I checked 6 multidisciplinary journals on Saturday, November 08, 2025 using the Crossref API. For the period November 01 to November 07, I found 13 new paper(s) in 4 journal(s).

Nature

GPT-4o mini: Non-social science research article
A probabilistic histological atlas of the human brain for MRI segmentation
Adrià Casamitjana, Matteo Mancini, Eleanor Robinson, Loïc Peter, Roberto Annunziata, Juri Althonayan, Shauna Crampsie, Emily Blackburn, Benjamin Billot, Alessia Atzeni, Oula Puonti, Yaël Balbastre, Peter Schmidt, James Hughes, Jean C. Augustinack, Brian L. Edlow, Lilla Zöllei, David L. Thomas, Dorit Kliemann, Martina Bocchetta, Catherine Strand, Janice L. Holton, Zane Jaunmuktane, Juan Eugenio Iglesias
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In human neuroimaging, brain atlases are essential for segmenting regions of interest (ROIs) and comparing subjects in a common coordinate frame. State-of-the-art atlases derived from histology1,2,3 provide exquisite three-dimensional cytoarchitectural maps but lack probabilistic labels throughout the whole brain: that is, the likelihood of each location belonging to a given ROI. Here we present NextBrain, a probabilistic histological atlas of the whole human brain. We developed artificial intelligence-enabled methods to align roughly 10,000 histological sections from five whole brain hemispheres into three-dimensional volumes and to produce delineations for 333 ROIs on these sections. We also created a companion Bayesian tool for automatic segmentation of these ROIs in magnetic resonance imaging (MRI) scans. We showcase two applications of the atlas: segmentation of ultra-high-resolution ex vivo MRI and volumetric analysis of Alzheimer’s disease using in vivo MRI. We publicly release raw and aligned data, an online visualization tool, the atlas, the segmentation tool, and ground truth delineations for a high-resolution ex vivo hemisphere used in validation. By enabling researchers worldwide to automatically analyse brain MRIs at a higher level of granularity, NextBrain holds promise to increase the specificity of findings and accelerate our quest to understand the human brain in health and disease.
GPT-4o mini: Non-social science research article
An ATP-gated molecular switch orchestrates human messenger RNA export
Ulrich Hohmann, Max Graf, LĂĄszlĂł TiriĂĄn, BelĂ©n Pacheco-Fiallos, Ulla Schellhaas, Laura Fin, Dominik Handler, Alex W. Philipps, Daria Riabov-Bassat, Rupert W. Faraway, Thomas PĂŒhringer, Michael-Florian Szalay, Elisabeth Roitinger, Julius Brennecke, Clemens Plaschka
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The nuclear export of messenger RNA (mRNA) is an important step in eukaryotic gene expression1. Despite recent molecular insights into how newly transcribed mRNAs are packaged into ribonucleoprotein complexes (mRNPs)2,3, the subsequent events that govern mRNA export are poorly understood. Here, we uncover the molecular basis underlying key events of human mRNA export, including the remodeling of mRNP-bound transcription-export complexes (TREX), the formation of export-competent mRNPs, the docking of mRNPs at the nuclear pore complex (NPC), and the release of mRNPs at the NPC to initiate their export. Our biochemical and structural data show that the ATPase DDX39/UAP56 acts as a central molecular switch that directs nucleoplasmic mRNPs from TREX to NPC-anchored TREX-2 complexes through its ATP-gated mRNA-binding cycle. Collectively, these findings establish a mechanistic framework for a general and evolutionarily conserved mRNA export pathway.
GPT-4o mini: Non-social science research article
The new frontier in understanding human and mammalian brain development
Tomasz J. Nowakowski, Patricia R. Nano, Katherine S. Matho, Xiaoyin Chen, Emily K. Corrigan, Wubin Ding, Yuan Gao, Matthew Heffel, Jaikishan Jayakumar, Harris S. Kaplan, Fae N. Kronman, Rothem Kovner, Camiel C. A. Mannens, Mengyi Song, Marilyn R. Steyert, Sridevi Venkatesan, Jenelle L. Wallace, Li Wang, Jonathan M. Werner, Di Zhang, Guohua Yuan, Guolong Zuo, Seth A. Ament, Carlo Colantuoni, Catherine Dulac, Rong Fan, Jesse Gillis, Arnold R. Kriegstein, Fenna M. Krienen, Yongsoo Kim, Sten Linnarsson, Partha P. Mitra, Alex A. Pollen, Nenad Sestan, Daniel J. Tward, Cindy T. J. van Velthoven, Zizhen Yao, Aparna Bhaduri, Hongkui Zeng
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Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide1, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.
GPT-4o mini: Non-social science research article
Millisecond lifetimes and coherence times in 2D transmon qubits
Matthew P. Bland, Faranak Bahrami, Jeronimo G. C. Martinez, Paal H. Prestegaard, Basil M. Smitham, Atharv Joshi, Elizabeth Hedrick, Shashwat Kumar, Ambrose Yang, Alexander C. Pakpour-Tabrizi, Apoorv Jindal, Ray D. Chang, Guangming Cheng, Nan Yao, Robert J. Cava, Nathalie P. de Leon, Andrew A. Houck
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Materials improvement is a powerful approach to reducing loss and decoherence in superconducting qubits, because such improvements can be readily translated to large-scale processors. Recent work improved transmon coherence by using tantalum as a base layer and sapphire as a substrate1. The losses in these devices are dominated by two-level systems with comparable contributions from both the surface and bulk dielectrics2, indicating that both must be tackled to achieve substantial improvements in the state of the art. Here we show that replacing the substrate with high-resistivity silicon markedly decreases the bulk substrate loss, enabling 2D transmons with time-averaged quality factors (Qavg) of 9.7 × 106 across 45 qubits. For our best qubit, we achieve a Qavg of 1.5 × 107, reaching a maximum Q of 2.5 × 107, corresponding to a lifetime (T1) up to 1.68 ms. This low loss also allows us to observe decoherence effects related to the Josephson junction, and we use an improved, low-contamination junction deposition to achieve Hahn echo coherence times (T2E) exceeding T1. We achieve these materials improvements without any modifications to the qubit architecture, allowing us to readily incorporate standard quantum control gates. We demonstrate single-qubit gates with 99.994% fidelity. The tantalum-on-silicon platform comprises a simple material stack that can potentially be fabricated at the wafer scale and therefore can be readily translated to large-scale quantum processors.
GPT-4o mini: Non-social science research article
Author Correction: The emergence of transcriptional identity in somatosensory neurons
Nikhil Sharma, Kali Flaherty, Karina Lezgiyeva, Daniel E. Wagner, Allon M. Klein, David D. Ginty
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GPT-4o mini: Non-social science research article
Myriad Aryne Derivatives from Carboxylic Acids
Chris M. Seong, Sallu S. Kargbo, Chia-Ling Yu, Daniel Gibney, Jan-Niklas Boyn, Courtney C. Roberts
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Densely substituted aromatic rings are ubiquitous in pharmaceuticals and agrochemicals1. For making aromatic molecules, aryne intermediates have synthetic potential that rivals most functional groups2. They readily react with nucleophiles, participate in pericyclic reactions, and activate inert σ-bonds. Despite their potential, arynes are currently used by a specialized community for mainly niche applications. The lack of widespread adoption of arynes is due to the undesirable means to generate them. Here, we report the design of an aryne precursor to overcome this prohibitive barrier. Readily available carboxylic acids are derivatized in a single step to a make a precursor which is then activated by blue light or by heat. Dozens of previously unknown aminated arynes, including pyridynes, are generated in this work, opening the door to drug discovery using aryne intermediates. We envision that future development of this precursor platform will allow even more decorated arynes to be accessed, further expanding the reach of aryne chemistry.
GPT-4o mini: Non-social science research article
Assessing phylogenetic confidence at pandemic scales
Nicola De Maio, Nhan Ly-Trong, Samuel Martin, Bui Quang Minh, Nick Goldman
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Phylogenetics has a central role in evolutionary biology and genomic epidemiology 1 . Assessing phylogenetic confidence and reliability is therefore crucial and the methods that do this, such as those derived from Felsenstein’s bootstrap 2 , are among the most widely used in modern science. However, these methods require enormous computational capacity, and are unsuitable for large datasets. Furthermore, most of these methods emerge from a focus on the membership of clades (groupings of taxa), which makes their results difficult to interpret in the context of genomic epidemiology. Here we propose subtree pruning and regrafting-based tree assessment (SPRTA), an efficient and interpretable approach to assess confidence in phylogenetic trees. SPRTA shifts the paradigm of phylogenetic support measurement from evaluating the confidence in clades to evolution histories and phylogenetic placement—for example, assessing whether a lineage evolved from another considered lineage, which is particularly valuable in genomic epidemiology. We use SPRTA to investigate a global public SARS-CoV-2 phylogenetic tree relating more than two million genomes, highlighting plausible alternative evolutionary origins of many SARS-CoV-2 variants, assessing reliability in the Pango outbreak lineage classification system 3 , and demonstrating the effect of phylogenetic uncertainty on inferred mutation rates. Our results show that SPRTA enables pandemic-scale and detailed probabilistic assessment of transmission and mutational histories. Our method introduces a new approach to assessing phylogenetic confidence, enhancing the interpretability of pandemic-scale phylogenetic analyses and improving our ability to prepare for and respond to future pandemics.
GPT-4o mini: Non-social science research article
Spatial dynamics of brain development and neuroinflammation
Di Zhang, Leslie A. Rubio Rodríguez-Kirby, Yingxin Lin, Wenqi Wang, Mengyi Song, Li Wang, Lijun Wang, Shigeaki Kanatani, Tony Jimenez-Beristain, Yonglong Dang, Mei Zhong, Petra Kukanja, Shuozhen Bao, Shaohui Wang, Xinyi Lisa Chen, Fu Gao, Dejiang Wang, Hang Xu, Cong Ma, Xing Lou, Yang Liu, Jinmiao Chen, Nenad Sestan, Per Uhlén, Arnold Kriegstein, Hongyu Zhao, Gonçalo Castelo-Branco, Rong Fan
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The ability to spatially map multiple layers of omics information across developmental timepoints enables exploration of the mechanisms driving brain development1, differentiation, arealization and disease-related alterations. Here we used spatial tri-omic sequencing, including spatial ATAC–RNA–protein sequencing and spatial CUT&Tag–RNA–protein sequencing, alongside multiplexed immunofluorescence imaging (co-detection by indexinng (CODEX)) to map dynamic spatial remodelling during brain development and neuroinflammation. We generated a spatiotemporal tri-omic atlas of the mouse brain from postnatal day 0 (P0) to P21 and compared corresponding regions with the human developing brain. In the cortex, we identified temporal persistence and spatial spreading of chromatin accessibility for a subset of layer-defining transcription factors. In the corpus callosum, we observed dynamic chromatin priming of myelin genes across subregions and identified a role for layer-specific projection neurons in coordinating axonogenesis and myelination. In a lysolecithin neuroinflammation mouse model, we detected molecular programs shared with developmental processes. Microglia exhibited both conserved and distinct programs for inflammation and resolution, with transient activation observed not only at the lesion core but also at distal locations. Overall, this study reveals common and differential mechanisms underlying brain development and neuroinflammation, providing a rich resource for investigating brain development, function and disease.
GPT-4o mini: Non-social science research article
Lineage-resolved atlas of the developing human cortex
Matthew G. Keefe, Marilyn R. Steyert, Tomasz J. Nowakowski
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The human neocortex is composed of diverse cell types1 that are generated during development according to spatially and temporally organized programmes initiated by neural stem cells2,3,4,5. Despite the growing number of studies that have captured snapshots of gene expression of single cells along the axis of differentiation and maturation, the underlying map of lineage relationships that link individual progenitor cells to specific subtypes of neurons and glia remains unknown, especially in humans. Here we applied prospective lineage tracing to map the manifold of human neural stem and progenitor cell differentiation across the developmental window encompassing neurogenesis and gliogenesis in human primary tissue. By profiling the clonal output of 6,402 progenitor cells, we created a lineage-resolved map of human cortical development. Here we show that cortical progenitors switch from glutamatergic to GABAergic (involving Îł-aminobutyric acid) neurogenesis around midgestation, which coincides with an onset of oligodendrocyte generation. Additionally, we find that truncated radial glia maintain a glutamatergic neurogenic potential for a protracted period during human cortical development. Unexpectedly, we find that late-born glutamatergic neurons derived from truncated radial glia exhibit molecular features of deep cortical layer neurons and may contribute to the expansion of the subplate region during midgestation.
GPT-4o mini: Non-social science research article
Accelerating the discovery of multicatalytic cooperativity
Marcus H. Sak, Richard Y. Liu, Eugene E. Kwan, Eric N. Jacobsen
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Cooperative catalysis, in which multiple catalytic units operate synergistically, underpins a variety of synthetically and mechanistically important organic reactions1–4. Despite its potential utility in new reactivity contexts, approaches to the discovery of cooperative catalysts have been limited, typically relying on serendipity or on prior knowledge of single-catalyst reactivity1,5. Systematic searches for unanticipated types of catalyst cooperativity must contend with vast combinatorial complexity and are therefore not undertaken6–10. Here, we describe a pooling–deconvolution algorithm, inspired by group testing11, that identifies cooperative catalyst behaviors with low experimental cost while accommodating potential inhibitory effects between catalyst candidates. The workflow was validated first on simulated cooperativity data, and then by experimentally identifying previously documented cooperativity between organocatalysts in an enantioselective oxetane-opening reaction. The workflow was then applied in a discovery context to a Pd-catalyzed decarbonylative cross-coupling reaction, enabling the identification of several ligand pairs that promote the target transformation at substantially lower catalyst loading and temperature than previously reported with single ligand systems.
GPT-4o mini: Non-social science research article
Lymphoid gene expression supports neuroprotective microglia function
Pinar Ayata, Jessica M. Crowley, Matthew F. Challman, Vinaya Sahasrabuddhe, Maud Gratuze, Sebastian Werneburg, Diogo Ribeiro, Emma C. Hays, Violeta DurĂĄn-Laforet, Travis E. Faust, Philip Hwang, Francisco Mendes Lopes, Chrysa Nikopoulou, Sarah Buchholz, Robert E. Murphy, Taoyu Mei, Anna A. Pimenova, Carmen Romero-Molina, Francesca Garretti, Tulsi A. Patel, Claudia De Sanctis, Angie V. Ramirez Jimenez, Megan Crow, Felix D. Weiss, Jason D. Ulrich, Edoardo Marcora, John W. Murray, Felix Meissner, Andreas Beyer, Dan Hasson, John F. Crary, Dorothy P. Schafer, David M. Holtzman, Alison M. Goate, Alexander Tarakhovsky, Anne Schaefer
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Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD) 1 . The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic 2 . Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation 3,4 . Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1 low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1 low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.
GPT-4o mini: Non-social science research article
Atomically accurate de novo design of antibodies with RFdiffusion
Nathaniel R. Bennett, Joseph L. Watson, Robert J. Ragotte, Andrew J. Borst, DĂ©JenaĂ© L. See, Connor Weidle, Riti Biswas, Yutong Yu, Ellen L. Shrock, Russell Ault, Philip J. Y. Leung, Buwei Huang, Inna Goreshnik, John Tam, Kenneth D. Carr, Benedikt Singer, Cameron Criswell, Basile I. M. Wicky, Dionne Vafeados, Mariana Garcia Sanchez, Ho Min Kim, Susana VĂĄzquez Torres, Sidney Chan, Shirley M. Sun, Timothy T. Spear, Yi Sun, Keelan O’Reilly, John M. Maris, Nikolaos G. Sgourakis, Roman A. Melnyk, Chang C. Liu, David Baker
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Despite the central role of antibodies in modern medicine, no method currently exists to design novel, epitope-specific antibodies entirely in silico. Instead, antibody discovery currently relies on immunization, random library screening or the isolation of antibodies directly from patients1. Here we demonstrate that combining computational protein design using a fine-tuned RFdiffusion2 network with yeast display screening enables the de novo generation of antibody variable heavy chains (VHHs), single-chain variable fragments (scFvs) and full antibodies that bind to user-specified epitopes with atomic-level precision. We experimentally characterize VHH binders to four disease-relevant epitopes. Cryo-electron microscopy confirms the binding pose of designed VHHs targeting influenza haemagglutinin and Clostridium difficile toxin B (TcdB). A high-resolution structure of the influenza-targeting VHH confirms atomic accuracy of the designed complementarity-determining regions (CDRs). Although initial computational designs exhibit modest affinity (tens to hundreds of nanomolar Kd), affinity maturation using OrthoRep3 enables production of single-digit nanomolar binders that maintain the intended epitope selectivity. We further demonstrate the de novo design of scFvs to TcdB and a PHOX2B peptide–MHC complex by combining designed heavy-chain and light-chain CDRs. Cryo-electron microscopy confirms the binding pose for two distinct TcdB scFvs, with high-resolution data for one design verifying the atomically accurate design of the conformations of all six CDR loops. Our approach establishes a framework for the computational design, screening and characterization of fully de novo antibodies with atomic-level precision in both structure and epitope targeting.
GPT-4o mini: Non-social science research article
Fair human-centric image dataset for ethical AI benchmarking
Alice Xiang, Jerone T. A. Andrews, Rebecca L. Bourke, William Thong, Julienne M. LaChance, Tiffany Georgievski, Apostolos Modas, Aida Rahmattalabbi, Yunhao Ba, Shruti Nagpal, Orestis Papakyriakopoulos, Dora Zhao, Jinru Xue, Victoria Matthews, Linxia Gong, Austin T. Hoag, Mircea Cimpoi, Swami Sankaranarayanan, Wiebke Hutiri, Morgan K. Scheuerman, Albert S. Abedi, Peter Stone, Peter R. Wurman, Hiroaki Kitano, Michael Spranger
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Computer vision is central to many artificial intelligence (AI) applications, from autonomous vehicles to consumer devices. However, the data behind such technical innovations are often collected with insufficient consideration of ethical concerns 1–3 . This has led to a reliance on datasets that lack diversity, perpetuate biases and are collected without the consent of data rights holders. These datasets compromise the fairness and accuracy of AI models and disenfranchise stakeholders 4–8 . Although awareness of the problems of bias in computer vision technologies, particularly facial recognition, has become widespread 9 , the field lacks publicly available, consensually collected datasets for evaluating bias for most tasks 3,10,11 . In response, we introduce the Fair Human-Centric Image Benchmark (FHIBE, pronounced ‘Feebee’), a publicly available human image dataset implementing best practices for consent, privacy, compensation, safety, diversity and utility. FHIBE can be used responsibly as a fairness evaluation dataset for many human-centric computer vision tasks, including pose estimation, person segmentation, face detection and verification, and visual question answering. By leveraging comprehensive annotations capturing demographic and physical attributes, environmental factors, instrument and pixel-level annotations, FHIBE can identify a wide variety of biases. The annotations also enable more nuanced and granular bias diagnoses, enabling practitioners to better understand sources of bias and mitigate potential downstream harms. FHIBE therefore represents an important step forward towards trustworthy AI, raising the bar for fairness benchmarks and providing a road map for responsible data curation in AI.
GPT-4o mini: Non-social science research article
Adenosine signalling drives antidepressant actions of ketamine and ECT
Chenyu Yue, Na Wang, Haojiang Zhai, Zhengwei Yuan, Yuting Cui, Jing Quan, Yu Zhou, Xiaofeng Fan, Hongshuang Wang, Zhaofa Wu, Huijie Mi, Wooping Ge, Yulong Li, Xiaohui Wang, Minmin Luo
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Ketamine and electroconvulsive therapy (ECT) achieve rapid remission in treatment-resistant depression. However, their mechanisms of action—the understanding of which is essential for refining therapeutic precision—remain unclear1,2,3. Here, using mouse models, we identify adenosine signalling as a central pathway that underlies the antidepressant effects of these interventions. Results from genetically encoded adenosine sensor experiments and real-time optical recordings reveal that both therapies induce strong adenosine surges in key mood-regulatory regions, including the medial prefrontal cortex and the hippocampus. Genetic or pharmacological disruption of A1 and A2A adenosine receptors abolishes their therapeutic effects, which establishes the essential role of adenosine signalling in antidepressant efficacy. Notably, adenosine signalling specifically in the medial prefrontal cortex drives antidepressant actions. Ketamine increases adenosine by modulating cellular metabolism to increase intracellular adenosine levels without causing neuronal hyperactivity. Leveraging this mechanism, we develop ketamine derivatives that enhance adenosine signalling and exhibit improved antidepressant efficacy with reduced side effects at therapeutic doses. Furthermore, acute intermittent hypoxia, a non-pharmacological intervention involving controlled reductions in oxygen levels, increases brain adenosine levels and produces antidepressant effects, paralleling the actions of ketamine and ECT. Our findings establish adenosine as a pivotal mediator of rapid-acting antidepressants and a tractable target for scalable, noninvasive therapeutics in major depressive disorder.
GPT-4o mini: Non-social science research article
Conservation and alteration of mammalian striatal interneurons
Emily K. Corrigan, Michael DeBerardine, Aunoy Poddar, Miguel Turrero GarcĂ­a, Sean de la O, Siting He, Harsha Sen, Mariana Duhne, Shanti Lindberg, Menygi Song, Matthew T. Schmitz, Karen E. Sears, Ricardo Mallarino, Joshua D. Berke, Corey C. Harwell, Mercedes F. Paredes, Fenna M. Krienen, Alex A. Pollen
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Mammalian brains vary in size, structure and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved1,2,3,4. Previous studies suggest that there is a primate-specific population of striatal inhibitory interneurons—the TAC3 interneurons5. However, broader taxonomic and developmental characterization is required to address novelty in cell-type evolution. Here we examine gene expression in inhibitory neurons across 10 mammalian species, spanning 160 million years of divergence from primates. We find that the initial class of newborn TAC3 interneurons specified during development represents an ancestral, medial ganglionic eminence (MGE)-derived striatal population that is also present in pig and ferret cortex. This discovery prompted a re-examination of Glires, including mice, which are thought to lack the TAC3 type5,6. Targeted enrichment of MGE precursors in mice revealed conservation of the TAC3 initial class, camouflaged by reduced expression of Tac2 (the mouse orthologue of TAC3) and a gain of Th expression. Extending our analysis to the adult striatum further supported the homology of primate TAC3 and mouse Th striatal interneurons, and also uncovered a rare Tac2 subpopulation in the mouse ventromedial striatum. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved, and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.
GPT-4o mini: Non-social science research article
Structural snapshots capture nucleotide release at the Ό-opioid receptor
Saif Khan, Aaliyah S. Tyson, Mohsen Ranjbar, Zixin Zhang, Jaskaran Singh, Gye Won Han, Cornelius Gati
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As a member of the G protein-coupled receptor superfamily, the ÎŒ-opioid receptor (MOR) activates heterotrimeric G proteins by opening the Gα α-helical domain (AHD) to enable GDP–GTP exchange, with GDP release representing the rate-limiting step1,2. Here, using pharmacological assays, we show that agonist efficacy correlates with decreased GDP affinity, promoting GTP exchange, whereas antagonists increase GDP affinity, dampening activation. Further investigating this phenomenon, we provide 8 unique structural models and 16 cryogenic electron microscopy maps of MOR with naloxone or loperamide, capturing several intermediate conformations along the activation pathway. These include four GDP-bound states with previously undescribed receptor–G protein interfaces, AHD arrangements and transitions in the nucleotide-binding pocket required for GDP release. Naloxone stalls MOR in a ‘latent’ state, whereas loperamide promotes an ‘engaged’ state, which is structurally poised for opening of the AHD domain and subsequent GDP release. These findings, supported by molecular dynamics simulations, identify GDP-bound intermediates and AHD conformations as key determinants of nucleotide exchange rates, providing structural and mechanistic insights into G protein activation and ligand efficacy with broad implications for G protein-coupled receptor pharmacology.
GPT-4o mini: Non-social science research article
Global satellite survey reveals uncertainty in landfill methane emissions
Matthieu Dogniaux, Joannes D. Maasakkers, Marianne Girard, Dylan Jervis, Jason McKeever, Berend J. Schuit, Shubham Sharma, Ana Lopez-Noreña, Daniel J. Varon, Ilse Aben
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Methane is a potent but short-lived greenhouse gas and rapid reductions of its anthropogenic emissions could help decrease near-term warming 1 . Solid waste emits methane through the decay of organic material, which amounts to about 10% of total anthropogenic methane emissions 2 . Satellite instruments 3 enable monitoring of strong methane hotspots 4 , including many strongly emitting urban areas that include solid waste disposal sites as most prominent sources 5 . Here we present a survey of methane emissions from 151 individual waste disposal sites across six continents using high-resolution satellite observations that can detect localized methane emissions above 100 kg h –1 . Within this dataset, we find that our satellite-based estimates generally show no correlation with reported or modelled emission estimates at facility scale. This reveals major uncertainties in the current understanding of methane emissions from waste disposal sites, warranting further investigations to reconcile bottom-up and top-down approaches. We also observe that managed landfills show lower emission per area than dumping sites, and that detected emission sources often align with the open non-covered parts of the facility where waste is added. Our results highlight the potential of high-resolution satellite observations to detect and monitor methane emissions from the waste sector globally, providing actionable insights to help improve emission estimates and focus mitigation efforts.
GPT-4o mini: Non-social science research article
Specificity, length and luck drive gene rankings in association studies
Jeffrey P. Spence, Hakhamanesh Mostafavi, Mineto Ota, Nikhil Milind, Tamara Gjorgjieva, Courtney J. Smith, Yuval B. Simons, Guy Sella, Jonathan K. Pritchard
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Standard genome-wide association studies (GWAS) and rare variant burden tests are essential tools for identifying trait-relevant genes 1 . Although these methods are conceptually similar, by analysing association studies of 209 quantitative traits in the UK Biobank 2–4 , we show that they systematically prioritize different genes. This raises the question of how genes should ideally be prioritized. We propose two prioritization criteria: (1) trait importance — how much a gene quantitatively affects a trait; and (2) trait specificity — the importance of a gene for the trait under study relative to its importance across all traits. We find that GWAS prioritize genes near trait-specific variants, whereas burden tests prioritize trait-specific genes. Because non-coding variants can be context specific, GWAS can prioritize highly pleiotropic genes, whereas burden tests generally cannot. Both study designs are also affected by distinct trait-irrelevant factors, complicating their interpretation. Our results illustrate that burden tests and GWAS reveal different aspects of trait biology and suggest ways to improve their interpretation and usage.
GPT-4o mini: Non-social science research article
Anti-progestin therapy targets hallmarks of breast cancer risk
Bruno M. SimĂ”es, Robert Pedley, Curtis W. McCloskey, Matthew Roberts, Austin D. Reed, Alecia-Jane Twigger, Pirashaanthy Tharmapalan, Amanda Caruso, Sara Cabral, Anthony J. Wilby, Hannah Harrison, Yuxi Zhou, Alice Greenhalgh, Suad A. Alghamdi, Martina Forestiero, Jesica Lopez-Muñoz, Jasmin Roche, Ren Jie Tuieng, Muhammad A. Khan, Steven Squires, Susan M. Astley, Elaine F. Harkness, AngĂ©lica Santiago-GĂłmez, Katherine Spence, Jessica Ritchie, Susan Pritchard, Yit Lim, Michael J. Sherratt, Sebastiano AndĂČ, Anthony Howell, D. Gareth Evans, Andrew P. Gilmore, Walid T. Khaled, Rama Khokha, Robert B. Clarke, Sacha J. Howell
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Breast cancer is the leading cause of cancer-related death in women worldwide 1 . Here, in the Breast Cancer-Anti-Progestin Prevention Study 1 (BC-APPS1; NCT02408770 ), we assessed whether progesterone receptor antagonism with ulipristal acetate for 12 weeks reduces surrogate markers of breast cancer risk in 24 premenopausal women. We used multilayered OMICs and live-cell approaches as readouts for molecular features alongside clinical imaging and tissue micromechanics correlates. Ulipristal acetate reduced epithelial proliferation (Ki67) and the proportion, proliferation and colony formation capacity of luminal progenitor cells, the putative cell of origin of aggressive breast cancers 2 . MRI scans showed reduction in fibroglandular volume with treatment, whereas single-cell RNA sequencing, proteomics, histology and atomic force microscopy identified extracellular matrix remodelling with reduced collagen organization and tissue stiffness. Collagen VI was the most significantly downregulated protein after ulipristal acetate treatment, and we uncovered an unanticipated spatial association between collagen VI and SOX9 high luminal progenitor cell localization, establishing a link between collagen organization and luminal progenitor activity. Culture of primary human breast epithelial cells in a stiff environment increased luminal progenitor activity, which was antagonized by anti-progestin therapy, strengthening this mechanistic link. This study offers a template for biologically informed early-phase therapeutic cancer prevention trials and demonstrates the potential for premenopausal breast cancer prevention with progesterone receptor antagonists through stromal remodelling and luminal progenitor suppression.
GPT-4o mini: Non-social science research article
Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology
Domenic Burger, Marianna Kashyrina, Lukas van den Heuvel, Hortense de La SeigliÚre, Amanda J. Lewis, Francesco De Nuccio, Inayathulla Mohammed, Jérémy VerchÚre, Cécile Feuillie, Mélanie Berbon, Marie-Laure Arotcarena, Aude Retailleau, Erwan Bezard, Marie-HélÚne Canron, Wassilios G. Meissner, Antoine Loquet, Luc Bousset, Christel Poujol, K. Peter R. Nilsson, Florent LaferriÚre, Thierry Baron, Dario Domenico Lofrumento, Francesca De Giorgi, Henning Stahlberg, François Ichas
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Multiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50–60 years and leading to death within a decade1,2,3. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn)4,5,6,7,8, the formation of which shows parallels with prion propagation9,10. While fibrils extracted from brains of individuals with MSA have been structurally characterized11, their ability to replicate in a protein-only manner has been questioned12, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B13,14, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice15—suggesting direct relevance to MSA—but lacks scrutiny at the atomic scale. Here we report high-resolution structural analyses of 1B fibrils and of fibrils extracted from diseased mice injected with 1B that developed GCIs (1BP). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1BP are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA11. Moreover, reinjection of crude mouse brain homogenates containing 1BP into new mice reproduces the same MSA-like pathology induced by the parent synthetic seed 1B. Our findings identify 1B as a synthetic pathogen capable of self-replication in vivo and reveal structural features of 1B and 1BP that may underlie MSA pathology, offering insights for therapeutic strategies.
GPT-4o mini: Non-social science research article
Dispersion-engineered multipass optical parametric amplification
Jan H. NĂ€gele, Tobias Steinle, Johann Thannheimer, Philipp Flad, Harald Giessen
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The amplification of extremely short laser pulses (under 100 fs) presents a fundamental challenge due to the trade-off between amplification bandwidth, efficiency and gain1. Conventional methods rely on complex optical set-ups with preprocessing and postprocessing steps2. Optical parametric amplification3 offers a high optical gain that scales with the length of the nonlinear medium at the expense of bandwidth, limiting its effectiveness for extremely short and intrinsically broadband ultrashort pulses, whose amplification requires a broad gain–bandwidth, high single-pass gain and simultaneously strong nonlinear interaction. Here we introduce a new multipass4 optical parametric amplification system that leverages dispersion-engineered dielectric mirrors to repeatedly focus the laser into a nonlinear gain crystal. The coatings simultaneously compensate for the group delay5 after each multipass step and suppress the idler wave and, therefore, backconversion. This approach achieves ×1,500 higher gain compared with single-pass amplification, a photon conversion efficiency of up to 81% (52% system conversion efficiency) and near Fourier-limited time–bandwidth products of the amplified pulses, while fully preserving the spatial beam quality. Our concept breaks the gain versus bandwidth barrier and achieves 12 THz at 41 dB gain. As our concept does not require specific gain materials, it is versatile and broadly applicable to ultrafast6 laser systems in quantum technologies7,8,9, attosecond physics10,11,12, material processing and ultrabroadband low-cost bio-imaging systems13,14. Our concept offers device sizes in the single-digit cubic centimetre range.
GPT-4o mini: Non-social science research article
Vector-stimuli-responsive magnetorheological fibrous materials
Junhong Pu, Haiqiong Li, Jin Liu, Ke Li, Xiaoming Tao
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Fibrous materials that provide reversible actuation 1,2 or adapt mechanical properties 3,4 in response to external stimuli hold great promise for smart textiles 5 , soft robotics 6 and wearable technologies 7 . Although considerable progress has been made in creating fibrous materials responsive to scalar stimuli such as voltage 8 , temperature 6 , humidity 2 and ion concentration 9 , these technologies often lack directional controllability and functional diversity 10–14 . Here we report a class of vector-stimuli-responsive magnetorheological fibrous materials, guided by our engineering model integrating the structural mechanics of textiles with the magnetics of soft magnetic materials. We mass-produced soft magnetic polymer composite fibres with optimized mechanical and magnetic properties, which we then assembled into concentric helical yarns. These yarns exhibited pronounced bending and stiffening properties controlled by the direction and magnitude of magnetic fields, allowing for customized fabrics with various actuation and stiffening functionalities. We demonstrated innovative smart textiles derived from those fabrics, including an active ventilation fabric for personal moisture management, an integrated conformable gripper for handling objects of varying shapes and stiffness, and a compact remote-controllable haptic finger glove that replicates the sensation of fabric hardness and smoothness. Our work provides insights into stimuli-responsive fibrous materials, elevating them from scalar to sophisticated vector control, heralding an era of smart textile innovation.
GPT-4o mini: Non-social science research article
Two residues reprogram immunity receptors for nitrogen-fixing symbiosis
Magdalini Tsitsikli, Bine Simonsen, Thi-Bich Luu, Maria M. Larsen, Camilla G. Andersen, Kira Gysel, Damiano Lironi, Christina Krönauer, Henriette RĂŒbsam, Simon B. Hansen, RenĂ© BĂŠrentsen, Jesper Lundsgaard Wulff, Sarah Holt Johansen, GĂŒlendam Sezer, Jens Stougaard, Kasper RĂžjkjĂŠr Andersen, Simona Radutoiu
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Receptor signalling determines cellular responses and is crucial for defining specific biological outcomes. In legume root cells, highly similar and structurally conserved chitin and Nod factor receptor kinases activate immune or symbiotic pathways, respectively, when chitinous ligands are perceived1. Here we show that specific amino acid residues in the intracellular part of the Nod factor receptor NFR1 control signalling specificity and enable the distinction of immune and symbiotic responses. Functional investigation of CERK6, NFR1 and receptor variants thereof revealed a conserved motif that we term Symbiosis Determinant 1 in the juxtamembrane region of the kinase domain, which is key for symbiotic signalling. We show that two residues in Symbiosis Determinant 1 are indispensable hallmarks of NFR1-type receptors and are sufficient to convert Lotus CERK6 and barley RLK4 kinase outputs to enable symbiotic signalling in Lotus japonicus.
GPT-4o mini: Non-social science research article
Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome
Varun K. Narendra, Tandrila Das, Linsey J. Wierciszewski, Rebecca J. Londoner, Joshua K. Morrison, Pia Martindale, Tessa Devine, Kevin Chen, Michael Trombetta, Yuzuka Kanno, Alejandro E. Casiano, Elisa de Stanchina, Caleb A. Lareau, Scott W. Lowe, Alexander D. Gitlin
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Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. UBA1 mutations in VEXAS lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and hematologic disease are unknown. Here, we employ somatic gene editing approaches to model VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 and RIPK3-MLKL, respectively. Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner. In contrast, Uba1 mutation in HSPCs induced an unfolded protein response and myeloid bias independently of RIPK3-Caspase-8. Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kinetic defect in Lys63/Met1 (i.e., linear) polyubiquitylation of inflammatory signaling complexes. Collectively, our results link VEXAS pathogenesis with that of rarer monogenic autoinflammatory syndromes; highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade; and support therapeutic targeting of the inflammatory cell death axis in VEXAS.
GPT-4o mini: Non-social science research article
Author Correction: TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2
Manolis Pasparakis, Gilles Courtois, Martin Hafner, Marc Schmidt-Supprian, Arianna Nenci, Atiye Toksoy, Monika Krampert, Matthias Goebeler, Reinhard Gillitzer, Alain Israel, Thomas Krieg, Klaus Rajewsky, Ingo Haase
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GPT-4o mini: Non-social science research article
Transcriptomic and spatial organization of telencephalic GABAergic neurons
Cindy T. J. van Velthoven, Yuan Gao, Michael Kunst, Changkyu Lee, Delissa McMillen, Anish Bhaswanth Chakka, Tamara Casper, Michael Clark, Rushil Chakrabarty, Scott Daniel, Tim Dolbeare, Rebecca Ferrer, Jessica Gloe, Jeff Goldy, Junitta Guzman, Carliana Halterman, Windy Ho, Mike J. Huang, Katelyn James, Rachel McCue, Beagan Nguy, Trangthanh Cardenas, Kara Ronellenfitch, Emma D. Thomas, Amy Torkelson, Chelsea M. Pagan, Lauren Kruse, Nick Dee, Lydia Ng, Jack Waters, Kimberly A. Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng
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The telencephalon of the mammalian brain contains multiple regions and circuits that have adaptive and integrative roles in a variety of brain functions. GABAergic neurons in the telencephalon are diverse; they have many circuit functions, and dysfunction of these neurons has been implicated in various brain disorders1,2,3. Here we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished using 611,423 young adult single-cell transcriptomes and 614,569 single-cell transcriptomes collected from multiple prenatal and postnatal developmental timepoints. We present a hierarchically organized adult telencephalic GABAergic neuronal cell-type taxonomy of 7 classes, 52 subclasses, 284 supertypes and 1,051 clusters, as well as a corresponding developmental taxonomy of 1,688 clusters across ages from embryonic day 7 to postnatal day 14. Detailed charting efforts reveal extraordinary complexity whereby relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types are often found in distant and diverse brain regions, indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Moreover, we find various spatial dimensions of both discrete and continuous variation among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal, preoptic and most pallidal GABAergic neuronal types emerge in a burst during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell-type taxonomy will serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community.
GPT-4o mini: Non-social science research article
Secretome translation shaped by lysosomes and lunapark-marked ER junctions
Heejun Choi, Ya-Cheng Liao, Young J. Yoon, Jonathan Grimm, Nan Wang, Luke D. Lavis, Robert H. Singer, Jennifer Lippincott-Schwartz
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The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.
GPT-4o mini: Non-social science research article
Targeting FSP1 triggers ferroptosis in lung cancer
Katherine Wu, Alec J. Vaughan, Jozef P. Bossowski, Yuan Hao, Aikaterini Ziogou, Seon Min Kim, Tae Ha Kim, Mari N. Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, Mingqi Han, Toshitaka Nakamura, Lidong Wang, Suckwoo Chung, Diane Simeone, David Shackelford, Yun Pyo Kang, Marcus Conrad, Thales Papagiannakopoulos
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Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1,2,3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown4,5. Here, using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.
GPT-4o mini: Non-social science research article
Continuous cell-type diversification in mouse visual cortex development
Yuan Gao, Cindy T. J. van Velthoven, Changkyu Lee, Emma D. Thomas, Rémi Mathieu, Angela P. Ayala, Stuard Barta, Darren Bertagnolli, Jazmin Campos, Trangthanh Cardenas, Daniel Carey, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Megan Chiang, Lindsey Ching, Michael Clark, Marie J. Desierto, Rebecca Ferrer, Jessica Gloe, Jeff Goldy, Nathan Guilford, Junitta Guzman, Carliana R. Halterman, Samantha D. Hastings, Daniel Hirschstein, Windy Ho, Katelyn James, Zoe Juneau, Naomi Martin, Rachel McCue, Emma Meyerdierks, Amanda C. Mitchell, Josh S. Nagra, Beagan Nguy, Thuc Nghi Nguyen, Paul Olsen, Alana A. Oyama, Nick Pena, Jacob Quon, Qingzhong Ren, Augustin Ruiz, Nadiya V. Shapovalova, Josef Sulc, Amy Torkelson, Alex Tran, Herman Tung, Nasmil Valera Cuevas, Justin Wang, Jeanelle Ariza, Delissa A. M. McMillen, Jack Waters, Michael Kunst, Kara Ronellenfitch, Boaz Levi, Michael J. Hawrylycz, Chelsea Pagan, Nick Dee, Kimberly A. Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng
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The mammalian cortex is composed of a highly diverse set of cell types and develops through a series of temporally regulated events1,2,3. Single-cell transcriptomics enables a systematic study of cell types across the entire timeline of cortical development. Here we present a comprehensive and high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex. The atlas is built from a single-cell RNA sequencing dataset of 568,654 high-quality single-cell transcriptomes and a single-nucleus Multiome dataset of 200,061 high-quality nuclei, which were densely sampled across the embryonic and postnatal developmental stages (from embryonic day 11.5 to postnatal day 56). We computationally reconstructed a transcriptomic developmental trajectory map of all excitatory, inhibitory and non-neuronal cell types in the visual cortex. Branching points that mark the emergence of new cell types at specific developmental ages and molecular signatures of cellular diversification are identified. The trajectory map shows that neurogenesis, gliogenesis and early postmitotic maturation in the embryonic stage give rise to all cell classes and nearly all subclasses in a staggered parallel manner. Increasingly refined cell types emerge throughout the postnatal differentiation process, including the late emergence of many cell types during the eye-opening stage and the onset of critical period, suggesting that there is continuous cell-type diversification at different stages of cortical development. Throughout development, there are cooperative dynamic changes in gene expression and chromatin accessibility in specific cell types. We identify cell-type-specific and temporally resolved gene regulatory networks that link transcription factors and downstream target genes through accessible chromatin motifs. Collectively, our study provides a detailed dynamic molecular map directly associated with individual cell types and specific temporal events that can reveal the molecular logic underlying the complex and multifaceted cortical cell type and circuit development.
GPT-4o mini: Non-social science research article
The importance of past rifting in large igneous province development
R. Kounoudis, I. D. Bastow, C. J. Ebinger, S. Goes, P. Zhou, M. Musila, C. S. Ogden, A. Ayele
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Lithospheric thin zones, such as recently failed rifts, are generally assumed to be weak spots where magmatism and deformation can concentrate during rifting and large igneous province development 1–3 . Yet, the Turkana Depression in East Africa, the site of the failed 66-million-year-old Anza Rift, did not experience the widespread flood magmatism seen on the adjacent Ethiopian Plateau, despite being a lithospheric thin spot when the region encountered hot plume material around 45 million years ago 4 . Here we jointly invert surface-wave and receiver function data to constrain crustal and upper-mantle seismic structure below the Depression to evaluate lithospheric thermo-mechanical modification. Evidence for thick lower crustal intrusions, ubiquitous below the uplifted Ethiopian Plateau 5,6 , is comparatively lacking below the Depression’s failed Anza Rift system, which ongoing East African rifting is circumnavigating, not exploiting. The mantle lithosphere below the Depression has also retained its cool, fast-wavespeed ‘lid’ character, contrasting the Ethiopian Plateau. Volatile depletion during failed Anza rifting probably rendered the thinned lithosphere refractory without later rejuvenation. Subsequent rifting and magmatism thus initiated away from the still-thin Anza Rift, in regions where fertile lithosphere enabled melting and the sufficient lowering of plate yield strength. Areas of thinned lithosphere are thus not necessarily persistent weak zones where significant extension and magmatic provinces will develop.
GPT-4o mini: Non-social science research article
Lymph node environment drives FSP1 targetability in metastasizing melanoma
Mario Palma, Milena Chaufan, Cort B. Breuer, Sebastian MĂŒller, Marie Sabatier, Cameron S. Fraser, Krystina J. Szylo, Mahsa Yavari, Alanis Carmona, Mayher Kaur, Luiza Martins Nascentes Melo, Feyza Cansiz, June Monge-Lorenzo, Midori Flores, Eikan Mishima, Toshitaka Nakamura, Bettina Proneth, Marcos Labrado, Yanshan Liang, Nicole Cayting, Lan Zheng, Tatiana Cañeque, Ludovic Colombeau, Adam Wahida, JosĂ© Pedro Friedmann Angeli, Alpaslan Tasdogan, Sheng Hui, RaphaĂ«l Rodriguez, Marcus Conrad, Nathan E. Reticker-Flynn, Jessalyn M. Ubellacker
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Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate–cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.
GPT-4o mini: Non-social science research article
Eight millennia of continuity of a previously unknown lineage in Argentina
Javier Maravall-LĂłpez, Josefina M. B. Motti, NicolĂĄs Pastor, MarĂ­a PĂ­a Tavella, Mariana Fabra, Pilar Babot, Mariano Bonomo, Silvia E. Cornero, Guillermo N. Lamenza, Diego Catriel Leon, Paula C. Miranda de Zela, Gustavo G. Politis, SofĂ­a C. Angeletti, G. Roxana CattĂĄneo, Mariana Dantas, Hilton Drube, Lucia G. Gonzalez Baroni, SalomĂłn Hocsman, AndrĂ©s D. Izeta, Reinaldo A. Moralejo, VerĂłnica Aldazabal, Diego M. Basso, Cristina BayĂłn, MarĂ­a Guillermina Couso, Ulises D’Andrea, Paula Del RĂ­o, GermĂĄn G. Figueroa, Romina Frontini, Mariela Edith Gonzalez, AndrĂ©s G. Laguens, Jorge G. MartĂ­nez, Pablo G. Messineo, Beatriz Nores, Daniel E. Olivera, Gisela M. Sario, AnalĂ­a Sbattella, Clara Scabuzzo, Aldana M. Tavarone, Rodrigo Vecchi, Kim Callan, Ella Caughran, Oscar Estrada, Trudi Frost, Lora Iliev, Aisling Kearns, Jack Kellogg, Kim-Louise Krettek, Ann Marie Lawson, Matthew Mah, Nihal Manjila, Adam Micco, Iris Patterson, Lijun Qiu, Xavier Roca-Rada, Gregory Soos, Peter A. Webb, J. Noah Workman, Nadin Rohland, Nick Patterson, Iosif Lazaridis, Lars Fehren-Schmitz, Cosimo Posth, Bastien Llamas, Swapan Mallick, DarĂ­o A. Demarchi, Graciela S. Cabana, David Reich, Rodrigo Nores
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The central Southern Cone of South America was one of the last regions of the globe to become inhabited by people1, and remains under-represented in studies of ancient DNA. Here we report genome-wide data from 238 ancient individuals spanning ten millennia. The oldest, from the Pampas region and dating to 10,000 years before present (bp), had distinct genetic affinity to Middle Holocene Southern Cone individuals, showing that differentiation from the central Andes and central east Brazil had begun by this time. Individuals dating to 4,600–150 bp primarily descended from a previously unsampled deep lineage of which the earliest representative is an individual dating to around 8,500 bp. This central Argentina lineage co-existed with two other lineages during the Mid-Holocene and, within central Argentina, this ancestry persisted for thousands of years with little evidence of inter-regional migration. Central Argentina ancestry was involved in three distinct gene flows: it mixed into the Pampas by 3,300 bp and seemingly became the main component there after 800 bp, with central Andes ancestry in northwest Argentina, and with tropical and subtropical forest ancestry in the Gran Chaco. In northwest Argentina, there was an increased rate of close-kin unions by 1,000 bp, paralleling the pattern in the central Andes. In the Paraná River region, a 400 bp individual with a Guaraní archaeological association clusters with Brazilian groups, consistent with Guaraní presence by this time.
