs. Whereas dPAG activity scales with running speed in P. maniculatus, neural activity in the dPAG of P. polionotus correlates poorly with movement, including during visually triggered escape. Moreover, optogenetic activation of dPAG neurons elicits acceleration in P. maniculatus but not in P. polionotus, and their chemogenetic inhibition during a looming stimulus delays escape onset in P. maniculatus to match that of P. polionotus. Together, we trace species-specific escape thresholds to a central circuit node, downstream of peripheral sensory neurons, localizing an ecologically relevant behavioural difference to a specific region of the mammalian brain.}, author = {Baier, Felix and Reinhard, Katja and Nuttin, Bram and Sans-Dublanc, Arnau and Liu, Chen and Tong, Victoria and Murmann, Julie Stefanie and Wierda, Keimpe and Farrow, Karl and Hoekstra, Hopi E.}, issn = {1476-4687}, journal = {Nature}, pages = {439--447}, publisher = {Springer Nature}, title = {{The neural basis of species-specific defensive behaviour in Peromyscus mice}}, doi = {10.1038/s41586-025-09241-2}, volume = {645}, year = {2025}, } @article{19278, abstract = {When two insulating, neutral materials are contacted and separated, they exchange electrical charge1. Experiments have long suggested that this ‘contact electrification’ is transitive, with different materials ordering into ‘triboelectric series’ based on the sign of charge acquired2. At the same time, the effect is plagued by unpredictability, preventing consensus on the mechanism and casting doubt on the rhyme and reason that series imply3. Here we expose an unanticipated connection between the unpredictability and order in contact electrification: nominally identical materials initially exchange charge randomly and intransitively, but—over repeated experiments—order into triboelectric series. We find that this evolution is driven by the act of contact itself—samples with more contacts in their history charge negatively to ones with fewer contacts. Capturing this ‘contact bias’ in a minimal model, we recreate both the initial randomness and ultimate order in numerical simulations and use it experimentally to force the appearance of a triboelectric series of our choosing. With a set of surface-sensitive techniques to search for the underlying alterations contact creates, we only find evidence of nanoscale morphological changes, pointing to a mechanism strongly coupled with mechanics. Our results highlight the centrality of contact history in contact electrification and suggest that focusing on the unpredictability that has long plagued the effect may hold the key to understanding it.}, author = {Sobarzo Ponce, Juan Carlos A and Pertl, Felix and Balazs, Daniel and Costanzo, Tommaso and Sauer, Markus and Foelske, Annette and Ostermann, Markus and Pichler, Christian M. and Wang, Yongkang and Nagata, Yuki and Bonn, Mischa and Waitukaitis, Scott R}, issn = {1476-4687}, journal = {Nature}, number = {8051}, publisher = {Springer Nature}, title = {{Spontaneous ordering of identical materials into a triboelectric series}}, doi = {10.1038/s41586-024-08530-6}, volume = {638}, year = {2025}, } @article{17468, abstract = {Oxygen redox chemistry is central to life1 and many human-made technologies, such as in energy storage2,3,4. The large energy gain from oxygen redox reactions is often connected with the occurrence of harmful reactive oxygen species3,5,6. Key species are superoxide and the highly reactive singlet oxygen3,4,5,6,7, which may evolve from superoxide. However, the factors determining the formation of singlet oxygen, rather than the relatively unreactive triplet oxygen, are unknown. Here we report that the release of triplet or singlet oxygen is governed by individual Marcus normal and inverted region behaviour. We found that as the driving force for the reaction increases, the initially dominant evolution of triplet oxygen slows down, and singlet oxygen evolution becomes predominant with higher maximum kinetics. This behaviour also applies to the widely observed superoxide disproportionation, in which one superoxide is oxidized by another, in both non-aqueous and aqueous systems, with Lewis and Brønsted acidity controlling the driving forces. Singlet oxygen yields governed by these conditions are relevant, for example, in batteries or cellular organelles in which superoxide forms. Our findings suggest ways to understand and control spin states and kinetics in oxygen redox chemistry, with implications for fields, including life sciences, pure chemistry and energy storage.