@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}, publisher = {Springer Nature}, title = {{RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity}}, doi = {10.1038/s41586-025-09852-9}, year = {2026}, } @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{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{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{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{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{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{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{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{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}, } @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{17463, abstract = {Allosteric modulation of protein function, wherein the binding of an effector to a protein triggers conformational changes at distant functional sites, plays a central part in the control of metabolism and cell signalling1,2,3. There has been considerable interest in designing allosteric systems, both to gain insight into the mechanisms underlying such ‘action at a distance’ modulation and to create synthetic proteins whose functions can be regulated by effectors4,5,6,7. However, emulating the subtle conformational changes distributed across many residues, characteristic of natural allosteric proteins, is a significant challenge8,9. Here, inspired by the classic Monod–Wyman–Changeux model of cooperativity10, we investigate the de novo design of allostery through rigid-body coupling of peptide-switchable hinge modules11 to protein interfaces12 that direct the formation of alternative oligomeric states. We find that this approach can be used to generate a wide variety of allosterically switchable systems, including cyclic rings that incorporate or eject subunits in response to peptide binding and dihedral cages that undergo effector-induced disassembly. Size-exclusion chromatography, mass photometry13 and electron microscopy reveal that these designed allosteric protein assemblies closely resemble the design models in both the presence and absence of peptide effectors and can have ligand-binding cooperativity comparable to classic natural systems such as haemoglobin14. Our results indicate that allostery can arise from global coupling of the energetics of protein substructures without optimized side-chain–side-chain allosteric communication pathways and provide a roadmap for generating allosterically triggerable delivery systems, protein nanomachines and cellular feedback control circuitry.}, author = {Pillai, Arvind and Idris, Abbas and Philomin, Annika and Weidle, Connor and Skotheim, Rebecca and Leung, Philip J.Y. and Broerman, Adam and Demakis, Cullen and Borst, Andrew J. and Praetorius, Florian M and Baker, David}, issn = {1476-4687}, journal = {Nature}, pages = {911–920 }, publisher = {Springer Nature}, title = {{De novo design of allosterically switchable protein assemblies}}, doi = {10.1038/s41586-024-07813-2}, volume = {632}, year = {2024}, } @article{14341, abstract = {Flows through pipes and channels are, in practice, almost always turbulent, and the multiscale eddying motion is responsible for a major part of the encountered friction losses and pumping costs1. Conversely, for pulsatile flows, in particular for aortic blood flow, turbulence levels remain low despite relatively large peak velocities. For aortic blood flow, high turbulence levels are intolerable as they would damage the shear-sensitive endothelial cell layer2,3,4,5. Here we show that turbulence in ordinary pipe flow is diminished if the flow is driven in a pulsatile mode that incorporates all the key features of the cardiac waveform. At Reynolds numbers comparable to those of aortic blood flow, turbulence is largely inhibited, whereas at much higher speeds, the turbulent drag is reduced by more than 25%. This specific operation mode is more efficient when compared with steady driving, which is the present situation for virtually all fluid transport processes ranging from heating circuits to water, gas and oil pipelines.