I checked 6 multidisciplinary journals on Friday, April 11, 2025 using the Crossref API. For the period April 04 to April 10, I found 14 new paper(s) in 5 journal(s).

Nature

GPT-4o mini: Non-social science research article
Universal photonic artificial intelligence acceleration
Sufi R. Ahmed, Reza Baghdadi, Mikhail Bernadskiy, Nate Bowman, Ryan Braid, Jim Carr, Chen Chen, Pietro Ciccarella, Matthew Cole, John Cooke, Kishor Desai, Carlos Dorta, Jonathan Elmhurst, Bryce Gardiner, Elliot Greenwald, Shashank Gupta, Parry Husbands, Brian Jones, Anthony Kopa, Ho John Lee, Arulselvan Madhavan, Adam Mendrela, Nicholas Moore, Lakshmi Nair, Aditya Om, Subie Patel, Rutayan Patro, Rob Pellowski, Esha Radhakrishnani, Sandeep Sane, Nicholas Sarkis, Joe Stadolnik, Mykhailo Tymchenko, Gongyu Wang, Kurt Winikka, Alexandra Wleklinski, Josh Zelman, Richard Ho, Ritesh Jain, Ayon Basumallik, Darius Bunandar, Nicholas C. Harris
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Over the past decade, photonics research has explored accelerated tensor operations, foundational to artificial intelligence (AI) and deep learning1,2,3,4, as a path towards enhanced energy efficiency and performance5,6,7,8,9,10,11,12,13,14. The field is centrally motivated by finding alternative technologies to extend computational progress in a post-Moore’s law and Dennard scaling era15,16,17,18,19. Despite these advances, no photonic chip has achieved the precision necessary for practical AI applications, and demonstrations have been limited to simplified benchmark tasks. Here we introduce a photonic AI processor that executes advanced AI models, including ResNet3 and BERT20,21, along with the Atari deep reinforcement learning algorithm originally demonstrated by DeepMind22. This processor achieves near-electronic precision for many workloads, marking a notable entry for photonic computing into competition with established electronic AI accelerators23 and an essential step towards developing post-transistor computing technologies.
GPT-4o mini: Non-social science research article
A Nd@C82-polymer interface for efficient and stable perovskite solar cells
Yuexin Lin, Zhichao Lin, Shili Lv, Yuan Shui, Wenjing Zhu, Zuhong Zhang, Wenhan Yang, Jinbo Zhao, Hao Gu, Junmin Xia, Danning Wang, Fenqi Du, Annan Zhu, Jin Liu, Hairui Cai, Bin Wang, Nan Zhang, Haibin Wang, Xiaolong Liu, Tao Liu, Chuncai Kong, Di Zhou, Shi Chen, Zhimao Yang, Tao Li, Wei Ma, Guojia Fang, Luis Echegoyen, Guichuan Xing, Shengchun Yang, Tao Yang, Wenting Cai, Meng Li, Wei Huang, Chao Liang
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A critical challenge in the commercialization of perovskite solar cells (PSCs) is the simultaneous attainment of high power conversion efficiency (PCE) and high stability. Employing polymers interfaces in PSCs can enhance durability by blocking water and oxygen, and by suppressing ions interdiffusion, but their electronic shielding poses a challenge for efficient and stable PSCs1–3. In this study, we report a magnetic endohedral metallofullerene Nd@C82-polymer coupling layer, which features ultra-fast electron extraction and in-situ encapsulation, thereby promoting homogeneous electron extraction and suppressing ions interdiffusion. The Nd@C82-polymer coupling layer in PSCs exhibited PCE of 26.78% (certified 26.29%) and 23.08% with an aperture area of 0.08 square centimetres and 16 square centimetres (modules), respectively. The unencapsulated devices retained ~82% of the initial PCE after 2,500 hours of continuous 1-sun maximum power point operation at 65 °C.
GPT-4o mini: Non-social science research article
Small molecules restore mutant mitochondrial DNA polymerase activity
Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S. Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V. Gruszczyk, Seoeun Lee, Katarina A. S. Johansson, Javier Miralles FustĂ©, Yonghong Shi, S. Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M. Griffin, Carlos Pardo-HernĂĄndez, Thomas A. Keating, Barbara KĂŒppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E. Jones, Xie Xie, Simon Giroux, Claes M. Gustafsson, Maria Falkenberg
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Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits 1 . More than 300 mutations in POLG , the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists 2 . Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.