Nature DOI suffix ≠ "/s...": Not a research article
Ultrashort laser pulse amplified by back-and-forth propagation
Christoph Heyl, Marc Hanna
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Ultrashort laser pulses are indispensable tools for sensing and measurement, but it is challenging to generate them at high powers. Quantum mechanics dictates that the more localized a laser pulse is in time, the wider the range of frequencies of its photons — ultrashort laser pulses are said to be ‘broadband’ because of their wide frequency range. The power of ultrashort laser pulses can be increased through amplification, but efficiently amplifying these pulses is difficult. However, in a paper in Nature, NĂ€gele et al.1 report a method that efficiently amplifies a weak, ultrashort laser pulse by overlapping it with a high-power laser pulse. The authors achieved this by bouncing the two pulses back and forth between two mirrors such that they repeatedly passed through a crystal. The mirrors were designed to reduce unwanted mismatch between the pulses, and the researchers demonstrate that this set-up transfers energy to the weaker pulse with high efficiency.
Nature DOI suffix ≠ "/s...": Not a research article
Pressure to publish is rising as research time shrinks, finds survey of scientists
Chris Simms
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Several thousand scientists from 113 countries say that the job pressures of being a researcher are rising.Credit: L. E. Baskow/Las Vegas Review-Journal/Tribune News Service via Getty Scientists feel that the pressure to publish is rising, but that the time and resources they have to do the necessary research are falling, according to a survey of 3,200 researchers. The results come from Elsevier’s 2025 Researcher of the Future report, which surveyed people from 113 countries between August and September, to assess how researchers view the evolving research landscape. About 68% of respondents said the pressure to publish their research is greater than it was two to three years ago and only 45% agreed that they have sufficient time for research (see ‘Researchers are feeling the pressure’). Another concern is uncertainty over funding — just 33% of respondents expect funding in their field to grow in the next 2–3 years. And that proportion fell to just 11% in North America, reflecting unprecedented cuts to US research funding this year. “As a researcher based in Brazil, I strongly relate to the survey’s findings, particularly the growing pressure to publish despite limited time and resources,” says Claudia Suemoto, a gerontologist at the University of São Paulo Medical School. “The demand for productivity has indeed increased in recent years, yet opportunities for funding and access to qualified personnel remain constrained in Brazil and other low- and middle-income countries.” Source: Elsevier Suemoto says this imbalance of high demands and restricted resources often forces researchers to do more with less, which could affect the quality and innovation of research. Comments researchers made as part of the survey indicate that the lack of time is down to factors including growing administrative and teaching demands and trying to identity and acquire funding. 'As a result, some researchers are surprised that the proportion of people who have enough time to do their work is so high. “I am amazed that 45% of scientists feel they have enough time for research. I do not know anyone who feels that way,” says Anastasia Borschevsky, an engineer at the University of Groningen in the Netherlands. Which researchers want to relocate? The survey also reveals that nearly 30% of the respondents are considering moving to a different country in the next two years for the sake of their career. “Scientists are used to moving country because of the dynamics of the job market,” says Jacco van Loon, an astronomer at Keele University in the United Kingdom, but he says politics now has a strong influence, too. Some 40% of researchers in the United States are likely to consider relocating (up 16 percentage points from a similar survey from Elsevier in 2022), but just 13% of those in China are thinking about it, down 22 percentage points from 2022. 75% of US scientists who answered Nature poll consider leaving “China has made it much more attractive for Chinese scientists to stay, whilst the government in the US has been unprecedently hostile towards scientists, especially on topics where the government has a diverging opinion and with regard to diversity and inclusion,” says van Loon. “So, I am not surprised by the statistics around desire to move country.” The relatively high proportion of respondents in the United States considering a move reflects data from a Nature poll in March, which showed that 75% of 1,600 US scientists were considering a move overseas after the election of President Donald Trump, with many saying they were looking for jobs in Europe and Canada.
Nature DOI suffix ≠ "/s...": Not a research article
From pangolins to primates: how I use zoo facilities to treat wild animals
Jack Leeming
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“One of the biggest threats to pangolins globally is habitat loss, but here in Singapore, road accidents are a larger immediate threat. We live in an urban city but we have a lot of wildlife all around us as well, so some encounters are inevitable. I work as a veterinarian at Mandai Wildlife Group, which manages the Singapore Zoo. In this image, taken in May, I’m examining Berani, a big male Sunda pangolin (Manis javanica), at our facilities in the zoo. Berani — which means brave in Malay — was a wild pangolin who first came to us after a probable traffic accident in 2018. His femur was fractured and we decided to help him by surgically implanting a metal plate to support healing. It was a tricky job: to avoid his scales we had to approach the bone from the medial aspect — the belly side — of the leg. He recovered from the surgery but developed a skin condition after some time, which is what my colleague and I are inspecting in this picture, with Berani under anaesthesia. The condition was a type of pemphigus, an autoimmune disorder for which he was eventually euthanized.
Nature DOI suffix ≠ "/s...": Not a research article
Developmental maps of the brain trace when cell types emerge
Emily Sylwestrak
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The brain’s vast diversity of cell types has long captivated neuroscientists, who first began organizing brain cells into atlases on the basis of their form, function or where they originated in embryonic development. In the past decade, advances in DNA- and RNA-sequencing technologies and computational analyses have helped to refine, or, in some cases, redefine, cell types — most commonly using transcriptomes, the complete set of RNA molecules produced by a cell. The result is a picture of adult cell types with unprecedented resolution. But early in development, cell identities are more like a motion picture than a single frame. A series of studies by the BRAIN Initiative Cell Atlas Network (BICAN) charts a new domain in brain-cell specification: time. Their work highlights the dynamic nature of gene expression and cell identity across the development of a single animal, or the evolution of a species.
Nature DOI suffix ≠ "/s...": Not a research article
How the rush for critical minerals is neglecting human needs
Daniel M. Franks, Paul Rogers, Fitsum Weldegiorgis, Lynda Lawson, Louise Gallagher, Natalie Gardner, Bora Aska, Johanna H. Linus, Shrey Varshney
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It was a meeting that shocked the world. On 28 February, Ukrainian President Volodymyr Zelenskyy met with US President Donald Trump in the Oval Office. Trump’s aim was “getting some of the rare earth” as payment for US weapons after Russia’s invasion of Ukraine in 2022. Negotiations broke down at the meeting, but later, on 30 April, Trump landed his deal. And he has been seeking other deals since, including signing a joint agreement with Australia on 21 October to secure critical-mineral and rare-earth supply chains. Climate change is devastating mining of minerals needed to fight it Access to minerals has long been an undercurrent of international relations, but rarely has it been so openly espoused, or so at odds with what the public thought those minerals were for. Once promoted as the minerals of the energy transition and digital transformations, Trump openly justifies critical minerals as the minerals of war. “We’re going to be
 taking it, using it for all the things we do,” Trump said in February, “including 
 weapons and the military” (see go.nature.com/47by3cn). Although minerals are at the centre of contemporary discussions on war, renewable energy and technology, they are also of immense relevance to human development, notably ending poverty in all its forms — the first priority of the UN Sustainable Development Goals (SDGs). Here we trace the national-security origins of the term critical minerals and what this implies for global inequality. We then draw lessons from how other natural resources have been reframed to show why a human-centred approach is essential to meet humanity’s needs for these minerals. Geopolitical origins Critical minerals have long been a focus of military planning. As early as the First World War, the War Industries Board compiled a list of strategic and critical minerals that were crucial to US industry and in short supply1. In 1921, the US Army General Staff adopted its first official list distinguishing between minerals that were ‘strategic’ for defence and industry; those that were ‘critical’ owing to shortages; and those that were ‘essential’ even if they didn’t meet either criteria. In 1944, the US Army and Navy Munitions Board developed a combined definition of ‘strategic and critical minerals’ as “those materials required for essential uses in a war emergency
the procurement of which [is] sufficiently uncertain for any reason to require prior provision for the supply thereof”1. Frequent changes to the lists, terminology and policy followed in the United States, but it was the 2010 ‘rare-earth crisis’ that triggered the contemporary interest by a wider array of countries. Metals are key to the global economy — but three challenges threaten supply chains On 7 September 2010, a Chinese fishing boat collided with two Japanese Coast Guard vessels off the Senkaku islands in the East China Sea. The arrest of the fishing-boat captain caused a diplomatic incident between the two nations. At around the same time, China halted exports of rare-earth elements (REEs), of which Japan was a major importer. This caused prices to skyrocket, revealing the economic vulnerability of countries when mineral supply chains are narrow. Japan’s response, which was to invest in diversification, stockpiling, recycling and alternatives, became a blueprint for wider efforts. It spurred the development of critical-minerals strategies and lists by the European Union (2011), the United States (2018), Australia (2019), Canada (2021), the United Kingdom (2022), India, Indonesia, Japan and South Korea (2023), and South Africa and New Zealand (2025). In 2022, many of these countries came together under the Minerals Security Partnership to coordinate efforts to improve supply security. These strategies and lists build on the US definition, refined over the past century: a critical mineral is a material that is essential to the economy or national security, has a supply chain vulnerable to disruption and is crucial for manufacturing a product. Critical-mineral confusion After the rare-earth crisis, and the 2015 Paris agreement, addressing climate change became a more urgent policy priority for various governments and international institutions, many of which began using the term critical minerals as though it meant the minerals of renewable energy. In truth, however, most critical minerals are not energy-transition minerals, and most energy-transition minerals are not critical minerals. For instance, roughly 60% of the critical minerals on the EU, US and Australian lists have no energy-transition use case2. Indeed, the EU includes coking coal on its list. Conversely, critical minerals make up less than 2% of energy-transition mineral demand (by volume). Mineral ingredients of concrete, such as sand and cement, which are crucial for renewable energy infrastructure, constitute 70% of demand2. Superpowers want to control critical mineral supplies — local communities need a stronger say Even when volume is set aside, many minerals needed for the energy transition do not feature on critical mineral lists2. Copper, for example, is essential to renewable energy but is not typically considered critical, given its diverse supply and limited vulnerability to disruption. There are exceptions, however, including South Korea, which includes it on its list. In other words, critical minerals are defined not as minerals that are important, but as those that are in a state that is vulnerable to disruption — critical as in ‘the critical care unit of a hospital’, not critical as in ‘society can’t live without them’. And although supply disruption is relevant, any attempt to plan for the energy transition should be concerned with all the minerals that are necessary, not just those with narrow supply chains. The mineral ingredients of concrete are important, yet they are absent from the discussion, or indeed any planning, even though they face huge affordability, sustainability and environmental issues3. Critical to whom? The realization that the term critical mineral is not a synonym for energy-transition mineral has led some institutions to seek alternatives. The United Nations Environment Programme and the Extractive Industries Transparency Initiative both use the term ‘transition mineral’. Chemists will immediately pick up the awkwardness of using this term because ‘transition metals’ are already known as a group of twelve elements in the d-block of the periodic table. Quarry workers cut slabs of limestone in Egypt.Credit: Ahmed Gamal/NurPhoto via Getty Similarly, the UN Secretary-General’s Panel on Critical Energy Transition Minerals used the term ‘critical energy transition minerals’ in its 2024 report4. Its remit was confined to those minerals necessary for constructing, producing, distributing and storing renewable energy and associated infrastructure. The African Union, too, avoided the term critical minerals in its Green Minerals Strategy, partly because of a desire to focus only on energy-transition minerals, but also because the term begs the question, critical to whom? Across African countries, it is common to hear the phrase, ‘critical minerals are not critical to us’. And they have a point. Most nations that have critical-mineral lists are industrialized and looking to shore up mineral imports. There are exceptions, including Australia, Canada and South Africa, who are mineral exporters. Their lists include minerals deemed critical not for themselves, but for import by their trading partners. The top exporters of raw critical minerals also have something in common: they lack a large industrial base. In the context of a mainly one-way flow of minerals from low- and middle-income countries (LMICs) to high-income nations, it is understandable that exporters might think that the global critical-minerals agenda is not focused on their own needs. Although they might — or might not — be able to secure a part of the processing value chain or revenue and employment from mineral extraction, ultimately the minerals are used elsewhere. The human turn A mineral-security agenda that is defined solely by the national-security priorities of industrialized nations is prone to geopolitical competition and neglect of the broader needs of humanity. The world has been here before — the concept of energy security was popularized as a national-security response to the 1970s oil crisis. Similarly, the concept of food security prioritized national availability. Only after the Nobel-prizewinning work of economist Amartya Sen in the early 1980s and 1990s identified that it is not broader disruptions to supply that cause famine, but the inaccessibility of food for those individuals who need it5, were these concepts reframed from a human-centred perspective. Impacts for half of the world’s mining areas are undocumented Sen would go on to help publish the first UN Human Development report with Pakistani economist Mahbub ul Haq in 1990, and they and others would define the phrase human security, in the 1994 version of the report6. Human security is ‘freedom from fear’ and ‘freedom from want’. It puts people at the centre of analysis — it imagines that the security of all people is much more than their physical safety, and it is intended to complement, not replace national security. The human-centred versions of food security, energy security and water security, which emphasize accessibility to all people, are now central ideas in the SDGs. Yet, that’s not the case for minerals. It is hard to believe it, but the 15,000-word SDG agenda Transforming Our World makes no reference to minerals — the only natural resource that is missing. Not only do minerals lack a relevant goal, but the resource, occupations, sector and activities do not appear in the agenda7. The omission of minerals from the SDGs has led overseas development assistance to the mineral sector to plummet to just under US$600 million of the $239 billion spent by 2021, representing 0.2%, among the lowest by sector.
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COVID-19 is spreading again — how serious is it and what are the symptoms?
Katie Kavanagh
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Surveillance data used to track the number of SARS-CoV-2 infections are less robust than during the pandemic.Credit: Orlando Sierra/AFP via Getty SARS-CoV-2 infections have been rising in the past month — global cases increased by more than 19,000 last month compared with the previous month, according to data posted on the World Health Organization (WHO) COVID-19 dashboard. But the real number of infections is much higher than that, researchers say, because countries are less focused on collecting data on the infection now than they were during the COVID-19 pandemic. “Surveillance is happening but it’s at a much lower level than it used to be. We don’t have a complete picture of virus circulation of the variants that are out there,” says Maria Van Kerkhove, interim director of the department of epidemic and pandemic management at the WHO in Geneva, Switzerland. “I think there’s a collective amnesia right now about COVID-19,” she adds. Even if people do test positive after using a home antibody test, there is no way to report a positive result in the community, says Antonia Ho, a clinical epidemiologist at the University of Glasgow, UK. Without high-quality surveillance data, Ho warns that health organizations are not well-prepared to recommend corresponding vaccine formulations and time their roll-out. “Surveillance is critical to really understand what’s circulating,” she says. How is COVID-19 being tracked? Although surveillance data that are used to track the absolute number of SARS-CoV-2 infections are less robust than during the pandemic, researchers are tracking information about the number of people with severe COVID-19 who require hospitalization. “Hospital-based surveillance is what we’re mostly doing. But we also have wastewater surveillance, which is quite a useful indicator of what’s happening in the community,” Ho says. Genomic analysis of samples containing the SARS‑CoV‑2 virus shows that the most common variants currently circulating globally are XFG, also known as Stratus or the ‘Frankenstein variant’, and NB.1.8.1, known as Nimbus. Stratus accounts for 76% of reported cases and is dominant in Europe and the Americas, whereas Nimbus is dominant in the Western Pacific region, accounting for 15% of cases, says Van Kerkhove. Researchers overlooked airborne diseases for centuries — then COVID-19 changed everything Stratus and Nimbus have similar symptoms to previous variants, including a fever, cough and runny nose, but the Nimbus variant has one distinct symptom: a ‘razor blade’ sore throat. These two variants are currently on the WHO’s list of ‘currently circulating COVID-19 variants under monitoring’ as of 4 September. Van Kerkhove says the latest information about SARS‑CoV‑2 strains is far from the complete picture of viral circulation. Even hospitalization data aren’t as complete as they were during the pandemic — fewer than 35 countries still report COVID-19 data. “That’s why we’re trying to make sure that countries are still doing sequencing,” says Van Kerkhove. However, she adds that the surveillance data currently available are sufficient to “provide information to governments related to the effectiveness of vaccines”. Is COVID-19 seasonal? Vaccination campaigns are focused on people over the age of 65 in the United States, or 75 in the United Kingdom and parts of Europe, and those with a weakened immune system who are older than 6 months. Michael Head, an epidemiologist at the University of Southampton, UK, says he would prefer a wider vaccine roll-out for younger populations as well. “It’s still not a pleasant infection, and vaccines do still have a significant public-health benefit, so they are a vital tool in addressing the threat posed by COVID-19.”
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Anosophoros
Christine Lucas
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“So you’re really leaving. Over a rat.” “It’s not as if I have a choice, Mother. I’m exiled. I won’t waste my time with appeals. You know how headstrong everyone on the council is.” Headstrong might be the wrong word choice here. Pigheaded, perhaps. Unfair to pigs, though. And bigoted to boot. “You’ll die out there, Penelope. Over a rat?” “Over Jeffrey. And he’s not just a rat. He’s Rattus rattus anosophoros.” He stirs in the side pocket of my jacket. He always reacts to my distress. Now it only adds to his own. He misses the familiar scent and texture of my lab coat’s pocket. I stroke his head. Soon, love. Wait until we’re out. “You can slap any fancy name on it, it’s still just a rat! And what about me? Your own mother?” A sniffle. Here come the waterworks. How predictable. And how damned effective. It’s the last time you break my heart, Mother. “You’ll manage. You always do.” I keep shoving things into my backpack: warm clothes, energy bars, ammo, med-kits, socks — one can never have too many socks in the wastelands. Or caramel-flavoured bars — to reminisce about the times I shared those with Jeffrey on my breaks. You keep sniffling. I keep my eyes on the task. I need to leave while the sun’s up to find shelter outside, in a world full of hungry, desperate survivors. Jeffrey’s warmth in my pocket adds to my resolve. I won’t be alone. Read more science fiction from Nature Futures And we’ve been through this before: you, sitting at the edge of my bed, weeping perfectly timed tears, clutching crumpled tissues now that you don’t have pearls to clutch any more, your back cemented straight in that proper, dignified posture. “How can you do this to me? After everything I’ve done for you? So you could study that nonsense of yours? That nano-stuff!” Well, that’s new. It’s the first time there’s the slightest pitch in your voice. You’ve never yelled at your black-sheep daughter, not when I moved away to study nanobiotechnology, not when you learnt I was gay, not even when I initially declined to join this gated community with trigger-happy armed guards. In the end, I caved; the early days of the plague terrified everyone. “I’m not doing anything to you.” I exhale slowly to briefly diffuse decades of pent-up frustrations. Your face is more drawn than usual — bloodshot eyes, smudged eye-liner. Sincere emotion at this late hour. I soften my voice. “I do owe you gratitude for my place here and my assignment at the lab. But we both know I’d never belong.” “You could.” “I highly doubt it.” I stuff the backpack’s pockets with dried fruit and veggies for Jeffrey. He stirs again, eager to climb out to get his treat, just as he climbed over his siblings despite his defects. Be patient, boy. Please. “My friend 
 Her son wants a wife. You could still have a place here, if you 
” “If I what? Be a part of the council’s plans to ‘repopulate the Earth’? No, thanks. You know I’m gay.” A snort. “Oh, please. We all experimented in college. It’s time to grow up, Penelope!” “That’s what I’m doing.” My backpack is as ready as it will ever be. I holster my handgun and secure my combat knife on my thigh. “I know, Mother. I know that I’m not the daughter you wanted, one you could be proud of, always the odd-one-out, your gay bookworm wallflower offspring. Or, rather wall-weed. Please, let’s not make our final moments together another battlefield. I’ll probably see enough fighting where I’m going.” Now you won’t look at me. Your fingers stroke my neatly folded lab coat next to you on the bed. “You’re wrong. I was proud seeing you in this 
 My little Penny, who’d find the cure, who’d save the world 
” Weary, raspy voice.
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Preprint site arXiv is banning computer-science reviews: here’s why
Davide Castelvecchi
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ArXiv will no longer accept review or position papers in computer science unless they have already been peer reviewed.Credit: Sharaf Maksumov/Alamy The oldest and best-known preprint repository, arXiv, has announced that it will no longer accept review or position papers in computer science. The website will make exceptions only for papers that have been previously accepted by a peer-reviewed venue, such as a journal or conference. These types of article were never officially on arXiv’s list of ‘accepted content types’, but they had previously been allowed at moderator discretion, said a blog post announcing the move on 31 October. arXiv management says the move was made necessary by a surge in low-quality papers, including many that appear to be written using generative artificial intelligence (AI) tools. “I think this is a wise move by arXiv,” says Richard Sever, chief science and strategy officer of the non-profit organisation openRxiv in New York City, which runs the biomedical-sciences preprint servers bioRxiv and medRxiv. He adds both of those platforms have had a ‘no narrative reviews’ policy from the outset. Rising rejection rates Preprints submitted to arXiv are checked by automated tools. Before going live on the site, around 20% of submissions are flagged to one of 240 volunteer moderators, says arXiv executive director Ramin Zabih, a computer scientist at Cornell University in Ithaca, New York. Until a year ago, only 2–3% of submissions were ultimately rejected by moderators, says Steinn Sigurðsson, an astrophysicist at Penn State University in University Park who is arXiv’s scientific director. But in the last year, that number has gone up to 10%. AI content is tainting preprints: how moderators are fighting back
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Surprise ‘tail’ found on an iconic galaxy may rewrite its history
Jenna Ahart
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Galaxy M61 sports a long stellar stream, which had not been spotted before now.Credit: NSF–DOE Vera C. Rubin Observatory/NOIRLab/SLAC/AURA/A. Romanowsky et. al. Mere months after its long-awaited debut, theVera C. Rubin Observatoryis beginning to deliver on its promise to rewrite cosmic history. The observatory’s colossal camera — perched atop a mountain in Chile — has yet to begin its official scientific survey. But just by perusing itsfirst test image, astronomers have uncovered a surprise: a trail of light — called a stellar stream — extending from a well-known galaxy, suggesting that the galaxy once tore apart a much smaller one. “This is the first stellar stream detected from Rubin,” says Sarah Pearson, an astrophysicist at the University of Copenhagen. “And it’s just a precursor for all of the many, many features we’ll find like this.” The authors reported their findings in the Research Notes of the American Astronomical Society1. A tail that tells tales The galaxy, named Messier 61, was first spotted in 1779 in the Virgo Cluster of galaxies and has caught the gaze of astronomers ever since. Hosting a slew of supernovae and churning out new stars at a surprisingly high rate, Messier 61 is what’s known as a starburst galaxy owing to its bounty of stellar activity. Astronomers have enlisted some powerhouse telescopes — including the James Webb Space Telescope and the Hubble Space Telescope — to unravel the galaxy’s structure. But “despite all of this intense study, no one had ever found this stellar stream”, says Aaron Romanowsky, an astronomer at San Jose State University in California and an author of the study. Major telescope hosts world’s largest digital camera: how it will transform astronomy
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How to fight climate change without the US: a guide to global action
Xiaoying You, Mariana Lenharo, Mohana Basu, Davide Castelvecchi, Jeff Tollefson
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When the world’s nations meet for COP30 in BelĂ©m, Brazil, on 10 November to lock down new commitments to limit dangerous climate change, it will be the first such conference since US President Donald Trump announced in January that his country would, for the second time, exit the landmark Paris climate treaty. Drill, baby drill? Trump policies will hurt climate ― but US green transition is underway Trump and his administration have championed fossil fuels, called climate change “the greatest con job ever perpetrated on the world” and rolled back federal funding and tax breaks for clean energy introduced under former president Joe Biden. The United States is the world’s second biggest greenhouse-gas emitter, accounting for 11% of global emissions. Although US emissions will continue to fall under Trump, they could increase by up to 470 million tonnes annually — more than three times the annual total from the Netherlands — over the next decade compared with what they would have been under Biden policies, according to an analysis led by researchers at Princeton University in New Jersey (J. Jenkins et al. Preprint at Zenodo https://doi.org/qbrm; 2025; see ‘Trump’s climate legacy’). Source: Repeat Project The US exit from the Paris accord will not become official until January 2026. Brazil’s President Luiz InĂĄcio Lula da Silva explicitly invited Trump to COP30. But the Trump administration is not expected to send any high-level representatives to the meeting, and many say that’s for the best. “Without the US, there’s still a chance the world could come together in BelĂ©m,” says Claudio Angelo, the international policy coordinator at ObservatĂłrio do Clima, a coalition of climate organizations, who is based in BrasĂ­lia. Whether that happens, and so whether humanity bends the emissions curve sufficiently to escape the most dangerous climate impacts, depends in large part on the actions of other big players. China is the world’s largest greenhouse-gas emitter, accounting for nearly one-third of the global total — and it is also the global leader in renewable energy. India and the European Union come after the United States, at 8% and 6 % of emissions, respectively. Brazil is expected to take on a bigger climate leadership role as host to COP30 and home to the Amazon, a major carbon sink. US states and cities are also pursuing their own clean-energy agendas. COP30, at which countries are expected to agree a round of more-aggressive climate targets, offers a glimpse of these actors’ plans. Will China take the lead on climate? In addition to being the world’s largest emitter, China has driven 90% of the growth in carbon dioxide emissions since 2015, the year the Paris agreement was adopted. But the country also leads the world when it comes to adopting clean energy and producing the equipment needed for the transition to a decarbonized economy, including solar panels, wind turbines and electric vehicles (see ‘China’s energy explosion’). Source: China Statistical Yearbook, China Electricity Council & Natl Energy Administration In September, China’s President Xi Jinping announced plans to reduce greenhouse-gas emissions by 7–10% from ‘peak levels’ by 2035. Although some say Beijing’s proposition falls short of expectations, as well as short of what is needed to prevent catastrophic climate change, others argue that it is compatible with the Paris treaty. Whether Washington’s climate U-turn affected China’s targets is hard to tell. Yao Zhe, a Beijing-based researcher at Greenpeace East Asia, suspects that it might have “demotivated” China to set higher targets, by lowering the bar for what was needed to look ambitious. But a more pressing factor, she says, is the country’s slower-than-expected economic growth since the COVID-19 pandemic, which has pushed policymakers to prioritize the economy over environmental and climate goals. And if the economy rebounds, then emissions could too. That Xi personally announced China’s latest climate targets signals a “very high-level commitment” to tackling climate change, says Belinda SchĂ€pe, a China analyst at the Centre for Research on Energy and Clean Air, a think tank in Helsinki. And it is actions — not projections — that matter. “Until now, China has a track record of overperforming on most of its climate commitments,” says Hu Min, co-founder of the Institute for Global Decarbonization Progress, a Beijing-based think tank. Trump will weaken climate action — the rest of the US must not follow suit China is unlikely to step straight into the leadership vacuum left by the United States because the countries have different statuses under the Paris agreement, SchĂ€pe says. Developed countries are expected to take the lead in cutting emissions, but China is classed as a developing country under the treaty. Another challenge for China when it comes to leading on climate is that it is still building coal-fired power plants. In 2024, the country was home to more than 90% of the coal-power capacity that broke ground around the world. The plan is to use the new facilities as back-ups for unpredictable renewable power. But analysts warn that the world might find it hard to accept a climate leader that is still expanding its coal programme. China could lead at COP30 by using its influence among developing countries to facilitate negotiations with developed ones, says Kim Vender, who researches China’s environmental governance at the Centre for EU-Asia Connectivity in Bochum, Germany. Many predict that China will work with Brazil to secure more money for developing countries’ efforts to mitigate climate-change impacts. Beijing has endorsed a Brazil-led finance programme aimed at preserving tropical forests, set to be launched in BelĂ©m. With the US federal government absent, China will have greater influence over global climate governance at COP30, but the world should expect leadership of a different flavour, says Yao. “They cannot expect China to do exactly what the US or other developed countries do.” Brazil’s net-zero potential As host of COP30, Brazil’s role is to serve as a neutral facilitator of negotiations: the government says it will “lead by example” on climate. It has every reason to want to: the country is at risk of severe consequences from climate change, as demonstrated by devastating floods in 2024 that displaced 500,000 and killed 185 people. One area where Brazil is well placed to lead in emissions reduction is by tackling deforestation. Forests act as sinks that remove carbon from the air; their destruction releases carbon and often paves the way for emissions-intensive agriculture. In Brazil, which is home to 60% of the Amazon — the world’s largest tropical rainforest — deforestation and agriculture drive the most emissions of any sector. Deforestation in the Amazon surged under former president Jair Bolsonaro (see ‘Brazil yo-yos on deforestation’) and reversing the trend “is not simple”, says Thelma Krug, coordinator of the scientific council for COP30, who is based in SĂŁo JosĂ© dos Campos. Source: Natl Inst. for Space Research (INPE), Brazil In September, Lula announced a US$1-billion investment in the Tropical Forests Forever Facility, a fund that will pay countries to protect endangered forests. “It would pay for something that has never been recognized: the effort developing countries make to keep parts of their territory intact,” says Krug. At COP30, Lula hopes to secure more contributions to the fund. On other commitments to slash emissions, Brazil could find it harder to lead by example. Its latest targets, announced in November 2024, have been criticized as not ambitious enough. Certain sectors of the Brazilian government still support projects that could drive up emissions, such as a highway cutting through the Amazon and oil drilling at the mouth of the Amazon River. But the country still has great potential for decisive action, says Philip Fearnside, an ecologist at the National Institute for Research in the Amazon in Manaus. He thinks that deforestation is still relatively straightforward to tackle, because it contributes little to Brazil’s economy. Although deforestation supports certain industries, halting it entirely would cause only a small dip in the country’s gross domestic product, according to a 2017 analysis (see go.nature.com/472midv) coordinated by Instituto Escolhas, a sustainability think tank in SĂŁo Paulo. And Brazil has thousands of kilometres of coastline suitable for wind power and ideal conditions for solar farms. Fearnside describes it as “one of the countries that has the easiest options for actually achieving zero emissions”. Brazil will invest US$1 billion in a fund to protect tropical forests such as the Amazon.Credit: Pablo Porciuncula/AFP/Getty India motors on climate goals India is charging ahead on its climate commitments under the Paris climate treaty. In June, its government announced that 50% of installed electricity generation capacity now comes from non-fossil-fuel sources — a milestone that was reached five years ahead of the 2030 deadline the nation had set. The achievement is part of broader progress towards the nation’s goal under the Paris agreement, which the US exit seems unlikely to dent. That’s because India will continue with its decarbonization agenda for the sake of its own energy security, says Rajani Ranjan Rashmi, a climate-policy researcher at The Energy and Resources Institute (TERI) in New Delhi. Self-reliant economic growth has been central to Prime Minister Narendra Modi’s governance — and to achieve that, India needs renewables such as wind and solar. Will US science survive Trump 2.0? What’s more, although India tied reducing its dependence on fossil fuels to funding from developed nations, it has made progress on that goal even though much of the cash has not materialized. “Ultimately, every large emerging country has to plan for itself,” says Rashmi. Alongside its expansion in renewables, India is heavily reliant on coal and is still building new capacity. The country, a developing nation under the Paris agreement, has argued that it needs the highly polluting fuel to power its economy and lift the population out of poverty, and that it doesn’t need to give up coal in the short term, given that its per capita emissions, and historic emissions, are low compared with those of developed nations. But, in 2025, a surge in power from renewable sources began to replace coal-powered energy in India. The actions of the US federal government could still disrupt India’s decarbonization efforts. India is expected to submit revised targets at COP30, but whether these will be even more ambitious than its current ones will depend on “global signals”, says Rashmi. The Trump administration’s disruption of global trade could affect the climate priorities of developing nations, including India. “Trump 2.0 is wielding a lot of economic weapons to subjugate trade partners and countries around the world,” says Avantika Goswami, a climate-policy researcher at the Centre for Science and Environment in New Delhi. Such pressure can shift the priorities of developing nations away from decarbonizing to, for example, building economic resilience or diversifying their trade partners, she says. Populism tests Europe’s Green Deal
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How I’m helping to cultivate science entrepreneurship in Brazil
Emma Ulker
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A course in disruptive innovation helped to cement João Paulo Longo’s science-entrepreneur ambitions.Credit: Victor Carlos Mello Da Silva While earning his dentistry degree at the University of Brasilia, João Paulo Longo joined Brazil’s Institutional Scientific Initiation Scholarship Programme (PIBIC), which gives undergraduates the opportunity to join research projects. The experience ignited a passion for research that led him to quit dentistry and pursue a PhD, during which a cosmetics company director sought his help in product development. These early career experiences, alongside a course on disruptive innovation at Harvard Business School in Boston, Massachusetts, cemented his ambition to be a science entrepreneur. Longo is now a nanotechnology researcher at the University of Brasilia, a role he combines with his position as a founder and researcher at Glia Innovation, a cosmetics business in Goiñnia. You pivoted from dentistry to nanotechnology. How and why did that happen? I worked as a dentist for three years after graduating, but my earlier involvement in the PIBIC, which I took part in in as an undergraduate in 2003, inspired me to start a research career and to undertake both a master’s and a PhD. My doctoral research was on the application of a photodynamic therapy — a drug activated by light — to treat oral infection in a 12-participant clinical study. It gave me an understanding of how to use basic science to solve practical problems. At that time, translational medicine, the practice of taking scientific discoveries from the laboratory to clinical settings to benefit human health, was not widespread in Brazil. What led you to combine academia and entrepreneurship? In 2010, two years into my PhD programme, I was invited by Leila Velez, a founder of Beleza Natural, a cosmetics company in Rio de Janeiro, to develop nanotechnology products, including nanostructured oils developed from biodiverse sources in Brazil. I was recommended by a friend working at the Brazilian National Confederation of Industry in Brasilia. It was an improbable relationship because, at that time, my field was nanotechnology and dentistry. We adapted some technologies for the cosmetics field. Five years on, I was in an academic role, teaching nanobiotechnology at the University of Brasilia and feeling unfulfilled in my career. Eureka moments were rare, as were opportunities to apply scientific knowledge to solve real-world problems. I felt that academia had grown increasingly competitive: success was tied to metrics, rather than to the practical application of knowledge, and researchers were judged mainly on publication numbers. So, in 2018, I enrolled in the Academia-Industry Training programme, a joint initiative between the Brazilian and Swiss governments supported by Brazil’s National Council for Scientific and Technological Development and SwissNex, a global network aimed at strengthening Switzerland’s profile as an innovation hotspot. The  programme taught me about innovation concepts, such as minimum viable products (MVPs). These are the most basic versions of new products and are released to customers to garner feedback. I deepened my understanding of innovation through an online course at the Harvard Business School, focused on disruptive strategy and innovation. It was led by Clay Christensen, a business consultant and academic who developed the theory of disruptive innovation — in which a product or service gradually displaces established competitors after starting at the bottom of the market. I was spending a lot of time interacting with science entrepreneurs and attending industry events, where I first learnt about a problem faced by cosmetics companies in Brazil. They were importing nanoparticles used for the dermal delivery of active ingredients. One company’s German supplier imposed a minimum supply quantity of 50 kilograms. In 2018, Cosmefar, a firm in Aparecida De Goiania, Brazil, contracted me to produce smaller quantities, after a mutual friend introduced me to its co-founder, pharmacist Guilherme Alves Ferreira. After working on this project and others, I set up Nanoceuticals in 2018 with Nichollas Camargo, a chemist at the University of Brasilia. The company develops nanoparticles for cosmetics, health and pharmaceutical products. It was a low-risk venture, in that we were not depending on venture capital. Instead, we used our own resources, revenue and personal funding to operate and scale up, growing client by client. How did the COVID-19 pandemic and its aftermath affect the business? We were starting to expand the team, when our sales suddenly dropped to zero. We innovated by using our technology to develop a polymer to replace Carbopol, the key ingredient in alcohol-based hand gels. It had almost sold out across Brazil. We generated the equivalent of one year’s revenue in four weeks, before Carbopol came back into supply. As the company expanded, we wanted to get broader expertise in peptide science, because of its key function in human health (peptides are short chains of amino acids that serve as the building blocks of protein). In 2022, Nanoceuticals merged with Plateinnove Biotechnology, a start-up in Campinas founded five years earlier by molecular biologist Sheila Siqueira Andrade. We named it Glia Innovations, inspired by Glial cells, which are key in supporting neural function — symbolizing the creation of new ideas. The merger was on an all-share basis, whereby the target company’s owners are paid in the acquiring company’s shares, with no cash involved. After the merger, we rapidly scaled up and began clinical trials in Brazil, including ones for anti-wrinkle and tooth-whitening treatments. We serve more than 80 cosmetics-industry clients in Brazil, Peru, Colombia, the United States, Indonesia, South Korea and India. How do your students benefit from your entrepreneurial background? I combine my Glia position with my academic post, and see my role as a link between research and innovation and industry. The university runs innovation and entrepreneurship courses for undergraduate and graduate students. All my lectures are based on translating science into real-world benefit with the potential to commercialize. Four new start-up companies were created last year, and three students have collaborated with corporations, developing new patents and creating products for diverse industries. One company is called Cooil, which uses nanotechnology to develop final cosmetic products. Another is BioDev, a software company specializing in custom-made digital solutions using artificial intelligence for the scientific  community. You could say that we are shaping a generation of science entrepreneurs. How does Glia embody disruptive innovation?
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Climate change is devastating mining of minerals needed to fight it
Tom Savige, Mark Quigley, Tim T. Werner
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To produce enough ‘critical metals’ such as copper, lithium and nickel to support the green-energy transition, the mining industry needs to boost operations two-to-fivefold worldwide by 20501. Geopolitical tensions, environmental damage and social conflicts will constrain this growth2. But another threat needs much more attention: climate change. Extraction of the very metals needed to address global warming will be increasingly impeded by the extreme weather that accompanies climate change. Thousands of critical-mineral mines are in sensitive environments, including deserts in Africa, highlands in the Andes and coastlines across the Asia-Pacific. Mining areas are already regularly exposed to hazards. In 2023 alone, wildfires forced Canadian mines to suspend operations, extreme rainfall flooded pits and cut off access roads in Australia, and ongoing drought in Chile threatened regional water supplies, mining operations and local communities3. How the rush for critical minerals is neglecting human needs The costs of such damage are growing as the planet warms. For example, over the past decade, excessive rainfall has led to losses of around Aus$3 billion (US$2 billion) for Australian copper mines (see Supplementary information). Under ‘business as usual’ production, without undertaking climate adaptation measures, the industry stands to lose Aus$7.5 billion as a result of heavy precipitation alone between now and 2050, equating to 50,000 tonnes of copper that could be used for energy-transition technologies. The consequences of mining disruptions will spiral across the global economy. Constrained supplies will mean that the energy transition is slower than projected. Mining communities and ecosystems will come under increasing strain3. An energy transition that ignores these threats will risk deepening social divides, undermining community trust and jeopardizing long-term sustainability. As the United Nations COP30 climate summit gets under way in BelĂ©m, Brazil, we call for more investment and planning to strengthen the resilience of critical-mineral supply chains. Steps include systematic reviews of climate hazard exposure, anticipation of future risks, and improved management of mining sites and their surroundings. Towards that end, we outline four key strategies. Plug data gaps To gauge risks, researchers first need to understand the mines themselves: where they are located, their scale and their landscapes, as well as production rates and physical inputs and outputs4. The details of how assets, such as dams for waste ‘tailings’, were built are also essential for assessing the risk of catastrophic failures5. Yet all these details are documented for fewer than half of mines, owing to under-reporting, the prevalence of small-scale operations and commercial or regulatory barriers that limit transparency or data standardization4. Mining companies need to generate and share data (covering production quantities, mineral by-products, resource inputs, supply chains and asset construction, for example) to help researchers to fill global data gaps. The vulnerabilities of infrastructure networks to climate hazards need to be assessed. Mines rely on water, fuel, electricity, railways, smelters, processing facilities and ports. In Chile, for example, copper production competes with the needs of communities and the environment in terms of water supplies6. To map the environment, baseline information needs to be collected on biodiversity, catchment hydrology and long-term water-quality trends. But again, such data and modelling are scarce. Over the coming decades, African mines will face scores of days that exceed heat-safety levels each year. Credit: Cynthia R Matonhodze/Bloomberg via Getty What’s more, the resilience of mining communities to extreme weather or dam bursts, for example, must be evaluated and adaptation plans developed accordingly. People’s preparedness, strengths and cultural practices influence how they manage hazards. Governance and economic systems, including the approval process for mining, environmental monitoring and health-and-safety standards, determine the extent to which risks can be anticipated and addressed. Public infrastructure, disaster planning and training can help people to cope during emergencies. Operators and researchers also need to look at how climate shapes and compounds the hazards to mines. Historical records of temperature, rainfall, storms and droughts can reveal how hazards have already shaped operations. Sharing lessons from previous adaptation actions across the industry can help mining sites to prepare for future risks. Looking further ahead, climate models can be used to project extremes of precipitation and temperature over the coming years and decades, even beyond a mine’s operating life. Access to modelling capacity and observational data varies globally, often to the detriment of low-income regions, which often lack the infrastructure to monitor and forecast the weather7. Metals are key to the global economy — but three challenges threaten supply chains Compiling all this knowledge, which can be challenging even for a single mine, requires more than open-access data sets. Information is fragmented across governments, companies, communities and researchers, and spans disciplines ranging from climate science and engineering to logistics and the social sciences. These silos obstruct resilience in the mining industry, as reports from the UN Environment Programme3 and the International Finance Corporation8 (part of the World Bank Group) highlight. The solution lies in integration: communication across climate and hazard science, engineering and operations, governance, communities and environmental systems9. Independent scientists need to be embedded within mining-company operations to ensure that climate data are communicated effectively. Mine operators also need to connect with communities for adaptation planning. Shared platforms need to be built, common indicators developed and equitable access to expertise assured. This will require more funding for climate scientists in industry, and for mining companies to build community resilience into their sustainability practices. The first step is for researchers and the mining industry to jointly undertake site-specific climate-risk analysis. Address known risks Although issues around corporate reporting limit the extent to which researchers can assess the entire critical-minerals sector8, the information that is already available points to troubling patterns that require action. Funding clearly needs to be put in place to help the mining sector adapt to threats from climate change. To get a sense of what the risks are, we examined climate projections for a representative set of 1,642 medium- and large-scale mines around the world that produce minerals needed for energy-transition technology (see Supplementary information for analysis). Sites were drawn from the International Council on Mining and Metals’ public database, and climate data from the Intergovernmental Panel on Climate Change’s Coupled Model Intercomparison Project10. Heat is one problem (see ‘Too hot to mine’). By 2050, 90% of mining sites are predicted to face increasing temperatures. The number of days per year deemed hazardous for human health (with temperatures exceeding 35 °C) will rise, particularly in areas that already contend with extreme heat, such as the Australian outback, Africa and the Amazon Basin. Analysis by T. Savige et al. For example, South Africa is the world’s leading producer of manganese (used in lithium-ion batteries), accounting for 37% of global supply. Most manganese mines in central and northern parts of the country are predicted to experience more than 80 days per year above 35 °C by 2050. Health-and-safety measures will be needed to minimize heat-related illness for workers, such as reductions in shift durations or limiting outdoor work during peak heat. And this will lower production, unless adaptation strategies are put in place or other mines come online elsewhere. Storms and extreme rainfall are also projected to increase overall. By 2050, annual precipitation levels are expected to rise at three in five (62%) of the sites we examined, notably mines across the central Andes in Peru, Bolivia and northern Argentina, including in areas historically thought of as being water-scarce. Flash floods might also curb mining operations (see ‘Exposure to floods’). Almost all (94%) of the sites we examined would see an increase in one-day maximum precipitation. Vanadium mines in China are particularly exposed, facing, on average, a 16% increase in their one-day maximum precipitation. Around 70% of the world’s vanadium, used in grid-storage batteries and high-strength steel, is supplied by China, with much of it coming from the environs of one city, Panzhihua. Source: Analysis by T. Savige et al. More detailed research is needed to form the basis of adaptation plans. Climate hazards are challenging to predict locally, and climate models need to be continually updated with the latest data, scaled appropriately to account for topography, and grounded with site-specific knowledge to produce the most accurate forecasts possible for each site7. The depth of knowledge needed calls for stronger links between researchers and mining companies. Sustaining this across the sector will require international research funding and collaboration, as well as building partnerships with community groups. Ample funding is available: a mine can attract billions of dollars in investments before delivering a return. If adaptation research received funds amounting to a modest percentage of the industry’s projected losses due to climate change, that could lower the costs of damage and operational downtime for mining companies and protect the energy transition. Embed climate risk assessments Governments and mining companies need to adapt how mines operate. This means integrating climate knowledge into every stage: exploration, planning, construction, production, closure and rehabilitation. For example, the Escondida mine, located at altitude in the arid Atacama desert in Chile, produces about 5% of global copper supply, and is expected to be operational until 2080. To ensure its water supply, Escondida invested US$3.4 billion in a desalination plant producing 215,000 cubic metres of water per day, transported from the coast up to the mine (see go.nature.com/49e9hyd).