}, author = {Scarselli, Davide and Lopez Alonso, Jose M and Varshney, Atul and Hof, Björn}, issn = {1476-4687}, journal = {Nature}, number = {7977}, pages = {71--74}, publisher = {Springer Nature}, title = {{Turbulence suppression by cardiac-cycle-inspired driving of pipe flow}}, doi = {10.1038/s41586-023-06399-5}, volume = {621}, year = {2023}, } @article{14610, abstract = {Endomembrane damage represents a form of stress that is detrimental for eukaryotic cells1,2. To cope with this threat, cells possess mechanisms that repair the damage and restore cellular homeostasis3–7. Endomembrane damage also results in organelle instability and the mechanisms by which cells stabilize damaged endomembranes to enable membrane repair remains unknown. Here, by combining in vitro and in cellulo studies with computational modelling we uncover a biological function for stress granules whereby these biomolecular condensates form rapidly at endomembrane damage sites and act as a plug that stabilizes the ruptured membrane. Functionally, we demonstrate that stress granule formation and membrane stabilization enable efficient repair of damaged endolysosomes, through both ESCRT (endosomal sorting complex required for transport)-dependent and independent mechanisms. We also show that blocking stress granule formation in human macrophages creates a permissive environment for Mycobacterium tuberculosis, a human pathogen that exploits endomembrane damage to survive within the host.}, author = {Bussi, Claudio and Mangiarotti, Agustín and Vanhille-Campos, Christian Eduardo and Aylan, Beren and Pellegrino, Enrica and Athanasiadi, Natalia and Fearns, Antony and Rodgers, Angela and Franzmann, Titus M. and Šarić, Anđela and Dimova, Rumiana and Gutierrez, Maximiliano G.}, issn = {1476-4687}, journal = {Nature}, pages = {1062--1069}, publisher = {Springer Nature}, title = {{Stress granules plug and stabilize damaged endolysosomal membranes}}, doi = {10.1038/s41586-023-06726-w}, volume = {623}, year = {2023}, } @article{18189, abstract = {Strongly interacting topological matter1 exhibits fundamentally new phenomena with potential applications in quantum information technology2,3. Emblematic instances are fractional quantum Hall (FQH) states4, in which the interplay of a magnetic field and strong interactions gives rise to fractionally charged quasi-particles, long-ranged entanglement and anyonic exchange statistics. Progress in engineering synthetic magnetic fields5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 has raised the hope to create these exotic states in controlled quantum systems. However, except for a recent Laughlin state of light22, preparing FQH states in engineered systems remains elusive. Here we realize a FQH state with ultracold atoms in an optical lattice. The state is a lattice version of a bosonic ν = 1/2 Laughlin state4,23 with two particles on 16 sites. This minimal system already captures many hallmark features of Laughlin-type FQH states24,25,26,27,28: we observe a suppression of two-body interactions, we find a distinctive vortex structure in the density correlations and we measure a fractional Hall conductivity of σH/σ0 = 0.6(2) by means of the bulk response to a magnetic perturbation. Furthermore, by tuning the magnetic field, we map out the transition point between the normal and the FQH regime through a spectroscopic investigation of the many-body gap. Our work provides a starting point for exploring highly entangled topological matter with ultracold atoms29,30,31,32,33.}, author = {Leonard, Julian and Kim, Sooshin and Kwan, Joyce and Segura, Perrin and Grusdt, Fabian and Repellin, Cécile and Goldman, Nathan and Greiner, Markus}, issn = {1476-4687}, journal = {Nature}, number = {7970}, pages = {495--499}, publisher = {Springer Nature}, title = {{Realization of a fractional quantum Hall state with ultracold atoms}}, doi = {10.1038/s41586-023-06122-4}, volume = {619}, year = {2023}, } @article{13096, abstract = {Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture as the defining terminal event1,2,3,4,5,6,7. Plasma membrane rupture was long thought to be driven by osmotic pressure, but it has recently been shown to be in many cases an active process, mediated by the protein ninjurin-18 (NINJ1). Here we resolve the structure of NINJ1 and the mechanism by which it ruptures membranes. Super-resolution microscopy reveals that NINJ1 clusters into structurally diverse assemblies in the membranes of dying cells, in particular large, filamentous assemblies with branched morphology. A cryo-electron microscopy structure of NINJ1 filaments shows a tightly packed fence-like array of transmembrane α-helices. Filament directionality and stability is defined by two amphipathic α-helices that interlink adjacent filament subunits. The NINJ1 filament features a hydrophilic side and a hydrophobic side, and molecular dynamics simulations show that it can stably cap membrane edges. The function of the resulting supramolecular arrangement was validated by site-directed mutagenesis. Our data thus suggest that, during lytic cell death, the extracellular α-helices of NINJ1 insert into the plasma membrane to polymerize NINJ1 monomers into amphipathic filaments that rupture the plasma membrane. The membrane protein NINJ1 is therefore an interactive component of the eukaryotic cell membrane that functions as an in-built breaking point in response to activation of cell death.