}, author = {Mondal, Soumyadip and Nguyen, Huyen T.K. and Hauschild, Robert and Freunberger, Stefan Alexander}, issn = {1476-4687}, journal = {Nature}, number = {8085}, pages = {601–605}, publisher = {Springer Nature}, title = {{Marcus kinetics control singlet and triplet oxygen evolving from superoxide}}, doi = {10.1038/s41586-025-09587-7}, volume = {646}, year = {2025}, } @article{18616, abstract = {By patterning an ultrathin layered structure with tiny wells, physicists have created and imaged peculiar states known as quantum scars — revealing behaviour that could be used to boost the performance of electronic devices.}, author = {Abanin, Dmitry and Serbyn, Maksym}, issn = {1476-4687}, journal = {Nature}, number = {8040}, pages = {825--826}, publisher = {Springer Nature}, title = {{Quantum scars make their mark in graphene}}, doi = {10.1038/d41586-024-03649-y}, volume = {635}, year = {2024}, } @article{17442, abstract = {Although eukaryotic Argonautes have a pivotal role in post-transcriptional gene regulation through nucleic acid cleavage, some short prokaryotic Argonaute variants (pAgos) rely on auxiliary nuclease factors for efficient foreign DNA degradation1. Here we reveal the activation pathway of the DNA defence module DdmDE system, which rapidly eliminates small, multicopy plasmids from the Vibrio cholerae seventh pandemic strain (7PET)2. Through a combination of cryo-electron microscopy, biochemistry and in vivo plasmid clearance assays, we demonstrate that DdmE is a catalytically inactive, DNA-guided, DNA-targeting pAgo with a distinctive insertion domain. We observe that the helicase-nuclease DdmD transitions from an autoinhibited, dimeric complex to a monomeric state upon loading of single-stranded DNA targets. Furthermore, the complete structure of the DdmDE–guide–target handover complex provides a comprehensive view into how DNA recognition triggers processive plasmid destruction. Our work establishes a mechanistic foundation for how pAgos utilize ancillary factors to achieve plasmid clearance, and provides insights into anti-plasmid immunity in bacteria. }, author = {Bravo, Jack Peter Kelly and Ramos, Delisa A. and Fregoso Ocampo, Rodrigo and Ingram, Caiden and Taylor, David W.}, issn = {1476-4687}, journal = {Nature}, number = {8018}, pages = {961--967}, publisher = {Springer Nature}, title = {{Plasmid targeting and destruction by the DdmDE bacterial defence system}}, doi = {10.1038/s41586-024-07515-9}, volume = {630}, year = {2024}, } @article{17284, abstract = {Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.}, author = {Gärtner, Florian R and Ishikawa-Ankerhold, Hellen and Stutte, Susanne and Fu, Wenwen and Weitz, Jutta and Dueck, Anne and Nelakuditi, Bhavishya and Fumagalli, Valeria and Van Den Heuvel, Dominic and Belz, Larissa and Sobirova, Gulnoza and Zhang, Zhe and Titova, Anna and Navarro, Alejandro Martinez and Pekayvaz, Kami and Lorenz, Michael and Von Baumgarten, Louisa and Kranich, Jan and Straub, Tobias and Popper, Bastian and Zheden, Vanessa and Kaufmann, Walter and Guo, Chenglong and Piontek, Guido and Von Stillfried, Saskia and Boor, Peter and Colonna, Marco and Clauß, Sebastian and Schulz, Christian and Brocker, Thomas and Walzog, Barbara and Scheiermann, Christoph and Aird, William C. and Nerlov, Claus and Stark, Konstantin and Petzold, Tobias and Engelhardt, Stefan and Sixt, Michael K and Hauschild, Robert and Rudelius, Martina and Oostendorp, Robert A.J. and Iannacone, Matteo and Heinig, Matthias and Massberg, Steffen}, issn = {1476-4687}, journal = {Nature}, pages = {645--653}, publisher = {Springer Nature}, title = {{Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis}}, doi = {10.1038/s41586-024-07671-y}, volume = {631}, year = {2024}, }