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Daily briefing: A guide to global climate change action
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Wildlife wonders and a Super Heavy — the month’s best science images
Flora Graham
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International PhD student numbers in US hold steady — for now
Dan Garisto
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Roughly 1.3 million international students and recent graduates enrolled in work training are in the United States for the 2025–26 academic year.Credit: Jonathan Wiggs/The Boston Globe/Getty International students in the United States have defied predictions of a huge downturn in their population. Data for the current academic year show that the number of international students — including PhD candidates and newly minted PhDs — has remained essentially flat, year-on-year. The administration of US President Donald Trump has shaken up the landscape of higher education, revoking student visas, cutting funds to institutions and implementing travel bans for selected countries. As a result, many higher-education researchers had expected significant numbers of overseas students to turn away from US academia. The great university shake-up: four charts show how global higher education is changing In July, NAFSA: Association of International Educators, a non-profit organization in Washington DC, predicted that the number of overseas students in the United States would decline by 15% between the previous academic year and this one. And in October, The New York Times reported a 20% drop in the number of students arriving in the United States in August 2025 compared with August 2024, a finding based on data from the US Department of Commerce. But data released by the US Department of Homeland Security (DHS) for September and October show almost no change in the population of international students and recent graduates in the United States between this year and last — and specialists say these data are more reliable than others. “It doesn’t appear to be as catastrophic as had been originally feared,” says Chris Glass, a higher-education researcher at Boston College in Massachusetts. Data points The DHS statistics, which are part of a database called the Student and Exchange Visitor Information System (SEVIS), track students enrolled in educational institutes and recent graduates gaining work experience in a programme called optional practical training (OPT). OPT is one of the largest foreign talent pipelines to the United States, feeding thousands of people into Amazon, Google and other leading companies. It is key for people doing PhDs in science, technology, engineering and mathematics (STEM) topics: between 2010 and 2022, 76% of recent graduates took part in it. According to SEVIS data, roughly 1.3 million international students and OPT participants are in the United States for the 2025–26 academic year — about the same as the number for the 2024–25 academic year. The total number of doctoral students also remained nearly the same year-on-year (see ‘Surprising stability’). Source: SEVIS, NAFSA: Association of International Educators SEVIS data do not distinguish between recent graduates involved in OPT and students still enrolled in educational institutes. Glass says that, given recent trends, the number of OPT participants might have grown by about 15% between 2024 and 2025. If so, that would mean a “modest single-digit enrolment decline”, leading the total number of students and graduates to remain flat. What, then, might explain the 20% decline in student arrivals in August recorded by the commerce department? The August arrival data “aren’t all that great of a proxy” for the international-student population, says Violet Buxton-Walsh, an immigration researcher at the Institute for Progress, a non-profit think tank in Washington DC. Many international students could have heeded advice to stay in the United States between the end of the 2024–25 school year and the start of the 2025–26 year. If they did, they would not have been included in the August arrivals data, Buxton-Walsh says. Others might have arrived in September rather than August because of visa delays. The relatively steady numbers might seem puzzling, given the headlines about the Trump administration’s anti-immigration actions. But “international students are incredibly resilient”, says Melissa Whatley, a higher-education researcher at the William & Mary School of Education in Williamsburg, Virginia. “They’re going to attend institutions and earn degrees under circumstances that we think might deter them.” Deterrence policy
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When will Africa have a Nobel prize in medicine?
Nicholas Aderinto
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African research saves millions of lives, from vaccine development to genomic surveillance and public-health interventions. Yet the continent has never produced a Nobel laureate in physiology or medicine who did the bulk of their prizewinning research in Africa. This absence reflects systemic barriers. Underfunded laboratories, limited access to top-tier journals and constrained mentorship pathways hinder the visibility and impact of African discoveries.
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Outside the window
Jiadong Jin
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Jin sat waiting, silent and still, as the full-brain digital back-up neared completion. Above him, the consciousness scanner buzzed quietly, reading every memory, mapping every neuron, preparing to create a cloud-bound digital self. The process of bestowing an immortal digital life on humans was expected to take about half an hour. To pass the time, Jin looked out of the window. The first thing that caught his eye was not anything outside the window, but his own reflection. The white hair, weathered by time, framed his face like a reminder etched in silver. It spoke, wordlessly, of his age — and the fear of death that had brought him here. Suspended above his head, the halo-like scanning ring evoked an old memory: the first time he got a perm as a teenager. Jin remembered the feeling of the heat coils, the nervous shuffling in the salon chair, the ring-shaped machine resting awkwardly on his scalp. His best friend had walked with him out of the salon, grinning and teasing: “Look at us! Curly-haired punks now!” But the laughter didn’t last. The war came, sudden and brutal. Both were conscripted, yet only one returned. That faithful friend died still a boy. Read more science fiction from Nature Futures As he lay dying, bloodied and fading, the boy grasped Jin’s hand with all his strength, murmuring, “Live well. Live happy. For my share, too.” The flood of memories made Jin a little uneasy. Death was truly cruel. A bitter smile tugged at his lips. Outside the window, laughter rang out, lifting Jin from his thoughts. A young couple strolled past, arms entwined, showing off their matching gene-tattoos — symbols of love encoded into flesh, celebrated with the swagger of the young. It reminded him of how, in his youth, he, too, had once got a love tattoo — her name, inked on his right arm. Jin remembered the warmth of that night. The beloved woman had curled up beside him, kissed his tattoo softly, and smiled. “Now,” she whispered, “my name will live on your body forever.” Her eyes shimmered with joy. She became his wife. Together they journeyed through years — youth, middle age, everyday happiness — until death finally pulled her away. Jin slowly raised his mechanical right arm. Her name was gone now, replaced by steel and circuitry. She had been wrong. And yet, she had been right — her name still lived in the chambers of his heart. A sting at the corner of his eye startled him. He didn’t want to cry here. With a thought, he ordered his artificial tear glands to shut down. The wetness never fell. A child’s sharp wail outside the window broke Jin’s reverie. A toddler had tripped and fallen, and now lay on the pavement, howling. His mother quickly scooped him up, singing a lullaby that seemed to carry magic in its melody. The boy’s cries softened into giggles. Nearby, the father summoned a recording drone. “Capture this,” he said, freezing that tender moment in time. Cameras and smartphones might have become relics, but the desire to preserve love in images had not aged a day. Jin thought of an old photograph — him as a baby, resting in his mother’s arms, her face radiant with love. And then he wondered: had his father, behind the lens, looked at them with the same warmth as the man outside the window? His mother had passed before uploading technology existed. For years after her death, his father clung to the old house, clung to the memories. Every time Jin visited, he would find him sitting by the window, turning the pages of dusty photo albums as if searching for something time had misplaced. By the time his father’s own end approached, uploading had become seamless. But he refused.
Nature DOI suffix ≠ "/s...": Not a research article
Japan’s first female prime minister doesn’t call herself a feminist — but the country needs her to tackle sexism in science
Misa Shimuta
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Sanae Takaichi is the first female prime minister of Japan.Credit: Tomohiro Ohsumi/Getty Japan struggles with gender equity. It ranked 118th out of 148 countries in the 2025 Global Gender Gap Index. Against this backdrop, the election of a woman, Sanae Takaichi, as Japan’s prime minister on 21 October is a milestone. But will her rise to the nation’s highest office serve as a catalyst for changing social attitudes? As a woman and a neuroscientist, I have been involved in large surveys on gender equality in Japanese academia, and I feel conflicted. There is hope. Japan’s ruling Liberal Democratic Party (LDP) and its coalition partner, the Japan Innovation Party (JIP), have released an agreement that pledges to “substantially expand” grants for scientific research and to “establish a system granting legal effect to the use of maiden names”. Both are promising for researchers, but the future of Japanese science will depend on how these policies are implemented. ‘Male-dominated campuses belong to the past’: the University of Tokyo tackles the gender gap Recent changes in party stances, which might shape the direction of Japan’s science and innovation policy, give cause for concern. The LDP’s former coalition partner, Komeito, has advocated for increasing stable base funding for universities and supporting women and early-career researchers. By contrast, the JIP prioritizes market-driven innovation, administrative efficiency and economic growth. Although science and technology promotion is included in its agenda, it has yet to articulate proposals for reforming research environments. One issue for women in academia is surnames. Japan is currently the only country that legally requires married couples to share the same family name — a system that Takaichi, a conservative, has defended. The naming law makes it difficult for women to maintain consistent publication records and professional identities. And it is a human-rights issue: the right to choose one’s own name. Takaichi has reportedly instructed the justice minister to review and expand the system for using maiden names alongside married names. This would help, but practical and legal challenges would remain. Having two surnames — one for the family register and one for everyday use — can create administrative confusion, domestically and abroad. I urge the government to adopt a more straightforward solution, such as allowing married couples to have separate surnames. Beyond this policy, addressing gender inequality is an urgent priority. According to a survey conducted in 2021 by the Japan Inter-Society Liaison Association Committee for Promoting Equal Participation of Men and Women in Science and Engineering, female researchers in Japan are promoted five to ten years later than their male counterparts, regardless of whether they have children (see go.nature.com/47rvdns). And the instability of the employment system is a major issue. Fixed-term research positions are prevalent, for postdoctoral fellows and faculty members. At an increasing number of universities, even full professors are not permanently employed. Longer contracts and tenure-track programmes are needed. Equity in science is a beautiful lie — and I’m done pretending
Nature DOI suffix ≠ "/s...": Not a research article
‘Teenage T. rex’ fossil is actually a different species
Katie Kavanagh
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This artistic interpretation shows a pack of Nanotyrannus attacking a juvenile Tyrannosaurus rex (front left).Credit: Anthony Hutchings A fossil once assumed to be of a young Tyrannosaurus rex is in fact that of a different species altogether, and the dinosaur it belongs to was a fully grown adult at the time of its death, palaeontologists have found. Facelift for T. rex: analysis suggests teeth were covered by thin lips The small tyrannosaur — named Nanotyrannus — is about half the length and one-tenth of the body mass of a fully grown T. rex — which led scientists to initially suspect the fossil belonged to a teenage T. rex. But the specimen has several distinct physical features, too. “Nanotyrannus is a small-bodied predator designed for speed. It’s very agile and has long powerful arms [that are] larger than those of the T. rex,” says Lindsay Zanno, a palaeontologist at North Carolina State University in Raleigh. Nanotyrannus also had a shorter tail than did T. rex and sharper, less curved teeth. The findings, published in Nature on 30 October1, come from the ‘Duelling Dinosaurs’ fossils — a Triceratops and a small tyrannosaur found tangled in combat in the Hell Creek Formation in Montana in 2006. The specimens date back to the latest Cretaceous period, around 67 million years ago. Small but ferocious To determine the Nanotyrannus’s age and growth rate, Zanno and her colleague James Napoli, a palaeontologist at Stony Brook University in New York, studied the growth rings present in a thin slice of one of the fossilized bones. These marks show how bone growth has slowed down and sped up with the seasons, creating layers like a tree trunk’s annual rings. The researchers compared the dinosaur’s growth rate with that of a crocodile, one of its closest living relatives.
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PhD training needs a reboot in an AI world
Alex Sen Gupta
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Since the release of the chatbot ChatGPT in late 2022, there has been frantic debate at universities about artificial intelligence (AI). These conversations have centred on undergraduate teaching — how to prevent cheating and how to use AI to improve learning. But a quieter, deeper disruption is unfolding in research, the other core activity of universities. A doctoral education has long been seen as the pinnacle of academic training, an apprenticeship in original thinking, critical analysis and independent enquiry. However, that model is now under pressure. AI is not just another research tool; it is redefining what research is, how it is done and what counts as an original contribution. How money, politics and technology are redefining the PhD experience Universities are mostly unprepared for the scale of disruption, with few having comprehensive governance strategies. Many academics remain focused on the failings of early generative AI tools, such as hallucinations (confidently stated but false information), inconsistencies and superficial responses. But AI models that were clumsy in 2023 are becoming increasingly fluent and accurate. AI tools can already draft literature reviews, write sophisticated code with human guidance and even generate hypotheses when provided with data sets. ‘Agentic’ AI systems that can set their own sub-goals, coordinate tasks and learn from feedback represent another leap forwards. If the current trajectory continues, we’re fast approaching a moment when much of the conventional PhD workflow can be completed, or at least be heavily supported, by machines. Unanswered questions This shift poses challenges for educators. What constitutes an original contribution becomes unclear when AI tools produce literature reviews, acquire and analyse data, and draft thesis chapters. Students might need to pivot from executing research tasks to framing questions and interrogating AI outputs. To explore what the near future of research training might look like, I conducted a role play simulating a PhD student working with a hypothetical AI assistant. I used Claude, a leading AI system built by the firm Anthropic in San Francisco, California. ‘Science saved my life’ — and it must save other at-risk scholars I fed the chatbot a detailed prompt (see Supplementary Information) describing a fictional AI research assistant called HALe — inspired by the AI character HAL 9000 from the science-fiction film 2001: A Space Odyssey. I gave HALe capabilities that are already under development and are likely to improve in coming years. These include accessing external databases, integrating environmental and biological data, and performing advanced analyses autonomously. I then played the part of the student, asking questions and responding to the chatbot’s replies. The dialogue was generated in a single, unedited session — offering a fictional, yet plausible, glimpse of how future doctoral research could unfold. The simulated goal was to complete a PhD project investigating how extreme ocean temperatures affect marine species — an ambitious task involving data synthesis, statistical modelling and writing a paper for publication. In this fictional scenario, HALe didn’t merely assist; it took initiative. It searched and extracted data from scientific literature, identified knowledge gaps, harmonized environmental and biological data sets, ran complex statistical analyses, interpreted the results, drafted a manuscript, suggested peer reviewers and even created an open-access data repository. The entire process, which would realistically take a student several months, played out in a short sequence of guided exchanges that might occupy just a few hours. What we stand to lose when foreign students are seen as a threat Although today’s AI models cannot yet perform these tasks with anything approaching full autonomy, the simulation was grounded in what current systems can already do with human guidance. For example, ChatGPT, Claude and other state-of the-art chatbots can draft credible literature reviews, propose hypotheses, suggest analytical approaches and generate code that — when reviewed and validated by a human — can process real data sets and produce meaningful outputs. They can even help to interpret statistical results and visualize findings. What struck me, while conducting this exercise, was how much of the conventional PhD process could now be driven and accelerated by AI. At times, it felt like working with a hyper-competent and astonishingly rapid research assistant. It was both exciting and unsettling. Of course, this simulation reflects a particular kind of project — analytical, data-rich and computational in nature. Experimental or field-based PhD programmes, especially those that require collecting samples, laboratory work or interacting with other people or with the natural world, will remain less susceptible to full automation. But even in these areas of science, AI is likely to play a growing part in experimental design, autonomous data collection, literature synthesis and post-experiment analysis. New skills This experience brought home how training in academic skills will need to be fundamentally reconsidered in an era of AI.
Nature DOI suffix ≠ "/s...": Not a research article
Safeguards for virology must be designed in partnership with the public
Caesar Alimsinya Atuire, Jonathan Ewbank
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Your Comment article was a welcome admission that the safety measures taken when researching potentially dangerous viruses can, very occasionally, be inadequate (M. Ott et al. Nature 646, 31–34; 2025). The authors propose that scientists from relevant fields should come together to produce international guidelines that bolster the management of this work. But the proposal omits a key stakeholder: the public.
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‘Memory foam’ skeleton in cells helps them to navigate
Joseph d’Alessandro, MĂ©lina L. HeuzĂ©
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The body is not an easy environment for cells to navigate. From immune cells patrolling for microbes to embryonic cells migrating to the sites where organs will form, and even cancer cells invading tissue, performing their functions means traversing a complex space of tangled meshworks, narrow tunnels and large obstacles. It is established that cells change shape to adapt to various environments but, writing in Nature Physics, Kalukula et al.1 report that cells can also retain a memory of past deformation. The researchers demonstrate, using experimental and theoretical models, that this memory is encoded in the cytoskeleton of each cell (the protein scaffold that gives it its shape), and that it supports efficient cell migration in non-uniform environments.
Nature DOI suffix ≠ "/s...": Not a research article
Google claims ‘quantum advantage’ again — but researchers are sceptical
Elizabeth Gibney
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Google researchers have made a fresh claim of quantum advantage — the ability of quantum computers to radically speed up calculations compared with their classical counterparts.
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‘Google Maps’ for Roman roads reveals vast extent of ancient network
Katie Kavanagh
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A data set nearly doubles the known length of roads used during the Roman Empire. Credit: Itiner-e, Artas Media, MINERVA A high-resolution digital map allows people to plan their routes along the ancient roads of the Roman Empire. Combining historical records with modern mapping techniques, researchers mapped hundreds of thousands of kilometres of roads. The findings nearly double the known length of Roman roads. The data set was published in Scientific Data on 6 November alongside an online platform called Itiner-e, which study co-author Tom Brughmans calls a “Google Maps for Roman roads”1. “It’s a growing resource for a community to keep on adding information to ensure that this remains the best representation of our knowledge of where all the roads in the Roman Empire were,” says Brughmans, an archaeologist at Aarhus University in Denmark. Brughmans hopes the data set will “revolutionize our understanding of how people, ideas and infectious diseases” spread 2,000 years ago. “Such insights can be used to better understand the challenges we face today,” he adds. Source: itiner-e.org Roman Google Maps Previous attempts to map the road networks of the Roman Empire had created incomplete data sets with low spatial resolution, and estimations for road locations rather than evidence-based reconstructions. “Although the roads are one of the best-known aspects of Roman history, it’s surprising how many details about them we still don’t know,” says Catherine Fletcher, a historian at Manchester Metropolitan University, UK. The researchers first identified Roman roads from previous studies, including atlases, surveys, historical sources, archaeological sources and existing milestones. They then compared this information to modern and historical aerial photographs, topographical maps and satellite imagery. The team digitized each road section with a high spatial resolution, then combined the sections into Itiner-e. The map includes nearly 300,000 kilometres of roads existing in around ad 150, when the empire was at its maximum territorial extent. Higher spatial analysis allowed the researchers to map 200,000 kilometres of secondary roads. By combining different sources, the researchers could map winding roads crossing difficult terrain with more accuracy, thereby improving on previous estimates based on unrealistic direct lines over, for example, mountain passes. The data set also reveals that the locations of only 3% of Roman roads are known with certainty. A further 7% are considered hypothetical, because they have been identified but not precisely located or verified across sources. The remaining roads are conjectured and based on fewer documented sources. “This was a huge surprise and a sobering realization,” says Brughmans. But “that 3% certainty figure isn’t a failure; it’s a ‘call to action’ that gives us a precise confidence map of what we don’t know and where to look next”.
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Chinese scientists increasingly lead joint projects with the UK, US and Europe
Mohana Basu
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Chinese researchers are more likely to lead projects with the United Kingdom and Europe than with the United States. Credit: Dai Bin/Xinhua/Alamy The number of Chinese scientists taking on leadership roles in international science projects is growing rapidly. They now lead more than half of all research projects with the United Kingdom, and are expected to lead an equal number of projects with Europe and with the United States in the next couple of years, according to a study1 published in the Proceedings of the National Academy of Sciences last week. Hongjun Xiang, a physicist at Fudan University in Shanghai, China, says the projections are consistent with what he has observed in the country, particularly in fields such as physics and engineering. But China needs to strengthen its leadership capabilities in disruptive basic research, “as Nobel-level original breakthroughs remain rare”, he adds. To understand how scientific leadership is changing, researchers analysed authorship data from nearly six million scientific publications. The team analysed ‘author contribution’ statements on journal manuscripts, in which each author’s role is described. When such statements weren’t available, the team developed a model that could predict leadership roles on the basis of author experience, citation histories and the ideas researchers brought from their previous work, says James Evans, a co-author and computational sociologist at the University of Chicago in Illinois. Researchers who conceived, designed and guided the project or offered mentorship were classified as leaders; first-year students, people providing tech support and those performing experiments under direction were considered followers. From there, Evans and his colleagues devised two parameters to assess the changes in scientific leadership in bilateral partnerships. Lead share describes the number of people in leadership roles from a given country. Lead premium is the ratio of leaders to followers on the paper. Rising leaders The team found that China’s lead share in US–China collaborations rose from 30% in 2010 to 45% in 2023. China’s lead premium, however, is progressing more slowly. Chinese scientists still have supporting roles in many of these projects, says Evans. They are more likely to lead projects when they work with groups in the United Kingdom and Europe, he adds. According to the research, in 2019, China’s lead share reached parity with the United Kingdom’s; it is likely to be on par with Europe lead share by 2025–27 and the US lead share by 2027–28. In some crucial technology areas, such as artificial intelligence, semiconductors and energy, Chinese leadership is further behind and is expected to catch up to the United States by 2030. Xiang says that, in the development of core technologies, such as semiconductors, the country faces significant ‘chokehold’ challenges, including the US government’s ban on selling NVIDIA AI chips to China since 2022. China’s dependency on US tech cannot be easily overcome, because it is rooted in decades of deep scientific research, says Xiang. “Addressing these structural imbalances is the key to our journey from being a big science country to a truly strong one, and continued international collaboration remains vital for this endeavour,” Xiang adds. But Evans says the findings upend the assumption that the United States can shut China out of global scientific opportunities by not collaborating with its researchers. Some US lawmakers want restrictions on research collaborations with Chinese institutions that work with the country’s military. Simulations show that “if the US were to stop collaborating with China on projects related to critical technologies — such as space, artificial intelligence or quantum computing — it would prove to be very costly for the US”, he says. Evans says that US–China collaborations, particularly in fields such as artificial intelligence, are more likely to be successful than work done separately. Cultural differences
Nature DOI suffix ≠ "/s...": Not a research article
Insiders warn how dismantling federal agencies could put science at risk
Virginia Gewin
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At the US Environmental Protection Agency, scientists say proposed cuts will gut research. Credit: Eric Lee/Bloomberg via Getty For 30 years, the US Environmental Protection Agency (EPA) has conducted controlled air-pollution studies at a state-of-the-art facility at the University of North Carolina at Chapel Hill. The facility is equipped to test numerous airborne pollutants, including ozone, diesel, wildfire smoke and chlorine. Data collected in its chambers have been pivotal to establishing stricter air-quality standards for deadly pollutants, and have been instrumental in protecting the health of people in the United States. However, in February, shortly after US President Donald Trump took office, the EPA — which is charged with protecting the nation’s environment and its people’s health — notified the university that it would not be renewing its lease. By May, research had ceased. “There are no other places with the capability of doing these studies on the wide range of pollutants that the Chapel Hill facility does,” says Robert Devlin, a former EPA researcher who worked at the facility until recently. In August, after almost 40 years at the agency, Devlin retired when his appointment was not renewed. How your research can survive a US federal grant termination The exposure laboratory was under the purview of the EPA’s Office of Research and Development (ORD), which pursued a broad swathe of independent research into air and water quality, toxicology, homeland security and waste management. It has been hit particularly hard by cuts the Trump administration has made to federal agency science. Internal documents suggest that lay-offs and voluntary early-retirement programmes have already reduced ORD’s 1,600-person staff by one-third. The remnants of ORD are expected to be folded into a new Office of Applied Science and Environmental Solutions (OASES) that reports directly to the EPA administrator, a presidential appointee. The reorganization has spooked agency scientists, who fear that research priorities might end up being set according to a political agenda. “One value that the EPA’s ORD provided was independent scientific review of proposed regulatory actions,” says former EPA toxicologist George Woodall, who retired in September after receiving a termination notice. In addition to cuts at the EPA, the administration has already cut or proposed cutting more than US$50 billion in research funding across the nation’s science agencies, with research on climate, ecosystems, renewable energy and health disparities particularly affected. Although the administration characterizes the cuts and reorganizations of federal research programmes as realigning them with the president’s priorities, critics say the aim is to remove environmental and health protections and other regulatory safeguards. The cuts to EPA staffing are “the biggest blow that agency has ever had”, says Christopher Sellers at Stony Brook University in New York, who interviews EPA scientists for the Environmental Data and Governance Initiative, a watchdog group for US federal environmental data. “It’s not just EPA. Science is being destroyed across many agencies,” says a senior ORD official who was put on administrative leave in June. It remains to be seen whether Congress will pass Trump’s proposed budget request for 2026. Meanwhile, a US government shutdown has been in place since 1 October, after lawmakers failed to agree on a funding bill for the current fiscal year. As Nature went to press, the shutdown had stretched into its fifth week, with no end in sight. Some 4,000 federal agency workers have been laid off since it began, with plans to reach around 10,000, according to the Office of Management and Budget. Demonstrators protest against US President Donald Trump’s plans to slash NASA’s budget.Credit: Graeme Sloan/Bloomberg via Getty At the US Centers for Disease Control and Prevention (CDC), 1,300 employees, including many investigating disease outbreaks and collecting data on infectious diseases, were fired on 10 October; roughly half of those were subsequently rehired. Agency watchdogs are concerned that cuts to CDC staff have paved the way for efforts to spread misinformation. On 22 September, the secretary for the Department of Health and Human Services, Robert F. Kennedy Jr, and Trump made a series of controversial claims about autism, most notably that use of the painkiller acetaminophen (also known as paracetamol) during pregnancy is a suspected cause — a claim that global public-health bodies say is not backed up by scientific evidence. As agencies lose scientific expertise and evidence-based guidance, the knock-on effects will be widespread and costly — to the economy, the environment, public health and the broader research enterprise. Agency scientists say the cuts will compromise a swathe of resources and initiatives, including hurricane forecasting, air-quality improvements, public protections against chemical exposure and efforts to monitor endangered species — science that falls under the government’s purview to protect citizens and the environment. Non-government entities and academic scientists typically cannot conduct coordinated research at the scale needed to inform US policy. Scientific agencies’ institutional knowledge will take years, if not decades, to replace, current and former federal scientists say. And early-career researchers fear that the cuts to federal agency science and funding will hurt their long-term career prospects. Nature spoke to 19 current and former federal agency scientists, covering the EPA, the CDC, NASA, the National Oceanic and Atmospheric Administration (NOAA), the US Geological Survey (USGS) and the National Institutes of Health (NIH), to find out what agency-directed research has been lost and what that will mean for the United States. Many of those currently employed by these agencies requested anonymity for fear of retribution. Nature contacted all six agencies for comment, but the CDC, NOAA, NIH and USGS did not respond. Environmental monitoring at risk Beyond air and water pollution, the EPA oversees tests to determine whether new chemicals — more than 2,000 of which enter commercial use each year — are hazardous to human health. EPA scientists expect that the Integrated Risk Information System, an EPA database of chemical data and risks, will be dismantled — a move industry groups have long been pushing for. This would “put the agency in a reactive rather than proactive mode” when it comes to chemical safety, says Jennifer Orme-Zavaleta, a former ORD principal deputy assistant administrator for science. On top of that, research on pressing environmental concerns has come to a standstill. At the EPA, a series of strategic planning meetings intended to map out future research priorities have not taken place. “We were really humming along,” says the senior ORD official, noting that the office was making progress on prioritizing research on PFAS, also known as forever chemicals, and microplastics. Determining how these pollutants get into the environment “would require the kind of research only EPA can do”, they add. When Nature asked the EPA for a response to the numerous criticisms about cuts to research programmes, a spokesperson pointed to the creation of OASES, “which will allow EPA to prioritize research and gold-standard science more than ever before and put it at the forefront of rule-makings and technical assistance to states”. Scientists at NASA also worry that crucial efforts to track the health of the planet (and its inhabitants) will not continue — among them, efforts to monitor greenhouse-gas emissions. “One of the first things I worry about is environmental monitoring,” says Jack Kaye, a former associate director for research at the Earth Science Division of NASA’s Science Mission Directorate, which is based in Washington DC. Field campaigns to track air pollutants, for example, require dozens of sophisticated instruments to monitor chemicals and meteorological conditions synchronously on land, in the air and from space, often for weeks at a time and with the involvement of multiple, sometimes international, partners, says Kaye. Jack Kaye says budget cuts are ‘devastating’.Credit: Yaitza Luna-Cruz Trump’s 2026 budget proposal — a spending blueprint currently in legislative limbo owing to the government shutdown — cuts dozens of active and planned NASA missions. One casualty is the pair of Orbiting Carbon Observatory satellites, which are key to tracking global carbon dioxide emissions, spotting early signs of drought and monitoring plant health. When asked about how this might compromise NASA’s ability to monitor the environment, a NASA spokesperson pointed to the president’s budget request, which says the satellites are not aligned with Trump’s priorities and are “climate missions beyond their prime mission”. NOAA has a similar global remit, investigating the complex relationship between the oceans and atmosphere. Investigating climate change has become a key research area, says Craig McLean, a former NOAA assistant administrator for research, who is based in Silver Spring, Maryland. In an effort to understand how the oceans shape the climate, he says, “We built satellites, ships, drifters, floats, gliders, models and other expertise.” But the Trump administration’s budget proposes axing the entire budget for NOAA’s office of oceanic and atmospheric research, a move Kaye calls “devastating” for the nation’s climate research. ‘We were ready for this’: meet the scientists suing the Trump administration to reinstate terminated grants The administration also proposed closing NOAA’s 10 research labs and 16 cooperative institutes, which focus on different research areas. One, the Atlantic Oceanographic and Meteorological Laboratory (AOML), based in Miami, Florida, models hurricanes using observations from ‘hurricane hunter’ flights, drones and gliders, says Robert Atlas, a former director of AOML. “Flying through a hurricane? I don’t see anyone else doing that,” adds McLean. On the basis of previous calculations, the loss of those observations would translate to a 20–40% decrease in hurricane forecast accuracy, which would result in not only increased economic losses — of $5 billion for each major hurricane striking the country — but also increased loss of life, says Atlas. These cuts seem to have been a bridge too far; the House of Representatives and the Senate have pressed forward with legislation to protect NOAA’s research labs and cooperative institutes. But not every agency has received congressional protection. At the USGS, the Ecosystems Mission Area, which monitors the health of species, communities and ecosystems, has been targeted for closure. The president’s 2026 budget request eliminated almost $300 million in funding for this area, which is responsible for studying invasive species, ecosystem restoration, wildlife disease and biodiversity, among other things. The USGS “does science to help preserve natural resources and public lands for the nation”, says an anonymous USGS researcher. “We’re not doing science for science’s sake; it’s about ensuring these resources are there for the next generation.” For example, the USGS conducts two major bird monitoring efforts, which both collect population data on hundreds of species, to inform conservation efforts and hunting regulations. “Academia isn’t going to run a bird survey,” says Sam Droege, a wildlife biologist who works at the USGS Bee Lab in Laurel, Maryland. “You don’t get tenure doing that.” Scientists across several agencies are raising the alarm about the administration’s push to shut down a wealth of climate-based research. One of the worst transgressions, say researchers, is Trump’s attempt to overturn a 2009 EPA finding that CO2 and other greenhouse gases harm human health. This legal finding, called the endangerment finding, authorizes the EPA to regulate these gases as part of the 1963 Clean Air Act, which empowers the agency to establish and enforce air-quality standards. “Now they are starting to proffer misinformation and putting a government seal on it,” says McLean. Agency scientists say that this, along with the decision to halt nearly all national climate-change research, will result in the country being unable to adapt to climate extremes, which will bring huge losses in food production and, ultimately, greater loss of human lives during natural disasters. In response to these criticisms, an EPA spokesperson wrote that the EPA’s proposal to rescind the endangerment finding is legal in nature and that “the agency considered a variety of sources and information in assessing whether the predictions made, and assumptions used, in the 2009 Endangerment Finding are accurate and consistent with the limits on EPA’s authority under Section 202(a) of the Clean Air Act”. Reclaiming the narrative
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Does gravity produce quantum weirdness? Proposal divides physicists
Davide Castelvecchi
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The nature of gravity — and whether it can be reconciled with quantum mechanics — is one of the biggest mysteries in physics. Most researchers think that at a fundamental level, all phenomena follow the principles of quantum physics, but those principles do not seem to be compatible with the accepted theory of gravity.
Nature DOI suffix ≠ "/s...": Not a research article
‘Biotech Barbie’ says the time has come to consider CRISPR babies. Do scientists agree?
Heidi Ledford
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Entrepreneur Cathy Tie’s company Manhattan Genomics will work on methods to edit the genomes of human embryos. Credit: Caitlyn Gaurano Cathy Tie left university to found her first biotechnology company at the age of 18. In the 11 years since, she has launched several more. Her first company helped genetic-testing firms to interpret their results; her second provides digital health-care services. Her latest venture, which announced some of its first key hires on 30 October, veers out of the mainstream. Tie, who has called herself Biotech Barbie, sometimes refers to her latest company as the Manhattan Project — the name used for the US effort to develop an atomic bomb in the 1940s — and now focuses her entrepreneurial ambitions on a controversial goal: altering the genomes of human embryos to prevent genetic disorders. Why CRISPR babies are still too risky — embryo studies highlight challenges “We have a duty to patients with incurable, debilitating diseases,” says Tie. “A majority of Americans are in support of this technology.” Plenty of scientists, however, are worried. Manhattan Genomics, the official name of her latest company, based in New York City, was launched this summer. Tie co-founded the firm with Eriona Hysolli, former head of biological sciences at Colossal Biosciences, a firm based in Dallas, Texas, that focuses on de-extincting species. Another company, Preventive in South San Francisco, California, announced on 30 October that it also intends to explore gene editing in human embryos. So far, neither company has revealed the details of its scientific plans, such as which diseases it will target, and which techniques it will use. Tie says Manhattan Genomics will conduct extensive research and safety testing before attempting to create gene-edited babies. Among the new consultants announced last week are a bioethicist and two scientists with expertise in non-human-primate reproductive biology — skills that would be needed for testing the safety of embryo editing. Even so, some researchers say it is much too early to consider commercializing gene-editing technologies for human embryos — a process that carries added safety risks and ethical quandaries compared with the gene-editing therapies that are currently on the market to treat blood conditions in children and adults. “The bar for safety is so, so, so, so high,” says Alexis Komor, a biochemist at the University of California San Diego, who studies gene-editing technologies. “We’re definitely not there yet.” CRISPR therapies For years, the gene-editing field has laboured in the shadow of He Jiankui, a Chinese biophysicist who, in 2018, announced that he had edited human embryos to bolster the resulting children’s resistance to HIV. Those embryos were implanted into the mother, and two gene-edited girls were born. He was then sentenced to three years in prison for “illegal medical practice”. (Tie and He had a personal relationship earlier this year, but Tie says the two have since parted and that He is not involved in Manhattan Genomics.) Scientists largely condemned his work, with many calling for a moratorium on all clinical uses of heritable gene editing in humans. Some countries have restrictions on such research. In the United States, for example, federal funds cannot be used for gene-editing studies in human embryos, and the US Food and Drug Administration cannot approve clinical use of genetically manipulated embryos. Amid this turmoil, gene editing in non-reproductive cells has raced ahead. The world’s first approved gene-editing therapy uses the DNA-snipping system called CRISPR–Cas9 to edit DNA in blood stem cells. The therapy, which was approved in 2023, treats two genetic blood disorders. Earlier this year, a related method called base editing was used to edit DNA in liver cells in a bespoke treatment for an infant with a metabolic disorder. Side effects But editing non-reproductive cells is different, ethically and scientifically, from editing embryos, says Junjiu Huang, a biologist who studies reproductive development at Sun Yat-sen University in Guangzhou, China. Gene-editing tools might behave differently in an embryo than in non-reproductive cells. Editing an embryo also means that genetic changes will be passed down to the next generation, with consequences that are difficult to predict. Unwanted DNA changes — a possibility with any gene-editing technology — could have more catastrophic effects in the embryo than in a single organ, because they can affect every cell in the body during crucial stages in development, says Komor. And a vanishingly small number of people would need to edit genes in their embryos, she says, given that many can already use genetic tests to screen embryos for disease-causing mutations. Tie and Hysolli note that methods used to edit genes have evolved considerably since He’s experiments. Newer techniques, such as base editing and another approach called prime editing, offer improved precision compared with conventional CRISPR–Cas9 editing. Neither of these techniques requires breaking both strands of DNA, a necessity for the original CRISPR gene-editing method and a step that can cause drastic chromosomal changes in embryos. “A lot of new advances have happened in the gene-editing space to make it safer and more accurate,” says Tie. Eriona Hysolli, who co-founded Manhattan Genomics, is a veteran of de-extinction company Colossal Biosciences.Credit: Caitlyn Gaurano But researchers are still learning the full gamut of unwanted genetic changes that base editing can cause, says Komor. Even less is known about newer methods such as prime editing, she adds. In 2015, Huang and his colleagues were the first to gene edit human embryos1. (The embryos were not implanted in a mother.) Since then, he has continued to work with embryos using base editing, and says the technique holds promise, but is not ready for the clinic. Hysolli agrees that the methods need to be studied further, particularly in embryos. The approach that Manhattan Genomics eventually chooses will be dictated at least in part by the diseases it decides to focus on first, she says. Huang describes the timing of Manhattan Genomics’ launch as “inappropriate”. The technology is not yet mature, he says; nor are the ethics, social consensus and legal framework for the technology’s use.
Nature DOI suffix ≠ "/s...": Not a research article
Sex, drugs and the conscious brain: Francis Crick beyond the double helix
Georgina Ferry
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Francis Crick served in the British Admiralty and conducted research into naval mines.Credit: GL Archive/Alamy Crick: A Mind in Motion — from DNA to the Brain Matthew Cobb Profile Books (2025) Francis Crick has gone down in history as half of a double act with James Watson — a duo perhaps almost as iconic as the double-helix structure of DNA that they proposed. The pair were immortalized in Watson’s sensational 1968 book, The Double Helix, with Crick painted as garrulous and cerebral and Watson as gauche but driven. Watson had initially described his first draft as a novel, yet other published accounts of the discovery and the personalities involved have stuck closely to the script ever since. In a magisterial new biography, Crick, zoologist and historian Matthew Cobb revisits the double-helix breakthrough, a discovery he discussed in forensic detail in his book Life’s Greatest Secret (2015). Yet, this time, the publication of the structure and the immediate aftermath of the discovery occupy just 41 pages. Instead, Cobb explores how Crick’s thinking, writing and interactions with others transcended that brilliant, yet contested, episode, revolutionizing molecular biology and influencing evolutionary and developmental biology, visual neuroscience and ideas about consciousness. A new vision for how evolution works is long overdue At the same time, he makes a more sustained attempt than either of Crick’s previous biographers (Matt Ridley and Robert Olby) to answer several questions. Who was Crick? What kind of person was he? What did he care about? Crick was notoriously reluctant to divulge personal information or even have his photograph taken. Combing through a remarkably comprehensive set of personal and professional archives with meticulous attention to detail, Cobb has reconstructed Crick’s relationships with those who were essential crew mates on his intellectual odyssey. Crick was born in 1916 in Northampton, a market town in the English Midlands, and grew up in a comfortable but not notably intellectual home. From an early age he had a burning desire to know why things were the way they were, a curiosity he satisfied by burying himself in the family copies of Arthur Mee’s eight-volume The Children’s Encyclopedia (1910). He did well enough at school to go to University College London to study physics, where he later began a PhD on the viscosity of water — “the dullest problem imaginable”, as Crick later said. Richard Dawkins book of the dead is haunted by ghosts of past works As Cobb explains, Crick’s future was transformed by his experiences during the Second World War. His PhD studies were interrupted when he was called up to serve in the British Admiralty, conducting research into naval mines — real-time problem-solving that suited his restless nature. In the Mine Design Department cafeteria he met Georg Kreisel, an Austrian refugee philosopher who had just graduated from the University of Cambridge, UK. Kreisel’s conversation and voluminous correspondence challenged Crick to sharpen his thinking and delighted him with their obscenities. Cobb makes the salacious letters part of the lifelong soundtrack to Crick’s intellectual endeavours. Also working at the Admiralty was the “vivacious, talented and tolerant” artist Odile Speed. She became Crick’s second wife in 1949; their partnership was one of mutual devotion that allowed for his numerous affairs. Odile helped to develop his interest in art and literature, ran their households, hosted exuberant parties and raised their children. In short, she provided an environment in which Crick had the luxury of devoting all of his energy to his intellectual life. Deciphering DNA’s code In the late 1940s, disillusioned with physics and inspired by physicist Erwin Schrödinger’s 1944 book What is Life?, Crick decided that the nature of life was the only question worth pursuing, other than the neural basis of consciousness. He began a new PhD project in structural biology at the Medical Research Council’s Unit for Research on the Molecular Structure of Biological Systems — later known as the Laboratory of Molecular Biology — in Cambridge, UK, where he worked for almost 30 years. Under the genial chairmanship of molecular biologist Max Perutz, Crick never had to teach or grapple with university administration: he applied for a grant only once in his life. He had the grace to admit that luck had played a part in his success, but to some extent he made his own luck. Cobb presents the double-helix story as much more of a collaboration with chemist Rosalind Franklin and biophysicist Maurice Wilkins at King’s College London than Crick and Watson acknowledged in their iconic 1953 paper (J. D. Watson and F. H. C. Crick Nature 171, 737–738; 1953). He exonerates Crick and Watson of theft, but not of bad manners. “They should have requested permission to use the data,” Cobb writes. “They did not.” James Watson and Francis Crick co-discovered the structure of DNA.Credit: SSPL/Getty The double-helix structure provided a springboard to understanding how information is transferred between DNA and the proteins it encodes. In Crick’s PhD thesis, he had called this the ‘central problem’ of biology. He tackled the issue with geneticist Sydney Brenner. Between them, they conceived the existence of messenger RNA, showed that the sequence of bases in mRNA acts as a code that dictates each protein’s amino-acid sequence and found that three bases encoded each amino acid (F. H. C. Crick et al. Nature 192, 1227–1232; 1961). It’s time to admit that genes are not the blueprint for life
Nature DOI suffix ≠ "/s...": Not a research article
Antibody drugs show promise for treating bird flu and HIV
Rachel Fieldhouse
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Future antibody therapies could target H5N1 avian influenza virus (green).Credit: Steve Gschmeissner/SPL Researchers are increasingly developing antibody therapies to treat infectious diseases. Therapies are being designed to reduce the severity of infections such as bird flu, and cure HIV and other chronic conditions. Synthetic antibodies could also make vaccines for diseases such as COVID-19 more effective. Antibodies are part of the immune system’s defence against infection. Scientists produce synthetic versions by combining B cells from mice and human cell lines. Most approved antibody drugs are for cancers and autoimmune diseases. Monoclonal antibodies are also widely used in antiviral therapies to treat severe infections caused by Ebola, respiratory syncytial virus (RSV) and the COVID-19 virus SARS-CoV-2, says Runhong Zhou, who studies immune responses at Hong Kong University. But past efforts to develop antivirals for avian influenza have not been as successful because the virus undergoes mutations that make treatment less effective, he adds. Antibody drugs for COVID-19 have also become less effective over time for the same reason. Bird flu treatment For H5N1 avian influenza, Zhou and his colleagues have developed an antibody that has two targets: the stem region of proteins on the surface of the virus and receptors on a person’s cells. In cell-based experiments, they found that the antibody neutralized multiple live strains of the bird flu virus and was superior to a model monoclonal antibody — which targets only one specific antigen — at stopping viral particles from attaching to or entering cells. Their results suggest that targeting the virus stem and host receptors at the same time “is a good strategy to enhance antibody efficacy”, Zhou says, who was among the teams presenting their findings in this field at the Pandemic Research Alliance International Symposium in Melbourne last week. But it is still unclear how long the protection will last, or whether antibody treatment can induce mutations in the virus that allow it to evade the immune system. Hsiang Hong, a medical student at Columbia University in New York City, is also part of a team using antibodies for H5N1. He says that he and his colleagues are developing a panel of monoclonal antibodies that target multiple parts of the H5N1 virus to track how it evolves over time and identify potential treatments that can target several variants of the virus. A helping hand Antibodies could also boost the efficacy of other treatments, such as vaccines, which need to be updated because most viruses mutate frequently as they evolve. Zhiwei Chen, an immunology researcher at the University of Hong Kong, says antibodies that can bind to highly conserved parts of SARS-CoV-2 could help vaccines to stay effective even as the virus mutates. Chen and his team have identified several areas of the SARS-CoV-2 particle surface that do not change when the virus undergoes mutation. They have also found that several antibodies that target these highly conserved areas were effective at neutralizing different coronaviruses, including SARS-CoV-1, which causes severe acute respiratory syndrome, variants of SARS-CoV-2 and some coronaviruses found in pangolins and bats.
Nature DOI suffix ≠ "/s...": Not a research article
Shadow scholars: inside Kenya’s multibillion-dollar fake-essay industry
Anna McKie
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In her work for the documentary Shadow Scholars, Patricia Kingori visited Kenya to meet academic ghostwriters.Credit: Anna Patarakina Four years ago, Patricia Kingori became one of the youngest women, and the youngest Black person, to be awarded a full professorship at the University of Oxford, UK. Her research as a sociologist focuses on understanding, exploring and documenting different forms of ethics and power in health, medicine and science. Her latest project, The Shadow Scholars, is a 138-minute documentary directed by Eloise King and executive-produced by 12 Years a Slave director Steve McQueen. It investigates a hidden multibillion-dollar industry: contract cheating. Kingori traces how students in the wealthy, industrialized countries of the global north outsource coursework to “shadow scholars” in Nairobi. An estimated 40,000 highly educated but underemployed young people ghostwrite everything from undergraduate essays to master’s dissertations and PhD theses, often producing several essays every day, with tight turnarounds. Kenya, where Kingori undertook doctoral research until political unrest forced her and her family to leave in 2007, is a hub for this global market. Surveys suggest that more than 70% of its online freelance workforce is engaged in ‘writing and translation’, which Kingori discovered is an oblique way of referring to fake-essay writing. This is not a new phenomenon: a 2018 paper estimated that at least one in seven graduates worldwide have used such services1. The UK, Irish and Australian governments, plus some US and Indian states, have taken steps to outlaw advertising by commercial ‘essay mills’. But despite such moves, demand continues to grow. Kingori’s film explores the issue by going to the writers themselves. In the documentary, Kingori also discusses her personal experience of having someone else take credit for her work. By sharing her story, she acknowledges that Kenya’s ghostwriters are just one small part of a “much bigger, systemic issue around the value of ideas, value of people, where knowledge comes from, who gets invited into spaces, who is removed”. What was your journey into academia? I grew up as a teen in a single-parent household in west London, after moving around a lot when I was younger, and was always really interested in how the world works. I stumbled across sociology and loved it, because it takes the ordinary and shows how extraordinary it really is, holding a mirror up to us as a society. I did my bachelor’s degree and my master’s at Royal Holloway, University of London. The latter was in medical sociology, exploring how social factors shape health and illness. I then worked for a few years as a research assistant before starting my PhD. Towards the end of my doctorate, I met Michael Parker, director of the bioethics Ethox Centre at the University of Oxford, at a conference. He was extremely supportive and encouraged me to stay in academia, at a time when I was ready to leave. How did you become interested in the work of shadow scholars in Kenya? In 2019, I went to an open meeting at the Oxford Internet Institute, a multidisciplinary department that researches digital technologies. The topic was the iLabour project, which looks at how people use the Internet for work. Kenya was listed as a hotspot for ‘writing and translation’, which turned out to be a euphemism for the fake-essay industry. I have a Kenyan background and, at the time, I was working on fakes and fabrications — my research into data fabrication in clinical trials had sparked an interest in fakes more generally — so I was intrigued. The Online Labour Index, an economic indicator produced by the Oxford Internet Institute, had lots of figures but little information on the people behind them. Was it difficult to get the shadow scholars to speak to you? Not at all. They were champing at the bit. They wanted the world to know they exist, because they are proud of their work, even if it is uncredited. Many said they liked seeing their writing used in real dissertations and articles (often for lofty institutions), even under someone else’s name. The challenge wasn’t persuading them to talk, but deciding whose stories to include. What was your biggest surprise from this work? The way in which power makes certain people invisible, and how long that’s been going on for. During our research, we were put in touch with Anne Manuel, the now-retired librarian at Somerville College at the University of Oxford. She recalled an oral history about Patricia Owtram, a Somerville student in the 1950s who is now 102. Owtram’s BLitt thesis had been taken in 1959 and published under the name of her supervisor in a scholarly publication, but in 2023 Somerville College was able to give it back to her with her own name on it. Shadow scholars have always existed: women, migrants, others excluded from mainstream academia. What also surprised me was how prejudice shapes assumptions. Tell people that one-quarter of a class had used a shadow scholar, and almost everyone will make an incorrect assumption about who has cheated. What can we learn from the shadow scholars? They can teach us a lot about dealing with pressure, deadlines and writer’s block — in the same way that we look to sports psychology for lessons in performance. We can learn a lot about how misconceptions and bias shape our understanding of expertise. When people actually accept that contract cheating exists, they imagine it’s out-of-work academics in the United Kingdom or the United States who are writing the articles. They can’t picture that it’s actually young, bright Africans in Kenya who might never have left the country, and yet have the skills to write PhD-level work. Their contribution is real, but long-standing assumptions about where knowledge is produced make it almost invisible. What do you think it says about higher education in the global north and global south? One of the things that really surprised me was the empathy that the Kenyan writers had for students in the global north. I thought they might say, “Oh, those lazy so-and-sos,” but actually they felt we’ve all been sold the same broken social contract: work hard, study hard and everything will be yours. But that dream hasn’t materialized. In the United States, especially — which accounts for a majority of the essay writers’ business — students are managing huge debts, working alongside their studies and scrambling for internships just to stay afloat. In Kenya, restrictions on visas for travel to places such as the United Kingdom and Australia, together with low wages, make it hard to leave the country, so education is no longer seen as a passport to a prosperous future. What are the biggest hurdles to tackling contract cheating?