}, author = {Degen, Morris and Santos, José Carlos and Pluhackova, Kristyna and Cebrero, Gonzalo and Ramos, Saray and Jankevicius, Gytis and Hartenian, Ella and Guillerm, Undina and Mari, Stefania A. and Kohl, Bastian and Müller, Daniel J. and Schanda, Paul and Maier, Timm and Perez, Camilo and Sieben, Christian and Broz, Petr and Hiller, Sebastian}, issn = {1476-4687}, journal = {Nature}, pages = {1065--1071}, publisher = {Springer Nature}, title = {{Structural basis of NINJ1-mediated plasma membrane rupture in cell death}}, doi = {10.1038/s41586-023-05991-z}, volume = {618}, year = {2023}, } @article{13119, abstract = {A density wave (DW) is a fundamental type of long-range order in quantum matter tied to self-organization into a crystalline structure. The interplay of DW order with superfluidity can lead to complex scenarios that pose a great challenge to theoretical analysis. In the past decades, tunable quantum Fermi gases have served as model systems for exploring the physics of strongly interacting fermions, including most notably magnetic ordering1, pairing and superfluidity2, and the crossover from a Bardeen–Cooper–Schrieffer superfluid to a Bose–Einstein condensate3. Here, we realize a Fermi gas featuring both strong, tunable contact interactions and photon-mediated, spatially structured long-range interactions in a transversely driven high-finesse optical cavity. Above a critical long-range interaction strength, DW order is stabilized in the system, which we identify via its superradiant light-scattering properties. We quantitatively measure the variation of the onset of DW order as the contact interaction is varied across the Bardeen–Cooper–Schrieffer superfluid and Bose–Einstein condensate crossover, in qualitative agreement with a mean-field theory. The atomic DW susceptibility varies over an order of magnitude upon tuning the strength and the sign of the long-range interactions below the self-ordering threshold, demonstrating independent and simultaneous control over the contact and long-range interactions. Therefore, our experimental setup provides a fully tunable and microscopically controllable platform for the experimental study of the interplay of superfluidity and DW order.}, author = {Helson, Victor and Zwettler, Timo and Mivehvar, Farokh and Colella, Elvia and Roux, Kevin Etienne Robert and Konishi, Hideki and Ritsch, Helmut and Brantut, Jean Philippe}, issn = {1476-4687}, journal = {Nature}, pages = {716--720}, publisher = {Springer Nature}, title = {{Density-wave ordering in a unitary Fermi gas with photon-mediated interactions}}, doi = {10.1038/s41586-023-06018-3}, volume = {618}, year = {2023}, } @article{19471, abstract = {Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands1,2,3,4,5. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVHCrh neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical ‘hunger neurons’ drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVHCrh neurons.}, author = {Douglass, Amelia May Barnett and Resch, Jon M. and Madara, Joseph C. and Kucukdereli, Hakan and Yizhar, Ofer and Grama, Abhinav and Yamagata, Masahito and Yang, Zongfang and Lowell, Bradford B.}, issn = {1476-4687}, journal = {Nature}, number = {7972}, pages = {154--162}, publisher = {Springer Nature}, title = {{Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis}}, doi = {10.1038/s41586-023-06358-0}, volume = {620}, year = {2023}, } @article{15130, abstract = {Cas12a2 is a CRISPR-associated nuclease that performs RNA-guided, sequence-nonspecific degradation of single-stranded RNA, single-stranded DNA and double-stranded DNA following recognition of a complementary RNA target, culminating in abortive infection1. Here we report structures of Cas12a2 in binary, ternary and quaternary complexes to reveal a complete activation pathway. Our structures reveal that Cas12a2 is autoinhibited until binding a cognate RNA target, which exposes the RuvC active site within a large, positively charged cleft. Double-stranded DNA substrates are captured through duplex distortion and local melting, stabilized by pairs of ‘aromatic clamp’ residues that are crucial for double-stranded DNA degradation and in vivo immune system function. Our work provides a structural basis for this mechanism of abortive infection to achieve population-level immunity, which can be leveraged to create rational mutants that degrade a spectrum of collateral substrates.}, author = {Bravo, Jack Peter Kelly and Hallmark, Thomson and Naegle, Bronson and Beisel, Chase L. and Jackson, Ryan N. and Taylor, David W.}, issn = {1476-4687}, journal = {Nature}, number = {7944}, pages = {582--587}, publisher = {Springer Nature}, title = {{RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2}}, doi = {10.1038/s41586-022-05560-w}, volume = {613}, year = {2023}, }