Nature DOI suffix ≠ "/s...": Not a research article
Can AI predict and limit online hate?
Chirantan Chatterjee
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In-person attacks on religious institutions in recent months have underscored the need to reflect on the role of artificial intelligence in both spreading and counteracting hate speech online. On the one hand, algorithms can amplify the spread of extreme social-media posts to increase engagement, and large language models sometimes produce biased outputs, reflecting prejudices in their training data. On the other hand, AI can detect online hate speech quickly and on a large scale.
Nature DOI suffix ≠ "/s...": Not a research article
Alzheimer’s decline slows with just a few thousand steps a day
Mariana Lenharo
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Cognition deteriorates less rapidly in people with Alzheimer’s disease who take at least 3,000 to 5,000 steps per day. Credit: Qilai Shen/Bloomberg/Getty When it comes to preventing Alzheimer’s disease, every step counts. For older people whose brains have begun to show molecular signs of the disease, but who have yet to display any cognitive symptoms, taking as few as 3,000 to 5,000 steps per day can help to stave off mental decline, a study finds1. That level of activity slows cognitive decline by three years, on average, the results show. And in similar individuals who walk further, taking 5,000 to 7,500 steps per day, decline slows by an average of seven years. The work also offers hints to how exercise alters the brain to offer this protection. “The very encouraging takeaway is that even a little bit of exercise seems to help,” says Wai-Ying Wendy Yau, a physician-scientist specializing in memory disorders at Harvard Medical School in Boston, Massachusetts, and a co-author of the study, which was published on 3 November in Nature Medicine. The research indicates that people don’t need to take 10,000 steps a day, a goal that is often touted but might be hard for some older individuals to attain, she says. Steps towards prevention The research team ran regular checks on 296 people participating in the Harvard Aging Brain Study, a programme that is investigating the early stages of Alzheimer’s. None of them had signs of cognitive impairment at the beginning of the study. Over up to 14 years, the team periodically assessed the participants — whose ages ranged from 50 to 90 — using cognitive tests and brain scans. Participants were also asked to wear pedometers to measure how many steps they took each day. The brains of people at a higher risk of Alzheimer’s disease usually show an abnormal build-up of two proteins: amyloid-ÎČ and tau. Although the relationship between the two proteins is not fully understood, amyloid-ÎČ levels begin to increase first, followed by tau levels. Cognitive decline seems to be more closely tied to the accumulation of tau. The benefits of taking 3,000 to 7,500 steps per day were apparent only for participants with high baseline levels of amyloid-ÎČ in their brains. Their mental decline was slowed — by three to seven years — compared with participants who were sedentary. The researchers didn’t see any further slowing of mental decline in participants who took more than 7,500 steps a day.
Nature DOI suffix ≠ "/s...": Not a research article
‘Mind-captioning’ AI decodes brain activity to turn thoughts into text
Max Kozlov
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Reading a person’s mind using a recording of their brain activity sounds futuristic, but it’s now one step closer to reality. A technique called ‘mind captioning’ generates descriptive sentences of what a person is seeing or picturing in their mind using a read-out of their brain activity, with impressive accuracy. The technique, described in a paper published today in Science Advances1, also offers clues for how the brain represents the world before thoughts are put into words. And it might be able to help people with language difficulties, such as those caused by strokes, to better communicate. The model predicts what a person is looking at “with a lot of detail”, says Alex Huth, a computational neuroscientist at the University of California, Berkeley. “This is hard to do. It’s surprising you can get that much detail.” Scan and predict Researchers have been able to accurately predict what a person is seeing or hearing using their brain activity for more than a decade. But decoding the brain’s interpretation of complex content, such as short videos or abstract shapes, has proved more difficult. Previous attempts have identified only key words that describe what a person saw rather than the complete context, which might include the subject of a video and actions that occur in it, says Tomoyasu Horikawa, a computational neuroscientist at NTT Communication Science Laboratories in Kanagawa, Japan. Other attempts have used artificial intelligence (AI) models that can create sentence structure themselves, making it difficult to know whether the description was actually represented in the brain, he adds. Horikawa’s method first used a deep-language AI model to analyse the text captions of more than 2,000 videos, turning each one into a unique numerical ‘meaning signature’. A separate AI tool was then trained on six participants’ brain scans and learnt to find the brain-activity patterns that matched each meaning signature while the participants watched the videos. The rise of brain-reading technology: what you need to know Once trained, this brain decoder could read a new brain scan from a person watching a video and predict the meaning signature. Then, a different AI text generator would search for a sentence that comes closest to the meaning signature decoded from the individual’s brain.
Nature DOI suffix ≠ "/s...": Not a research article
Meet the ‘Wee-rex’. Tiny tyrannosaur is its own species
Benjamin Thompson, Shamini Bundell
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Nature DOI suffix ≠ "/s...": Not a research article
China should undertake more risky research to close the Nobel gap
Alex J. Yang, Sanhong Deng, Richard B. Freeman
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As of this year, only one China-based scientist has won a Nobel in natural science — Tu Youyou, in 2015, for work developing the anti-malaria drug artemisinin. Yet China invests more in research and development than any other country besides the United States, and the Chinese Academy of Sciences leads the Nature Index, which ranks institutes according to their research outputs.
Nature DOI suffix ≠ "/s...": Not a research article
My funding applications are taking up too much time. How can I stay focused on my research?
Xiaoying You
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The problem Dear Nature, I am a young faculty member at a university in China, passionate about my research and eager to contribute to my field. However, I’m increasingly overwhelmed by the pressure to secure grants from the National Natural Science Foundation of China (NSFC). In our academic evaluation system, success in obtaining NSFC funding has become a crucial metric for career advancement — affecting promotions, tenure and even annual performance assessments. Young scholars spend many hours crafting grant proposals, often at the expense of actual research, such as conducting experiments, analysing data and writing papers. The stress is immense: the fear of repeated rejection not only threatens our career prospects but also erodes our confidence and enthusiasm for science. How can I navigate this pressure? Should I prioritize grant-writing skills over research itself, or is there a way to reconcile the need for funding with my original passion for scientific inquiry? — A frustrated young academic The advice This is by no means a unique challenge. Your frustration will resonate with plenty of academics around the world who, like you, are battling to secure funding. Moreover, the pressure often soars for early-career researchers aiming for tenure. But the competition for funding seems to be particularly fierce in China. A grant from the National Natural Science Foundation of China (NSFC) — the main funding source for basic research in the country — is often expected in the Chinese system for a tenure position. However, owing to the growing number of applicants, the success rate has dropped rapidly over the past decade: from around 22% in 2016 to a little over 12% this year. Many young Chinese scholars say that workload pressure also comes from their ‘up or out’ contracts, which mean that they have six years to secure tenure or otherwise face dismissal. Nature talked to four China-based researchers, who shared their thoughts on the grant struggle and how to tackle it. Put research ahead of the funding Xu Chi, an ecologist at Nanjing University, obtained his first NSFC grant in 2009, and now reviews grant proposals for the organization. Xu says that better writing skills can certainly help, but what will really make your proposal stand out is whether the topic is “important, novel and unique”. “It is also important that the candidate can showcase that he or she is the right person to carry the project to the finishing line,” Xu notes. “For that, the candidate should explain their advantages and unique selling points.” Improving your grant-writing skills and research “should not be an either/or choice,” adds Guo Tong, dean of the School of Civil Engineering in Southeast University in Nanjing. Guo, who has won seven NSFC grants since 2007, says that writing a grant proposal can help an applicant to clarify a project’s methodology and set achievable milestones. “In this way, grant writing can actually strengthen one’s science rather than replace it,” he explains. Change your mindset Tong Xinzhao, a bioinformatician at the Xi’an Jiaotong–Liverpool University (XJTLU) in Suzhou, says she faced a similar dilemma last year after her fourth NSFC grant application was rejected. “Am I doing this research because this is something I really want to pursue, or am I doing this research just to get funding and get on the career ladder?” Tong recalls asking herself at the time. In the end, she realized that she would want to work on her chosen topic regardless of the outcome of her next application. “That decision helped me clear my mind,” she said. “Suddenly, I stopped feeling the pressure. I felt light. And my preparation also seemed easier.” Guo agrees, saying that even if a proposal is not funded, it can still be a valuable road map for your work. Guo says that a mindset shift is often necessary. “A paper reports completed work — data, results and conclusions. A proposal, on the other hand, is about the future,” he explains. “This requires shifting from describing what you have done, to convincing others of what you can achieve and why it matters.” It is also crucial that you introduce your research question in a detailed and logical way in your proposal, according to Tong. She says that Chinese reviewers often look for a particular format for that: the general landscape of your field; what problems need to be resolved; what others have tried before; what is left to be resolved; and what you can do to fill the knowledge gap. “In a nutshell, the goal is to break the current research ceiling and dig a bit deeper,” she explains.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Custom-made gene-editing therapy for children to enter clinical trial
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Biggest black-hole outburst ever seen records death throes of a star
Jenna Ahart
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The slow consumption of a star by a black hole (artist’s illustration) unleashed a blaze of light that remained bright even after five years. Credit: Caltech/R. Hurt (IPAC) Black holes can get energy boosts by ‘snacking’, although their dish of choice is rather different from our own. Analysis suggests that the most luminous burst of light ever detected from a black hole — a fireworks show that was, at its peak, more than 10 trillion times brighter than the Sun — flared up as the black hole gobbled up a star that was at least 30 times as massive as the Sun. The findings were published on 4 November in Nature Astronomy1. When astronomers first laid eyes on the object in 2018, they didn’t realize it was a superflare. After noticing the object brighten, researchers zeroed in on it with the Palomar Observatory’s 5.1-metre Hale Telescope. But a graph of the light emitted by the object proved disappointing. “It didn’t seem nearly as interesting as we thought it was,” says Matthew Graham, an astronomer at the California Institute of Technology in Pasadena and a co-author of the paper. However, in 2023, the team noticed that, even after five years, the black hole remained peculiarly bright. So they took a closer look using the W. M. Keck Observatory in Hawaii, which revealed that the object was roughly 3 million kiloparsecs, or 10 billion light years, away. To appear so bright at such a great distance, the jets of light must have been particularly luminous. Astronomers now say that the flare is 30 times more luminous than any previously detected blaze of light from a black hole. A trick of the light? The authors investigated several possible causes of the flare. Perhaps there was a supernova near the black hole, or the flare was merely a trick of the light, appearing much brighter than it was in reality because of gravity’s warping effects. But the team found that neither explanation matched well with observations.
Nature DOI suffix ≠ "/s...": Not a research article
First-ever atlas of brain development shows how stem cells turn into neurons
Miryam Naddaf
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Developing human brain tissue containing rosette structures (pink and blue) surrounded by neurons (green).Credit: Nano et al./Nature Neurosci.; Jose Soto/Bhaduri Lab/UCLA Scientists have created the most detailed maps yet of how our brains differentiate from stem cells during embryonic development and early life. In a Nature collection including five papers published yesterday, researchers tracked hundreds of thousands of early brain cells in the cortices of humans and mice, and captured with unprecedented precision the molecular events that give rise to a mixture of neurons and supporting cells. “It’s really the initial first draft of any ‘cell atlases’ for the developing brain,” says Hongkui Zeng, executive vice-president director of the Allen Institute for Brain Science in Seattle, Washington, and a co-author of two papers in the collection. Biggest brain map ever details huge number of neurons and their activity These atlases could offer new ways to study neurological conditions such as autism and schizophrenia. Researchers can now “mine the data, find genes that may be critical for a particular event in a particular cell type and at a particular time point”, says Zeng. “We have a very exciting time coming,” adds Zoltán Molnár, a developmental neuroscientist at the University of Oxford, UK, who was not involved with any of the studies. The work is part of the BRAIN Initiative Cell Atlas Network (BICAN) — a project launched in 2022 by the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative at the US National Institutes of Health with US$500 million in funding to build reference maps of mammalian brains. Patterns of development Two of the papers map parts of the mouse cerebral cortex — the area of the brain involved in cognitive functions and perception. Zeng and her colleagues focused on how the visual cortex develops from 11.5-day-old embryos to 56-day-old mice. They created an atlas of 568,654 individual cells and identified 148 cell clusters and 714 subtypes1. “It’s the first complete high-resolution atlas of the cortical development, including both prenatal and postnatal” phases, says Zeng. One surprise, she says, was how many neurons continued to take up specialized identities after birth, particularly between day 11, when newborn mice open their eyes for the first time, to day 21. Another study focused on brain development in human fetuses. How different types of brain cell emerge “is a long-standing question in developmental neurobiology”, says Tomasz Nowakowski, a neuroscientist at the University of California, San Francisco. He and his colleagues created a family tree map of human cortical cells2 using brain tissue collected from eight human fetuses at various stages of development. Brain tissues, assemble! Inside the push to build better brain models They identified 6,402 progenitor cells in these tissues and inserted a unique DNA ‘barcode’ into each one. When the cells divide, the barcodes are copied and passed on to their daughter cells — allowing researchers to track which stem cells generated which types of brain cell. Nowakowski and his team found that, in fetuses that are less than 20 weeks old, progenitor cells were mostly developing into excitatory neurons, which relay electrical signals to activate other neurons. But after 20 weeks, the cells shifted to generating inhibitory neurons, which halt neuronal communication. “This shows how these progenitors transition from one type into the other,” says Molnár. The team also observed that the generation of other types of brain cell — called astrocytes and oligodendrocytes — in humans “seems to be much more continuous and protracted” than in mice, Nowakowski adds. “We actually don’t know what controls all these developmental programmes and switches, or why they occur in development and especially at such precise moments,” says Nowakowski. Addressing these questions will be a key goal for future studies, he adds.
Nature DOI suffix ≠ "/s...": Not a research article
Can AI be truly creative?
Jo Marchant
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Pianita number 17 is a short, haunting piece for the piano. Set in the D minor key, its poignant chords and softly ascending arpeggios convey a sense of lost love, yet with enough novelty — dissonant notes and an eerie timing shift — to lift the piece out of clichĂ©. What searing life experiences, then, did the composer pour into this work? None, as it turns out. Because this music was produced by an artificial-intelligence model, trained on thousands of hours of YouTube videos. For decades, psychologists have thought of creativity as a key trait that would set us apart from machines, even as they surpassed us in intelligence and skill. But now, a wave of generative AI models, which create new content based on learning from huge data sets, is throwing shade on this idea. AI ‘scientists’ joined these research teams: here’s what happened These models exploded onto the scene in November 2022 when the California AI firm OpenAI released ChatGPT, a hugely popular AI chatbot. Powered by the large language model (LLM) GPT-3.5, ChatGPT was able to produce convincing text and images in response to simple prompts. Models that were even more impressive quickly followed. From poetry and video to ideas and music, AI-generated content now rivals many human-made works, meaning that the standard scientific definitions of creativity struggle to distinguish between people and computers. The progress since 2022 has been “absolutely mind-blowing”, says Simon Colton, who studies computational creativity at Queen Mary, University of London. “All of my colleagues are scrambling to catch up, like ‘What? What just happened?’” So should we accept that AI is now creative? Or change the definition to safeguard human creativity? Researchers on both sides argue that the stakes are high — not just for AI’s creative potential, but for our own. Machine ingenuity The debate over whether machines can be creative isn’t new. In the 1840s, Ada Lovelace, who collaborated on a prototype of the first digital computer, the Analytical Engine, insisted that despite the model’s impressive abilities, “it has no pretensions whatever to originate anything” and is limited to “whatever we know how to order it to perform”. More than a century later, many scientists still held the same opinion, but in 1950, mathematician Alan Turing provocatively argued the reverse: that there was no human faculty that couldn’t one day be replicated by computers. Some 50 years later, machines began to rival even the most talented humans at specific tasks. In 1997, IBM’s Deep Blue computer beat the reigning chess world champion. Google DeepMind’s AlphaGo program achieved a similar feat for the game of Go in 2015. In 2019, Google unveiled the Bach Doodle, which could harmonize short melodies in the style of the German composer Johann Sebastian Bach. But researchers agree that what’s happening now with generative AI is different from anything seen or heard before. Creativity is difficult to characterize and measure, but researchers have coalesced on a standard definition: the ability to produce things that are both original and effective. They also have a range of tests for it, from interpreting abstract figures to suggesting alternative uses for a brick. From 2023 onwards, researchers in fields from business to neuroscience started reporting that AI systems can rival humans in such tests, and people often struggled to distinguish AI-generated and human-produced content, whether it was a poem, a scientific hypothesis or a smartphone app1. “People started saying, ‘Hey, generative AI does well on creativity tests, therefore it’s creative,’” says Mark Runco, a cognitive psychologist at Southern Oregon University in Ashland, and a founding editor of the Creativity Research Journal. The best-performing humans still have the edge over machines, however. One study2 compared short stories written by humans with pieces generated by popular chatbots. Although some of the AI-generated stories were judged to be as good as attempts by amateur human writers, experts rated the AI stories as much poorer in quality than professional stories published in The New Yorker, complaining that they lacked narrative endings, rhetorical complexity and character development. A separate experiment concluded that when it came to dreaming up new functions for everyday objects, LLMs couldn’t match the innovative capacity of a group of five-year-old children3. Scientific spark In science, generative AI tools have achieved impressive results for tightly defined problems, such as predicting the 3D structures of proteins. But they can struggle with broader challenges. First, they lack the experience and context to come up with fruitful suggestions in a real-world research environment. When a team at Stanford University in California asked both LLMs and humans to generate research proposals in computer science, the AI suggestions were initially rated by reviewers as more novel and effective. But after testing the proposals, reviewers noticed design flaws: for instance, some AI-generated ideas were computationally too expensive to execute easily, and others failed to refer to previous research, whereas the human ideas were more feasible1. Some AI models might also struggle with the imaginative leaps required to generate truly new insights in science. In a March study4, AI researchers Amy Ding at Emylon Business School in Lyons, France, and Shibo Li at Indiana University in Bloomington asked a recent version of ChatGPT (ChatGPT-4) to uncover the roles of three genes in a hypothetical regulatory system. The researchers asked the chatbot to come up with hypotheses and to design experiments; these were then performed using a computer-simulated laboratory and the results were fed back to the AI. AI tools such as the Nobel-prizewinning AlphaFold, which predicts protein structures from amino-acid sequences, have revolutionized some areas of science.Credit: Alecsandra Dragoi for Nature Compared with human scientists who were given the same task, the chatbot proposed fewer hypotheses and conducted fewer experiments. Unlike the humans, it didn’t revise its hypotheses or conduct any new experiments after receiving the results, and it failed to reveal the correct regulatory mechanism. After just one round of research, it confidently concluded that its original ideas were correct, even though they were not supported by the data. Ding and Li conclude that ChatGPT-4, at least, doesn’t have the necessary creative spark to notice and interpret anomalous results, or to ask surprising and important questions. Humans often conduct experiments out of curiosity, the researchers point out, then try new ideas to explain their results. But ChatGPT-4 was “stubborn” — unable to adjust its thinking in the face of fresh evidence. Will AI ever win its own Nobel? Some predict a prize-worthy science discovery soon The researchers suggest that achieving the curiosity and imagination needed for truly groundbreaking discoveries might require going beyond the deep neural networks — hierarchical layers of inter-connected nodes — that underlie generative AI. Although these excel at recognizing statistical patterns, they can struggle with flexible, outside-the-box thinking. That is “very difficult to do when you’re training on huge amounts of data,” agrees Colton, “which is, by definition, inside the box.” Alternative AI architectures could increase the potential for creativity, although research is at an early stage. Ding and Li highlight “neuromorphic” AI, which is modelled on the dynamic, self-organizing processes of the brain. Meanwhile, Colton is excited about neurosymbolic AI. In this approach, deep neural networks that glean patterns from data are combined with symbolic rules and reasoning, with the symbolic part being closer to explicit, abstract thought. The addition could equip AI systems with more flexibility to break out beyond their training, he says. “You can say, ‘You’ve seen this rule in the data, but what if that wasn’t true?’” Trust the process No matter how impressive the models become, however, should they ever be described as creative? Some researchers argue that, before attributing creativity to AI, society must think more carefully about what this quality really is. James Kaufman, an educational psychologist at the University of Connecticut in Storrs and the author of several books on creativity, argues that we need to understand the process of creating rather than just looking at the end result. “AI can produce a creative product, sure,” he says. “But it doesn’t go through a creative process. I don’t think it’s a creative entity.” For Runco, too, the idea of creative AI ignores important qualities that humans use in their creative output. He argues that, whereas neural networks follow algorithms, people use subjective emotions, aesthetics, personal values and lived experience to make creative decisions and imaginative leaps that might not seem logical or rational, but which express a person’s unique perspective, or self. To capture these human aspects, Runco suggests amending the standard definition of creativity to include ‘authenticity’, or being true to oneself, as well as ‘intentionality’ — an intrinsic motivation or drive that includes both the curiosity to begin a creative process and the judgement to know when to stop. Some types of AI model can assess their output and improve by themselves, says Caterina Moruzzi, a philosopher studying creativity and AI at the Edinburgh College of Art, UK, but they can still only move towards a goal provided by a human user. “What they still cannot do, and the question is whether they will ever be able to, is to give themselves their own goals.” This AI-generated work, exhibited by Refik Anadol at the Serpentine North Gallery in London, was made from images of coral reefs and rainforests.Credit: Dan Kitwood/Getty For Jon McCormack, who studies computational creativity at Monash University in Melbourne, Australia, even high-quality AI creations are “parasitic” on the human creativity that went into their training material. “They’re not able to come up with art movements or independently want to be an artist.”
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: UK science is ‘bleeding to death’, says report
Flora Graham
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Proceedings of the National Academy of Sciences

GPT-4o mini: Non-social science research article
Eliminating intercrystalline side effects for stable lithium metal batteries
Xingwei Sun, Yang Feng, Jiangtao Yu, Yong Lu, Shuo Xu, Ying Jiang, Haixia Li, Zhenhua Yan, Kai Zhang, Jun Chen
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Lithium metal is widely recognized as the ultimate anode material for next-generation lithium batteries due to its superior specific capacity. However, microscopic crystallographic heterogeneity caused by crystal faces and grain boundaries leads to nonuniform lithium deposition, thereby undermining the stability of lithium metal anode. This study systematically investigates the intricate impact of grain boundaries on the structural characteristics, deposition behavior, and electrochemical properties of lithium metal. We demonstrate that grain boundaries serve as preferential nucleation sites, exacerbating morphological heterogeneity. Although eliminating preexisting grain boundaries from substrate facilitates homogeneous lithium nucleation and enhances electrochemical performance, this approach does not address the deposition issues originating from the intercrystalline regions of newly deposited grains. Furthermore, the continuous expansion of the intercrystalline network disrupts single-crystal structure and accelerates anode degradation, imposing a critical constraint on performance enhancement. This work unveils a previously overlooked intercrystalline-driven failure mechanism and provides insights for realizing dendrite-free lithium batteries.
GPT-4o mini: Non-social science research article
Loss of calcium-dependent protein kinases OsCPK5 and OsCPK13 leads to NLR-dependent resistance in rice
Zhanchun Wang, Shibo Yu, Wencai Xu, Han Peng, Xuan Zhou, Anja Liese, Lilan Chen, Guitao Zhong, Chen Zhong, Xianya Deng, Libo Han, Na Liu, Justin Lee, Tina Romeis, Dingzhong Tang, Wei Wang
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Calcium (Ca 2+ ) signaling plays a crucial role in plant immunity, regulating both pattern-triggered immunity (PTI) through cell-surface receptors and effector-triggered immunity (ETI) via intracellular nucleotide-binding, leucine-rich repeat receptors (NLRs). Calcium-dependent protein kinases (CPKs/CDPKs) serve as key Ca 2+ sensors and signal transducers in these processes. In this study, we demonstrate the relevance of two rice CPKs, OsCPK5 and OsCPK13, for rice blast resistance. Both are Ca 2+ -responsive kinases, with potential in planta heteromer formation enhancing their phosphorylation/signaling functions. Single oscpk5 and oscpk13 mutants exhibit impaired early PTI responses and enhanced susceptibility to rice blast fungus, suggesting that these kinases are essential for effective immunity. Surprisingly, although it is also defective in PTI, the oscpk5 / 13 double mutant displays enhanced resistance to rice blast. An NLR protein OsCPK5/13-ASSOCIATING RESISTANCE PROTEIN 1 (OsCARP1), which is physically associated with both OsCPK5 and OsCPK13, is genetically required for the heightened resistance of oscpk5 / 13. Furthermore, OsCARP1-induced cell death in Nicotiana benthamiana can be suppressed by the expression of OsCPK5 and OsCPK13. Based on these findings, we postulate that the positive blast resistance roles of OsCPK5 and OsCPK13 are guarded by OsCARP1, thus leading to OsCARP1-dependent ETI resistance in the oscpk5 / 13 double mutant or upon manipulation by still unknown pathogen effectors during infection. Our results offer insights into how plants counteract potential pathogen attack on key Ca 2+ signaling immune components.
GPT-4o mini: Non-social science research article
Energetically expensive dynamo action in Earth’s basal magma ocean
Nathanaël Schaeffer, Stéphane Labrosse, Jonathan M. Aurnou
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Previous studies focusing on the electrical conductivity and thermal evolution of an early magma ocean at the base of Earth’s mantle have found that basal magma ocean (BMO) convection could have produced the ancient geomagnetic field. By advances in high-resolution dynamo modeling, we find that convection in a thin BMO-like spherical shell is able to sustain strong magnetic fields, including axial dipolar fields similar to current day field structure. However, integrating our dynamo results with improved thermal evolution models and taking the planet’s rapid rotation into account using rotating convective turbulence models implies that an Earth-like magnetic field was unlikely to have been generated in the BMO, a finding relevant to the interpretation of ancient paleomagnetic signatures, Earth’s global-scale dynamics, and long-term planetary evolution. Large uncertainties still remain, calling for refined models of deep Earth thermal and mineralogical processes, accurate determination of prefactors in convective scaling laws, and fully coupled core-BMO dynamo simulations. Nonetheless, our work highlights that BMO-type dynamos intrinsically require a larger product of electrical conductivity and velocity than core-type dynamos, and that they are similarly rotationally constrained, so that velocities are significantly reduced compared to nonrotating estimates.
GPT-4o mini: Non-social science research article
From sequence to scaffold: Computational design of protein nanoparticle vaccines from AlphaFold2-predicted building blocks
Cyrus M. Haas, Naveen Jasti, Annie Dosey, Joel D. Allen, Rebecca Gillespie, Jackson McGowan, Elizabeth M. Leaf, Max Crispin, Cole A. DeForest, Masaru Kanekiyo, Neil P. King
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Self-assembling protein nanoparticles are being increasingly utilized in the design of next-generation vaccines due to their ability to induce antibody responses of superior magnitude, breadth, and durability. Computational protein design offers a route to nanoparticle scaffolds with structural and biochemical features tailored to specific vaccine applications. Although strategies for designing self-assembling proteins have been established, the recent development of powerful machine learning (ML)–based tools for protein structure prediction and design provides an opportunity to overcome several of their limitations. Here, we leveraged these tools to develop a generalizable method for designing self-assembling proteins starting from AlphaFold2 predictions of oligomeric protein building blocks. We used the method to generate six 60-subunit protein nanoparticles with icosahedral symmetry, and single-particle cryoelectron microscopy reconstructions of three of them revealed that they were designed with atomic-level accuracy. To transform one of these nanoparticles into a functional immunogen, we reoriented its termini through circular permutation, added a genetically encoded oligomannose-type glycan, and displayed a stabilized trimeric variant of the influenza hemagglutinin receptor-binding domain through a rigid de novo linker. The resultant immunogen elicited potent receptor-blocking and neutralizing antibody responses in mice. Our results demonstrate the practical utility of ML–based protein modeling tools in the design of nanoparticle vaccines. More broadly, by eliminating the requirement for experimentally determined structures of protein building blocks, our method dramatically expands the number of starting points available for designing self-assembling proteins.
GPT-4o mini: Non-social science research article
Peptide vaccine formulations with structurally distinct STING agonist drugamers induce discrete, efficacious antitumor responses
Kefan Song, Dinh Chuong Nguyen, Yonghui Wang, Simbarashe Jokonya, Omeed Yazdani, Drew L. Sellers, Patrick S. Stayton, Suzie H. Pun
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Peptide therapeutic cancer vaccines are an attractive treatment modality for their safety and manufacturability but have been hindered in clinical translation by low immunogenicity and insufficient CD8 + T cell activation. We developed virus-inspired polymers for endosomal release (VIPER) to address systemic and intracellular delivery obstacles, but durable antitumor immunity remained elusive. Adjuvants stimulating innate immunity, such as stimulator of interferon genes (STING) agonists, can enhance vaccine potency but risks systemic toxicity and improper immune activation. We developed STING “drugamers” with cathepsin-cleavable linkers and dendritic cell (DC)-targeting moieties for intracellular delivery of STING agonists to DCs. We explored two different STING drugamer structures: a hydrophilic statistical polymer “polySTING” and a diblock polymer “NPSTING” that forms into nanoparticles. PolySTING achieved higher systemic STING agonist delivery, whereas NPSTING is more efficient in delivering STING agonists into inguinal lymph nodes (LNs). Both drugamer platforms enhanced STING activation and DC maturation compared to the free drug. When combined with VIPER, NPSTING generated more antigen-presenting DCs in the LNs and more antigen-responsive CD8 + T cells in the spleens, whereas polySTING generated more tumor-infiltrating CD8 + T cells and CD8 + DCs. Both VIPER–STING drugamer platforms demonstrated efficacy in a B16-OVA melanoma model and a MC38 colon cancer model. Combination treatment with anti-PD-1 immune checkpoint inhibitor results in tumor remission and tumor immunity in a subset of mice. This study highlights how an endosomolytic peptide vaccine platform combined with two structurally different drugamers induce superior antitumor responses through distinctive mechanisms.
GPT-4o mini: Non-social science research article
Reply to Uzoigwe: DLW is safe and validated
Amanda McGrosky, Amy Luke, Jennifer Rood, Hiroyuki Sagayama, Klaas R. Westerterp, William W. Wong, Yosuke Yamada, John R. Speakman, Herman Pontzer
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GPT-4o mini: Non-social science research article
Mobile species’ responses to surrounding land use generate trade-offs and synergies among nature’s contributions to people
Sophie A. O’Brien, Jason M. Tylianakis, Dean P. Anderson, Andrea Larissa Boesing, Hao Ran Lai, GaĂ«tane Le Provost, Peter Manning, Margot Neyret, Nico BlĂŒthgen, Kirsten Jung, Paul Magdon, Sandra MĂŒller, NoĂ«lle V. Schenk, Michael Scherer-Lorenzen, Sandra Lavorel
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Agricultural landscapes provide material, nonmaterial, and regulating contributions that affect human well-being (nature’s contributions to people, NCP). The responses of these NCP to land-use patterns depend on supporting biota with different habitat requirements, generating trade-offs and synergies. Predictions from spatially explicit modeling of NCP trade-offs and synergies could inform land-use decisions, but these do not typically account for the effects of land-use patterns on the movement of NCP-providing species, nor for interactions among NCP providers. To explore spatial trade-offs and synergies in eight indicators of NCP, we used Bayesian models that allow for interactions among land uses and among NCP using data from 150 grassland sites across rural Germany. We found that spatial arrangements of forest and open habitat influenced many beneficial NCP: acoustic diversity, birdwatching potential, natural enemy abundance, and pollination. In particular, the amount and proximity of land uses in the surrounding landscape, especially forest and open habitat, drove the supply of most NCP. However, detrimental NCP provided by smaller-bodied taxa (herbivory and pathogen infection) responded weakly to landscape factors. Multiple NCP provided by a given taxon responded differently to their surrounding landscape (e.g., bird-provided beneficial caterpillar predation and detrimental seed predation), leading to trade-offs and synergies among NCP over short distances. These were caused by different rates and directions of response to amount and location of land uses. Resulting spatial predictions revealed that the ratio of beneficial to detrimental NCP was maximized in areas with a high (≄95%) area of grassland or mixed forest-grassland (70:30%), rather than purely forest-dominated areas. This suggests promoting seminatural vegetation in agricultural landscapes to provide greater-than-additive benefits to net NCP supply.
GPT-4o mini: Non-social science research article
Creating a large designer cellulosome in yeast to boost ethanol production
Zeba Khatoon, Marimuthu Anandharaj, Tzu-Ho Chen, Chi-Chia Wu, Jan-Fang Cheng, Tsui-Ling Hsu, Hsiao-Ching Lin, Jui-Jen Chang, Wen-Hsiung Li
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Cellulosic biomass represents a promising feedstock for biofuel and biochemical production. However, its recalcitrant structure strongly hinders enzymatic degradation. Cellulosomes are large multienzyme complexes, highly efficient at degrading cellulose. A cellulase in a cellulosome has a dockerin domain that binds to a cohesin module on the CipA (cellulosome integrating protein A). In a native cellulosome all cohesins are identical, so that the cellulase types and their positions in a CipA cannot be controlled. Here, we constructed the largest designer CipA known to date. Using innovative techniques, we synthesized a designer CipA gene that encodes nine distinct cohesins and two cellulose-binding modules, which we named DCipA2B9C . Then, we fused nine distinct fungal cellulases separately with nine distinct dockerins for their precise positioning on DCipA2B9C to achieve enzyme proximity-effect. We constructed three yeast hosts to compare their performances. First, an enzyme host (EH) secretes nine dockerin-fused cellulases, including endoglucanases (EgIII-a, EgIII-m, and EgIII-c), exoglucanases (CBHII-j and EXG2-r), ÎČ-glucosidases (BGS-f and BGS-l), and cellulase boosters, including a LPMO-t and CDH-b. Second, the scaffoldin host (SH) expresses DCipA2B9C. Third, the cellulosome-9 host expresses DCipA2B9C and nine dockerin-fused cellulases. Native-PAGE and ELISA confirmed specific interactions between dockerins and cohesins. Additionally, native-PAGE, SDS-PAGE, and LC-MS verified the successful assembly of the multienzyme complex. Our performance evaluation showed that coculturing of EH and SH outperformed the cellulosome-9 host. It degraded microcrystalline cellulose efficiently to produce 14.29 g/L bioethanol, which surpassed all previously constructed yeast cellulosomes by fourfold or more. In summary, our study provides an effective approach to biomass degradation.
GPT-4o mini: Non-social science research article
Molecular drivers of RNA phase separation
Vysakh Ramachandran, Davit A. Potoyan
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RNA molecules play central roles in the assembly and regulation of biomolecular condensates, often in concert with proteins containing low complexity RNA-binding domains. Recently, it has been shown that RNA can phase-separate in the absence of any proteins. Unlike protein-based condensates, RNAs condensates are strongly influenced by magnesium ions which play crucial roles in their dynamics and thermodynamics, giving rise to base-specific lower critical solution temperatures (LCSTs). The molecular basis and functional significance of sequence and ion-dependent LCST behavior RNA condensates have yet to be elucidated. Here, we use atomistic simulations to systematically dissect the driving forces underlying the sequence-, ion-, and temperature-dependent phase behaviors of RNA condensates. By choosing RNA tetranucleotides alongside their ssDNA counterpart and chemically modified analogs, we map equilibrium thermodynamic profiles and structural ensembles across various external conditions. Our results show that magnesium ions promote LCST behavior by inducing local disorder-order transitions within RNA structures. Additionally, the base chemistry and the 2’hydroxyl group of the ribose sugar further modulate this LCST response. In agreement with experiments, we find that the thermal stability of RNA condensates follows the order G n > A n > C n > U n , governed by the balance of base stacking and hydrogen bonding interactions. Moreover, our simulations reveal that posttranslational nucleotide modifications can fine-tune the threshold of RNA self-assembly and the resulting condensate structures.
GPT-4o mini: Non-social science research article
Mapping the placental galectin-3 interactome identifies CD9 and ITGB1 as functional glycoprotein counterreceptors during syncytialization
Abigail E. Reeves, Gil-Suk Yang, Sabyasachi Baboo, Jolene K. Diedrich, Pranali Bedekar, Shaheen A. Farhadi, Arun Wanchoo, Christopher Bratcher, Gregory A. Hudalla, John R. Yates, Mia L. Huang
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The fetomaternal interface is replete with glycan-binding proteins (GBPs) that can interact with cell surface glycoprotein counterreceptors to regulate placental function. Here, we interrogate the role of galectin-3, a GBP that controls placental trophoblast syncytialization, an important differentiation process where progenitor cytotrophoblast cells fuse to produce the multinucleated syncytiotrophoblast. The molecular mechanism of galectin-3-mediated fusion has not yet been elucidated in part due to the difficulty of studying glycan-GBP binding events in live cells. To overcome these challenges, we employ a proximity labeling strategy to identify the galectin-3 interactome. From this interactome dataset, we selected and validated CD9 and integrin beta 1 as functional counterreceptors of galectin-3 and showed that CD9 is glycosylated with an N-linked glycan at a rare noncanonical sequon. Furthermore, we present evidence that galectin-3 acts to physically alter the fluidity of the cellular membrane, and it does not activate canonical syncytialization signaling pathways. Overall, we report that galectin-mediated binding events and their corresponding functions in cell biology can be precisely regulated by select glycoproteins at specific glycosites.
GPT-4o mini: Non-social science research article
Predicted molecules followed by experimental validation for protecting human neurons from oxidative stress–induced cytotoxicity
Xuyu Yang, Joo-Youn Lee, Farbod Moghadam, Joseph Steiner, Soo-Kyung Kim, Neha Ganjur, Adrian J. de Almenara, Brian M. Stoltz, Y. Peng Loh, William A. Goddard
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Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no effective drugs for treatment. We discovered and reported earlier that neurotrophic factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive dysfunction in AD mouse models. We then predicted computationally and validated experimentally that CPE interacts with a pharmacophore of six residues on the 5-HT1E receptor (HTR1E) to activate the ERK-BCL2 signaling pathway leading to protection of human neurons against oxidative stress–induced cell death. We now report using this pharmacophore for in silico virtual screening of ~6 million small molecules to discover candidates with similar binding and neuroprotective properties as CPE. This in silico search identified a molecule (Z124) that was verified experimentally to bind to HTR1E with protective efficacy comparable to NF-α1/CPE but requiring a higher concentration. Next, we carried out R-group design optimization based on Z124 to identify 4 compounds predicted to have much better efficacy than Z124. These compounds were synthesized and tested for neuroprotective activity. All four compounds showed binding to HTLA-HTR1E cells comparable to CPE. We determined the Kd for two of these compounds: R9, 1.38 ± 0.2 nM, and R10, 2.1 ± 0.2 nM, to be over 15 times better than CPE. Furthermore, all four new compounds showed protective activity against oxidative stress–induced cytotoxicity in human HEK293 cells stably transfected with HTR1E, as well as human primary neurons. Mechanistically, R9 and R10 activated ERK phosphorylation and increased the mitochondria prosurvival protein, BCL2, making them excellent candidates for further development as a drug to treat neurodegenerative diseases.
GPT-4o mini: Non-social science research article
The temporal dynamics of self-control
Paul E. Stillman, James D. Wilson, David A. Kalkstein, Melissa J. Ferguson
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Self-control—the ability to pursue long-term goals over short-term temptations—is a critical faculty of human cognition, but the cognitive processes enabling self-control are not well understood. Traditional models have focused on impulse inhibition: effortfully inhibiting prepotent motor responses toward a temptation, yielding a stage-based evolution of choice. Other models emphasize dynamic competition between goal and temptation, yielding a more integrative evolution of choice. Although these models represent fundamentally different conceptions of self-control, current methods are inadequate for investigating real-time dynamics, leaving the question of which model best describes self-control unresolved. We investigate these models using mouse-tracking: a dynamic, real-time measure of decision-making in which we measure participants’ computer mouse movements as they navigate tradeoffs between immediate and delayed gratification (e.g., $5 today vs. $20 in 3 mo). We develop a quantitative approach that integrates the rich spatial and temporal information contained in mouse trajectories, and find evidence for both impulse inhibition and dynamic competition. Notably, impulse inhibition is less frequent, occurring in only one-quarter of choices favoring larger later rewards over smaller sooner ones. We further find substantial individual variability on who relies on impulse inhibition, with more present-biased individuals more likely to use impulse inhibition to choose larger-later options. Finally, our approach reveals the diverse variability within impulse inhibition and dynamic competition, and accounting for this variability greatly strengthened models predicting out-of-sample choices. Our findings clarify the mechanisms underlying self-control and introduce a robust tool for quantifying real-time decision-making dynamics.
GPT-4o mini: Non-social science research article
LHFPL5 is required for maximal activation of the mechanotransduction channel in cochlear hair cells
Xufeng Qiu, Jose P. Llongueras, Lili Yin, Christopher Cunningham, Ulrich MĂŒller
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Mechanoelectrical transduction (MET) channels in cochlear hair cells are gated by tip links through a mechanism that is poorly defined. LHFPL5 interacts with the tip-link component PCDH15 and the MET-channel component TMC1, suggesting that LHFPL5 regulates channel activation by mechanical force. To test this hypothesis, we analyzed MET in hair cells from mice expressing an LHFPL5 mutant protein lacking three N-terminal amino acids. These mutant mice suffer from recessive deafness, and MET is drastically impaired in cochlear hair cells. The resting open probability of the MET channels is increased in the mutants, while unitary channel conductance, adaptation, and tonotopic channel properties remain unaltered. Unlike in other LHFPL5 mutants, MET channel proteins are still present at normal levels in stereocilia of mutant mice. We conclude that LHFPL5 is required for maximal mechanical activation of MET channels in cochlear hair cells thereby affecting the hair bundle sensitivity to mechanical stimulation and thus the sound sensitivity of the auditory sense organ.
GPT-4o mini: Non-social science research article
Stimuli-responsive STING nanovaccine for systemic therapy of HPV-induced cancers
Shuang Chen, Shuyue Ye, Gang Huang, Zhichen Sun, Qiang Feng, Maggie Wang, Raymundo Pantoja, Baran D. Sumer, Jinming Gao
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In recent years, therapeutic cancer vaccines have been extensively investigated, aiming to boost cancer-specific T cells crucial for antitumor activity. The effectiveness of these vaccines is often limited by insufficient immune activation and suboptimal antigen delivery. Stimulator of interferon genes (STING) is an important immune signaling protein that activates host defense genes against infection and cancer. Clinical evaluation of small-molecule STING agonists has shown tepid antitumor responses with immune-related toxicities, particularly when they are administered systemically. To overcome these limitations, we report a stimuli-responsive STING nanovaccine for treating human papillomavirus (HPV)-induced cancers. The nanovaccine consists of di-amidobenzimidazoles (diABZI) conjugated to a STING-activating polymer, PSC7A, through an azobenzene linker as an adjuvant, and HPV16 E7 protein as an antigen. The nanovaccine is responsive to acidic pH and NAD(P)H quinone oxidoreductase 1 (NQO1), which enhances antitumor immunity with reduced systemic toxicity. Upon intravenous injection, the STING nanovaccine (25 to 30 nm in diameter) achieved efficient codelivery of E7 protein and STING agonists to the myeloid cell populations in the secondary lymphoid organs and tumors. Interestingly, PSC7A uptake induces NQO1 expression in dendritic cells and macrophages for accelerated diABZI cleavage and STING activation. This results in efficient production of E7-specific CD8 + T cells and robust antitumor response in late-stage TC-1 and metastatic MLM3 tumor models. This study illustrates a systemic STING nanovaccine design that allowed not only tumor regression but also markedly reduced systemic toxicity for innate activation to achieve cancer-specific T cell immunity.
GPT-4o mini: Non-social science research article
Mechanism of controlled radical initiation in radical SAM GTP 3’,8-cyclase
Haoran Pang, Di Li, Qinglin Wu, Pan Zhang, Weitao Yang, Alexey Silakov, Pei Zhou, Kenichi Yokoyama
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Metalloenzymes couple substrate binding and formation of oxidative intermediates to minimize unwanted side reactions. However, the molecular details of such coupling frequently remain ambiguous. Radical S -adenosyl-L-methionine (SAM) enzymes constitute one of the largest groups of metalloenzymes and catalyze various radical-mediated reactions. While radical SAM enzymes significantly accelerate the conserved radical initiation reaction, the reductive cleavage of SAM into 5â€Č-deoxyadenosyl radical (5â€Č-dA‱), the molecular mechanism of this rate acceleration is largely unexplored. Here, using MoaA, aradical SAM enzyme in the molybdenum cofactor (Moco) biosynthesis, as a model, we reveal the mechanism of substrate-triggered radical initiation. We first elucidated the intact active site structure of MoaA using solution NMR characterization of the C-terminal tail, which was disordered in the reported crystal structures, and its computational docking into the MoaA structure. Together with the comprehensive functional validation, we show that MoaA uses its conformationally flexible C-terminal tail with two conserved Gly residues (GG motif) at the C-terminus as a sensor to detect substrate guanosine 5â€Č-triphosphate (GTP) binding and trigger reductive SAM cleavage. Importantly, mutations that disrupt this regulatory mechanism cause Moco deficiency disease in humans. Comparison of these observations with other radical SAM enzymes provides insight into the general mechanism of substrate-triggered radical initiation in radical SAM enzymes.
GPT-4o mini: Non-social science research article
eATP sensing by the purinergic receptor PA2072 for allosteric modulation in intracellular c-di-GMP signaling
Yan Zhang, Xiaojing Gao, Yunjie Xiao, Yajing Duan, Wangxin Xiao, Yangyang Xu, Tingting Yang, Huimin Zhang, Cheng Chen, Shuo Shi, Xun-Cheng Su, Xinghua Jin, Jiaqing Zhao, Haitao Yang, Guowei Yin, Wensu Yuan, Zefang Wang, Weidong Huang, Zhi Lin
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Extracellular ATP (eATP) has emerged as a crucial signaling molecule across eukaryotic and prokaryotic domains, modulating diverse cellular functions by activating purinergic receptors to initiate intracellular signaling cascades. However, the structural and molecular mechanisms underlying eATP sensing and signaling by prokaryotic receptors remain largely unknown. Here, we demonstrate that the receptor PA2072 in Pseudomonas aeruginosa is responsible for recognizing eATP to down-regulate intracellular cyclic di-GMP levels. The periplasmic CHASE4 domain of PA2072 specifically binds and hydrolyzes eATP, exhibiting ATPase activity both in the presence and absence of a divalent cation cofactor. Structural elucidation of the PA2072 CHASE4 domain in its monomeric and complex states unveils an exquisite molecular switch governed by the oligomeric state. ATP hydrolysis by the catalytically active monomeric form is coupled to homodimerization, concomitantly deactivating its ATPase activity and initiating intracellular phosphodiesterase activity. These findings open avenues for understanding interkingdom eATP signaling and developing targeted therapeutic interventions.
GPT-4o mini: Non-social science research article
Dynamic changes of dopamine neuron activity and plasticity at different stages of negative reinforcement learning
Qiangqiang Cheng, Wenqing Liu, Li Yao, Shuyuan Xu, Chunling Wei, Qiaohua Zheng, Meilin Wu, Jing Han, Zhiqiang Liu, Wei Ren, Zongpeng Sun
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Research indicates that midbrain dopaminergic neurons encode reward prediction error (RPE) signals involved in positive reinforcement learning. However, studies on dopamine’s role in negative reinforcement learning (NRL) are scarce. Learning to escape aversive stimuli is vital for survival and may differ significantly from positive reinforcement in behavior and neural mechanisms. This study employs footshocks as aversive stimuli to investigate neural activity, synaptic transmission, and intrinsic excitability in a NRL paradigm using fiber photometry and ex vivo electrophysiology. Results show that inescapable footshocks initially increase activity in substantia nigra pars compacta (SNc) dopaminergic neurons, which later shifts to reflect shock termination as exposure increases. Electrophysiological observations reveal increased intrinsic excitability and excitatory synaptic transmission in SNc neurons, with decreased inhibitory transmission. After mice learn to escape the shock by nose-poking, dopaminergic activity shifts from shock termination to shock onset. Furthermore, inhibitory input increases, while excitatory input decreases after learning, with intrinsic excitability returning to baseline levels. This indicates that SNc dopaminergic neurons exhibit RPE-like signals in response to aversive stimuli, with their intrinsic excitability adjusting according to expectations of shock termination. These findings enhance our understanding of RPE encoding in negative reinforcement learning and may inform therapeutic strategies for disorders caused by environmental factors such as aversive stimuli.
GPT-4o mini: Non-social science research article
Revisiting the high-dimensional geometry of population responses in the visual cortex
Dean A. Pospisil, Jonathan W. Pillow
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Recent advances in large-scale recording technology have spurred inquiries into the high-dimensional geometry of the neural code. However, characterizing this geometry from noisy neural responses, particularly in datasets with more neurons than trials, poses major statistical challenges. We address this problem by developing tools for the accurate estimation of high-dimensional signal geometry. We apply these tools to investigate the geometry of representations in the mouse primary visual cortex. Previous work has argued that these representations exhibit a power law, in which the i th principal component falls off as 1 / i . Here, we show that response geometry in V1 is better described by a broken power law, in which two different exponents govern the falloff of early and late eigenmodes of population activity. Our analysis reveals that later modes decay more rapidly than previously suggested, resulting in a substantially lower-dimensional representation that is concentrated in early modes. We thus characterize the stimulus encoding of these dominant population modes. We find properties of population coding in the mouse primary visual cortex that underscore its greater tractability relative to single-neuron characterization. Specifically, we find these modes encode visual features with far higher fidelity than single neurons, and these features are easier to characterize than the tuning of single neurons: both classical and deep network models of V1 achieve more than 25 % better predictive performance for eigenmodes than single neurons. Overall, our approach overturns prior results and reveals emergent structure in a population sensory representation.
GPT-4o mini: Non-social science research article
MDFIC2 is a PIEZO channel modulator that can alleviate mechanical allodynia associated with neuropathic pain
Abdella M. Habib, Shengnan Li, Chenjing Zhang, Meijun Ji, Nancy Osorio, Virginie Penalba, Jesus M. Torres, Samuel J. Gossage, Mehdi A. Rezai, Amy F. Geard, Ahad A. Rahim, Ahmed M. M. Mahmoud, Sonia Santana-Varela, Jun Zhou, Jing Zhao, John N. Wood, Andrei L. Okorokov, Xuelong Zhou, James J. Cox, Bertrand Coste
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PIEZO channels are mechanical force sensors involved in various biological processes, including somatosensation. To date, only a few PIEZO-binding partners have been identified, including MyoD-family inhibitor proteins (MDFI and MDFIC). Here, we show that MDFIC2, a third member of the MDFI protein family with an as-yet-unknown function, is expressed in a subset of nociceptive sensory neurons. MDFIC2 modulates both PIEZO1 and PIEZO2 gating properties by slowing their kinetics and shifting mechanical sensitivity to higher forces. Interestingly, Mdfic2 is downregulated in mouse neuropathic pain models in which mechanical allodynia is a hallmark symptom. We found that intrathecal administration of adeno-associated virus vector encoding MDFIC2 cDNA reduces mechanical sensitivity and attenuates mechanical allodynia in the spared nerve injury neuropathic pain model. These findings demonstrate a mechanism for regulating mechanosensation and highlight a potential therapeutic route for treating mechanical allodynia.
GPT-4o mini: Non-social science research article
GH25 lysozyme mediates tripartite interkingdom interactions and microbial competition on the plant leaf surface
Zarah Sorger, Priyamedha Sengupta, Klara Beier-Heuchert, Jaqueline Bautor, Jane E. Parker, Eric Kemen, Gunther Doehlemann
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Microbial communities inhabiting plants have emerged as crucial factors in regulating plant health and defense against disease-causing pathogens. The yeast Moesziomyces bullatus ex. Albugo (MbA) on Arabidopsis produces a glycoside hydrolase 25 (GH25) protein that regulates the leaf microbiome by antagonizing the pathogenic oomycete Albugo laibachii . Applying MbA or GH25 rescued Arabidopsis thaliana shoot fresh weight under A. laibachii infection, highlighting their crop protection potential. Interaction assays revealed no antagonistic activity of GH25 against other plant pathogenic oomycetes or fungi besides A. laibachii . We identified a community of bacteria closely associated with A. laibachii. Three of these bacteria are inhibited by GH25 and one of them, Curtobacterium sp. could override the inhibition of A. laibachii by MbA . This points to a tripartite antagonism where Curtobacterium and A. laibachii protect each other from MbA . Moreover, Curtobacterium selectively inhibits other A. laibachii -associated bacteria not targeted by MbA but that themselves suppress A. laibachii . This study uncovers an interkingdom network where GH25 lysozyme shapes microbial interactions between yeast, oomycete, and associated bacteria.
GPT-4o mini: Non-social science research article
Microfluidic networks using isotachophoresis
Alexandre S. Avaro, Shahab Mirjalili, Andrew D. Griffiths, Juan G. Santiago
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The development of microfluidic technologies has enabled chemical and biological analysis systems with increased functionality, complexity, and parallelization. These functionalities often drive the creation and control of complex and dynamic fluidic architectures. Introduced here is a class of microfluidic network based on isotachophoresis (ITP), an electrokinetic process that can extract and purify samples, selectively transport, mix, and aliquot (split) samples in a system with no moving parts. Presented is a theoretical framework to describe these networks. The framework relies on the coupling between a one-dimensional description of ITP and two-dimensional, transient graphs to describe the dynamic evolution of ITP networks. We leverage this framework to create numerical simulations of branched ITP circuits. We build, control, and experimentally study a variety of ITP networks. These systems automatically split and merge ITP zones, enabling complex sample manipulation with minimal external control. The model captures the experimentally observed sample dynamics. We demonstrate an example system where an ITP network is used to control and quantify parallel CRISPR-Cas enzymatic reactions. The methods described here are generally applicable to highly complex topologies and may offer a basis for easily reconfigurable, electric field-driven microfluidic systems. Networks generally offer broad potential for automated chemical and biochemical analysis and lab-on-a-chip integration.
GPT-4o mini: Non-social science research article
Symmetry transitions beyond the nanoscale in pressurized silica glass
Zhen Zhang, Zhencheng Xie, Walter Kob
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Silica is the paradigmatic network glass-former and understanding its response to pressure is essential for comprehending the mechanical properties of silica-based materials and the behavior of silicate melts in the Earth’s interior. While pressure ( P )-induced changes in the short-range structure—particularly the breakdown of tetrahedral symmetry—have been well documented, structural transformations on larger length scales, important for many material properties, remain poorly understood. Here, we numerically investigate the three-dimensional structure of silica glass as a function of compression up to P ≈ 100 GPa. Using a many-body correlation function, we reveal a complex medium-range order: While for P â‰Č 10 GPa, one finds tetrahedral, octahedral, and cubic symmetries, the structure at higher P s exhibits alternating cubic and octahedral particle arrangements. The P -dependence of the corresponding structural correlation length displays two distinct maxima, which permits to rationalize the anomalous compressibility of silica. The identified complex structural organization on intermediate range scales is the result of a pressure-and scale-dependent interplay between directional bonding, packing efficiency, and network stiffness. Since these competing effects are common in network glass-formers, the identified three-dimensional medium-range order, and hence the physical properties of the glass, are expected to be universal features of such materials under extreme conditions.
GPT-4o mini: Non-social science research article
Long-chain unsaturated free fatty acids control gut motility via nitrergic ganglia of the enteric nervous system
Jun-Hao Zhang, Zhi-Hui Jiang, Ji Xuan, Yang Liao, Peng-Peng Li, Ye Wang, Han Wang, Tian-Tian Qiu, Ze-Xu Chen, Ke-Hui Qiu, Yu-Wei Zhou, Jing-Xin Ye, Jian-Feng Gong, Jun Jiang, Ling Ni, Hong-Feng Ma, Xue-Na Zhang, Hua-Qun Chen, Min-Sheng Zhu, Xin Chen
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Although mechanical tension from luminal distension is a primary regulator of gut motility, we reveal a parallel chemosensory pathway wherein long-chain unsaturated free fatty acids (LUFFAs) from dietary or enterobacterial sources directly modulate gastrointestinal motor function. Using ex vivo and in vivo contractility assays in human and murine intestinal tissues, we found that LUFFAs, particularly Omega-3 fatty acids, suppressed spontaneous contractions and delayed intestinal transit in a double bond-dependent manner. Mechanistically, selective activation of free fatty acid receptor 1/4 (FFAR1/4) on nitrergic myenteric ganglia triggered a rise in intracellular calcium and nitric oxide release, inducing smooth muscle relaxation independent of epithelial signaling. Genetic ablation of Ffar4 in enteric neurons or defect in enteric nitrergic ganglia abolished LUFFAs-mediated motility suppression and ameliorated colonic dysmotility induced by pathologically elevated LUFFAs levels. Our findings establish nitrergic ganglia as critical chemosensors translating dietary or enterobacterial lipid signals into gut motor responses.
GPT-4o mini: Non-social science research article
Choosing structure over complexity: POMDPs for emerging diseases and invasive species
Iadine Chades
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GPT-4o mini: Non-social science research article
Neuronal normalization in monkey MT is an intensity-weighted average
Chery Cherian, John H. R. Maunsell
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Normalization is a fundamental and ubiquitous neuronal computation that stabilizes activity across populations of neurons and preserves stimulus selectivity. While it is observed throughout the visual system, normalization may be particularly important in higher visual areas, where neurons have large receptive fields (RFs) that are frequently presented with multiple stimuli under natural viewing conditions. Yet it remains unclear how a population of neurons, with diverse selectivities and offset RFs, responds to complex scenes in which given stimuli engage different RFs more effectively than others. Here, we investigated how normalization varies with the spatial offset of stimuli from the centers of neurons’ RFs in the macaque monkey middle temporal area. We found that existing models of normalization perform poorly when stimuli appear in arbitrary RF locations. Instead, an intensity-weighted normalization model, in which intensity is defined as the product of stimulus contrast and a location-specific RF weight, is required to closely account for normalization. Intensity-weighted normalization furthermore explains a systematic increase in contrast sensitivity at sites closer to the field center. Finally, intensity-weighted normalization reveals that spontaneous activity contributes to normalization in a manner indistinguishable from experimental stimuli.
GPT-4o mini: Non-social science research article
Stability through plasticity: Finding robust memories through representational drift
Maanasa Natrajan, James E. Fitzgerald
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Memories are believed to be stored in synapses and retrieved by reactivating neural ensembles. Learning alters synaptic weights, which can interfere with previously stored memories that share the same synapses, creating a trade-off between plasticity and stability. Interestingly, neural representations change even in stable environments, without apparent learning or forgetting—a phenomenon known as representational drift. Theoretical studies have suggested that multiple neural representations can correspond to a memory, with postlearning exploration of these representation solutions driving drift. However, it remains unclear whether representations explored through drift differ from those learned or offer unique advantages. Here, we show that representational drift uncovers noise-robust representations that are otherwise difficult to learn. We first define the nonlinear solution space manifold of synaptic weights for fixed input–output mappings, which allows us to disentangle drift from learning and forgetting and simulate drift as diffusion within this manifold. Solutions explored by drift have many inactive and saturated neurons, making them robust to weight perturbations due to noise or continual learning. Such solutions are prevalent and entropically favored by drift, but their lack of gradients makes them difficult to learn and nonconducive to future learning. To overcome this, we introduce an allocation procedure that selectively shifts representations for new stimuli into a learning-conducive regime. By combining allocation with drift, we resolve the trade-off between learnability and robustness.
GPT-4o mini: Non-social science research article
Glycolipid nanoparticles target the spleen and detarget the liver without charge
Kara Gentry, Liming Lian, Hyejin Kim, Ozgenur Celik, Camille Jones, Ananda R. Podilapu, Avraham Shakked, David Loughrey, Ryan Zenhausern, Bora Jang, Jessie Doan, Sebastian Rudden, James E. Dahlman
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Lipid nanoparticles (LNPs) formulated with a neutral helper lipid can deliver RNA to the liver in humans. However, clinically relevant delivery to other tissues has remained challenging. To avoid the liver, scientists often add antibodies or helper lipids with a permanent charge. Here, we report an alternative approach: antibody- and charge-independent liver detargeting. Using DNA barcoding to test 109 chemically distinct LNPs in vivo, we found that replacing a neutral helper lipid with a neutral glycolipid reduced liver delivery and increased splenic delivery. Consistent with this differential tropism, these glycolipid nanoparticles caused differences in downstream cellular signaling in vivo compared to traditional LNPs. These data suggest that extrahepatic LNPs can be designed without the imposition of a net negative or positive charge.
GPT-4o mini: Non-social science research article
HIV-1 Vif and Vpr cooperatively modulate the cell cycle to maximize per-cell virion production
Madison Bandini, Dhaval Ghone, Edward L. Evans, Aussie Suzuki, Nathan M. Sherer
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The HIV type 1 (HIV-1) accessory proteins Virion Infectivity Factor (Vif) and Viral Protein R (Vpr) are essential for efficient virus replication in vivo. Vif mediates degradation of host restriction factor APOBEC3G, while Vpr modulates the host cell proteome in ways that promote virion infectivity and viral gene expression. In cycling cells including CD4+ T cells, Vif and Vpr also severely impact cell cycle progression for reasons that remain unknown. Here, we combined live-cell imaging with virological assays to define the relative impacts of Vif and Vpr on the cell cycle and single-cell virion production. We demonstrate that Vif and Vpr’s effects on the cell cycle are markedly distinct, with Vif arresting cells in mitosis, while Vpr causes a G2 phase delay followed by endoreplication and reversion of cells into a “pseudo-G1” cell state lacking G2 markers. When coexpressed, Vpr’s capacity to bypass mitosis acts to suppress cytotoxicity associated with Vif-mediated cell cycle arrest, with the two proteins cooperating to extend the infected cell’s time in interphase as much as fivefold. Vpr-driven endoreplication also caused duplication of transcriptionally active proviral genomes, yielding a correlative ~twofold increase in per-cell viral gene expression. Based on these findings, we propose that Vif and Vpr coordinately regulate the cell cycle to prolong the infected cell’s lifespan and maximize single-cell virion output.
GPT-4o mini: Non-social science research article
Two exceptionally preserved biotas from North Dakota reveal cryptic Ordovician shelf ecologies
Giovanni Mussini, Nicholas J. Butterfield
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The Ordovician saw one of the greatest evolutionary radiations in the Earth’s history, precipitating the assembly of modern animal-dominated ecologies in the aftermath of the Cambrian Explosion. However, Ordovician nonmineralized faunas are rare and mostly sample ecologically marginal settings. We describe small carbonaceous fossils (SCFs), including semiarticulated elements preserving submicrometric detail, from epicratonic deposits of the Deadwood and Winnipeg formations (ND). The Osterberg SCFs, associated with biostratigraphically informative conodonts and graptolites, record two successive biotas of Cambrian-Tremadocian (the “lower Osterberg” biota) and Darriwilian (the “upper Osterberg” biota) ages, demonstrating a long-term persistence of high-quality, Burgess Shale-type microfossil preservation after the end of the Cambrian. Their components open a window on normal marine, well-oxygenated Ordovician shelf habitats, revealing taxa and functional morphologies unrecorded by coeval macrofossils. These include specialized grazing and predatory molluskan radulae, triturative crustaceomorph molars, the oldest known eurypterid-type cuticles, and microphagous priapulid worms. The Osterberg fossils attest to an Ordovician co-occurrence of cryptic taxa and feeding adaptations, reminiscent of the most ecologically modern Cambrian biotas, alongside classic later-Paleozoic forms like colonial zooplankton and biomineralized early vertebrates. By contrast, they do not record classic Burgess Shale-style taxa typical of marginal or deeper-water Ordovician assemblages. These results demonstrate a lasting presence of cryptic, modern-style shelf faunas throughout the earliest Paleozoic, suggesting that exceptional Ordovician macrofossil sites are unrepresentative of the broader state of their coeval biosphere.
GPT-4o mini: Non-social science research article
Sticking around: σ factor dynamics and implications for transcription elongation
Rachel A. Mooney, Robert Landick
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GPT-4o mini: Non-social science research article
Glycosylated cannabinoids meet computational enzyme design
Joseph M. Jez
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GPT-4o mini: Non-social science research article
Beyond reweighting: On the predictive role of covariate shift in effect generalization
Ying Jin, Naoki Egami, Dominik RothenhÀusler
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Many existing approaches to generalizing statistical inference amid distribution shift operate under the covariate shift assumption, which posits that the conditional distribution of unobserved variables given observable ones is invariant across populations. However, recent empirical investigations have demonstrated that adjusting for shifts in observed variables (covariate shift) is often insufficient for generalization. In other words, covariate shift does not typically “explain away” the distribution shift between populations. As such, addressing the unknown yet nonnegligible shift in the unobserved variables given observed ones (conditional shift) is crucial for generalizable inference. In this paper, we present empirical evidence from two large-scale multisite replication studies indicating that covariate shift can help predict the strength of unknown conditional shift. Analyzing 680 studies across 65 sites, we find that even though the conditional shift is nonnegligible, its strength can often be bounded by that of the observable covariate shift. This pattern only emerges when the two sources of shifts are quantified by our proposed standardized, pivotal measures. We then interpret this phenomenon by connecting it to similar patterns that can be theoretically derived from a random distribution shift model. Finally, we demonstrate that exploiting the predictive role of covariate shift leads to reliable and efficient uncertainty quantification for target estimates in generalization tasks with partially observed data. Overall, our empirical and theoretical analyses highlight an alternative perspective on the problem of distributional shift, generalizability, and external validity.
GPT-4o mini: Non-social science research article
Reprogramming tumor microenvironment via systemic delivery of TLR3 agonist and manganese nanoparticle
Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P. Schwendeman, Yu Leo Lei, James J. Moon
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Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn 2+ ) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn 2+ . To achieve systemic codelivery of TLR3 agonist and Mn 2+ , we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn 2+ coordination lipid nanoparticle (PLCMP). When administered intravenously in tumor-bearing mice, PLCMP successfully accumulated in tumor, induced innate immune activation, generated tumor-specific T cells, and exerted antitumor efficacy in TLR3- and STING-dependent manner without triggering overt toxicity. Moreover, PLCMP in combination with α-PD-1 therapy achieved long-lasting antitumor efficacy in multiple murine tumor models. Furthermore, vaccination with PLCMP carrying TC-1 tumor antigen peptide elicited strong antigen-specific CD8 + T cell responses and remodeled the tumor microenvironment, resulting in robust therapeutic efficacy. Overall, these results show that simultaneous activation of the TLR3 and STING pathways via PLCMP provides a promising strategy for immunotherapy and vaccination against cancer.
GPT-4o mini: Non-social science research article
Parental investment and body temperature explain encephalization in vertebrates
Zitan Song, Michael Griesser, Carel P. van Schaik
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The systematic variation in relative brain size among vertebrate classes remains poorly understood. Here, based on the expensive brain hypothesis, we propose that two broad constraints explain much of the variation: 1) the ability to produce large offspring, and so provide them with the energy required for constructing larger brains, and 2) the ability to sustain continuously high body temperatures, because cooler and varying brain temperatures reduce brain performance and thus fitness. We therefore predicted that encephalization (major evolutionary increases in brain size) only happened where changes in physiology or natural history created these abilities. First, comparative analyses across all major vertebrate classes (n = 2600 species) revealed that protecting or provisioning eggs or embryos is associated with larger newborns. Subsequent analyses at the class level confirmed that newborn size and adult brain size underwent correlated evolution in birds, mammals, and cartilaginous fishes, but not in other fishes, amphibians, and reptiles. Second, we found a positive relationship between mean body temperature and brain size within each class (albeit sometimes insignificant). Third, a combined analysis across all vertebrates revealed a positive interaction between the effects of body temperature and newborn size. In conclusion, encephalization became most pronounced in vertebrate lineages that can both produce large offspring, reflecting internal fertilization with matrotrophy, and sustain high body temperature, partly linked to endothermy.
GPT-4o mini: Non-social science research article
cGAS-agonistic spherical nucleic acids reprogram the glioblastoma immune microenvironment and promote antitumor immunity
Akanksha S. Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Lisa A. Hurley, Serena Tommasini-Ghelfi, Jungsoo Park, Connor M. Forsyth, Bin Zhang, Jason Miska, Amy B. Heimberger, Chad A. Mirkin, Alexander H. Stegh
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The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS–STING) pathway is an important DNA-sensing mechanism that increases T cell trafficking and activation in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore, direct STING targeting using synthetic cyclic dinucleotides (CDNs) is an attractive strategy for treating lymphocyte-depleted and myeloid cell–enriched tumors, such as glioblastoma (GBM). However, inadequate bioavailability and poor cellular accumulation limit the clinical development of CDNs, particularly for noninvasive administration strategies. Spherical nucleic acids (SNAs) have emerged as promising modular constructs for creating therapeutic lead compounds for many diseases, including different forms of cancer. Here, we report the development of cGAS-activating SNAs that consist of gold nanoparticle cores functionalized with a shell of densely packed interferon-stimulatory DNA oligonucleotides (ISD 45 -SNAs). These nanostructures bind to cGAS, the sensor of cytosolic dsDNA upstream of STING, promoting the catalytic production of endogenous CDNs and downstream STING activation more potently than clinically tested CDNs. When administered intranasally or intratumorally to poorly immunogenic syngeneic GBM mouse models, ISD 45 -SNAs inhibit tumor growth more effectively than CDNs and promote long-term animal subject survival through specific cGAS–STING pathway activation. ISD 45 -SNAs induce a proinflammatory immune microenvironment enriched with effector T cells and proinflammatory macrophages. When coadministered with immune checkpoint inhibitors (ICI), they abolish GBM tumor development and induce long-term antiglioma immunity. These studies establish ISD 45 -SNAs as an immune-stimulatory modality for triggering innate and adaptive immune responses and increasing ICI efficacy for GBM treatment.
GPT-4o mini: Non-social science research article
Local control of T cell fate in lymph nodes safely and durably reverses myelin-driven autoimmunity
Senta M. Kapnick, Emily A. Gosselin, Shannon J. Tsai, Robert S. Oakes, Zahra A. Habibabady, Marian A. Ackun-Farmmer, Sean T. Carey, Shrey A. Shah, Ruochen Shen, Eugene Froimchuk, Haleigh B. Eppler, Christopher J. Bridgeman, Alexis A. Yanes, Ryan A. McIlvaine, Maeesha Noshin, Lisa H. Tostanoski, Sheneil K. Black, Xiangbin Zeng, Agnes Azimzadeh, Richard N. Pierson, Jonathan S. Bromberg, Christopher M. Jewell
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Development of tolerogenic, antigen-specific immunotherapies could overcome limitations of existing treatments for inflammatory autoimmune diseases by achieving potent, durable remission without impacting healthy immune surveillance. Here, we deliver diffusion-limited polymer depots to lymph nodes to locally guide T cell fates for the treatment of multiple sclerosis (MS), an autoimmune disease that occurs when the immune system mistakenly attacks myelin. In preclinical MS models, depots loaded with myelin self-antigen and tolerizing cues mediate localized retention of activated CD4 T cells, promote myelin-specific regulatory T cells, and reshape inflammation in the central nervous system (CNS) to eliminate lesions. Selective disease reversal is achieved with a single treatment that induces long-lasting remission without hindering healthy responses to vaccine challenge with foreign antigen. Furthermore, depots offer favorable chemistry and manufacturing control features and are well tolerated in non-human primates. This work supports a clinically feasible concept for inducing safe, effective, antigen-specific tolerance without systemic or repeated dosing.
GPT-4o mini: Non-social science research article
Underestimated input of terrestrial dissolved organic carbon to the ocean
Yuanbi Yi, Andrew J. Tanentzap, Chen He, Julian Merder, Helena Osterholz, Hongyan Bao, Jeffrey A. Hawkes, Ruanhong Cai, Si-Liang Li, Quan Shi, Sheng Xu, Chuanlun Zhang, Cong-Qiang Liu, Meixun Zhao, Ding He
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The contribution of terrestrial dissolved organic matter (DOM) to the ocean has been an enigma for decades. Tracking terrestrial DOM in the ocean has proven challenging due to factors such as the instability of terrestrial biomarkers, indistinguishable carbon isotopes from biogeochemical fractionation, and similar chemical composition between terrestrial and oceanic DOM. Here, we show that the terrestrial contribution to oceanic organic carbon pools is 1.7 to 2.5 times higher than previously assumed, highlighting the need to adjust global carbon cycle models. We derive these estimates by bridging high-performance liquid chromatography with ultra-high resolution mass spectrometry to investigate the presence of terrestrial molecules that are transported from rivers to the ocean and estimate their contribution to oceanic DOM. We identified 269 molecular formulae (MF) that are likely transported from land to the ocean. These formulae exhibited resistance to biological and photochemical degradation in incubation experiments, and were widely distributed in global rivers, marginal seas, and open oceans, suggesting that they are ubiquitous in inland and ocean waters and have a similar source. By relating the abundances of terrestrially derived MF to dissolved organic carbon concentrations, and radiocarbon measurements, we estimated that 16.7 to 25.0% of oceanic DOM is likely derived from rivers.
GPT-4o mini: Non-social science research article
An ADAR2-mimic base editor for efficient C-to-U RNA editing in vivo
Chenhui Hao, Niubing Zhang, Ouyang Mo, Ping Chen, Qian Liu, Xiang Cheng, Xuan Li, Pei Hao
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RNA base editing has the capability to rewrite genetic codes while offering improved safety due to its reversibility and temporal-spatial tunability. The development of cytosine-to-uridine editors faces issues of DNA mutagenic activity of APOBECs and the large-size anchoring domains associated with immunogenicity due to their microbial origin. To address these issues, we took an approach by returning to the original formula of adenosine deaminase acting on RNA (ADAR), i.e., to convert ADAR2 to a cytosine deaminase acting on RNA by introducing 17 mutant substitutions derived from RESCUE-S—it is named ADAR2-mimic base editor for C-to-U RNA editing (AMBER). AMBER displays similar sequence contexts preference to that of RESCUE, and exhibits robust performance across various tested cell lines. By applying AMBER to correct several pathogenic transcript mutations, we achieved substantial editing with efficiency ranging from 8 to 38%. For example, for the Pah mutant (c.788T>C) that caused phenylketonuria in mice, AMBER had an editing efficiency of 19.7% in HEK293T cells. Additionally, concurrent bystander editing of target transcripts was mitigated by two alternate strategies. To demonstrate its effectiveness in vivo, we applied AMBER in C57BL/6 mice, and observed gRNA-dependent editing with ~21% on-target efficiencies at 72 h post injection, which remained detectable up to 1 wk. RNA-sequencing analysis of the mouse liver transcriptome revealed minimal off-target effects and no significant changes to endogenous RNA editing events. These results highlight AMBER as a promising therapeutic tool for repairing T-to-C mutations, offering great potential for the treatment of genetic diseases.
GPT-4o mini: Non-social science research article
Unveiling FERONIA receptor kinase–mediated cellular mechanisms with a small-molecule inhibitor
Mengze Sun, Baiyan Lu, Ying Yang, Junping Fan, Weiwei Ren, Xiaonan Chu, Yihui Gao, Jun Wu, Jue Wang, Han Ke, Zhiwen Liu, Shaojun Dai, Xiaoguang Lei, Chao Li
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Since its initial identification as the receptor for Rapid Alkalinization Factor 1 (RALF1), FERONIA (FER) receptor kinase has emerged as a central signaling hub coordinating plant development, stress adaptation, and immune responses. Nevertheless, fundamental questions persist regarding the precise mechanisms of FER-mediated signal transduction and its context-dependent functional specialization in multicellular processes. Here, we develop Ferovicin (FRV), a small-molecule inhibitor that specifically disrupts FER kinase activity, thereby enabling mechanistic dissection of FER. Cocrystallization and mutational analysis show that FRV selectively binds to the ATP-binding pocket of the kinase domain of FER and inhibits its kinase activity. Assisted by the FRV tool and quantitative phosphoproteomics, we characterized a series of signaling pathways and networks regulated by RALF1 and FER. Notably, our analysis reveals that RALF1 activates FER through phosphorylation at Ser695, which subsequently inhibits H + -ATPase1/2 via phosphorylation at Ser899. This mechanism leads to apoplastic alkalinization and regulates cell expansion in the root meristem. Given the conservation of FRV binding sites in FER proteins across land plant species, FRV will serve as a valuable tool for dissecting FER signaling mechanisms as well as facilitating agricultural applications.
GPT-4o mini: Non-social science research article
The geometry of jamming algorithms in the random Lorentz gas
Giampaolo Folena, Patrick Charbonneau, Peter K. Morse, Rafael DĂ­az HernĂĄndez Rojas, Federico Ricci-Tersenghi
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Deterministic optimization algorithms unequivocally partition a complex energy landscape into inherent structures (ISs) and their respective basins of attraction. Can these basins be defined solely through geometric principles? This question is paramount to understanding hard sphere jamming, a key model of disordered matter. We here address the issue by proposing a geometric class of gradient descent–like algorithms, which we use to study a system in the hard-sphere universality class, the random Lorentz gas. The statistics of the resulting ISs is found to be strictly inherited from those of Poisson–Voronoi tessellations. The landscape roughness is further found to give rise to a hierarchical organization of ISs, which various algorithms explore differently. In particular, greedy and reluctant schemes tend to favor ISs of markedly different densities. The resulting ISs nevertheless robustly exhibit a universal force distribution, thus confirming the geometric nature of the jamming universality class. Along the way, the physical origin of a dynamical Gardner transition is identified.
GPT-4o mini: Non-social science research article
Quantum higher-order Fourier analysis and the Clifford hierarchy
Kaifeng Bu, Weichen Gu, Arthur Jaffe
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We propose a mathematical framework that we call quantum, higher-order Fourier analysis. This generalizes the classical theory of higher-order Fourier analysis, which led to many recent advances in number theory and combinatorics. We define a family of “quantum measures” on linear transformations on a Hilbert space, that reduce in the case of diagonal matrices to the uniformity norms introduced by Timothy Gowers. We show that our quantum measures and our related theory of quantum higher-order Fourier analysis characterize the Clifford hierarchy, an important notion of complexity in quantum computation. In particular, we give a necessary and sufficient analytic condition that a unitary is an element of the k th level of the Clifford hierarchy.
GPT-4o mini: Non-social science research article
Conformational regulation of two essential activators of bacterial cell elongation
Morgan S. A. Gilman, Irina Shlosman, Daniel D. Samé Guerra, Masy Domecillo, Elayne M. Fivenson, Claire Bourett, Thomas G. Bernhardt, Nicholas F. Polizzi, Joseph J. Loparo, Andrew C. Kruse
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The peptidoglycan (PG) cell wall is critical for bacterial growth and survival and is a primary antibiotic target. MreD is an essential accessory factor of the Rod complex, which carries out PG synthesis during elongation, yet little is known about how MreD facilitates this process. Here, we present the cryoelectron microscopy structure of Thermus thermophilus MreD in complex with another essential Rod complex component, MreC. The structure reveals that a periplasmic-facing pocket of MreD interacts with multiple membrane-proximal regions of MreC. We use single-molecule FRET to show that MreD controls the conformation of MreC through these contacts, inducing a state primed for Rod complex activation. Using Escherichia coli as a model, we demonstrate that disrupting these interactions abolishes Rod complex activity in vivo. Our findings reveal the role of MreD in bacterial cell shape determination and highlight its potential as an antibiotic target.
GPT-4o mini: Non-social science research article
Methanogenic archaea encoding Pyrrolysine maintain ambiguous amber codon usage
Katie E. Shalvarjian, Grayson L. Chadwick, Paloma I. Pérez, Philip H. Woods, Victoria J. Orphan, Dipti D. Nayak
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Natural genetic code expansion is a phenomenon wherein an additional amino acid is encoded by a stop codon. These nonstandard amino acids are beneficial as they facilitate novel biochemical reactions. However, code expansion leads to ambiguity at the recoded stop codon, which can either be read-through or terminated. Pyrrolysine (Pyl) is encoded by the amber codon (TAG/UAG) and is widespread in archaea, where it is required for methylamine-mediated methanogenesis, an environmentally important metabolism. Mechanisms to conditionally suppress the amber stop codon for Pyl installation during protein synthesis have not been identified. In the model methanogen, Methanosarcina acetivorans, we demonstrate that the UAG codon encodes dual meaning as stop and Pyl. Our data suggest that expression of Pyl biosynthesis and incorporation genes is tuned to the cellular demand for Pyl, which might allow these archaea to navigate ambiguous stop decoding in response to environmental cues.
GPT-4o mini: Non-social science research article
Changing minds epigenetically: Germline genes in neurons disrupt animal behavior
Emily Teets, Aakanksha Singhvi
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GPT-4o mini: Non-social science research article
Doubting doubly labeled water
Chika Edward Uzoigwe
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GPT-4o mini: Non-social science research article
Global profiling of polyketide synthases in facultative multicellular eukaryotes
Markus GĂŒnther, Rosa Herbst, Nico Ueberschaar, Daniela Hildebrandt, Lisa Reimer, Pierre Stallforth
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Polyketides represent a structurally diverse class of natural products with a wide range of biological functions, including antimicrobial activity, defense responses, developmental regulation, pigmentation, and intercellular and intracellular communication signals. The social amoeba Dictyostelium discoideum harbors 40 polyketide synthase (PKS) genes, yet the specific and collective functions remain poorly understood. PKSs require activation by the phosphopantetheinyl transferase DiSfp, which converts inactive apoenzymes into functional holo forms. Disruption of the DiSfp gene abolished the production of PKS-derived metabolites across all developmental stages. Integrated phenotypic, transcriptomic, and metabolomic analyses revealed impaired growth in liquid culture, defects in macropinocytosis, aberrant chemotaxis, and diminished spore formation, associated with altered expression of genes regulating these processes. Comparative metabolomic profiling of the mutant identified candidate polyketide metabolites across different developmental stages, providing a valuable resource for targeted identification and isolation of previously undescribed compounds. This study establishes a functional link between the PKS machinery and the metabolic and developmental networks of D. discoideum , highlighting the essential roles of polyketides in cellular physiology and offering a framework for future polyketide discovery.
GPT-4o mini: Non-social science research article
Gene drives, species complexes, and the risks of collateral damage
Christophe Boëte
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GPT-4o mini: Non-social science research article
Abscisic acid regulates iron accumulation in plant seeds via the PYLs–bHLH IVc–YSLs module
Hongyun Zhao, Juntao Jiang, Cun Wang, Yuan Zheng
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Abscisic acid (ABA) is pivotal in seed development, yet its role in iron (Fe) homeostasis remains unclear. Here, we reveal a PYLs–bHLH IVc–YSLs module that mediates ABA-dependent suppression of seed Fe accumulation in Arabidopsis . During seed maturation, ABA receptors PYLs directly interact with bHLH34/104/115 transcription factors, blocking their binding to YSL1/3 promoters to inhibit Fe transport. Conversely, Fe deficiency triggers bHLH104/115 to repress ABA2 , reducing ABA biosynthesis and PYL expression to derepress YSL1/3 expression—a feedback loop balancing Fe and ABA levels. Genetic analyses confirm that this module governs Fe loading, as ABA-deficient mutants ( aba2-1 , nced6-1 ) and pyr1 pyl124 quadruple mutants accumulate higher Fe, while bhlh34 104 115 phenocopies ysl1 ysl3 Fe deficiency. Our findings establish ABA as a dual regulator that safeguards Fe homeostasis by preventing toxicity during maturation while enabling adaptive Fe storage under deficiency. This mechanistic insight opens avenues for bioengineering crops with enhanced seed Fe content, addressing global nutritional challenges.
GPT-4o mini: Non-social science research article
Modulating antigen processing through metal–organic frameworks to bias adaptive immunity
Ezra Cho, Meredith A. Davis, Julia A. Nowak, Mayayi Izzo, Anna Maria Ferrante, Fanrui Sha, Julian S. Magdalenski, Omar K. Farha, Michelle H. Teplensky
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Vaccines induce specific immunity through antigen uptake and processing. However, while nanoparticle vaccines have elevated uptake, the impact of intracellular protein release and how this affects processing and downstream responses are not fully understood. Herein, we reveal how tuning unmodified antigen release rate, specifically through modulation of metal–organic framework (MOF) pore size, influences the type and extent of raised adaptive immunity. We use two MOFs in the NU-100x series with 1.4 nm difference in pore diameter, employ facile postsynthesis loading to achieve significant internalization of model protein antigen ovalbumin ( ca. 1.4 mg/mg), and observe distinct antigen release and intracellular processing profiles influenced by MOF pore size. We investigate how this difference in release biases downstream CD8 + , T H 1, and T H 2 T cell responses. Ovalbumin-loaded NU-1003 induced 1.8-fold higher CD8 + :CD4 + T cell proliferation ratio and displayed 2.2-fold greater ratio of CD4 + T H 1:T H 2 cytokines compared to ovalbumin-loaded NU-1000. Antigen released from NU-1000 in vivo exhibited stronger antigen-specific IgG responses, which is dependent on CD4 + T cells (up to ninefold stronger long-term antibody production and 5.9-fold higher IgG1:IgG2a ratio), compared to NU-1003. When translated to wild-type SARS-CoV-2 receptor-binding domain (RBD) protein, RBD-loaded NU-1000 induced 60.5-fold higher IgG1:IgG2a compared to NU-1003. Wild-type RBD-loaded NU-1000 immunization also induced a greater breadth of epitope recognition compared to NU-1003, as evidenced by increased binding antibodies to the Omicron RBD variant. Overall, this work highlights how antigen release significantly influences immunity induced by vaccines and offers a path to employ unmodified antigen release kinetics to drive personalized protective responses.
GPT-4o mini: Non-social science research article
Scaffold vaccination for prevention of orthopedic device infection
Alexander M. Tatara, Shanda Lightbown, Shawn Kang, Wei-Hung Jung, Hamza Ijaz, Jean C. Lee, Sandra B. Nelson, Michael Super, David J. Mooney
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Staphylococcus aureus is the leading cause of global bacterial mortality. While S. aureus can cause a variety of diseases, orthopedic device infections are particularly challenging due to the need for additional surgeries with associated morbidity. Conventional vaccine technology has failed to prevent S. aureus orthopedic device infection in animal models and clinical trials. In this study, injectable scaffold vaccines are presented as a modality to augment host immunity and mitigate orthopedic device infection. These scaffold vaccines increased cytokine production, antigen-specific cell-mediated immune responses, and humoral responses. When loaded with a pool of antigens collected via an engineered human opsonin, these scaffold vaccines decreased the bacterial burden against methicillin-susceptible and methicillin-resistant S. aureus (MRSA) strains in a murine model of orthopedic device infection. Scaffold vaccination was ~100× more effective in decreasing S. aureus burden compared to prior published immunotherapy attempts in murine models of orthopedic device infection. Scaffold vaccination was also effective when using a monovalent protein-based antigen. Scaffold vaccination is an alternative strategy to facilitate more robust immunity in scenarios where conventional bolus vaccines have not been effective.
GPT-4o mini: Non-social science research article
Divergent evolutionary dynamics of benign and malignant tumors
George Butler, Joanna Baker, Sarah R. Amend, Kenneth J. Pienta, Chris Venditti
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Benign and malignant (cancerous) tumors differ markedly in their impact on organismal fitness, yet studies in comparative oncology rarely distinguish between them. Using a Bayesian phylogenetic framework across birds and mammals, we show that while both tumor types increase in prevalence with body mass, only the prevalence of malignant tumors is negatively associated with the rate of body size evolution—suggesting that adaptive mechanisms of cancer defense are associated with rapidly evolving lineages. Additionally, the rate of lineage diversification is positively associated with the prevalence of both tumor types in birds but not mammals, potentially reflecting differences in genome architecture and speciation dynamics. Together, these results highlight distinct macroevolutionary drivers of benign versus malignant tumor prevalence and underscore the value of treating tumor types separately in comparative oncology.
GPT-4o mini: Non-social science research article
Suppression of pair beam instabilities in a laboratory analogue of blazar pair cascades
Charles D. Arrowsmith, Francesco Miniati, Pablo J. Bilbao, Pascal Simon, Archie F. A. Bott, Stephane Burger, Hui Chen, Filipe D. Cruz, Tristan Davenne, Anthony Dyson, Ilias Efthymiopoulos, Dustin H. Froula, Alice Goillot, Jon T. Gudmundsson, Dan Haberberger, Jack W. D. Halliday, Tom Hodge, Brian T. Huffman, Sam Iaquinta, G. Marshall, Brian Reville, Subir Sarkar, Alexander A. Schekochihin, Luis O. Silva, Raspberry Simpson, Vasiliki Stergiou, Raoul M. G. M. Trines, Thibault Vieu, Nikolaos Charitonidis, Robert Bingham, Gianluca Gregori
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The generation of dense electron–positron pair beams in the laboratory can enable direct tests of theoretical models of γ -ray bursts and active galactic nuclei. We have successfully achieved this using ultrarelativistic protons accelerated by the Super Proton Synchrotron at (CERN). In the first application of this experimental platform, the stability of the pair beam is studied as it propagates through a meter-length plasma, analogous to TeV γ -ray-induced pair cascades in the intergalactic medium. It has been argued that pair beam instabilities disrupt the cascade, thus accounting for the observed lack of reprocessed GeV emission from TeV blazars. If true, this would remove the need for a moderate strength intergalactic magnetic field to explain the observations. We find that the pair beam instability is suppressed if the beam is not perfectly collimated or monochromatic, hence the lower limit to the intergalactic magnetic field inferred from γ -ray observations of blazars is robust.
GPT-4o mini: Non-social science research article
Chemokine/cytokine-releasing biomaterials induce in situ tertiary lymphoid–like structures and enhance antitumor immunity
Rana Falahat, James J. Mulé
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Despite the growing recognition of tertiary lymphoid structures (TLSs) as valuable prognostic markers in certain cancer types, detailed studies on their development and therapeutic function remain limited. This is partially due to the lack of appropriate preclinical animal models. In this study and based on our earlier work [D. Coppola et al., Am. J. Pathol. 179 , 37–45 (2011); J. L. Messina et al., Sci. Rep. 2 , 765 (2012)], we hypothesized that encapsulating lymphoid chemokines and cytokines in controlled-release biomaterials would allow for their sustained delivery to the local tissue microenvironment, promote immune T-cell and B-cell accumulation, and lead to the in situ formation of TLS-like structures. To test this hypothesis, we encapsulated CCL19, CCL21, CXCL13, and lymphotoxin-α1ÎČ2 in lipid-coated microparticles (MPs) and embedded them in a biodegradable thermosensitive hydrogel designed to gel rapidly and release encapsulated payloads at injection sites over several days. In mice, subcutaneous injections of chemokine/cytokine-releasing MPs in hydrogel led to a substantial increase in CD45 + immune cell accumulation within newly developed structures surrounding the residual hydrogel after 3 wk. This influx was accompanied by a marked increase in the numbers of CD19 + B cells and CD3 + T cells. Using a mouse model of melanoma, we further show these induced structures can suppress tumor growth by promoting tumor antigen-specific T-cell responses. These findings indicate that chemokine/cytokine-releasing MPs in hydrogel can induce lymphoid structures resembling TLSs, highlighting their potential both as preclinical models for elucidating mechanisms regulating TLS formation and as platforms for therapeutic interventions against tumors.
GPT-4o mini: Non-social science research article
Impact of biomanufacturing protein fibers on achieving sustainable development
Benjamin D. Allen, Baljit Ghotra, Birgit Kosan, Philipp Köhler, Marcus Krieg, Christoph Kindler, Michael Sturm, Melik C. Demirel
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Biomanufactured fibers produced through fermentation processes provide a promising pathway to decouple textile production from agricultural land. This would free up arable land for food cultivation and contribute to the United Nations Sustainable Development Goal 2: Zero Hunger. Protein fibers from natural sources such as cocoon silk, collagen, and soy have attracted attention since the last century. However, commercial production declined with the rise of cheaper synthetic fibers and competition for food crops. Recently, renewed interest in protein fibers has emerged as a means to minimize plastic pollution, fueled by advances in fermentation, even though challenges related to yield, costs, and industrial spinning persist. Here, we studied a lyocell-based technique for spinning protein fibers using yeast biomass purified through an enzymatic method. We demonstrated that the enzymatic approach produces insoluble proteins that can be continuously spun for over 100 h of production time. Pilot-scale production exhibited stable spinning behavior with high viscosity and consistency quality. We achieved fiber fineness between 1.7 and 2.2 dtex, with strength values reaching 23 cN/tex, which is 50% higher than those of natural protein fibers such as wool. Life cycle assessment indicates that fermentation-based protein fibers require significantly less land and water than natural fibers while providing a reduced environmental footprint. Techno-economic analysis indicates a cost of $6 per kilogram at a production rate of 6,750 t annually. Adopting biomanufacturing-based protein fibers marks a significant advancement toward a future where fiber needs are fulfilled without compromising the planet’s capacity to nourish its growing population.
GPT-4o mini: Non-social science research article
Drug-loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy
Jinjin Wang, Xisha Huang, Qiangqiang Shi, Kelsey L. Swingle, Alex G. Hamilton, Ningqiang Gong, Michael J. Mitchell
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Bispecific T cell engager (BiTE) therapeutics that link T cells and tumor cells to induce tumor cell lysis have demonstrated great success in the clinic for the treatment of many cancers. However, T cell exhaustion in the tumor microenvironment leads to tumor cell escape and BiTE therapy resistance. Herein, we developed a drug-loaded bispecific T cell nanoengager (NanoBiTE) to overcome this obstacle. NanoBiTE is composed of a mesoporous silica nanoparticle encapsulating the adenosine A2A receptor antagonist PBF-509 as a core, with a lipid layer surface coating as a shell and modification with anti-CD19 and anti-CD3 antibodies for tumor and T cell binding, respectively. Like the traditional BiTE blinatumomab, NanoBiTE can engage T cells with CD19 + tumor cells to promote tumor cell lysis. However, unlike blinatumomab, which tends to induce T cell exhaustion, we showed that the release of PBF-509 from NanoBiTE suppressed the A2AR pathway and substantially improved tumor cell killing induced by NanoBiTE. Moreover, NanoBiTE treatment led to substantially reduced tumor burden in vivo in a humanized mouse model. Our results demonstrate that NanoBiTE is a safe and potent bispecific therapy that can also reduce T cell exhaustion for cancer immunotherapy.
GPT-4o mini: Non-social science research article
Exploring evolutionary trajectories of drug resistance
Linfeng Hu, Aoxuan Zhang, Arieh Warshel
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Drug resistance poses a major global health challenge, necessitating the development of effective therapeutic strategies. The main challenge is to predict drug-resistant mutations and design drugs that retain efficacy against such evolving targets. Our previous effort in computing the vitality value has provided a framework in assessing drug resistance. While promising, the approach lacked accuracy due to insufficient information about mutation tendencies and protein stability. In this study, we used the Stanford University HIV Drug Resistance Database and observed that drug resistance, usually quantified as K i mutant / K i WT , exhibits a positive correlation with the Maximum Entropy energy, E M a x E n t . However, both drug resistance and vitality are also correlated with the number of mutations, indicating that the virus cannot easily gain resistance through specific mutational pathways and must sacrifice stability and function to escape inhibition. To overcome this number dependence, we looked for a system with less extensive mutagenesis and chose HCV protease. In this case, resistance substitutions cluster at low E M a x E n t values, reflecting a limited mutational space. This restricted landscape enables E M a x E n t to predict evolutionary pathways of resistance and to guide the identification of robust therapeutic candidates.
GPT-4o mini: Non-social science research article
Switching the strict substrate specificities of the ÎČ-ketoacyl-acyl carrier protein synthases, FabH and BioZ
Xudong Hang, Lin Zhang, Yanqiang Huang, Yuanyuan Hu, Qi Zeng, John E. Cronan, Liang Zhang, Hongkai Bi
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The ÎČ-ketoacyl-acyl carrier protein (ACP) synthases are pivotal elongation enzymes that catalyze the condensation of acyl-CoA or acyl-ACP with malonyl-ACP to produce ÎČ-ketoacyl-ACP. Among these, the homologous enzymes FabH (ÎČ-ketoacyl-ACP synthase III) and the recently characterized BioZ play crucial roles, initiating the biosynthetic pathways for fatty acids and biotin, respectively. FabH primarily utilizes acetyl-CoA as the primer substrate, whereas BioZ exclusively condenses the longer glutaryl-CoA, which contains a charged ω-carboxyl group. Despite their similar catalytic mechanisms, the molecular bases for the strict substrate specificities remain undetermined. Here, we report crystal structures of the BioZ: glutaryl-CoA cocrystalized complexes and demonstrate the ability to swap the physiological functions and substrate specificities between FabH and BioZ. This functional interchange was achieved by grafting the ÎČ8-α9 loop plus residue Ala317 of Agrobacterium tumefaciens BioZ to Escherichia coli FabH, resulting in a shift in substrate preference from acetyl-CoA to glutaryl-CoA. The reverse manipulations of BioZ resulted in FabH activity. These data identify the structural elements as the minimal determinants of substrate specificity and enzyme function. These findings provide valuable insights into the molecular mechanisms of substrate recognition and catalysis by FabH and BioZ and offer a foundation for the development of targeted therapeutic strategies against these enzymes.
GPT-4o mini: Non-social science research article
Receptive fields from single-neuron recording and MRI reveal similar information coding for binocular depth
Andrew J. Parker, Ivan Alvarez, Alessandro Mancari, I. Betina Ip, Kristine Krug, Holly Bridge
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The population receptive field (pRF) approach to functional measurement of the sensory properties of magnetic resonance (MR)-identified locations in the human brain was extended to include the third dimension of binocular depth. In total, pRFs were extracted from nine different visual areas (V1, V2, V3, V3AB, V4, V5, V7, Ventral Occipital Cortex: VOC, Lateral Occipital Cortex: LOC) of the human cortex and, where possible, comparisons were made with electrophysiological recordings from homologous areas in the macaque cortex. Human and macaque V1 showed strikingly similar information profiles for the encoding of binocular depth. Further, both human and macaque V5 showed consistent changes in preferred binocular depth of the stimulus, dependent on whether the stimuli were binocularly correlated or anticorrelated. Across the nine areas of the visual cortex explored, the population profiles of pRFs for binocular depth showed evidence of a greater responsiveness to relative depth in higher visual cortical areas, again consistent with the findings from macaque electrophysiology. Overall, the pRF measures of cortical response were more sensitive to fine-scale differences of binocular depth, compared with many existing electrophysiological measures of tuning for binocular depth. Our results show that the pRF method can be extended beyond the characterization of RFs in retinotopic coordinates to reveal higher-order, derived visual properties. The parallels between noninvasive, MR-based measures of pRFs in humans and the electrophysiological recordings of single neurons in experimental animals make a further step toward validation of the pRF methodology.
GPT-4o mini: Non-social science research article
Controlling intracellular processing to enhance spherical nucleic acid immune stimulation
Janice Kang, Michelle H. Teplensky, Jasper W. Dittmar, Michael Evangelopoulos, Jeongmin Hwang, Chad A. Mirkin
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To mount a robust and durable immune response, the antigen in a vaccine must be processed efficiently in the appropriate intracellular compartment. Here, we report an approach for optimizing the antigen processing pathway and efficiency by using the modular design of spherical nucleic acid (SNA) nanostructures. We utilized the substrate specificity of endoplasmic reticulum aminopeptidase1 (ERAP1), a protease known to generate major histocompatibility complex class I (MHC I) epitopes in the endoplasmic reticulum, to design two ERAP1-responsive peptide linkers (EPLs). The peptide linkers append the peptide antigen onto the SNAs to bias the processing pathway toward ERAP1 and to vary the antigen processing efficiency. The two EPLs varied ERAP1 antigen processing efficiency by 10-fold. Subsequently, the EPLs increased colocalization of the antigen with ERAP1 by up to ca. 58% when compared to an SNA that did not employ this linker. The EPL that drove more efficient cleavage, augmented antigen surface presentation by 30%, ex vivo CD8 + T cell proliferation by fivefold, and in vivo generation of proinflammatory and effector memory CD8 + T cells by 5% and 18%, respectively. Furthermore, the more efficiently processed EPL-containing SNA resulted in a 2.5-fold more effective inhibition of E.G7-OVA lymphoma tumors in vivo. Taken together, these findings underscore the importance of the deliberate and rational design of vaccine structures to spatially bias antigen processing and elevate its processing efficiency to augment immune stimulation.
GPT-4o mini: Non-social science research article
The RANK/RANKL axis controls vascular dynamics in the bone marrow
Takeshi Kaneko, Shinya Yari, Junichi Kikuta, Yoshiki Omatsu, Shigeto Seno, Sumire Kikuchi, Kazuma Sato, Kentaro Fujii, Takao Sudo, Tetsuo Hasegawa, Kunimaro Furuta, Qianqian Guo, Samar H. Ibrahim, Kosuke Muraoka, Yoshiaki Okada, Yoshiaki Kubota, Daisuke Okuzaki, Yasuhiro Kobayashi, Atsushi Kumanogoh, Nobuyuki Udagawa, Takashi Nagasawa, Josef M. Penninger, Masaru Ishii
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Receptor activator of nuclear factor kappa B ligand (RANKL) is an essential cytokine that induces osteoclastic differentiation by monocyte-macrophage lineage precursors. Here, we showed that in addition to its conventional action, RANKL controls vascular permeability in the bone marrow, where it facilitates the mobilization of hematopoietic monocytic cells, including osteoclast precursors, and resultantly regulates bone metabolism. RANK, a cognate receptor for RANKL, is abundantly expressed in sinusoidal endothelial cells and controls vascular permeability by regulating the expression patterns of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. High RANKL expression was detected in perivascular C–X–C motif chemokine ligand 12-abundant reticular (CAR) stromal cells. Specific deletion of RANKL expression in CAR cells abrogated the vascular leakage, suggesting that perivascular RANKL is responsible for controlling permeability. In summary, our study revealed a role for RANK/RANKL signaling as a gatekeeper of bone marrow sinusoids in vivo.
GPT-4o mini: Non-social science research article
The role of active mRNA–ribosome dynamics and closing constriction in daughter chromosome separation in Escherichia coli
Chathuddasie I. Amarasinghe, Mu-Hung Chang, Jaana MĂ€nnik, Scott T. Retterer, Maxim O. Lavrentovich, Jaan MĂ€nnik
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The mechanisms by which two sister chromosomes separate and partition into daughter cells in bacteria remain poorly understood. A recent theoretical model has proposed that out-of-equilibrium central dogma reactions involving mRNA and ribosomes play a significant role in this process. Here, we test this idea in the Escherichia coli model system using high-throughput fluorescence microscopy in microfluidic devices. We compare our experimental observations with predictions from a reaction–diffusion model that includes central dogma-related reactions and excluded volume interactions between ribosomal subunits, polysomes, and chromosomal DNA. Our results show that the nonequilibrium reactions of ribosomes cause them to aggregate at the midcell, and this process facilitates the separation of the two daughter chromosomes. However, the observed effects are weaker in live cells than our one-dimensional reaction–diffusion model predicts. Rather than relying solely on active mRNA–ribosome dynamics, our data suggest that the closing division septum via steric interactions and potentially entropic forces between two DNA strands coupled to cell elongation act as additional mechanisms to ensure faithful partitioning of the nucleoids to two daughter cells.
GPT-4o mini: Non-social science research article
Extracellular nanobody screening using conformationally stable GPCR variants
Xin Zhang, Kaixuan Gao, Jia Nie, Hengyu Meng, Xiaoou Sun, Jiawei Zhao, Xiangyu Liu
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G protein–coupled receptors (GPCRs) are prominent drug targets that have attracted intensive efforts in drug screening. Binding-based screening methods for GPCR ligands often require conformationally stable, purified receptors. However, obtaining large quantities of GPCRs in stable states, particularly with unoccupied extracellular ligand-binding pockets and especially in their active conformations, remains challenging due to the inherent dynamic nature of these receptors. To address this challenge, we propose a universal approach for stabilizing GPCRs in specific conformations. Using the M1 muscarinic acetylcholine receptor (M1R) as a model, we successfully stabilized M1R in its active conformation through de novo design of a fusion protein, and further demonstrated the generalizability of this strategy by applying it to other GPCRs. We screened a synthetic yeast display library of nanobodies against both the stabilized active-state and previously reported inactive-state M1R, identifying several nanobodies that specifically recognize each conformation. This method not only facilitates the stabilization of GPCRs in desired states but also provides valuable tools for developing more selective therapeutic agents, enhancing drug discovery efficiency and specificity.
GPT-4o mini: Non-social science research article
BRAF inhibition increases TGFÎČ2 production and stimulates metastasis in mice with endogenous BRAF V600E -induced hepatocellular carcinoma
Jaroslaw Cisowski, Ahmed Ezat El Zowalaty, Sama I. Sayin, Piotr Czarnota, Tomasz Gromowski, Ella A. Eklund, Muhammad Kashif, Angana A. H. Patel, Antonio Molinaro, Per Lindahl, Clotilde Wiel, Volkan I. Sayin, Martin O. Bergo
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The MEK–ERK pathway is a key driver of hepatocellular carcinoma (HCC) pathogenesis, and BRAF mutations, particularly BRAF V600E , can contribute to its activation. Although BRAF V600E mutations are rare in human HCC, they do occur, yet their physiologic impact in liver cells, especially when combined with frequent comutations in tumor suppressor genes, remains poorly understood. Moreover, the effect of BRAF inhibitors on HCC progression and metastasis is not well-defined. Therefore, we developed mouse models with hepatocyte-specific BRAF V600E expression and Trp53 or Cdkn2a deletion to assess tumor development, subtypes, and metastatic patterns. We found that BRAF V600E expression caused hepatomegaly, vascular congestion, and ductal reactions, and led to reduced liver function and early mortality. Codeletion of Trp53 or Cdkn2a markedly increased primary liver tumor incidence and enabled sarcomatoid metastasis. While the BRAF inhibitor PLX4720 effectively reduced primary tumors and extended survival, it paradoxically increased sarcomatoid metastases. Mechanistically, PLX4720 and other RAF inhibitors induced TGFÎČ2 expression which promoted epithelial-to-mesenchymal transition (EMT) and enhanced tumorigenicity. The effects of RAF inhibitors on TGFÎČ2 expression were validated in BRAF V600E -mutant human melanoma cells. We conclude that BRAF V600E drives diverse primary tumors but only one type of metastasis and that RAF inhibition, while effective against primary tumors, may promote metastasis through TGFÎČ2-mediated EMT. Although RAF inhibitors remain promising therapies, their unintended role in enhancing metastasis raises concerns that may extend beyond liver cancer to other BRAF V600E -driven malignancies.
GPT-4o mini: Non-social science research article
Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell–generated cGAMP
Alexander M. Cryer, Pere Dosta, Michelle Z. Dion, Leonardo de la Parra Soto, Eliz Amar-Lewis, Gabriela Garcia de Leon Carmona, Alejandro Abraham Espinosa Pérez, Diego Fernando Ruiz Aguilar, Triana Huerta, Beatriz Nicolås Ruiz, Nathalie Nicole Casteele Hernandez, Yael Soria, Natalie Artzi
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Cancer cells comprise a significant proportion of the tumor microenvironment (TME) and often have compromised expression or repression of cyclic GMP-AMP (cGAMP) synthase (cGAS), which prevents effective stimulation of interferon genes (STING) signaling. Here, we leverage the cancer cells and hijack their cellular machinery for increased production of cGAMP, differing from conventional strategies whereby synthetic STING agonists are delivered to immune cells in the TME as a bolus dose, are rapidly cleared and can cause systemic toxicity. Increasing evidence suggests that cGAMP derived from cancer cells can act on proximal immune cells, activating STING, contributing to an antitumor immune response. We used lipid nanoparticles (LNPs) to deliver mRNA coding for cGAS which catalyzes the production of cGAMP. We observed dramatic increases in extracellular and intracellular cGAMP when cancer cells were transfected with cGAS mRNA and genomic DNA, the substrate for cGAS. We confirmed that cGAS and cGAMP are functional due to activation of immune cells, through a combination of extracellular transfer and cell–cell contact mechanisms. Treatment of syngeneic murine melanoma with cGAS LNPs reduced tumor growth significantly and further benefit was observed upon combination with immune checkpoint blockade (anti-PD-1). Moreover, we found increased activation in CD8 + T cells, NK cells, macrophages, and dendritic cells in the TME post treatment with cGAS LNPs. These findings highlight how cancer cells can be used to actively contribute to their own elimination and may be a broadly applicable strategy for delivery of other reprogramming molecules to cancer cells and wider therapeutic combinations.
GPT-4o mini: Non-social science research article
The synergy of methylphenidate- and reconsolidation-based extinction normalizes ventromedial prefrontal function in drug addiction
Ahmet O. Ceceli, Sarah G. King, K. Rachel Drury, Natalie McClain, John Gray, Priyanthi S. Dassanayake, Jeffrey H. Newcorn, Daniela Schiller, Nelly Alia-Klein, Rita Z. Goldstein
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Drug-related memories can hinder abstinence goals in drug addiction. Promoting nondrugmemories via ventromedial prefrontal cortex (vmPFC)- and amygdala-guided extinctionyields mixed success. Postretrieval extinction (RE) destabilizes and updates memoriesduring reconsolidation, improving extinction. Supplementing RE, we tested methylphenidate(MPH), a dopamine agonist that promotes PFC-dependent learning and memory in cocaineuse disorder (CUD). In a proof-of-concept double-blind randomized clinical trialusing a within-subjects design, participants received oral MPH (20 mg) or placebobefore the retrieval of some of the conditioned stimuli (CS) (i.e., reminded CS+ vs.nonreminded CS+) followed by extinction; lab-simulated drug-seeking was measuredthe following day. Lower vmPFC activity following nonreminded CS+ (standardextinction) under placebo replicated the putative impairments in CUD; separately, RE (trend) and MPH conditions recruited the vmPFC, and RE’s vmPFC-reliance correlatedwith drug-seeking only under placebo. Crucially, MPH-combined RE normalized cortico-limbicprocessing, bypassing the vmPFC and its amygdala connectivity. Pharmacologically-enhanced drug memory modulation may inform intervention development for addictionrecovery.
GPT-4o mini: Non-social science research article
Direct and in situ examination of Li + transport kinetics in an isotope-labeled solid–electrolyte interphase
Xiaofei Yu, Stefany Angarita-Gomez, Yaobin Xu, Peiyuan Gao, Jun-Gang Wang, Xin Zhang, Minyung Song, Hao Jia, Wu Xu, Xiaolin Li, Hsin-Mei Kao, Yingge Du, Zhijie Xu, Janet S. Ho, Kang Xu, Perla B. Balbuena, Chongmin Wang, Zihua Zhu
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Solid–electrolyte interphase (SEI) is the critical component in all advanced battery chemistries, whose ionic transport and electron leakage behaviors remain least understood among all battery components. Here, using unique in situ liquid secondary ion mass spectroscopy on isotope-labeled SEI, assisted by cryogenic transmission electron microscopy and constrained ab initio molecular dynamics simulation, we answer the question regarding the Li + transport mechanism across SEI and quantitatively determine the Li + mobility therein. We unequivocally unveil that Li + transport in SEI mainly follows a mechanism of successive displacement. We further reveal that in accordance with the spatial dependence of SEI structure across the thickness, the apparent Li + self-diffusivity continuously drops from the SEI–electrolyte side to the SEI–electrode side (6.7 × 10 −19 m 2 /s to 1.0 × 10 −20 m 2 /s), setting a quantitative gauging of both ionic transport behavior of the SEI layer against the underlying electrode and the rate-limiting step of battery operation. This direct study on Li + kinetics in SEI fills part of the decade-long knowledge gap about the most important component in advanced batteries and provides more precise guidelines for the tailoring of interphasial chemistries for future battery chemistries.
GPT-4o mini: Non-social science research article
Amino acid insufficiency impairs hepatic vitamin A mobilization in mice
Chintan T. Bhavsar, Youn-Kyung Kim, Flavio C. Rodriguez-Polanco, Brian A. Zalma, Esther M. Lopez, Saad A. Farooq, Maria Ibrahim, Eileen White, Tracy G. Anthony, Loredana Quadro
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Retinol-binding protein 4 (RBP4) is the sole specific serum carrier of vitamin A, delivering it from the hepatic stores to the peripheral organs in a complex with retinol (ROH) and transthyretin (TTR). Regulators of hepatic mobilization aside from vitamin A status itself are ill-defined. Here, we show that amino acid (AA) insufficiency by diet (low-protein, leucine-devoid diet) or drug (asparaginase, ASNase) elevated liver RBP4 without depleting hepatic retinoid stores. In addition, ASNase reduced liver TTR protein. Furthermore, circulating ROH–RBP4–TTR levels were attenuated, and retinoid levels in peripheral organs were perturbed. To understand the basis for elevated RBP4 in the liver, we isolated total and polysomal mRNA to assess gene-specific translation. ASNase significantly reduced Rbp4 mRNA translation, indicating that elevated hepatic RBP4 protein was not due to increased protein synthesis. In contrast, ASNase reduced Ttr mRNA abundance but not its translation. Global deletion of the AA insufficiency sensor, general control nonderepressible 2 (GCN2), lessened ASNase-induced RBP4 protein accumulation in the liver but did not rescue circulating ROH–RBP4 levels. These effects were replicated by chemical inhibition of GCN2 in ASNase-exposed primary hepatocytes. Finally, hepatocyte-specific knockout of autophagy-related 7, an enzyme involved in autophagy and protein secretion, fully rescued circulating ROH–RBP4–TTR and normalized liver RBP4 and TTR during ASNase. Overall, our findings identify AA insufficiency to modulate hepatic ROH–RBP4 mobilization independent of vitamin A status.
GPT-4o mini: Non-social science research article
Chemical compensation to mechanical loss in cell mechanosensation
Qin Ni, Zhuoxu Ge, Anindya Sen, Yufei Wu, Jinyu Fu, Alice Amitrano, Nitish Srivastava, Konstantinos Konstantopoulos, Sean X. Sun
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Mammalian cells sense and respond to environmental changes using a complex and intelligent system that integrates chemical and mechanical signals. The transduction of mechanical cues into chemical changes modulates cell physiology, allowing a cell to adapt to its microenvironment. Understanding how the chemical and mechanical regulatory modules interact is crucial for elucidating mechanisms of mechanosensation and cellular homeostasis. In this study, we find that cells exhibit nonmonotonic changes in cell volume and intracellular pH when subjected to physical stimuli and varying degrees of actomyosin cytoskeleton disruption. We find that these nonmonotonic responses are mediated by a chemical compensation mechanism, where the attenuation of actomyosin activity stimulates the activity of PI3K/Akt pathway. This, in turn, activates sodium-hydrogen exchanger 1 (NHE1), resulting in elevated intracellular pH and increased cell volume. Furthermore, we identify a competitive interaction between the PI3K/Akt and MAPK/ERK pathways—two major regulators of cell proliferation and motility. This competition modulates the chemical compensation based on the relative activities of these pathways. Our mathematical modeling reveals the network structure that is essential for establishing the nonmonotonic response. Interestingly, this regulatory system is altered in HT1080 fibrosarcoma, highlighting a potential mechanistic divergence in cancer cells in contrast to their normal-like counterpart, such as NIH 3T3 and HFF-1 fibroblasts. Overall, our work reveals a compensatory mechanism between chemical and mechanical signals, providing an infrastructure to elucidate the integrated mechanochemical response to environmental stimuli.
GPT-4o mini: Non-social science research article
A viral Cyclin D homolog protein hijacks the metabolic stress sensor SESN2 to promote primary effusion lymphoma growth
Mingjun Lin, Guanya Li, Xinyu Tang, Ru Li, Yinan Li, Lijie Wang, Zeyu Xu, Liansheng Liu, Enguo Ju, Jian Shang, Shanping He, Tingting Li
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Metabolic pathways are typically dysregulated in cancer to support critical cellular processes. In response to metabolic disturbances, cancer cells preferentially manipulate stress sensors to enhance their adaptability. Sestrin 2 (SESN2), a highly conserved protein induced by various stressors, is implicated in this adaptation. Mutations and alterations of SESN2 are prevalent among cancer patients, suggesting a potential role in tumor progression. However, the functions and regulation of SESN2 in cancer, particularly in virus-induced cancer, remain largely unknown. In this study, we demonstrate that latent infection with Kaposi’s sarcoma–associated herpesvirus (KSHV) stabilizes and upregulates SESN2 by inhibiting its proteasomal degradation across multiple cell lines. Notably, KSHV-encoded vCyclin, a homolog of cellular Cyclin D, directly interacts with SESN2 and promotes its stabilization by recruiting the deubiquitinase OTUB1, thereby blocking SESN2 polyubiquitination and proteasomal degradation. Moreover, vCyclin- and OTUB1-mediated stabilization of SESN2 activates AMP-activated protein kinase (AMPK), which supports the survival and growth of KSHV-driven primary effusion lymphoma cells. Importantly, the lysine at residue 74 of vCyclin is crucial for its cytosolic localization, OTUB1 recruitment, and subsequent SESN2 upregulation and AMPK activation. These findings unveil a regulatory mechanism for SESN2 involving vCyclin and OTUB1, positioning them as potential therapeutic targets for diseases associated with AMPK dysregulation.
GPT-4o mini: Non-social science research article
Robert Haselkorn (1934–2025): Pioneer in molecular biology and microbiology
Susan S. Golden, David J. DeRosier, James E. Dahlberg, Louis A. Sherman, Bianca Brahamsha
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Robert Haselkorn (1934–2025) began a long and impactful career during the early years of nucleic acids research when the foundations of molecular biology were being laid. Focusing first on plant viruses, and then also bacteriophage, he hit upon a cyanophage—a cyanobacterial virus—that led his group to establish cyanobacterial strains as model organisms for fundamental bacterial research. He established that the specialized cells called heterocysts that are differentiated by multicellular Anabaena ( Nostoc ) are the sites of biological nitrogen fixation, and went on to reveal mechanisms of prokaryotic development. The Haselkorn lab became a leader more broadly in prokaryotic gene, and later genome, sequencing and annotation. Appreciated for his generosity and unwavering support of his lab members, and his contributions to creating a field of cyanobacterial molecular genetics, his impact continues across molecular biology and microbiology through those whose creativity he encouraged.
GPT-4o mini: Non-social science research article
Structural basis for a potent human neutralizing antibody targeting a conserved epitope on the H7 hemagglutinin head
Junxin Li, Min Wang, Yang Yang, Limin Zhang, Lvyan Liu, Wei Yang, Yun Peng, Xu Zhang, Bin Yuan, Qi Peng, Xiaolu Yang, Yixin Chen, George F. Gao, Yi Shi, Xiaochun Wan
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Zoonotic H7N9 avian influenza virus infection remains a global concern because of its pandemic potential. Therefore, developing effective antibodies and vaccines against H7N9 is vital for preventing and controlling major outbreaks. Here, we isolated a human VH3-30 gene-encoded antibody, designated 6Y13, from a survivor of H7N9 infection. This antibody recognized the hemagglutinins (HAs) of the representative H7 subtype zoonotic viruses spanning two decades of antigenic evolution and potently neutralized epidemic H7N9 viruses in vitro. Moreover, 6Y13 conferred complete protection in mice against lethal H7N9 challenge in both prophylactic and therapeutic experiments. Structural analysis by cryoelectron microscopy indicated that 6Y13 binds to a unique conserved site on the HA head, distinct from the receptor-binding site and lateral patch. Nevertheless, 6Y13 efficiently blocked viral receptor binding without interfering with HA receptor binding, independent of Fc-mediated steric hindrance. Our findings provide a promising therapeutic candidate against pan-H7 subtype viruses and are beneficial for the design of H7 subtype influenza vaccine immunogens.
GPT-4o mini: Non-social science research article
Electromechanically induced membrane restructuring enables learning and memory
Peter T. Podar, Dima Bolmatov, Teshani Kumarage, Rana Ashkar, Ariana Adkisson, Olivia Ziemer, Victoria Sullivan, Ahmed S. Mohamed, Joseph. S. Najem, C. Patrick Collier, John Katsaras
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Human neural networks of interconnected neurons have evolved to be remarkably efficient and are capable of learning and memory through the brain’s synaptic plasticity, including short-term plasticity (STP), and long-term potentiation (LTP) and depression (LTD). These activity-dependent mechanisms induce changes in synaptic efficiency over both transient and extended timescales. Understanding the molecular basis of learning and memory is central to deciphering brain function and advancing therapeutics for neurodegenerative diseases. Here, we report that lipid bilayers with embedded gramicidin A ion channels can structurally reorganize when interrogated using a neurologically inspired electrical stimulation protocol, adopting metastable structures with enhanced STP response and emergent LTP or LTD. Specifically, voltage-induced electrocompression is found to restructure membranes, driving them into nonequilibrium steady states with enhanced stability and increased ionic conductivity, leading to stronger and persistent membrane ion conductance. These results show how membrane restructuring and emergent complexity may regulate synaptic plasticity at the molecular level.
GPT-4o mini: Non-social science research article
ENKD1 attenuates antibacterial immunity by facilitating TRIM21-mediated RUBCN degradation to suppress LC3-associated phagocytosis
Caimeng Song, Lulu Sun, Jie Wang, Shujun Liu, Wenqing Xu, Cai Zhang, Jun Zhou, Tianliang Li, Yan Li
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Microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP) plays a critical role in host defense against invading pathogens, including Listeria monocytogenes ( Listeria. monocytogenes ) , Salmonella typhimurium ( S. typhimurium ) , and Francisella novicida ( F. novicida ) . However, the precise regulatory mechanisms controlling LAP remain poorly understood. Here, we identify enkurin domain-containing protein 1 (ENKD1) as a key negative regulator of LAP during infection with these pathogens. Macrophages infected with L. monocytogenes (10403S), S. typhimurium (ATCC14028), or F. novicida (U112) exhibit significant ENKD1 downregulation. ENKD1-deficient macrophages display enhanced antibacterial activity, characterized by increased LAP, higher reactive oxygen species production, enhanced LC3 lipidation on phagosomes, and improved phagosome-lysosome fusion. In vivo, ENKD1 - deficient mice ex hibited improved bacterial clearance in the liver and spleen, with notable survival benefits. Mechanistically, ENKD1 interacts with the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21), which mediates degradation of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN) through K48-linked polyubiquitination, thereby dampening RUBCN’s role in LAP. Our findings reveal an ENKD1–TRIM21–RUBCN axis that suppresses LAP, providing insights into antibacterial immune regulation and suggesting potential therapeutic strategies to enhance host defense against intracellular pathogens.
GPT-4o mini: Non-social science research article
Hund’s flat band in a frustrated spinel oxide
Dongjin Oh, Alexander Hampel, Joshua P. Wakefield, Peter C. Moen, Steef Smit, Xiangyu Luo, Marta Zonno, Sergey Gorovikov, Mats Leandersson, Craig Polley, Asish K. Kundu, Anil Rajapitamahuni, Elio Vescovo, Chris Jozwiak, Aaron Bostwick, Eli Rotenberg, Masahiko Isobe, Manish Verma, Matteo Crispino, Martin Grundner, Fabian B. Kugler, Olivier Parcollet, Ulrich Schollwöck, Hidenori Takagi, Andrea Damascelli, Giorgio Sangiovanni, Joseph G. Checkelsky, Antoine Georges, Riccardo Comin
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Electronic flat bands associated with quenched kinetic energy and heavy electron mass have attracted great interest for promoting strong electronic correlations and emergent phenomena such as high-temperature charge fractionalization and superconductivity. Intense experimental and theoretical research has been devoted to establishing the rich nontrivial metallic and heavy fermion phases intertwined with such localized electronic states. Here, we investigate the transition metal oxide spinel LiV 2 O 4 , an enigmatic heavy fermion compound lacking localized f orbital states. We use angle-resolved photoemission spectroscopy and dynamical mean-field theory to reveal a kind of correlation-induced flat band with suppressed interatomic electron hopping arising from intra-atomic Hund’s coupling. The appearance of heavy quasiparticles is ascribed to a proximate orbital-selective Mott state characterized by fluctuating local moments as evidenced by complementary magnetotransport measurements. The spectroscopic fingerprints of long-lived quasiparticles and their disappearance with increasing temperature further support the emergence of a high-temperature “bad” metal state observed in transport data. This work resolves a long-standing puzzle on the origin of heavy fermion behavior and unconventional transport in LiV 2 O 4 . Simultaneously, it opens a path to achieving flat bands through electronic interactions in d -orbital systems with geometrical frustration, potentially enabling the realization of exotic phases of matter such as the fractionalized Fermi liquids.
GPT-4o mini: Non-social science research article
Modeling protein–small molecule conformational ensembles with PLACER
Ivan Anishchenko, Yakov Kipnis, Indrek Kalvet, Guangfeng Zhou, Rohith Krishna, Samuel J. Pellock, Anna Lauko, Gyu Rie Lee, Linna An, Justas Dauparas, Frank DiMaio, David Baker
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Modeling the conformational heterogeneity of protein–small molecule interactions is important for understanding natural systems and evaluating designed systems but remains an outstanding challenge. We reasoned that while residue-level descriptions of biomolecules are efficient for de novo structure prediction, for probing heterogeneity of interactions with small molecules in the folded state, an entirely atomic-level description could have advantages in speed and generality. We developed a graph neural network called PLACER (protein-ligand atomistic conformational ensemble resolver) trained to recapitulate correct atomic positions from partially corrupted input structures from the Cambridge Structural Database and the Protein Data Bank; the nodes of the graph are the atoms in the system. PLACER accurately generates structures of diverse organic small molecules given knowledge of their atom composition and bonding. When given a description of the larger protein context, it builds up structures of small molecules and protein side chains for protein–small molecule docking. Because PLACER is rapid and stochastic, ensembles of predictions can be readily generated to map conformational heterogeneity. In enzyme design efforts described here and elsewhere, we find that using PLACER to assess the accuracy and preorganization of the designed active sites results in higher success rates and higher activities; we obtain a preorganized retroaldolase with a k cat / K M of 11,000 M −1 min −1 , considerably higher than any pre–deep learning design for this reaction. We anticipate that PLACER will be widely useful for rapidly generating conformational ensembles of small molecule and small molecule–protein systems and for designing higher activity preorganized enzymes.
GPT-4o mini: Non-social science research article
A multivalent nanobody–drug conjugate to prevent and treat influenza virus infections
Thibault J. Harmand, Laura Pietrok, Helen Rich, Rhogerry Deshycka, Laney Flanagan, Aaron Accardo, Novalia Pishesha, Hidde L. Ploegh
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We describe the production and use of nanobody drug conjugates that comprise of VHH kappa , a nanobody that recognizes mouse immunoglobulin kappa light chains, and one or more copies of the small molecule influenza virus neuraminidase (NA) inhibitor, zanamivir. Such compounds achieve half-life extension of zanamivir, while recruiting polyclonal immunoglobulins of all isotypes regardless of specificity to infected cells for antibody-dependent cell-mediated cytotoxicity and complement-dependent cellular cytotoxicity. Since the influenza A virus (IAV) NA is a tetramer, we produced VHH kappa adducts with 1, 2, or 4 zanamivir molecules attached in a site-specific manner, to allow multivalent engagement of NA. Administration of a VHH kappa adduct modified with 4 zanamivir molecules (VHH kappa –Zan 4 ) was ~10-fold more potent in protection against infection with IAV than VHH kappa –Zan carrying only a single zanamivir molecule. VHH kappa –Zan 4 can be given intranasally to confer full protection against a lethal IAV challenge. The neutralizing antibody titers in the respiratory mucosa and in the circulation, as well as the serum IgG antibody response against the hemagglutinin and nucleoprotein, are higher in VHH kappa –Zan 4 treated mice that survived the lethal challenge than in controls infected with a sublethal dose of virus. VHH kappa –Zan 4 affords protection even when given intranasally weeks prior to a challenge with a lethal dose of IAV. This type of adduct can therefore be applied prophylactically and therapeutically and does not require prior immunization for protection against a lethal dose of IAV.
GPT-4o mini: Non-social science research article
Structural immunotherapy: Harnessing chemical design to build powerful next-generation therapeutics
Michelle H. Teplensky, Julianna N. Bourgeois, Sergej Kudruk, Sarah Hurst Petrosko, Chad A. Mirkin
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Structural immunotherapy relies on the structural features of immunotherapeutics in addition to component identity to influence biodistribution, intra- or extracellular localization, target engagement, and processing kinetics. This strategy is poised to redefine how immunotherapeutics mobilize immunity against disease and transform our ability to harness structure–function relationships to enhance clinical outcomes.
GPT-4o mini: Non-social science research article
Secreting salt glands constrain cuticle fracture to enhance desalination efficiency
Melissa H. Mai, Fulton E. Rockwell, Juan M. Losada, Nya Nicholson, Zhigang Suo, N. Michele Holbrook
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Plants responding to excessive soil salinity by discharging brine onto their leaf surface risk dehydration through the osmotic continuity between the living tissue and the surface brine, which further enriches with evaporation. Cuticle cracks have long been identified as essential for salt to reach the leaf surface but enable a potentially desiccating continuity between the brine and the gland interior. Using the secreting salt gland of Nolana mollis as a model system, we integrate mathematical modeling, imaging, and physiological measurements to examine the mechanical and biochemical processes required for efficient salt removal. We find that the subcuticular space between the concentrated surface brine and the more dilute secreting cell eases the energetic limits of active salt secretion by reducing the concentration gradient of salt across the cell membrane. We show that crack size plays a critical role in balancing the osmotic and pressure gradients required for salt removal without runaway foliar desiccation.
Strategic analysis of dissent and self-censorship
Joshua J. Daymude, Robert Axelrod, Stephanie Forrest
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Expressions of dissent against authority are an important feature of most societies, and efforts to suppress such expressions are common. Modern digital communications, social media, and Internet surveillance and censorship technologies are changing the landscape of public speech and dissent. Especially in authoritarian settings, individuals must assess the risk of voicing their true opinions or choose self-censorship, voluntarily moderating their behavior to comply with authority. We present a model in which individuals strategically manage the tradeoff between expressing dissent and avoiding punishment through self-censorship while an authority adapts its policies to minimize both total expressed dissent and punishment costs. We study the model analytically and in simulation to derive conditions separating defiant individuals who express their desired dissent in spite of punishment from self-censoring individuals who fully or partially limit their expression. We find that for any population, there exists an authority policy that leads to total self-censorship. However, the probability and time for an initially moderate, locally adaptive authority to suppress dissent depend critically on the population’s willingness to withstand punishment early on, which can deter the authority from adopting more extreme policies.
Recent immigration raids increased student absences
Thomas S. Dee
Full text
Local immigration raids expanded dramatically across the United States during the first 2 mo of 2025. Anecdotal accounts suggest that these raids increased student absences from schools because parents fear being separated from their children. This study evaluates this claim using a daily time series of school absences spanning the current and two prior school years from five school districts serving communities subject to recent and unexpected raids in California’s Central Valley. The results indicate that recent raids coincided with a 22 percent increase in daily student absences with particularly large increases among the youngest students. These increased absences underscore the broader policy relevance of this immigration enforcement in terms of their impact on schools, childhood stress, and opportunities to learn.
The 2020 US Decennial Census is more private than you (might) think
Buxin Su, Weijie J. Su, Chendi Wang
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The US Decennial Census serves as the foundation for many high-profile policy decision-making processes, including federal funding allocation and redistricting. In 2020, the Census Bureau adopted differential privacy to protect the confidentiality of individual responses through a disclosure avoidance system that injects noise into census data tabulations. The Bureau subsequently posed an open question: Could stronger privacy guarantees be obtained for the 2020 US Census compared to their published guarantees, or equivalently, had the privacy budgets been fully utilized? In this paper, we address this question affirmatively by demonstrating that the 2020 US Census provides significantly stronger privacy protections than the officially published guarantees suggest at each of the eight geographical levels, from the national level down to the block level. This finding is enabled by our precise tracking of privacy losses using f -differential privacy, applied to the composition of private queries across these geographical levels. Our analysis reveals that the Census Bureau introduced unnecessarily high levels of noise to meet the specified privacy guarantees for the 2020 Census. Consequently, we show that noise variances could be reduced by 15.08% to 24.82% while maintaining nearly the same level of privacy protection for each geographical level, thereby improving the accuracy of privatized census statistics. We empirically demonstrate that reducing noise injection into census statistics mitigates distortion caused by privacy constraints in downstream applications of private census data, illustrated through a study examining the relationship between earnings and education.
The lower boundary of workplace mistreatment: Do small slights matter?
Michal Hodor, Liat Eldor, Peter Cappelli
Full text
Recent research in psychology, management, and more recently in economics, highlights the role of individual managers and their behavior in shaping employee performance. While emerging literature on harmful managerial behavior has focused primarily on severe forms of workplace mistreatment, especially various types of harassment, much less is known about its boundary conditions: How minor can a manager’s bad behavior be and still negatively affect employee performance? We study what appears to be a very minor workplace mistreatment—failing to deliver an expected birthday gift and greeting card on time—and examine its effect on subsequent employee performance. Using a dynamic difference-in-differences approach with detailed data from a national retail chain, we find that this small slight leads to over a 50% increase in employee absenteeism and a reduction of more than two working hours per month. Our analysis suggests that emotional responses to perceived workplace mistreatment drive the results. These findings indicate that even modest slights can meaningfully harm employee performance.

Science

GPT-4o mini: Non-social science research article
Direct targeting and regulation of RNA polymerase II by cell signaling kinases
Preeti Dabas, Meritxell B. Cutrona, Wojciech Rosikiewicz, Ryan P. Kempen, Patrick Rodrigues, John Bowling, Mollie S. Prater, Walter H. Lang, Adithi Danda, Zhi Yuan, Beisi Xu, Shondra M. Pruett-Miller, Gang Wu, Taosheng Chen, Aseem Z. Ansari
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Distinct phosphorylation marks are placed on the carboxyl-terminal domain (CTD) of RNA polymerase II (Pol II) during different stages of gene transcription. These phospho-CTD marks function as a molecular recognition code for the recruitment of stage-specific effector proteins. Querying ~80% of the human kinome, we identified 117 kinases that phosphorylate the CTD with a high degree of positional selectivity. The unifying characteristic linking these diverse kinases is that they selectively regulate Pol II at signal-responsive genes. An example of such “direct-at-gene” Pol II regulation is displayed by epidermal growth factor receptor (EGFR), a cell surface receptor tyrosine kinase. More broadly, our atlas of CTD kinases implicates Pol II as a direct regulatory end point for signal-transducing kinases that govern cellular physiology and contribute to the etiology of numerous diseases.
GPT-4o mini: Non-social science research article
Repair of DNA double-strand breaks leaves heritable impairment to genome function
Susanne Bantele, Irene Mordini, Alva Biran, Nicolas Alcaraz, Gijs Zonderland, Alice Wenger, Nils Krietenstein, Anja Groth, Jiri Lukas
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Upon DNA breakage, a genomic locus undergoes alterations in three-dimensional chromatin architecture to facilitate signaling and repair. Although cells possess mechanisms to repair damaged DNA, it is unknown whether the surrounding chromatin is restored to its naĂŻve state. We show that a single DNA double-strand break (DSB) within a topologically associated domain (TAD) harboring conformation-sensitive genes causes lasting chromatin alterations, which persist after completion of DNA repair and feature topological rearrangements and loss of local RNA species. These newly acquired features of postrepair chromatin are transmitted to daughter cells and manifest as heritable impairments of gene expression. These findings uncover a hitherto concealed dimension of DNA breakage, which we term postrepair chromatin fatigue and which confers heritable impairment of gene function beyond DNA repair.
GPT-4o mini: Non-social science research article
Shear-induced bubble nucleation in magmas
Olivier Roche, Jean-Michel Andanson, Alain Dequidt, Christian Huber, Olivier Bachmann, David Pinel
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The nucleation of gas bubbles in magmas is fundamental to controlling the dynamics of volcanic eruptions. In this study, we addressed nucleation in a volatile-saturated liquid triggered by viscous shear, which is ubiquitous in volcanic environments. By combining laboratory experiments, theoretical analysis, and numerical simulations, we investigated the conditions under which the mechanical energy associated with shearing favors the formation and growth of gas molecule nuclei in a liquid supersaturated with volatiles. Our results reveal that the critical shear stress for nucleation decreases as the volatile supersaturation increases. Dimensional analysis applied to natural systems shows that shear-induced nucleation is likely to occur in volcanic conduits, which has implications for magma degassing processes and eruptive styles.
GPT-4o mini: Non-social science research article
Probing critical phenomena in open quantum systems using atom arrays
Fang Fang, Kenneth Wang, Vincent S. Liu, Yu Wang, Ryan Cimmino, Julia Wei, Marcus Bintz, Avery Parr, Jack Kemp, Kang-Kuen Ni, Norman Y. Yao
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At continuous phase transitions, quantum many-body systems exhibit complex, emergent behavior. Most notably, at a quantum critical point, correlations decay as a power law, with exponents determined by a set of universal scaling dimensions. Experimentally probing such power law correlations is extremely challenging, owing to the interplay between decoherence, the vanishing energy gap, and boundary effects. In this work, we used a Rydberg quantum simulator to adiabatically prepare critical ground states of both a one-dimensional ring and a two-dimensional square lattice. By accounting for and tuning the openness of our quantum system, which is well-captured by a single phenomenological length scale, we directly observed power law correlations and extracted the corresponding scaling dimensions. Our work complements recent studies of quantum criticality that use the Kibble-Zurek mechanism and digital quantum circuits.
GPT-4o mini: Non-social science research article
Multi-timescale frequency-phase matching for high-yield nonlinear photonics
Mahmoud Jalali Mehrabad, Lida Xu, Gregory Moille, Christopher J. Flower, Supratik Sarkar, Apurva Padhye, Shao-Chien Ou, Daniel G. SuĂĄrez-Forero, Mahdi Ghafariasl, Yanne Chembo, Kartik Srinivasan, Mohammad Hafezi
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Integrated nonlinear photonics struggles to deliver wafer-scale functional device yields: Nanometer-level fabrication variations compromise the strict frequency-phase matching mandated by energy- and momentum-conserving nonlinear processes. We introduce nested frequency-phase matching, a passive scheme that relaxes these constraints, and implement it in a two-timescale lattice of commercially available silicon nitride (SiN) coupled ring resonators for harmonic generation. The nested lattice simultaneously generates ultrabroad bandwidth light in the fundamental-, second-, third-, and fourth-harmonic bands and achieves 100% multifunctional wafer-scale device yield, all passively and without geometry fine-tuning. Distinct spatial and spectral signatures confirm the predicted relaxation of frequency-phase matching, establishing a scalable route for chip-scale nonlinear optics. Our approach provides possibilities for integrated frequency conversion and synchronization, self-referencing, precision metrology, squeezed-light sources, and nonlinear optical computing.
GPT-4o mini: Non-social science research article
River metabolism in the contiguous United States: A West of extremes
Taylor Maavara, Zimin Yuan, Andrew M. Johnson, Shuang Zhang, Kelly S. Aho, Craig B. Brinkerhoff, Laura A. Logozzo, Peter Raymond
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River metabolism is among the most uncertain fluxes in the global carbon cycle. We present estimates for gross primary productivity (GPP) and ecosystem respiration (ER) for more than 175,000 rivers across the contiguous United States (CONUS), including metabolic responses to extreme hydrological conditions. Our model predicts an annual GPP in CONUS rivers of 10.1 teragrams of carbon per year and an ER of 18.7 teragrams of carbon per year, which implies that net ecosystem productivity (NEP; where NEP = GPP – ER) is a small contributor to river carbon dioxide emissions. More than 70% of river metabolism occurs in the West, where regions of both extreme heterotrophy and autotrophy exist. Autotrophy is prominent across the West and is sensitive to drought, particularly in understudied biomes such as arid desert shrublands, which may indicate that global riverine uptake of carbon dioxide is higher than hypothesized.
GPT-4o mini: Non-social science research article
Unlocking the potential of brassinosteroids: A path to precision plant engineering
Nemanja Vukaơinović, Trevor M. Nolan, Eugenia Russinova
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Brassinosteroids are essential plant hormones that play a central role in regulating growth, development, and stress responses. Their impact on plant architecture and productivity makes them attractive targets for crop improvement. Recent findings reveal that brassinosteroid signaling is more complex than previously thought, involving multiple layers of regulation and cross-talk with other pathways. Cutting-edge technologies, such as single-cell analysis, proteomics, and advanced imaging in model plants, are beginning to uncover this complexity at cellular resolution. Applying these tools to crop species could reveal previously unknown signaling components and enable precise plant engineering. Because mutations in this pathway often cause widespread, unintended effects, future strategies must focus on fine-tuned tissue- or organ-specific modulation. This Review highlights how new insights could drive innovative, targeted crop enhancement.
GPT-4o mini: Non-social science research article
Extreme warming of Amazon waters in a changing climate
Ayan Santos Fleischmann, Fabrice Papa, Stephen K. Hamilton, John Melack, Bruce Forsberg, Adalberto Val, Walter Collischonn, Leonardo Laipelt, JĂșlia Brusso Rossi, Bruno Comini de Andrade, Bruna Mendel, Priscila Alves, Maiby Bandeira, Lady CustĂłdio, Maria CecĂ­lia Gomes, DĂ©bora Hymans, Isabela Keppe, Raize Mendes, Renan Nascimento, Paula dos Santos Silva, Camila Vieira, Rodrigo Xavier, AndrĂ© Zumak, Anderson Ruhoff, Wencai Zhou, Sally MacIntyre, Eduardo G. Martins, Naziano Filizola, RogĂ©rio Marinho, Ednaldo Bras Severo, Mariana Frias, Renata D. Alquezar, Lucas Lauretto, Waleska Gravena, AndrĂ© Coelho, Hilda ChĂĄvez-PĂ©rez, Susana Braz-Mota, Michel Chamy, Daniel Medeiros Moreira, Leandro Guedes Santos, JosĂ© R. Pacheco Peleja, Miriam Marmontel
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In 2023, an unprecedented drought and heat wave severely affected Amazon waters, leading to high mortality of fishes and river dolphins. Five of 10 lakes monitored had exceptionally high daytime water temperatures (over 37°C), with one large lake reaching up to 41°C in the entire approximately 2-meter-deep water column and up to 13°C of diel variation. Modeling showed that high solar radiation, reduced water depth and wind speed, and turbid waters were the main drivers of the high temperatures. This extreme heating of Amazon waters follows a long-term increase of 0.6°C/decade revealed by satellite estimates across the region’s lakes between 1990 and 2023. With ongoing climate change, temperatures that approach or exceed thermal tolerances for aquatic life are likely to become more common in tropical aquatic systems.
GPT-4o mini: Non-social science research article
Cosmic dust reveals dynamic shifts in central Arctic sea-ice coverage over the past 30,000 years
Frank J. Pavia, Jesse R. Farmer, Laura Gemery, Thomas M. Cronin, Jonathan Treffkorn, Kenneth A. Farley
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Arctic sea-ice loss affects biological productivity, sustenance in coastal communities, and geopolitics. Forecasting these impacts requires mechanistic understanding of how Arctic sea ice responds to climate change, but this is limited by scarce long-term records. We present continuous 30,000-year reconstructions of sea-ice coverage from the Arctic Ocean based on measurements of two isotopes, thorium-230 and extraterrestrial helium-3, whose burial ratio changes with sea-ice coverage. We found that the central Arctic was perennially covered by sea ice during the last glaciation. Sea-ice cover retreated during the deglaciation approximately 15,000 years ago, culminating in seasonal sea-ice coverage in the warm early Holocene, before ice coverage increased into the late Holocene. Sea-ice changes closely correlate with biological nutrient consumption, supporting projections of a nutrient-starved central Arctic Ocean with continued sea-ice loss.
GPT-4o mini: Non-social science research article
The anti-inflammatory activity of IgG is enhanced by co-engagement of type I and II Fc receptors
Andrew T. Jones, Alessandra E. Marino, Tetyana Martynyuk, Stylianos Bournazos, Jeffrey V. Ravetch
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Intravenous immunoglobulin (IVIG) administered at high doses is used to treat a wide array of autoimmune diseases. Studies in murine models have identified that the anti-inflammatory activity of IVIG is dependent on sialylation of the N-linked glycan on the CH2 domain of immunoglobulin G (IgG), the type I IgG inhibitory Fc receptor FcγRIIB, and the type II Fc receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). We hypothesized that DC-SIGN, a C-type lectin, may directly interact with glycans on FcγRIIB, augmenting its ability to bind sialylated IgG. We found that Fc-engineering sialylated IgG1 to enhance its affinity for FcγRIIB resulted in a molecule that was more potent than IVIG in reducing the inflammatory sequelae of antibody or T cell–mediated autoimmune diseases, providing the basis for a class of potent anti-inflammatory therapeutics.
GPT-4o mini: Non-social science research article
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT
Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis
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Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT’s enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.
GPT-4o mini: Non-social science research article
A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis
Tuan-Anh Nguyen, Jung-Ming G. Lin, Anne-Sophie M. C. Marques, Maximilian Fottner, Ludwig G. Bauer, Andreas Reicher, Diana Daum, Lorenzo Scrofani, Yusi Liu, Carol Cheng, Luna D’Angelo L.d.D., Juan Sanchez, Christoph Bueschl, Nara Marella, Pisanu Buphamalai, Florian Traversi, MaĆĄa BereĆĄ, Herwig P. Moll, Marton Siklos, Jakob-Wendelin Genger, Gerald Hofstaetter, Ludovica Villanti, Monika Malik, Christoph Klimek, Kathrin Runggatscher, Bettina Guertl, Jesper S. Hansen, Sarah Dobner, Olga Babosova, Tina Becirovic, Laura P. M. H. de Rooij, Emilio Casanova, Anna Koren, D. Sean Froese, David S. Rosenblatt, Kristaps Klavins, Andreas Bergthaler, Jörg Menche, J. Thomas Hannich, Miriam Abele, Sara Sdelci, Kathrin Lang, Kilian V. M. Huber, Stefan Kubicek
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Folate metabolism is intricately linked to purine de novo synthesis through the incorporation of folate-derived one-carbon units into the purine scaffold. By investigating chemical and genetic dependencies caused by mutations in methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1), we discovered a key role for Nudix hydrolase 5 (NUDT5) in regulating purine de novo synthesis. Genetic depletion and selective chemical degradation showed that a scaffolding role, rather than NUDT5 enzymatic activity, was causing this phenotype. NUDT5 interacted with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of purine de novo synthesis, to repress the pathway in response to increased purine abundance. Through this mechanism, loss of NUDT5 mediates resistance to purine analogs in cancer treatment and prevents adenosine toxicity in MTHFD1 deficiency.
GPT-4o mini: Non-social science research article
Experimental evidence for nodal superconducting gap in moiré graphene
Jeong Min Park, Shuwen Sun, Kenji Watanabe, Takashi Taniguchi, Pablo Jarillo-Herrero
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Understanding the nature of superconductivity in magic-angle graphene remains challenging. A key difficulty lies in discerning the different energy scales in this strongly interacting system, particularly the superconducting gap. Here, we report simultaneous tunneling spectroscopy and transport measurements of magic-angle twisted trilayer graphene. This approach allows us to identify two coexisting V-shaped tunneling gaps with different energy scales: a distinct low-energy superconducting gap that vanishes at the superconducting critical temperature and magnetic field, and a higher-energy pseudogap. The superconducting tunneling spectra display a linear gap-filling behavior with temperature and magnetic field and exhibit the Volovik effect, consistent with a nodal order parameter. Our work suggests an unconventional nature of the superconducting gap and establishes an experimental framework for multidimensional investigation of tunable quantum materials.
GPT-4o mini: Non-social science research article
Postdomestication selection of MKK3 shaped seed dormancy and end-use traits in barley
Morten E. JĂžrgensen, Dominique Vequaud, Yucheng Wang, Christian B. Andersen, Micha Bayer, Amanda Box, Katarzyna B. Braune, Yuanyang Cai, Fahu Chen, Jose A. Cuesta-Seijo, Haoran Dong, Geoffrey B. Fincher, Zoran Gojkovic, Zihao Huang, Benjamin Jaegle, Sandip M. Kale, Flavia Krsticevic, Pierre-Marie Le Roux, Antoine Lozier, Qiongxian Lu, Martin Mascher, Emiko Murozuka, Shingo Nakamura, Martin Ude Simmelsgaard, Pai R. Pedas, Pierre A. Pin, Dagmara Podzimska-Sroka, Kazuhiro Sato, Manuel Spannagl, Magnus W. Rasmussen, Joanne Russell, Miriam Schreiber, Hanne C. Thomsen, Nina W. Thomsen, Sophia Tulloch, Cynthia Voss, Birgitte Skadhauge, Nils Stein, Eske Willerslev, Robbie Waugh, Christoph Dockter
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Anthropogenic selection of grain traits such as dormancy has shaped the developmental trajectories of crops. In cereals, shortening dormancy provides rapid and even post-harvest germination, but increases the risk of weather-induced pre-harvest sprouting (PHS) with yearly harvest losses beyond 1 billion USD. Our understanding of how, why, when and where cereal dormancy diversification arose is fragmentary. Here, we show in the founder crop barley ( Hordeum vulgare ) that dormancy is primarily regulated through a mosaic of locus haplotypes comprising copy-number variation and inherent kinase activity of Mitogen-activated protein kinase kinase 3 ( MKK3 ). We provide evidence supporting the historical selection of specific MKK3 haplotypes that shape dormancy levels according to changing climatic pressures and outline a genetic framework for breeders to balance grain dormancy and PHS-avoidance.
GPT-4o mini: Non-social science research article
Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex
Chao Li, Xue-Nan Sun, Jan-Bernd Funcke, Lauri Vanharanta, Xavier Prasanna, Kaitlynn Gov, Yan Li, Megan Virostek, Chanmin Joung, Nolwenn Joffin, Kristiina Kanerva, Abel Szkalisity, Waldemar Kulig, Leon Straub, Shiuhwei Chen, Joselin Velasco, Ayanna Cobb, Davide La Padula, May-Yun Wang, Toshiharu Onodera, Csaba Vörös, Dae-Seok Kim, Min Kim, Oleg Varlamov, Yang Li, Chen Liu, Andrea R. Nawrocki, Shangang Zhao, Da Young Oh, Zhao V. Wang, Ruth Gordillo, Joel M. Goodman, R. Max Wynn, W. Mike Henne, Ilpo Vattulainen, Yan Han, Elina Ikonen, Philipp E. Scherer
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The microprotein adipogenin (Adig) is predominantly expressed in adipose tissues. Here, we found that Adig interacts with seipin to form a stable, rigid complex. We present the structure of the seipin-Adig complex at an overall resolution of ~3.0 angstroms. The structure revealed that mammalian seipin assembles into two distinct oligomeric forms: undecamers and dodecamers. Adig selectively bound to the dodecameric form and enhanced seipin assembly by bridging and stabilizing adjacent subunits. Functionally, this complex promoted lipid droplet development at both early and late stages. In transgenic mice, adipocyte-specific overexpression of Adig increased fat mass and enlarged lipid droplets, whereas Adig deletion disrupted triglyceride accumulation in brown adipose tissues. Thus, Adig can modulate lipid storage through its structural and functional interactions with seipin.
GPT-4o mini: Non-social science research article
Strengthening Ni alloys with nanoscale interfaces of negative excess energy
J. X. Li, Z. H. Jin, X. Y. Li, K. Lu
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The strength of nanograined and nanotwinned metals is limited by the inherent instability of grain or twin boundaries below a length scale of typically about 10 nanometers. From experimental and density functional theory calculations, we found that the coherent interfaces between face-centered-cubic and hexagonal-close-packing lattices with a negative excess energy were more stable than twin boundaries in supersaturated Ni(Mo) solution. The negative excess-energy interface can be produced at extremely high density in Ni(Mo) solution with average spacing as small as about 1 nanometer, which inhibits plastic deformation and elevates the strength close to the theoretical value of the alloys. The measured Young’s modulus of the Ni(Mo) alloys increases obviously with the interface density, reaching 254.5 gigapascals, well above that of the same compositional metallic glass and intermetallic compound (Ni 3 Mo).
GPT-4o mini: Non-social science research article
Ultrafast inverse chirality-induced spin selectivity observed by THz emission
Yifan Dong, Aeron McConnell, Matthew P. Hautzinger, Md Azimul Haque, Andrew H. Comstock, Pius M. Theiler, Joseph M. Luther, Peter C. Sercel, Dali Sun, Matthew C. Beard
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Chirality-induced spin selectivity (CISS) phenomena arise from an interplay among structural chirality, electron spin orientation, and charge current. Steady-state observations such as magnetoresistance offer little insight into the timescales that govern the spin-charge interconversion and often conflate interfacial and bulk phenomena. By contrast, inverse CISS involves the conversion of spin to a charge current. Using terahertz (THz) emission spectroscopy, we directly measured an ultrafast charge current due to inverse CISS with picosecond time resolution. Polarity and polarization analysis of the THz emission map the induced charge current direction upon spin injection. We found that a charge current is generated along the spin orientation that changes direction with stereochemical configuration. These observations directly demonstrate the inherent coupling between spin and charge currents in chiral systems, offering key insights into their fundamental dynamics.
GPT-4o mini: Non-social science research article
The origin of hepatocellular carcinoma depends on metabolic zonation
Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J. Siegwart, Stephen S. Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu
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The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. While the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown if cancers arise from some zones but not others, and if there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 and Arid2 mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), showed that position and metabolic context determine clone fates. Ctnnb1/Arid2 -driven cancers were much more likely to arise in zone 3. The zone 3 genes Gstm2 and Gstm3 were required for efficient HCC initiation, in part through inhibition of ferroptosis. In the liver, the zonal determinants of HCC development can reveal metabolic vulnerabilities of cancer.
GPT-4o mini: Non-social science research article
Cryo–electron microscopy visualization of RAD51 filament assembly and end-capping by XRCC3-RAD51C-RAD51D-XRCC2
Luke A. Greenhough, Lorenzo Galanti, Chih-Chao Liang, Simon J. Boulton, Stephen C. West
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Homologous recombination repairs DNA double strand breaks and protects stalled replication forks, but how the five RAD51 paralogs contribute to these processes remains unclear. Mutations in the RAD51 paralogs are linked to heritable breast and ovarian cancers and the cancer-prone disease Fanconi anemia. In this work, we show that the RAD51 paralogs assemble into two distinct heterotetrameric complexes, RAD51B-RAD51C-RAD51D-XRCC2 (RAD51B complex) and XRCC3-RAD51C-RAD51D-XRCC2 (XRCC3 complex). The RAD51B complex promotes dynamic adenosine triphosphate hydrolysis–dependent assembly of RAD51 filaments, whereas the XRCC3 complex stably caps the 5â€Č-termini of RAD51 filaments to promote homologous pairing, as visualized by cryo–electron microscopy. Highly conserved across evolution, these complexes reveal insights into RAD51 filament formation and capping during DNA repair and replication fork stabilization.
GPT-4o mini: Non-social science research article
Homogenized chlorine distribution for >27% power conversion efficiency in perovskite solar cells
Zhuang Xiong, Qian Zhang, Kai Cai, Haitao Zhou, Qi Song, Zhaoyang Han, Shuaiqing Kang, Yaowen Li, Qi Jiang, Xingwang Zhang, Jingbi You
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The spatial heterogeneity of halogen distribution in perovskite thin films represents a critical factor currently limiting both the power conversion efficiency and stability of solar cells. We identified pronounced through-film inhomogeneity in chlorine distribution in formamidinium lead iodide films, with the generally used additive methylammonium chloride. We demonstrated that incorporating alkali metal oxalates could effectively homogenize the chlorine distribution. These compounds underwent thermal dissociation, releasing alkali metal cations that selectively bound chloride ions, which considerably suppressed surface defects and eliminated interfacial barriers. A certified steady-state power conversion efficiency (PCE) of 27.2% (device area and measured mask area: 0.108 square cm and 0.074 square cm, respectively) in perovskite solar cells was achieved, and devices retained 86.3% of their initial PCE after 1529 hours of continuous maximum power point tracking (MPPT) under 1 Sun condition. Moreover, the unpassivated device maintained 82.8% of its original PCE under MPPT at 85°C aging under 1 Sun illumination after 1000 hours.
GPT-4o mini: Non-social science research article
Preventing hypocontractility-induced fibroblast expansion alleviates dilated cardiomyopathy
Ross C. Bretherton, Isabella M. Reichardt, Kristin A. Zabrecky, Abigail Nagle, Logan R. J. Bailey, Darrian Bugg, Sasha Smolgovsky, Amy L. Gifford, Timothy S. McMillen, Alex J. Goldstein, Kristina B. Kooiker, Galina V. Flint, Amy Martinson, Jagdambika Gunaje, Franziska Koser, Elizabeth Plaster, Wolfgang A. Linke, Michael Regnier, Farid Moussavi-Harami, Nathan J. Sniadecki, Cole A. DeForest, Jennifer Davis
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Cardiomyocyte hypocontractility underlies inherited dilated cardiomyopathy (DCM). Yet, whether fibroblasts modify DCM phenotypes remains unclear despite their regulation of fibrosis, which strongly predicts disease severity. Expression of a hypocontractility-linked sarcomeric variant in mice triggered cardiac fibroblast expansion from the de novo formation of hyperproliferative mechanosensitized fibroblast states, which occurred prior to eccentric myocyte remodeling. Initially, this fibroblast response reorganized fibrillar collagen and stiffened the myocardium, albeit without depositing fibrotic tissue. These adaptations coincided with heightened matrix–integrin receptor interactions and diastolic tension sensation at focal adhesions within fibroblasts. Targeted p38 deletion arrested these cardiac fibroblast responses in DCM mice, which prevented cardiomyocyte remodeling and improved contractility. p38-mediated fibroblast responses were essential regulators of DCM severity, marking a potential cellular target for therapeutic intervention.
GPT-4o mini: Non-social science research article
Deep generative models design mRNA sequences with enhanced translational capacity and stability
He Zhang, Hailong Liu, Yushan Xu, Haoran Huang, Yiming Liu, Jia Wang, Yan Qin, Haiyan Wang, Lili Ma, Zhiyuan Xun, Xuzhuang Hou, Timothy K. Lu, Jicong Cao
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Despite the success of messenger RNA (mRNA) COVID-19 vaccines, extending this modality to more diseases necessitates substantial enhancements. We present GEMORNA, a generative RNA model that uses transformer architectures tailored for mRNA coding sequences (CDSs) and untranslated regions (UTRs) to design mRNAs with enhanced expression and stability. GEMORNA-designed full-length mRNAs exhibited up to a 41-fold increase in firefly luciferase expression compared with an optimized benchmark in vitro. GEMORNA-generated therapeutic mRNAs achieved up to a 15-fold enhancement in human erythropoietin (EPO) expression and substantially elicited antibody titers of COVID vaccine in mice. Additionally, GEMORNA’s versatility extends to circular RNA, substantially enhancing circular EPO expression and boosting antitumor cytotoxicity in chimeric antigen receptor T cells. These advancements highlight the vast potential of deep generative artificial intelligence for mRNA therapeutics.
Science abstract < 200 char.: Not a research article
Protect Iraq’s Mesopotamian Marshes
Sarmad Dashti Latif
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Science abstract < 200 char.: Not a research article
Britain must step up on AI policy
George Breckenridge
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Science abstract < 200 char.: Not a research article
A foundation of trust
Sofia Moutinho
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A 3-decade partnership between archaeologists and the Kuikuro people offers a model of collaboration—and documents the complexity of early Amazonian societies
Science abstract < 200 char.: Not a research article
Cell signaling meets gene transcription
Richard Young
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Receptor tyrosine kinases directly regulate RNA polymerase II in the nucleus
Science abstract < 200 char.: Not a research article
Thinning of DOE advisory bodies dismays researchers
Adrian Cho
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Department of Energy scraps committees that served as conduits to distinct research communities
Science abstract < 200 char.: Not a research article
In Science Journals
Rachel Wood, Jake S. Yeston, Jesse Smith, Ian S. Osborne, Jelena Stajic, Angela Hessler, Christiana N. Fogg, Dorothy Hallberg, Madeleine Seale, Di Jiang, Yevgeniya Nusinovich, Sarah H. Ross, Stella M. Hurtley, Phil Szuromi, Marc S. Lavine, Leslie Ferrarelli, Mark Aldenderfer
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Highlights from the Science family of journals
Science abstract < 200 char.: Not a research article
Unbiased discovery of neuronal architectures
Jordan W. Squair, Michael A. Skinnider, Gregoire Courtine
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Comparative whole-brain and single-cell analyses identify neurons orchestrating neurological functions
Science abstract < 200 char.: Not a research article
Tree rings from ancient coffins offer clues to Earth’s past
Taylor Mitchell Brown
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Wood from gravesites can help reconstruct historic temperatures, droughts, and floods
Science abstract < 200 char.: Not a research article
Frankenstein and the problem of abandonment Frankenstein; or, The Modern Prometheus Mary Shelley Lackington, Hughes, Harding, Mavor, & Jones, 1818. 280 pp.
Dov Greenbaum
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A new adaptation of the cautionary tale is an opportunity to reflect on scientific stewardship
Science abstract < 200 char.: Not a research article
The role of organizations in fostering innovation
Imran Rasul
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Science abstract < 200 char.: Not a research article
FDA export restrictions threaten collaboration
Kaili Zhang, Jingyi Niu, Zhiyong Li
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Science abstract < 200 char.: Not a research article
The normalization of (almost) everything: Our minds can get used to anything, and even crises start feeling normal
Rachit Dubey
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Our minds can get used to anything, and even crises start feeling normal
Science abstract < 200 char.: Not a research article
Understanding nature and nurture: Statistical and AI innovations uncover how genes and environment shape human health
Jiacheng Miao
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Statistical and AI innovations uncover how genes and environment shape human health
Science abstract < 200 char.: Not a research article
Seipin-adipogenin controls lipid storage in fat cells
Jin Wu, Hongyuan Yang
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A protein complex promotes the expansion of lipid droplets during the formation of mature adipocytes
Science abstract < 200 char.: Not a research article
The need for a global effort to attend to human neural organoid and assembloid research
Sergiu P. Pașca, Paola Arlotta, Philip Campbell, Alta Charo, John H. Evans, Nita Farahany, Fred H. Gage, Peter Godfrey-Smith, Insoo Hyun, Arnold R. Kriegstein, Lucia Melloni, Guo-Li Ming, Jonathan D. Moreno, Jeremy Sugarman, Sally Temple, Giuseppe Testa, Henry T. Greely
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A continuing international process is needed to monitor and advise this rapidly progressing field
Science abstract < 200 char.: Not a research article
When ‘we’ turns wicked
Sorin M. S. Krammer
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Science abstract < 200 char.: Not a research article
Platforms of power The Age of Extraction: How Tech Platforms Conquered the Economy and Threaten Our Future Prosperity Tim Wu Knopf, 2025. 224 pp.
Simson L. Garfinkel
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A legal scholar pushes for net neutrality and other actions to rein in tech monopolies
Science abstract < 200 char.: Not a research article
Antarctic glacier’s retreat is fastest in modern history
Hannah Richter
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Tides and glacial earthquakes caused record ice loss at Hektoria Glacier
Science abstract < 200 char.: Not a research article
Biomedical philanthropy promises dramatic expansion and AI focus
Jon Cohen
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Entering its second decade, the Chan Zuckerberg Initiative will make science the core mission for its founders’ billions
Science abstract < 200 char.: Not a research article
AI hallucinates because it’s trained to fake it till it makes it
Celina Zhao
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Teaching chatbots to say “I don’t know” could curb falsehoods but harm business model
Science abstract < 200 char.: Not a research article
Shrinking interconnects beyond copper
Mehrdad T. Kiani, Judy J. Cha
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Quantum materials can speed up the information processing in a computer chip
Science abstract < 200 char.: Not a research article
In Other Journals
Madeleine Seale, Marc S. Lavine, Jesse Smith, Corinne Simonti, Stella M. Hurtley, Mattia Maroso, Phil Szuromi
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Editors’ selections from the current scientific literature
Advancing research on financial stability and climate-related financial risk
William Pizer, James Stock
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Climate change–related natural disasters such as floods, fires, and storms devastate communities, and their massive costs continue to grow. But as climate risks increase, financial risk management infrastructure is not keeping pace. Analytical tools on which investors, regulators, central banks, and governments depend were largely built for a 20th-century climate and a fossil fuel–dominated economy. Policy-makers need a sounder understanding of which climate-related risks pose a threat to the financial system and macroeconomy, as well as the potential channels through which those risks operate. Although the US government recently disbanded its main efforts to understand and address these risks, it is vital that such work continues. Climate change is not a distant environmental issue, but a present financial and macroeconomic concern that will affect all of us, whether we accept it or not.

Science Advances

GPT-4o mini: Non-social science research article
Efficient launching of shear phonons in photostrictive halide perovskites
Dmytro O. Horiachyi, Mikhail O. Nestoklon, Ilya A. Akimov, Artur V. Trifonov, Nikita V. Siverin, Nataliia E. Kopteva, Alexander N. Kosarev, Dmitri R. Yakovlev, Vitalyi E. Gusev, Melina Fries, Olga Trukhina, Vladimir Dyakonov, Manfred Bayer
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Optical generation of coherent transverse phonons by femtosecond light pulses is appealing for sub-terahertz high-speed active control of material properties. Lead-free double-perovskite semiconductors, such as Cs 2 AgBiBr 6 , attract particular interest in this respect due to their structural phase transition and strong carrier-lattice coupling. Here, we reveal that the giant anisotropic photostriction in halide perovskites with tetragonal crystal structure provides an efficient nonthermal tool for generating coherent transverse phonons. Using time-domain Brillouin spectroscopy, we observe transverse and longitudinal acoustic phonons with comparable amplitudes in the tetragonal phase of Cs 2 AgBiBr 6 below the temperature of 122 kelvins, while, in the cubic phase, only longitudinal phonons are generated. The polarization of the transverse phonons is dictated by the projection of the crystal c axis on the surface plane, which leads to a prominent anisotropic polarization response in the detection. The generated strain pulses correspond to soft transverse acoustic eigenmodes with a strong temperature dependence of dispersion, providing an additional degree of freedom for hypersonic manipulation.
GPT-4o mini: Non-social science research article
Pfs230 domain 12 is a potent malaria transmission–blocking vaccine candidate
Maartje R. Inklaar, Roos M. de Jong, Dari F. Da, Lisanne L. Hubregtse, Maartje Meijer, Karina Teelen, Ezra T. Bekkering, Sanne Grievink, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Rianne Stoter, Hikaru Nagaoka, Takafumi Tsuboi, Eizo Takashima, Cornelia G. Spruijt, Michiel Vermeulen, Roch K. Dabire, Emmanuel Arinaitwe, Anna Cohuet, Teun Bousema, Matthijs M. Jore
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Malaria transmission–blocking vaccines (TBV) target sexual stage parasites that are transmitted to mosquitoes and are critical for spread of the pathogen. The clinically most advanced TBV candidate contains part of the Pro-domain (Pro) and Domain 1 (D1) of Plasmodium falciparum surface protein Pfs230. Subunit vaccines that contain other domains of Pfs230 have so far failed to induce functional antibodies. Here, we produced eight single-domain fragments of Pfs230 in Drosophila melanogaster S2 cells and assessed their immunogenicity in mouse immunizations. In addition to D1-specific antibodies, antibodies raised against D12 showed strong functional transmission-reducing activity in membrane feeding assays with cultured parasites, an activity that was complement dependent. Murine D12-specific antibodies further reduced mosquito transmission of parasites acquired from naturally infected parasite carriers. The D12 antigen was recognized by sera from an all-age cohort of individuals who had been naturally exposed to P. falciparum with antibody levels increasing with age. In conclusion, we identified Pfs230D12 as a promising TBV candidate.
GPT-4o mini: Non-social science research article
Stretchable complementary integrated electronics based on elastic dual-type transistors
Yongcao Zhang, Kyoseung Sim, Hyunseok Shim, Faheem Ershad, Shubham Patel, Yingshi Guan, Cunjiang Yu
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Complementary integrated circuits in an elastic format are essential for systems toward emerging applications in wearable health monitors, soft robotics, and implantable medical devices. However, their development is very nascent, largely owing to the imbalance of p- and n-type elastic transistors. Here, we report fully stretchable complementary integrated electronics combining elastic n-type transistors based on metallic carbon nanotube (CNT)–oped poly{[ N , N â€Č-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5â€Č-(2,2â€Č-bithiophene)} with p-type transistors using semiconducting CNT networks. The layered elastomer-semiconductor-elastomer architecture provides both type transistors with stable, well-matched electrical characteristics up to 50% strain. Using these components, we demonstrate stretchable digital logic gates—including inverters, NAND, and NOR—which retain function under large strain. As a system-level demonstration, a complementary inverter active matrix integrated with a single-electrode triboelectric nanogenerator array realizes a stretchable tactile sensing skin. The stretchable complementary integrated electronics demonstrated here hold promise in many fields, particularly these require seamless integration with dynamic living systems.
GPT-4o mini: Non-social science research article
Substantially underestimated winter CO 2 sources of the Southern Ocean
Siqi Zhang, Peng Chen, Kelsey Bisson, Cédric Jamet, Paolo Di Girolamo, Davide Dionisi, Yongxiang Hu, Zhenhua Zhang, Kun Shi, Delu Pan
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The size and control mechanism of the Southern Ocean’s carbon fluxes remain highly uncertain due to sparse winter observations. Here, we integrate satellite light detection and ranging (LIDAR) measurements with machine learning to assess the Southern Ocean air-sea CO 2 fluxes between 2007 and 2020. We reveal that CO 2 outgassing south of 50°S was underestimated by up to 40% in previous studies. While the midlatitude Southern Ocean (30° to 50°S) strengthens as a carbon sink, the high-latitude region (50° to 90°S) shows Southern Annular Mode (SAM)–modulated alternation between uptake and outgassing. The air-sea CO 2 partial pressure difference (Δ p CO 2 ) increasingly dominates flux variability over wind-driven transfer velocity. We propose a framework involving three latitudinal loops with differing p CO 2 controls: (i) Antarctic (salinity/sea ice), (ii) polar front (atmospheric CO 2 /chlorophyll), and (iii) subpolar (sea surface temperature/CO 2 ). The findings underscore the winter processes’ critical role and necessitate year-round observations to understand Southern Ocean’s global carbon cycle impact.
GPT-4o mini: Non-social science research article
Functional divergence of tandem duplicate SCPL acyltransferase genes reveals convergent evolution of chicoric acid biosynthesis
Yuting Xiang, Tingting Liang, Ruixi Yang, Hsihua Wang, Alisdair R. Fernie, Yang Zhang, Rao Fu
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Chicoric acid, a caffeic acid derivative exhibiting diverse bioactivities, has been identified in more than 60 plant species. Here we report an alternative biosynthetic pathway in lettuce ( Lactuca sativa ). BAHD acyltransferases catalyze the synthesis of chlorogenic acid, which serves as the acyl donor for four serine carboxypeptidase-like (SCPL) acyltransferases (LsSCPL1-4) encoded by tandemly duplicated genes. LsSCPL2 and LsSCPL4 catalyze the synthesis of chicoric acid using caftaric acid as the acyl acceptor. In contrast to the BAHD acyltransferases found in Echinacea species, LsSCPL1 and LsSCPL3 alter their substrate preferences through key amino acid substitutions and use tartaric acid as the acyl acceptor to synthesize caftaric acid. These tandemly duplicated SCPL genes are observed across several evolutionarily related species within the tribe Cichorieae. These findings illustrate the convergent evolution of chicoric acid biosynthesis in Asteraceae and highlight the complexity of acyltransferase activity in specialized metabolism in plants.
GPT-4o mini: Non-social science research article
Real-time decoding of full-spectrum Chinese using brain-computer interface
Youkun Qian, Changjiang Liu, Peixi Yu, Xingchen Ran, Shurui Li, Qinrong Yang, Yang Liu, Lei Xia, Yijie Wang, Jianxuan Qi, Erda Zhou, Junfeng Lu, Yuanning Li, Tiger H. Tao, Zhitao Zhou, Jinsong Wu
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Speech brain-computer interfaces (BCIs) offer a promising means to provide functional communication capacity for patients with anarthria caused by neurological conditions such as amyotrophic lateral sclerosis (ALS) or brainstem stroke. Current speech decoding research has predominantly focused on English using phoneme-driven architectures, whereas real-time decoding of tonal monosyllabic languages such as Mandarin Chinese remains a major challenge. This study demonstrates a real-time Mandarin speech BCI that decodes monosyllabic units directly from neural signals. Using the 256-channel microelectrocorticographic BCI, we achieved robust decoding of a comprehensive set of 394 distinct syllables based purely on neural signals, yielding median syllable identification accuracy of 71.2% in a single-character reading task. Leveraging this high-performing syllable decoder, we further demonstrated real-time sentence decoding. Our findings demonstrate the efficacy of a tonally integrated, direct syllable neural decoding approach for Mandarin Chinese, paving the way for full-coverage systems in tonal monosyllabic languages.
GPT-4o mini: Non-social science research article
A network of basolateral amygdala projection neurons contributes to stress-induced activation of the hypothalamic-pituitary-adrenal axis
Robert J. Aukema, Gavin N. Petrie, Benjamin K. Lau, Lauren T. Seabrook, Samantha L. Baglot, John P. Christianson, Jaideep S. Bains, Maria Morena, Stephanie L. Borgland, Matthew N. Hill
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The basolateral amygdala (BLA) is reliably activated by psychological stress in both humans and rodents and influences diverse behavioral and physiological processes involved in stress adaptation. However, functional organization of distinct BLA circuits and their contribution to stress-induced activation of the neuroendocrine response is unclear. We establish four major findings in adult male rats: (i) BLA projection neurons are necessary and sufficient for stress-induced neuroendocrine activation; (ii) projection populations have a heterogeneous spatial distribution across the BLA; (iii) diverse BLA populations targeting the prelimbic cortex, nucleus accumbens, bed nucleus of stria terminalis, central amygdala, lateral hypothalamus, and ventral hippocampus are activated by acute stress, with the location of activated populations biased toward the medial basal amygdala; and (iv) inhibition of singular projections does not recapitulate global inhibition of BLA projection neurons. Together, this suggests that a network of BLA projection populations is broadly activated by acute stress and collectively contribute to neuroendocrine regulation.
GPT-4o mini: Non-social science research article
Thalamo-hippocampal pathway determines aggression and self-harm
Jane Jung, In-Jee You, Sora Shin
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Aggression and self-harm are maladaptive coping strategies that often occur in individuals with a history of early life trauma (ELT), yet their underlying neural mechanisms remain unclear. Here, we identify L-type calcium channel (LTCC)–expressing thalamic nucleus reuniens (RE) as a critical component regulating both behaviors. ELT-induced excessive LTCC activity in vesicular glutamate transporter 2 (vGlut2) RE neurons and its corresponding effects on persistent neuronal activation contribute to increasing susceptibility to aggression and self-harm. Activation of vGlut2 RE neurons projecting to ventral hippocampus (vCA1), but not medial prefrontal cortex, promotes these behaviors in control mice. Furthermore, we found that RE neurons modulate two distinct subsets of vCA1 neurons, with one projecting to the hypothalamus to drive aggression and another to the basal amygdala to mediate self-harm. Our findings uncover how LTCC functions in the RE-to-vCA1 neural pathway increase the risk of aggression and self-harm, highlighting potential therapeutic targets for mitigating destructive behaviors following early adversity.
GPT-4o mini: Non-social science research article
Engineered probiotic restores GLP-1 signaling to ameliorate fiber-deficiency exacerbated colitis
Leonie Brockmann, Carlotta Ronda, Logan T. Schwanz, Yiming Qu, Daniel W. Shneider, Chrystal F. Mavros, Ivaylo I. Ivanov, Govind Bhagat, Harris H. Wang
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Western diets reduced in fiber promote dysbiosis and exacerbate colitis, with short-chain fatty acids (SCFAs) from fiber fermentation known to regulate glucagon-like peptide 1 (GLP-1) secretion. Whether GLP-1 dysregulation directly links diet-induced dysbiosis to colitis severity, and if this pathway can be therapeutically targeted independently of dietary fiber, remains unclear. Here, we show that dextran sulfate sodium (DSS)–induced colitis severity correlates with compensatory GLP-1 increases, while receptor blockade worsens damage, confirming GLP-1’s protective role during colitis. Fiber deficiency impaired L cell function and GLP-1 release, increasing colitis susceptibility. GLP-1 receptor agonist reversed these effects, restoring barrier integrity and accelerating recovery. We engineered a probiotic, releasing a microbial peptide, that locally elevates GLP-1, which normalized gut parameters in fiber-deprived mice and alleviated colitis via GLP-1–dependent mechanisms, including improved metabolism, antimicrobial defenses , and barrier restoration. Our findings mechanistically connect fiber deficiency to colitis through GLP-1 and demonstrate that probiotic-mediated GLP-1 modulation can bypass dietary fiber requirements to maintain gut homeostasis.
GPT-4o mini: Non-social science research article
Intrinsically charge-generating polymers with long-lived free carriers for efficient photon-to-hydrogen conversion
Yunzhi Wang, Partha Maity, Yinglu Jia, Baiqiao Liu, Lingyun Zhao, Yanru Li, Weiwei Li, Zhuping Fei, Martin Heeney, Suzana P. Nunes, Wan-Lu Li, Omar F. Mohammed, Huabin Zhang
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A single organic semiconductor typically struggles with inefficient intrinsic charge generation due to large binding energy ( E B  ≈ 0.5 electron volts) of Frenkel excitons, particularly in narrow-bandgap organic semiconductors that exhibit near-infrared (NIR) absorption. Here, we develop double-cable polymer–based nanoparticles (NPs), enabling single-component organic photocatalysts to achieve NIR photon absorption and generate long-lived free charges simultaneously. as -DCPIC, a double-cable polymer with donor polymer (PBDB-T) as electron-donating conjugated backbones and pendent NIR acceptor (TPDIC) as the electron-deficient side chains, offers potential for self-sustained photoelectric conversion. Consequently, as -DCPIC NPs exhibit significantly enhanced hydrogen evolution performance (11.88 mmol per hour per gram) compared to pristine PBDB-T or TPDIC NPs. Transient absorption spectroscopy elucidates the effective electron-hole separation inside as -DCPIC NPs, whereas decay kinetics monitor the long-lived free carriers (109 nanoseconds) in as -DCPIC NPs. Our findings demonstrate that double-cable polymers provide a powerful platform for establishing efficient single-component organic photocatalysts to generate long-lived reactive charges.
GPT-4o mini: Non-social science research article
l -Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer’s synaptic deficits
Jacopo Di Lucente, Jennyfer Tena, Yuanyuan Bai, Catelynn C. Shafer, Ulises Ruiz Mendiola, Elizabeth K. Neumann, Xi Chen, Carlito B. Lebrilla, Izumi Maezawa, Lee-Way Jin
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Fucosylation, a major glycan modification, has been shown to influence neuronal and microglial mechanisms, but whether unconjugated free l -fucose can affect brain function is unknown. l -Fucose can be transported into cells and metabolized by fucokinase (FCSK) via the poorly understood salvage pathway. Using mouse hippocampal slices, we showed that l -fucose enhanced excitatory neurotransmission and long-term potentiation (LTP) through regulation of presynaptic release. Such effects required l -fucose be metabolized through the FCSK-driven salvage pathway, suggesting a metabolic-signaling mechanism. Human Alzheimer’s disease (AD) and 5xFAD mouse brains showed signs of fucose hypometabolism with impaired l -fucose signaling. Such abnormalities were corrected by exogenous l -fucose, exemplified by rectification of LTP deficits in 5xFAD hippocampus. A dietary l -fucose supplement, which increased cerebral free l -fucose levels and up-regulated FCSK to drive the salvage pathway, mitigated synaptic and behavioral deficits of 5xFAD mice. Our data suggest an unrecognized neuromodulatory function of free l -fucose and reveals its therapeutic potential for AD.
GPT-4o mini: Non-social science research article
Peptide-MHC–targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells
Ellen J. K. Xu, Blake E. Smith, Winiffer D. Conce Alberto, Michael J. Walsh, Birkley Lim, Megan T. Hoffman, Li Qiang, Ariana Barreiro, Emma N. Finburgh, Jiayi Dong, Andrea Garmilla, Qingyang Henry Zhao, Caleb R. Perez, Stephanie A. Gaglione, Connor S. Dobson, Michael Dougan, Stephanie K. Dougan, Michael E. Birnbaum
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Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate effective antitumor responses. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions that can affect treatment efficacy. Therefore, additional tools are needed to engineer TILs to have increased potency while mitigating manufacturing challenges. Here, we present a strategy for pseudotyping retroviruses with peptide–major histocompatibility complexes (pMHCs) for antigen-specific gene delivery to CD8 T cells and validate therapeutic impact in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses specifically deliver function-enhancing cargos while simultaneously activating and expanding antitumor T cells. This targeting precision enables in vivo engineering of tumor-specific T cells, resulting in improved overall survival in B16F10-bearing mice. Together, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific T cells directly in vivo, with the potential to substantially streamline engineered cell therapy production.
GPT-4o mini: Non-social science research article
Neural correlates of phosphene perception in blind individuals: A step toward a bidirectional cortical visual prosthesis
Fabrizio Grani, Cristina Soto-SĂĄnchez, Alfonso Rodil Doblado, Rocio Lopez Peco, Pablo Gonzalez-Lopez, Eduardo Fernandez
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Blindness is one of the most impactful disabilities in human lives. Cortical prostheses could one day restore functional vision in some blind subjects, but their success will depend on integrating advanced technologies to realize the therapeutic benefits they promise. Most previous studies in humans used electrodes only for stimulation, which has made it challenging to precisely control the appearance of individual phosphenes. Herein, we implanted an intracortical microelectrode array of 100 electrodes in the visual cortex of two blind volunteers. We recorded the neural activity around the electrodes while performing electrical stimulation to induce visual perceptions. Besides showing how stimulation parameters influence perceptual thresholds, perceived brightness, and the minimum interval required to distinguish separate stimuli, our results indicate that subjective visual experience can be accurately predicted from the recorded neural activity. These results highlight the potential for using the neural activity of neighboring electrodes to accurately infer and control visual perceptions in cortical visual prostheses.
GPT-4o mini: Non-social science research article
Nonfluorinated membrane with a decentralized ion-transport network enables efficient and sustainable polysulfide redox flow batteries
Feiran Wang, Shuang Luo, Jiafeng Lei, Fei Ai, Ka Lok Leung, Jun Fan, Yi-Chun Lu
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Polysulfide-based redox flow batteries are promising for long-duration energy storage, owing to ultralow-cost/earth-abundant active materials and full decoupling of power and energy. However, their practical application has been prevented by poor cycle life resulting from polysulfide crossover and a heavy reliance on costly fluorinated membranes (Nafion 117, USD $800 to $3500 per square meter), along with the environmental concerns. Here, we develop a nonfluorinated sulfonated polyethersulfone (SPES)–based membrane with decentralized ion-transport channels, achieving a 20 times higher ionic selectivity at a markedly reduced cost (USD $12 to $66 per square meter) compared to the commercial Nafion membrane. The low-cost SPES-based membrane enabled stable cycling of polysulfide-ferrocyanide redox flow batteries with a high coulombic efficiency (>99.9%) and energy efficiency (average >75%) for 1600 cycles (>6 months). This strategy demonstrated polysulfide-based redox flow batteries with a record longevity using a low-cost and sustainable membrane, paving the way for their practical commercialization.
GPT-4o mini: Non-social science research article
Mind captioning: Evolving descriptive text of mental content from human brain activity
Tomoyasu Horikawa
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A central challenge in neuroscience is decoding brain activity to uncover mental content comprising multiple components and their interactions. Despite progress in decoding language-related information from human brain activity, generating comprehensive descriptions of complex mental content associated with structured visual semantics remains challenging. We present a method that generates descriptive text mirroring brain representations via semantic features computed by a deep language model. Constructing linear decoding models to translate brain activity induced by videos into semantic features of corresponding captions, we optimized candidate descriptions by aligning their features with brain-decoded features through word replacement and interpolation. This process yielded well-structured descriptions that accurately capture viewed content, even without relying on the canonical language network. The method also generalized to verbalize recalled content, functioning as an interpretive interface between mental representations and text and simultaneously demonstrating the potential for nonverbal thought–based brain-to-text communication, which could provide an alternative communication pathway for individuals with language expression difficulties, such as aphasia.
GPT-4o mini: Non-social science research article
Charting the nanotopography of inner hair cell synapses using MINFLUX nanoscopy
Rohan Kapoor, Hyojin Kim, Evelyn Garlick, Maria Augusta do R. B. F. Lima, Klara Esch, Torben Ruhwedel, Wiebke Möbius, Fred Wolf, Tobias Moser
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The cochlea encodes sounds into neural signals at the synapses of inner hair cells (IHCs) and spiral ganglion neurons (SGNs) with remarkable fidelity. To achieve high rates of precise synaptic transmission over long periods, IHCs use ribbon-type active zones (AZs). To understand synaptic sound encoding, we need to decipher the underlying molecular topography of these synapses, which has remained challenging because of technological limitations. Here, we applied three-dimensional minimal flux optical nanoscopy to mouse IHC-SGN synapses to chart the positions of key pre- and postsynaptic proteins with single-digit nanometer resolution. We demonstrate that nanoclusters of ion channels and their interacting proteins govern the topography of AZs and postsynaptic densities (PSDs). We count synaptic proteins and their nanoclusters and determine their spatial organization, feeding into computational modeling of AZ function. In conclusion, this study reveals a nanocluster-based molecular AZ and PSD topography, likely serving as functional modules in synaptic sound encoding.
GPT-4o mini: Non-social science research article
Adhesive nonfibrotic bioelectronic interfaces on diverse peripheral nerves for long-term functional neuromodulation
Hyunmin Moon, Bastien F. G. Aymon, Jue Deng, Tao Zhou, Vincent Prevosto, Fan Wang, Jingjing Wu, Xuanhe Zhao
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Bioelectronic devices implanted on peripheral nerves offer potential for the treatment and rehabilitation of clinical diseases. However, the foreign body reaction and the subsequent fibrous capsule formation at the device–peripheral nerve interface severely limit their efficacy and longevity in vivo. Here, we describe a robust bioadhesive strategy that can establish nonfibrotic bioelectronic interfaces on diverse peripheral nerves—occipital, vagus, deep peroneal, sciatic, tibial, and common peroneal nerves—for up to 12 weeks. Our approach inhibits the infiltration of immune cells into the interface, thereby preventing the formation of fibrous capsules in the inflammatory microenvironment. We demonstrate that our adhesive bioelectronic device with nonfibrotic interfaces maintains long-term blood pressure regulation in a spontaneously hypertensive rat model over 4 weeks. Furthermore, we confirm minimal accumulation of macrophages, smooth muscle actin, and collagen at nonfibrotic bioelectronic interfaces after 12 weeks of device implantation with nerve stimulation, supporting long-lasting neuromodulation without fibrosis.
GPT-4o mini: Non-social science research article
In situ structure of a gap junction–stomatin complex
Nils Rosenkranz, Alexandra N. Birtasu, Konstantin Wieland, Lisa Rehm, Rachita Sharma, Atal Vats, Sina Manger, Aayush Srivastava, Abhishek Bhattacharya, Gerhard Hummer, Achilleas S. Frangakis, Alexander Gottschalk
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Gap junctions (GJs) are intercellular channels that mediate electrical signals and transfer of small molecules. They are crucial for brain, heart, and other organ functions. While molecular structures of purified homomeric GJs are available, information of in situ structures is lacking. In vivo, GJs can form heteromers with different functionalities and may associate with other proteins. Here, we analyzed Caenorhabditis elegans GJs by cryo–electron tomography and subtomogram averaging. We observed hexagonal arrays of GJs at cellular junctions in primary embryonal cells that displayed distinct wide and narrow conformations. Moreover, we found a cap-like, cytosolic protein assembly enclosing the channel pore. We propose that the cap is formed by the stomatin UNC-1, known to interact with UNC-9 innexins. This is corroborated by matching AlphaFold3 models of UNC-1 multimers with our subtomogram average structure; by expressing GFP-tagged UNC-1, leading to cap structures with additional density; and by coarse-grained MD simulations. UNC-1/stomatin rings may affect GJ formation or functions, possibly beyond nematodes.
GPT-4o mini: Non-social science research article
Spatially confined hydration for robust underwater adhesion
Gang Lu, Rui Ma, Jian Lu, Yuanhao Chang, Ming Li, Eduardo Saiz
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Underwater adhesion has long been limited by interfacial water’s paradoxical role as both bonding mediator and failure initiator. We present a confined hydration adhesive tape (CHAT) that harnesses water as a molecular architect through spatial hydration management. By confining water penetration to sub–8-micrometer depths, we create a dynamic interface where hydration-activated hydrogen bonds enable adaptive, high-density interfacial connections, and hydrophobic nanodomains maintain bulk integrity via entropic water exclusion. This orchestrated hydration yields an interfacial toughness of 6 kilojoules per square meter (>1.8× literature benchmarks; 1.4 to 3.8× commercial tapes), while preserving stability across harsh conditions (pH 1 and 13, 3.5% saline). Multiscale experiments and simulations reveal water’s triple role as a hydrogen bond catalyst at the interface, a dynamical reorganizer of supramolecular networks, and a mechanical decoupler of interfacial adhesion/bulk cohesion. By establishing interfacial water as a design variable rather than a compromise, CHAT opens avenues for marine, biomedical, and industrial applications where water-resistant adhesion is critical.
GPT-4o mini: Non-social science research article
Attenuated LMCT photocatalysis enables C─H allylation of methane and other gaseous alkanes
Andrés M. Álvarez-Constantino, Pol Martínez-Balart, Sergio Barbeira-Arån, Álvaro Velasco-Rubio, Martín Fañanås-Mastral
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The functionalization of methane, ethane, and other gaseous alkanes represents a central goal in chemistry, though synthetic tools that allow their straightforward conversion into high-value products are still rare. Here we report a general and mild photocatalytic methodology for the direct C─H allylation of gaseous alkanes. This protocol provides an efficient tool to convert these raw materials into synthetically versatile products, as illustrated by its application to the telescoped conversion of methane and ethane into important pharmaceutical intermediates and the nonsteroidal estrogen dimestrol. Successful implementation of the method requires the use of a FeCl 3 ·6H 2 O/collidine system that serves as an efficient ligand-to-metal charge transfer (LMCT) photocatalyst. Mechanistic studies highlight the crucial role of an in situ formed L n FeCl 4 − (L = collidinium) species in which stabilizing hydrogen bond interactions are key to prevent competing alkane C─H chlorination by attenuating the Fe─Cl bond reactivity, securing a kinetically compatible catalytic regime that provides an efficient platform for the C─H allylation reaction.
GPT-4o mini: Non-social science research article
Terahertz antiferromagnetic dynamics induced by ultrafast spin currents
Sanjay René, Artem Levchuk, Amr Abdelsamie, Zixin Li, Pauline Dufour, Arthur Chaudron, Florian Godel, Pascale Gemeiner, Brahim Dkhil, Jean-Baptiste Moussy, Karim Bouzehouane, Stéphane Fusil, Vincent Garcia, Michel Viret, Jean-Yves Chauleau
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Insulating antiferromagnets are anticipated as the main protagonists of ultrafast spintronics, with their intrinsic terahertz dynamics and their ability to transport spin information over long distances. However, ultrafast transfer of spin angular momentum to an antiferromagnetic insulator remains to be demonstrated. Here, studying the picosecond and subpicosecond dynamics of ferromagnetic metal/antiferromagnetic insulator bilayers, we evidence the generation of coherent terahertz excitations in the antiferromagnet combined with a modulation of the demagnetization behavior in the ferromagnet. We thus demonstrate that magnetic information can indeed be propagated into antiferromagnetic spin waves at picosecond timescales, thereby opening an avenue toward ultrafast manipulation of magnetic information.
GPT-4o mini: Non-social science research article
PLAMseq enables the proteo-genomic characterization of chromatin-associated proteins and protein interactions in a single workflow
Lourdes GonzĂĄlez-Vinceiro, Carmen Espejo-Serrano, MarĂ­a Eugenia Soler-Oliva, Emily Soto-Hidalgo, MarĂ­a Luisa Mateos-MartĂ­n, Daniel Rico, Cristina GonzĂĄlez-Aguilera, RomĂĄn GonzĂĄlez-Prieto
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Chromatin immunoprecipitation and coimmunoprecipitation assays are common approaches to characterize the genomic localization and protein interactors, respectively, for a protein of interest. However, these approaches require the use of specific antibodies, which often face sensitivity and specificity issues. On the basis of TurboID, we developed proximity-labeled affinity-purified mass spectrometry and sequencing (PLAMseq), which enables, in the same workflow, identification of the genomic loci and the interacting proteome of a protein of interest. Moreover, PLAMseq can also be applied to specifically map protein interactions and ubiquitin(-like)–modified proteins. We validated PLAMseq with two well-characterized proteins, RNA polymerase II, and CTCF, with excellent robustness and reproducibility. Next, we applied PLAMseq to characterize histone H1 SUMOylation, in which study has remained elusive due to the lack of specific reagents, and found that SETDB1 binds to SUMOylated histones H1.2 and H1.4 that also colocalize with H3K9me3 at repetitive regions of the genome.
GPT-4o mini: Non-social science research article
Energy landscape–engineered iontronics enable artificial thermoreceptors for augmented bioinspired thermosensation
Fan Li, Hua Xue, Xiuzhu Lin, Juan Wang, Juan Li, Hongran Zhao, Tong Zhang
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Biological thermoreception extends beyond mere temperature detection, capturing nuanced cues such as sunlight, wind chill, humidity, and object contact. However, artificial thermoreceptors rarely match the acuity and perceptual richness with their biological counterpart, leaving a critical gap in thermosensory functionality for human-machine integration. Here, we introduce a structurally programmed iontronic platform that leverages energy landscape engineering in a heterogeneous polymer electrolyte to establish a continuous distribution of potential wells hosting a continuum of ionic carrier states. This architecture enables semiconductor-like thermally activated conduction by ionic carriers, achieving detection of temperature variations as small as 8 mK. Building on this platform, we develop a biomimetic ionic skin that interprets airflow, humidity, solar irradiation, thermal conductivity variations, and evaporative cooling through thermal cues, mirroring the multifaceted thermoreception of biological skin. This work complements the existing research paradigm of iontronics by integrating solid-state physics principles. The artificial thermoreceptor thus narrows the gap between artificial and biological thermosensation, advancing human-machine integration and biohybrid systems.
GPT-4o mini: Non-social science research article
Structural basis of herpesvirus helicase-primase inhibition by pritelivir and amenamevir
Andrey G. Baranovskiy, Qixiang He, Yoshiaki Suwa, Lucia M. Morstadt, Nigar D. Babayeva, Ci Ji Lim, Tahir H. Tahirov
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Widespread herpesvirus infections are associated with various diseases. DNA replication of human herpes simplex virus type 1 (HSV-1) requires a helicase-primase (HP) complex of three core proteins: UL5, UL52, and UL8. This complex unwinds viral DNA and synthesizes primers for DNA replication, making it an attractive antiviral target. Although HP inhibitors pritelivir and amenamevir were identified through screening, their binding mechanisms remain unclear. Here, we report cryo–electron microscopy structures of HSV-1 HP bound to a forked DNA template alone and in complex with pritelivir or amenamevir. The structures reveal a bilobed architecture highlighting HP coordinated action at the replication fork and providing a structural basis for HP inhibition by illustrating precisely how pritelivir and amenamevir block helicase activity. Data lay a solid foundation for the development of improved antiviral therapies.
GPT-4o mini: Non-social science research article
Concurrent selection of internal goals and external sensations during visual search
Baiwei Liu, Freek van Ede
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Flexible goal-directed behavior relies on selecting relevant internal goal representations and external sensations. Yet, these selection processes have classically been studied in isolation, leaving unclear how they are coordinated in time to support behavior. To address this, we developed a visual search task to simultaneously track selection among internal search goals held in working memory and external search targets in the environment. Capitalizing on sensitive gaze and neural markers, we provide proof-of-principle evidence in humans that internal and external selection processes do not necessarily take turns in a strictly serial manner but can develop concurrently. These concurrent processes are supported by largely nonoverlapping neural activity patterns in the human brain and can be performed effectively even when engaging opposite spatial locations in working memory and perception. Our findings challenge views portraying brain states as being either internally or externally focused and bring insight into how internal and external selection processes work together to yield efficient search behavior.
GPT-4o mini: Non-social science research article
Electrical excitation of self-hybridized exciton polaritons in a van der Waals antiferromagnet
Jonas D. Ziegler, Sotirios Papadopoulos, Antti J. Moilanen, Marcelo MartĂ­nez, Qia Lin, Kseniia Mosina, Takashi Taniguchi, Kenji Watanabe, Zdenek Sofer, Florian Dirnberger, Lukas Novotny
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The coupling of light with excitations in matter is one of the most important concepts to make photons interact, crucial for the development of efficient optoelectronic devices. In materials with exceptionally strong light-matter interaction, excitons can hybridize with photons without the need of an external cavity. Here, we report the electrical excitation of such self-hybridized polaritons in the van der Waals antiferromagnet CrSBr. We exploit an unconventional excitation via energy transfer from tunneling electrons in graphene tunnel junctions to strongly bound excitons in proximate CrSBr layers. This enables us to excite CrSBr crystals ranging in thickness from a bilayer up to 250 nanometers, with the strong linear polarization of the electroluminescence confirming the excitonic origin. We assign the electrically excited emission to self-hybridized exciton polaritons, highlighting the strong coupling between optical excitations and confined photon modes in CrSBr. Our findings not only offer an efficient method to generate polaritons electrically but also create opportunities for future spintronic devices.
GPT-4o mini: Non-social science research article
Creation of a black hole bomb instability in an electromagnetic system
M. Cromb, M.C. Braidotti, A. Vinante, D. Faccio, H. Ulbricht
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The amplification and generation of electromagnetic radiation by a rotating metallic or lossy cylinder, first proposed by Zel’dovich in the 1970s, is closely linked to quantum friction, energy extraction from rotating black holes, and runaway mechanisms such as black hole bombs. Although advances such as acoustic analogs of the Zel’dovich effect and the observation of negative resistance in low-frequency electromagnetic models have been reported, genuine positive signal gain, spontaneous emission of electromagnetic waves, and runaway amplification have not previously been verified. Here, we provide the first experimental demonstration that a mechanically rotating metallic cylinder acts as an amplifier of a rotating electromagnetic field mode. Moreover, when combined with a low-loss resonator, the system becomes unstable and operates as a generator seeded only by noise. The exponential runaway amplification of spontaneously generated electromagnetic modes is observed, establishing the electromagnetic analog of the Press-Teukolsky black hole bomb and paving the way to experimental tests of quantum friction from vacuum fluctuations.
GPT-4o mini: Non-social science research article
Endogenic heat at Enceladus’ north pole
Georgina Miles, Carly J. A. Howett, Francis Nimmo, Douglas J. Hemingway
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The long-term survival of Enceladus’ ocean depends on the balance between heat production and heat loss. To date, the only place where a direct measurement of Enceladus’s heat loss has been made is at the south pole. Here, we show that the north pole also emits heat at a greater rate than can be explained by purely passive models. By comparing winter and summer observations taken with the Cassini Composite InfraRed Spectrometer, we find a winter temperature ~7 kelvin warmer than passive modeling predicts, accounting for uncertainties in emissivity and thermal inertia. An additional endogenic heat flux of 46 ± 4 milliwatts per square meter is required to match the observed radiance. The implied local shell thickness is 20 to 23 kilometers—consistent with the higher end of thickness models based on gravity, topography, and libration measurements. This work provides a previously unidentified constraint for models of tidal heat production, shell thickness, and the long-term evolution of Enceladus’ ocean.
GPT-4o mini: Non-social science research article
Oligo-CALL: A next-generation barcoding platform for studying resistance to targeted therapy
Yingzhuo Liu, Yi Ban, Dingcheng Gao
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Understanding therapy resistance requires deconvolving heterogeneous cell populations and tracking clonal trajectories. While CRISPR-based cellular barcoding is powerful for lineage tracing, many platforms suffer from low efficiency and limited compatibility with single-cell transcriptomics. We developed Oligo-CALL (Oligonucleotide-inducible CRISPR transcriptional activator–Assisted Lineage Labeling), an advanced barcoding system enabling precise lineage tracing, live clone isolation, and seamless integration with single-cell RNA sequencing. Applied to lung cancer cells treated with a KRAS G12C inhibitor, Oligo-CALL identified clones consistently enriched posttreatment, supporting a model of predestined resistance. Oligo-CALL achieved >95% efficiency in linking lineage identity to transcriptomes, uncovering diverse clone-specific pathways with underlying resistance. Paired analysis of barcode-matched clones from naĂŻve and resistant populations revealed transient and fixed resistance phenotypes. Notably, DNA repair pathways are recurrently altered in resistant clones, and inhibition of poly(adenosine 5â€Č-diphosphate–ribose) polymerase synergizes with KRAS G12C inhibition to overcome resistance. Together, Oligo-CALL provides a versatile platform for dissecting lineage evolution and molecular dynamics of targeted therapy resistance.
GPT-4o mini: Non-social science research article
Computational discovery and experimental validation of high–refractive index HfS 2 nanoresonators
Xavier Zambrana-Puyalto, Mark Kamper Svendsen, Amalie H. SĂžndersted, Avishek Sarbajna, Joakim P. Sandberg, Albert L. Riber, Georgy Ermolaev, Tara Maria Boland, Gleb Tselikov, Valentyn S. Volkov, Kristian S. Thygesen, SĂžren Raza
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High–refractive index dielectric materials can enhance many optical technologies by enabling efficient light manipulation in waveguides, metasurfaces, and nanoscale resonators. Van der Waals materials, which are anisotropic semiconductor materials, are particularly promising due to their excitonic response and strong in-plane polarizability. Here, we perform ab initio calculations to determine the refractive index of over a hundred anisotropic semiconductor materials, many of them van der Waals in nature. Our computational screening reveals both established and less-explored promising materials, including hafnium disulfide (HfS 2 ), which exhibits an in-plane refractive index above 3 and large anisotropy in the visible range. We confirm these properties through ellipsometry and develop a nanofabrication process for HfS 2 , demonstrating Mie-resonant nanodisks. This is achieved by mitigating the air sensitivity of HfS 2 through storage in controlled environment or encapsulation. Our work provides a comparative overview of high-index van der Waals materials and establishes HfS 2 as a promising material for visible-range photonics.
GPT-4o mini: Non-social science research article
Alveolar macrophages initiate the spatially targeted recruitment of neutrophils after nanoparticle inhalation
Qiongliang Liu, Lin Yang, Chenxi Li, Lianyong Han, Juliet Wilmot, Guo Yang, Riccardo Leinardi, Qiaoxia Zhou, Andreas Schröppel, David Kutschke, Judith Secklehner, Ali Önder Yldirim, François Huaux, Dagmar Zeuschner, Leo M. Carlin, Markus Sperandio, Otmar Schmid, Tobias Stoeger, Markus Rehberg
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Lung resident immune cells are essential for initiating defenses against inhaled air pollutants, including nanoparticles (NPs), which contribute to pulmonary disease progression. Here, lung intravital microscopy was used to examine the pulmonary innate immune responses in mice, during acute aerosol exposure to carbon NPs, a common environmental pollutant, or fluorescent quantum dot NPs. We found that inhaled NPs triggered rapid, neutrophil recruitment, localized to alveolar NP deposition hotspots, orchestrated by alveolar macrophages (AMs) through both their motility and phagocytic activity. AM motility inhibition in the alveoli via intercellular adhesion molecule–1/LFA-1 blockade reduced neutrophil recruitment, as did impaired AM phagocytosis through C5a receptor 1/Fc-γ receptor I inhibition or by stealth NP surfaces. In addition, cellular degranulation inhibition indicated the importance of spatially focused cytokine release in neutrophil recruitment. Collectively, our study elucidates AM-epithelial interactions as a critical key event for NPs triggered neutrophilia, with AM motility and phagocytosis driving recruitment and site-specific immune responses in the alveolar microenvironment.
GPT-4o mini: Non-social science research article
Records of mantle geodynamics and atmospheric escape in Archean quartz
Félix Vayrac, Guillaume Avice, Xinmu J. Zhang, Rita Parai, Pascal Philippot
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Early planetary degassing and atmospheric escape are two major, yet unconstrained, processes that shaped early Earth. Modeling predicts that the atmospheric 20 Ne/ 22 Ne ratio is sensitive to solar-Ne mantle degassing over geological time. Until the Great Oxidation Event, atmospheric escape progressively depletes the atmosphere in Xe, leaving an isotopic imprint. However, the quantity of xenon in the ancient atmosphere remains largely unknown. In this study, we analyzed noble gases in Archean hydrothermal quartz fluid inclusions and show that a modern atmospheric 20 Ne/ 22 Ne ratio was almost reached 2.7 Ga ago, implying intense mantle degassing during the first 1.7 billion years of Earth’s history, three orders of magnitude higher than today. Furthermore, we determine an Archean atmospheric Xe/Kr ratio, 2.3 times higher than today, consistent with models of Xe depletion over time through atmospheric escape.
GPT-4o mini: Non-social science research article
Landscape-wide cosmogram built by the early community of Aguada Fénix in southeastern Mesoamerica
Takeshi Inomata, Daniela Triadan, VerĂłnica A. VĂĄzquez LĂłpez, Melina GarcĂ­a HernĂĄndez, Juan Carlos Fernandez-Diaz, Ashley E. Sharpe, Claudia Alvarado, Atasta Flores, Xanti Ceballos, Kelsey E. Hanson, Ran Chen, Timothy Beach, Takayuki Omori, Hiroo Nasu, Kazuo Aoyama, Keitaro Yamada, Ikuko Kitaba, Takeshi Nakagawa
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There is growing recognition that societies without prominent hierarchies could build large constructions. Scholars are debating what motivated many people to participate in these construction projects. We investigated the site of Aguada Fénix, Mexico, which features the oldest and largest monumental architecture in the Maya area. Using light detection and ranging (LiDAR) and excavations, we documented a site plan composed of nested cross forms built between 1050 and 700 BCE. Its center was marked by a large cruciform cache containing the earliest known directional color symbols in Mesoamerica. The overall pattern consisted of 9- and 7.5-kilometer-long axes delineated by canals and corridors. The builders constructed canals, measuring up to 35 meters wide and 5 meters deep, and a dam to supply them with lake water. Although the canals appear unfinished, this site plan exceeded or rivaled the extents of later Mesoamerican cities. Aguada Fénix was probably designed as a cosmogram, which likely attracted people from a broad area.
GPT-4o mini: Non-social science research article
Universality in the small scales of turbulent Taylor-Couette flow
Julio M. Barros, Christian Butcher, Pinaki Chakraborty
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From a humble kitchen blender to the vast galactic disks, rotating turbulent flows exhibit remarkable diversity. They are also replete with puzzling features. A notable example is the energy spectrum of a widely studied rotating flow—the turbulent Taylor-Couette (TC) flow. Previous studies have shown that, unlike other canonical turbulent flows, it does not obey Kolmogorov’s universal power law or any other power law. Here, we report measurements of the energy spectra in turbulent TC flow from unique “flying-wire” experiments where a rotating probe sweeps through the flow. In contrast with previous studies, which focused primarily on spectral power laws, we analyze spectral data collapse. Through this broader approach, we show that, contrary to the prevailing understanding, the spectral structure of small scales in turbulent TC flow is in excellent accord with the potent paradigm of Kolmogorov’s small-scale universality.
GPT-4o mini: Non-social science research article
DKK3-LRP1 complex and a chemical inhibitor regulate AÎČ clearance in models of Alzheimer’s disease
Ruihan Yang, Lin Wang, Yue Li, Jian Zhu, Juxian Wang, David Schlessinger, Jian Sima
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Impaired clearance of amyloid-ÎČ (AÎČ) contributes to Alzheimer’s disease (AD) pathogenesis, but its upstream modulators remain poorly defined. We report secreted Dickkopf (DKK) proteins—DKK1 through DKK4—as previously unrecognized ligands of low-density lipoprotein receptor–related protein 1 (LRP1), a principal AÎČ clearance receptor. Analyses of cells derived from a patient with AD, postmortem tissue, and 5×FAD mice reveal that DKK1 and DKK3 are elevated in AD and reduce AÎČ uptake and degradation in neurons and astrocytes. Mechanistically, DKKs inhibit AÎČ clearance by competitively binding LRP1 and promoting its internalization. In 5×FAD mice, DKK3 overexpression worsens, while knockout improves, AÎČ pathology and cognitive outcomes. A targeted high-throughput screen of ~3000 compounds identified SJ-300 as a potent and selective inhibitor of the DKK3-LRP1 interaction. SJ-300 restores AÎČ clearance and rescues cognitive function and neuropathology in 5×FAD mice. These findings uncover DKK3-LRP1 axis as a contributor for AÎČ metabolism and nominate SJ-300 as a promising therapeutic candidate for AD intervention.
GPT-4o mini: Non-social science research article
Mothers facing greater environmental adversity experience increased costs of reproduction
Euan A. Young, Erik Postma, Virpi Lummaa, Hannah L. Dugdale
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Evolutionary theory of aging predicts that women with increased reproductive effort live shorter lives, but evidence is inconsistent. These inconsistencies could be because environmental conditions influence how much a mother’s life span is reduced when having more children, i.e., their life-span cost of reproduction. Using a structural equation measurement model, we compare how reproductive effort affects the life span of 4684 women exposed across different life stages, or not at all, to the Great Finnish Famine. We find that life-span costs of reproduction became higher in mothers exposed to the famine during reproduction and, for these mothers, amounted to lower life expectancies of ~0.5 years per child. Conversely, reproduction did not shape the life spans of mothers not exposed to the famine or exposed postreproduction or during development. This natural experiment reveals how environmental adversity can influence reproductive costs, providing a biological explanation for previous inconsistent findings while showing how reproductive behavior has shaped the evolution of aging in humans.
GPT-4o mini: Non-social science research article
Reefal regions were biodiversity hotspots throughout the Phanerozoic
Roger A. Close, Roger B. J. Benson, Wolfgang Kiessling, Erin E. Saupe
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Reefs are important hotspots of marine biodiversity today and have acted as cradles of diversification in the geological past. However, we know little about how the diversity of reef-supporting regions varied through deep time, and how this differed from other regions. We quantified regional diversity patterns in reef-supporting and non–reef-supporting regions in the fossil record of Phanerozoic marine invertebrates. Diversity in reef-supporting regions is on average two- to threefold higher than in non–reef-supporting regions and has been remarkably stable over timescales of tens to hundreds of millions of years. This signal is present in both reefal and non-reefal facies within reef-supporting regions, suggesting that reefs enriched diversity in surrounding environments. Sepkoski’s “Modern Fauna,” an assemblage of higher taxa that includes gastropods, bivalves, and echinoids, has been a key component of reef-supporting regions since the Paleozoic, contrasting with its later rise to dominance in non–reef-supporting regions during the later Mesozoic-Cenozoic.
GPT-4o mini: Non-social science research article
NAD + reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C
Ruixue Ai, Lipeng Mao, Xurui Jin, Carlos Campos-Marques, Shi-qi Zhang, Junping Pan, Maria Jose Lagartos-Donate, Shu-Qin Cao, Beatriz Barros-Santos, Rita NĂłbrega-Martins, Filippos Katsaitis, Guang Yang, Chenglong Xie, Xiongbin Kang, Pingjie Wang, Manuele Novello, Yang Hu, Linda Hildegard Bergersen, Jon Storm-Mathisen, Hidehito Kuroyanagi, Beatriz Escobar-Doncel, NoemĂ­ Villaseca GonzĂĄlez, Farrukh Abbas Chaudhry, Zeyuan Wang, Qiang Zhang, Guang Lu, Ioannis Sotiropoulos, Zhangming Niu, Guobing Chen, Rajeevkumar Raveendran Nair, Joana Margarida Silva, Oscar Junhong Luo, Evandro Fei Fang
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Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD + ) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD + enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD + augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD + -induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD + -induced memory improvement in pathological Tau–bearing mice. We propose that NAD + reduces AD pathologies, at least partially, via amplification of the NAD + - EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.
GPT-4o mini: Non-social science research article
Calcium-based synaptic and structural plasticity link pathological activity to synaptic reorganization in Parkinson’s disease
Cathal McLoughlin, Justus A. Kromer, Madeleine Lowery, Peter A. Tass
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Motor symptoms of Parkinson’s disease (PD) are associated with dopaminergic neuronal loss. Widespread synaptic reorganization and neural activity changes, including exaggerated beta oscillations and bursting, follow dopamine depletion (DD) of the basal ganglia (BG). Our computational model examines DD-induced neural activity changes and synaptic reorganization in the BG subcircuit comprising the subthalamic nucleus and globus pallidus externus. Calcium-dependent synaptic and structural plasticity mechanisms were incorporated, allowing neural activity to alter network topology. We show how hyperactivity of indirect pathway striatal projection neurons (iMSN) can induce synaptic connectivity changes consistent with PD animal models. Our results suggest that synaptic reorganization following DD results from a series of homeostatic calcium–based synaptic changes triggered by iMSN hyperactivity. While this structural plasticity functions as a compensatory mechanism in the cascade of changes following elevated iMSN input from striatal DD, it may become compromised if iMSN and cortical inputs show substantial bursting activity.
GPT-4o mini: Non-social science research article
Drivers of canyon incision in the Peruvian Andes: Tectonics, precipitation, and drainage basin capture
Jennie Plasterr, Nadine McQuarrie, Eitan Shelef, Sarah Falkowski, Paul R. Eizenhöfer, Todd A. Ehlers
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The drivers behind the marked 2- to 3-km relief canyons carved into the ca. 3.7-km-high Andean Plateau remain debated, with proposed triggers ranging from plateau surface uplift to precipitation-enhanced erosion. We integrate a surface processes model with published cross-section–derived estimates of structural geometry, kinematics, and shortening rates, as well as precipitation estimates from global atmospheric circulation models, to assess whether the geometry, sequential fault motion, and resulting surface uplift can reproduce plateau morphology. Endorheic basins form where uplift on faults exceeds incision. A decrease in shortening after ~10 Ma allows rivers to compete with uplift and incise into endorheic basins at the plateau edge. Two modeled basin capture events at ~7 to 5 Ma and ~3.5 to 0.5 Ma, coupled with climate-driven discharge fluctuations, markedly increase rivers’ discharge, erosion, and sediment transport, facilitating canyon incision and highlighting the importance of basin captures in canyon formation along the northeastern edge of the Andean Plateau.
GPT-4o mini: Non-social science research article
Dopamine and serotonin cotransmission filters striatonigral synaptic activity via 5-HT1B receptor activation
Maya Molinari, Alina Aaltonen, Ori J. Lieberman, David Sulzer, Emanuela Santini, Anders Borgkvist
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The substantia nigra pars reticulata (SNr), a key basal ganglia output nucleus, is modulated by dopamine (DA) believed to be released locally from midbrain DA neurons. Although DA has been proposed to regulate γ-aminobutyric acid (GABA) release from medium spiny neuron (MSN) terminals via presynaptic D1 receptors, the precise mechanisms remain unclear. Using presynaptic optical recordings of synaptic vesicle fusion, calcium influx in D1-MSN synapses together with postsynaptic patch-clamp recordings from SNr neurons, we found that DA inhibits D1-MSN GABA release in a frequency-dependent manner. Unexpectedly, this effect was independent of DA receptors and instead required 5-HT1B receptor activation. Using two-photon serotonin biosensor imaging in slices and fiber photometry in vivo, we demonstrate that DA enhances extracellular serotonin in the SNr via inhibition of serotonin reuptake. Our results suggest that serotonin mediates DAergic control of basal ganglia output and contributes to the therapeutic actions of dopaminergic medications for Parkinson’s disease and psychostimulant-related disorders.
GPT-4o mini: Non-social science research article
Quantifying widespread hydrothermal chimneys on the East Pacific Rise flanks between 9°43â€Č and 57â€ČN
Jyun-Nai Wu, Ross Parnell-Turner, Daniel J. Fornari, Thibaut Barreyre, Jill M. McDermott
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Hydrothermal circulation at mid-ocean ridges drives the exchange of heat and matter from Earth’s interior to the global ocean and supports deep-sea life. Away from the ridge axis, however, the spatial extent of hydrothermal discharge remains enigmatic. Using near-bottom data for a 25-kilometer-long section of the East Pacific Rise between 9°43â€ČN and 9°57â€ČN, we show that considerable hydrothermal flow occurs at variable distances from the ridge axis. Mapping the seafloor and water column along this segment using an autonomous underwater vehicle, we identified 448 candidate hydrothermal chimneys. More than half of them lie outside the axial summit trough, indicating that hydrothermal fluids discharge over a larger area than previously thought. Water column measurements show that >27% of mapped constructs are likely to be venting actively. Our results indicate that widespread active hydrothermal flow occurs over the near-axis region, with important implications for constraining total heat flux along mid-ocean ridges and for identifying previously unexplored benthic habitats.
GPT-4o mini: Non-social science research article
Human stem cell-derived ÎČ cells expressing an optimized CD155 reduce cytotoxic immune cell function for application in type 1 diabetes
Matthew E. Brown, Jessie M. Barra, Marcus R. Pina, James Proia, Todd M. Brusko, Holger A. Russ
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Insulin-producing ÎČ cell replacement therapies show promise for treating type 1 diabetes (T1D), but challenges such as donor shortages and immune rejection persist. Stem cell–derived ÎČ cells (sBC) provide a renewable source but remain susceptible to immune attack. We engineered human pluripotent stem cells to express either the wild type (WT) or a high-affinity mutant (Mut) variant (rs1058402, G>A; Ala 67 Thr) of the natural killer (NK) and T cell checkpoint inhibitor CD155 before differentiation into sBC. Modified sBC maintained up-regulated CD155 expression and showed enhanced binding to co-receptor ligands. Co-culture studies revealed CD155-expressing sBC suppressed autoreactive CD8 + T cell and NK cell activation, reducing immune cell–mediated sBC destruction and cytotoxic molecule secretion by preferentially engaging the coinhibitory receptor TIGIT. This protection was lost with TIGIT blockade, affirming the role of CD155-TIGIT signaling in antagonizing immune cell cytotoxicity. Our findings suggest that high-affinity CD155 expression enhances immune evasion of sBC, improving their potential as a therapy for T1D.
GPT-4o mini: Non-social science research article
Single-nucleus profiling highlights the all-brain echinoderm nervous system
Periklis Paganos, Jack Ullrich-LĂŒter, Alba AlmazĂĄn, Danila Voronov, Jil Carl, Anne-C. Zakrzewski, Berit Zemann, Maria Lorenza Rusciano, Tiphaine Sancerni, Maria Schauer, Oğuz Akar, Filomena Caccavale, Maria Cocurullo, Giovanna Benvenuto, Jenifer Carol Croce, Carsten LĂŒter, Maria Ina Arnone
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Metazoans comprise diverse tissues and cell types, each essential for the organismal survival. Most of these types are established early in embryogenesis and persist into adulthood. In indirectly developing sea urchins, however, the continuity between embryonic and adult stages is interrupted by a planktonic larval stage that undergoes complete metamorphosis. While gene regulatory networks controlling embryonic and larval lineages are well studied, the molecular and morphological identities of postmetamorphic cell types remain poorly understood. Here, we reconstructed the cell atlas of postmetamorphic Paracentrotus lividus juveniles using single-nucleus transcriptomics, revealing conservation of regulatory mechanisms. We identified signatures of eight distinct cell type groups and analyzed 29 neuronal families, including 15 unique photoreceptor types. By combining transcriptomics, spatial analysis, and ultrastructure, we identified vertebrate neuronal and opsin homologs expressed across the juvenile. These findings show that the echinoderm body plan is predominantly head-like and exhibits an “all-brain” organization.
GPT-4o mini: Non-social science research article
Xenopus IgX informs engineering strategies of IgM and IgG hexamers
Ruixue Zhang, Chenggong Ji, Shuhan Li, Ningning Li, Ning Gao, Junyu Xiao
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Polymeric immunoglobulins are essential components of the immune system in jawed vertebrates. While mammalian immunoglobulin M (IgM) typically forms a pentamer linked by the joining chain (J-chain), Xenopus laevis IgX can assemble into a J-chain–independent polymer. Here, we present the cryo–electron microscopy (cryo-EM) structure of IgX, revealing its hexameric configuration. By incorporating the IgX tailpiece into human IgM, we achieved efficient IgM hexamer formation. Truncating IgM’s natural tailpiece to a range of 11 to 16 residues also substantially enhanced hexamerization efficiency. Furthermore, introducing a shortened IgM tailpiece to IgG resulted in effective IgG hexamer formation. We further show that the engineered IgM and IgG hexamers targeting CD20 demonstrated robust complement-dependent cytotoxicity (CDC) against several B lymphoma cells. In addition, the IgG-Fc hexamer functioned as a decoy, attenuating CDC in cell cultures. These findings deepen our understanding of polymeric immunoglobulin evolution and introduce innovative strategies for the development of IgM- and IgG-based biologics.
GPT-4o mini: Non-social science research article
Sea surface warming and ocean-to-atmosphere feedback driven by large-scale offshore wind farms under seasonally stratified conditions
Hyodae Seo, César Sauvage, Christoph Renkl, Julie K. Lundquist, Anthony Kirincich
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Offshore wind farms may induce changes in the upper ocean and near-surface atmosphere through coupled ocean-atmosphere feedbacks. Yet, the role of air-sea interactions mediated by offshore wind farms remains poorly understood. Using fully coupled ocean-atmosphere-wave model simulations for seasonally stratified conditions along the US East Coast, we show that simulated cumulative reductions in wind stress due to large-scale wind farm clusters lead to sea surface warming of 0.3° to 0.4°C and a shallower mixed layer. This warming drives upward heat fluxes, destabilizing the atmospheric boundary layer and enhancing wind stress, which partially offsets wake-induced wind deficits. These wake-ocean interactions influence near-surface meteorology and air-sea fluxes, suggesting that a coupled modeling approach may be necessary for assessing potential oceanographic impacts of offshore wind developments. However, ocean coupling exerts limited influence on winds at turbine-relevant heights or within downstream wakes, resulting in minimal impact on long-term energy. These findings suggest that models without ocean coupling may be adequate for wind energy applications.
GPT-4o mini: Non-social science research article
Dynamically autofocused 3D pulsed laser micromachining enables advanced 3D bioelectronics
Massimo Mariello, Joseph G. Troughton, Yixuan Leng, Ziming Wang, Nuzli Karam, Lawrence Coles, José Gonzålez-Martínez, Kawsar Ali, Daniel J. Rogers, Madeline Lancaster, Christopher M. Proctor
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Advancing next-generation bioelectronic interfaces requires devices that are soft, miniaturized, and seamlessly integrated with biological tissues. However, conventional fabrication methods, primarily based on UV photolithography, struggle to meet these needs, relying on hazardous chemicals, labor-intensive processes, and planar, layer-by-layer construction. To overcome these limits, we introduce dynamically autofocused 3D pulsed laser micromachining (d-3DPLM) using a nanosecond pulsed near-infrared laser. This approach enables rapid, cost-effective structuring of diverse materials, including thin films, metal foils, and bulk metal blocks, supporting monolithic, multilayer bioelectronics with complex 3D architectures such as microneedles and deployable elements. d-3DPLM achieves high-resolution ablation and patterning for conformable and functional device geometries. Demonstrated applications include electro-haptic patches, in vitro multielectrode diagnostic arrays, and wireless contact lenses for red light therapy. By broadening the design and manufacturing landscape for bioelectronic systems, this versatile method paves the way for improved performance, unique functionality, and enhanced integration with living tissue.
GPT-4o mini: Non-social science research article
Regiocontrolled hydrobromination of unactivated alkenes via direct and chain-walking pathways
Minseok Kim, Seunghoon Han, Changseok Lee, Sungwoo Hong
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The development of regioselective methods for C(sp 3 )─Br bond formation in unactivated alkenes remains a fundamental challenge in organic synthesis. Herein, we report a nickel hydride–catalyzed method that enables regiocontrolled hydrobromination of both terminal and internal alkenes through strategic deployment of an N -fluoropyridinium oxidant. The method features two complementary approaches: direct hydrobromination of alkenes with high proximal selectivity and a chain-walking strategy that enables switchable site-selective functionalization in extended alkyl chains. Notably, temperature-controlled reaction parameters enable regiodivergent access to ÎČ- or Îł-brominated products from identical alkenes with excellent selectivity. The protocol demonstrates broad functional group tolerance and enables late-stage functionalization of pharmaceuticals. Mechanistic studies, including deuterium labeling, radical clock experiments, and density functional theory calculations, revealed a radical-mediated pathway featuring temperature-dependent regioselectivity in the chain-walking process. This unified method provides a versatile platform to access diverse alkyl bromides and offers fundamental insights into selective C─Br bond construction through direct and chain-walking pathways.
GPT-4o mini: Non-social science research article
From breaking rules to making rules in materials science
Bharat Jalan
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The role of universities in society
MichÚle Belot, Lea Cassar, Karoline Ströhlein
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This study examines public views on universities’ societal roles beyond education and research. A representative sample of 2089 U.S. citizens evaluates whether universities should engage in initiatives such as diversity, equity, and inclusion (DEI), free speech, and environmental sustainability, benchmarking views against corporations. We include an incentivized experiment asking respondents to allocate money between universities based on performance on various dimensions. Results show broad support for engagement in initiatives related to environmental sustainability, well-being, and free speech but opposition to political engagement. Views on DEI are polarized: Women and liberals reward universities excelling in DEI but conservatives and men penalize them, even when academic performance is equal. These findings highlight the polarization surrounding universities’ societal roles.
Source framing triggers systematic bias in large language models
Federico Germani, Giovanni Spitale
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Large language models (LLMs) are increasingly used to evaluate text, raising urgent questions about whether their judgments are consistent, unbiased, and robust to framing effects. Here, we examine inter- and intramodel agreement across four state-of-the-art LLMs tasked with evaluating 4800 narrative statements on 24 different topics of social, political, and public health relevance, for a total of 192,000 assessments. We manipulate the disclosed source of each statement to assess how attribution to either another LLM or a human author of specified nationality affects evaluation outcomes. Different LLMs display a remarkably high degree of inter- and intramodel agreement across topics, but this alignment breaks down when source framing is introduced. Attributing statements to Chinese individuals systematically lowers agreement scores across all models and, in particular, for DeepSeek Reasoner. Our findings show that LLMs’ own judgment of agreement with narrative statements exhibit systematic bias from framing effects, with substantial implications for the neutrality and fairness of LLM-mediated information systems.
Intersectional inequalities in social ties
Samuel Martin-Gutierrez, Mauritz N. Cartier van Dissel, Fariba Karimi
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Social networks are shaped by complex, intersecting identities that drive our connection preferences. These preferences create tie inequalities: Systematic differences in the number of links members of different groups accumulate. Understanding tie inequalities is critical because they contribute to disparities in social capital, with downstream consequences for access to opportunities and resources. Previous research has examined the impact of single-dimensional identities on tie disparities, but when multiple identities intersect, network disadvantages accumulate nonlinearly, disproportionately harming individuals belonging to several disadvantaged groups. However, how multidimensional connection preferences affect network dynamics and amplify or mitigate differences in ties remains unknown. Using a network model, we characterize the effects of multidimensional preferences and attribute correlation. We find that correlation creates counterintuitive tie inequalities unobservable in one-dimensional systems. We calibrate the model with high school friendship data and derive closed-form expressions for tie inequalities, which reproduce the empirical patterns with remarkable accuracy. Our findings have substantial implications for addressing intersectional inequalities in social networks.
International trade regulations take a limited bite out of the shark fin trade
Diego Cardeñosa, Elizabeth A. Babcock, Stanley K. Shea, Huarong Zhang, Kevin A. Feldheim, Feng Yang, Stephan W. Gale, Daniel Fernando, Akshay Tanna, Luke Warwick, Demian D. Chapman
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International trade is a major driver of shark overexploitation. In 2013, five threatened shark species were listed on Appendix II of the Convention on International Trade of Endangered Species to regulate global trade and promote recovery. Once listed, any uncertified, unreported export of these species became illegal. Minimal trade was reported from 2015 to 2021, yet fins from four of these species were common in the world’s largest shark fin hub (Hong Kong) throughout this period, indicating substantial and sustained illegal trade. Seventy three of 90 shark fin–exporting nations (81%) have never reported any trade of these species. Mixed stock analysis of a market sample of fins from one listed species revealed six populations of origin but only three were from regions where trade was reported. Broader application of CITES compliance mechanisms is necessary to combat widespread illegal trade of shark fins and realize the conservation potential of these trade regulations.
Agreement, polarization, or both? Americans’ views of universities
Brian Powell
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Responses to university policies and practices point to both consensus and polarization in the American public.
The direct financial costs of having a family member incarcerated
Garrett Baker, Sarah Jobe, Sarah Sernaker, Christopher Wildeman
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Using original data from the Family Incarceration Costs Survey, we present national estimates of the direct financial costs of family member incarceration. We find that most Americans with an incarcerated family member provide them direct financial support. The median monthly direct expense among those who contribute is $172, which represents 6% of their household income. On average, Blacks and Hispanics incur higher direct expenses than whites despite their lower household incomes. Men and women contribute similar amounts, but these direct expenses reflect a larger share of women’s household income. Poor families’ direct expenses are comparable to those of affluent families and are similar to their spending on health care, utilities, and car-related costs. Together, these results suggest that familial incarceration is a prominent line item that strains marginalized families’ already-tight household budgets and is a substantial yet underappreciated mechanism through which mass incarceration has reshaped the texture of American poverty in recent decades.
Focusing on family finances reveals actual cost of incarceration
Karin Martin
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An estimate of incarceration’s financial burden reveals that families contribute 6% of household income for an incarcerated family member’s food, calls, and direct support.
Hug fans or follow celebrities? How nationalism is reinforced on Chinese social media
Ji Yeon Hong, Yong H. Kim, Han Zhang, Tianzhu Qin
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How nationalism spreads and is reinforced has long been debated. This study examines how nationalistic messages and sentiments propagate on Chinese social media, focusing on interactions between celebrities and fans. We analyzed more than 8 million Weibo microblogs and comments, classified their content using machine-learning techniques, and examined the dynamics between celebrities and fans. Contrary to conventional wisdom, our findings reveal that fans exert a stronger influence on celebrities than vice versa in spreading nationalism. Fans often shape the nationalist narratives that celebrities amplify, with those aligned with specific political leanings (e.g., within the state-conformist camp) having a greater influence. These results highlight the critical role of grassroots online communities in shaping nationalism in nondemocratic contexts, offering insights into the dynamic interactions between the masses and influential figures in reinforcing nationalist ideologies and sentiments.