GPT-4o mini: Non-social science research article
Seismic imaging of a basaltic Lesser Antilles slab from ancient tectonics
Xusong Yang, Yujiang Xie, Catherine A. Rychert, Nicholas Harmon, Saskia Goes, Andreas Rietbrock, Lloyd Lynch, character(0), Colin G. Macpherson, Jeroen Van Hunen, Jon Davidson, Marjorie Wilson, Robert Allen, Jenny Collier, Jamie J. Wilkinson, Timothy J. Henstock, John-Michael Kendall, Jonathan D. Blundy, Joan Latchman, Richard Robertson
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At subduction zones, lithospheric material descends through the upper mantle to the mantle transition zone (MTZ), where it may continue to sink into the lower mantle or stagnate 1,2 . Several factors may be important in influencing this flow, including chemical heterogeneity 3–5 . However, tight constraints on these mantle flows and the exact factors that affect them have proved challenging. We use P-to-S receiver functions to image the subducting slab and the MTZ beneath the Lesser Antilles subduction zone. We image a singular, superdeep (>700 km) 660-km discontinuity over a 200-km-wide zone within the slab, accompanied by nearby double 660 discontinuity phases (normal and superdeep). Combined geodynamic and waveform modelling shows that this observation cannot be explained by temperature effects in typical mantle compositions but requires a large basalt-rich chemical anomaly, strongest in the location of the singular, deep 660. The inferred basalt signature is near the proposed location of a subducted extinct spreading ridge 6,7 , where basalt is probably present in greater proportions. Our finding suggests that past tectonic events impart chemical heterogeneity into slabs, and the heterogeneities, in turn, may affect the inherent tendency of the slab to sink.
GPT-4o mini: Non-social science research article
Giant electrocaloric effect in high-polar-entropy perovskite oxides
Feihong Du, Tiannan Yang, Hua Hao, Shangshu Li, Chenhang Xu, Tian Yao, Zhiwu Song, Jiahe Shen, Chenyun Bai, Ruhong Luo, Donglin Han, Qiang Li, Shanyu Zheng, Yingjing Zhang, Yezhan Lin, Zhenhua Ma, Haotian Chen, Chenyu Guo, Jiawang Feng, Shengyi Zhong, Ruilin Mai, Guodong Hou, Haixin Qiu, Meng Xie, Xin Chen, Yakun Yuan, Dong Qian, Dao Xiang, Xuefeng Chen, Zhengqian Fu, Genshui Wang, Hanxing Liu, Jiangping Chen, Guang Meng, Xiangyang Zhu, Long-Qing Chen, Shujun Zhang, Xiaoshi Qian
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Materials with a high electrocaloric effect (ECE)1,2 tend to favour a disordered yet easily tunable polar structure. Perovskite ferroelectrics3 stand out as ideal candidates owing to their high dielectric responses and reasonable thermal conductivity. The introduction of multielement atomic distortions induces a high-polar-entropy state4 that notably increases the ECE by effectively overcoming the constraints imposed by highly ordered, polar-correlated perovskite structures. Here we developed a lead-free relaxor ferroelectric with strong polar disorder through targeted multielement substitution at both the A and B sites of the perovskite, effectively distorting the lattice structure and inducing a variety of nanoscale polar configurations, polymorphic polar variants and non-polar regions. A combination of these multielement-induced features led to an increased density of interfaces, significantly enhancing the polar entropy. Remarkably, a high ECE for an entropy change of about 15 J kg−1 K−1 under a 10 MV m−1 field is observed for the material across a broad temperature range exceeding 60 °C. The formation of ultrafine, dispersed, multiphase lattice configurations leads to high-polar-entropy ferroelectric oxides with a high ECE and a long lifetime of over 1 million cycles that are suitable for manufacturing multilayer ceramic capacitors for practical electrocaloric refrigeration applications.
GPT-4o mini: Non-social science research article
Near-field photon entanglement in total angular momentum
Amit Kam, Shai Tsesses, Yigal Ilin, Kobi Cohen, Yaakov Lumer, Lior Fridman, Stav Lotan, Anatoly Patsyk, Liat Nemirovsky-Levy, Meir Orenstein, Mordechai Segev, Guy Bartal
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Photons can carry angular momentum, which is conventionally attributed to two constituents—spin angular momentum (SAM), which is an intrinsic property related to the polarization, and orbital angular momentum (OAM), which is related to the photon spatial distribution. In paraxial optics, these two forms of angular momentum are separable1, such that entanglement can be induced between the SAM and the OAM of a single photon2,3 or of different photons in a multi-photon state4. In nanophotonic systems, however, the SAM and the OAM of a photon are inseparable5,6, so only the total angular momentum (TAM) serves as a good quantum number7,8,9. Here we present the observation of non-classical correlations between two photons in the near-field regime, giving rise to entanglement related to the TAM. We entangle those nanophotonic states by coupling photon pairs to plasmonic modes and use quantum imaging techniques10,11 to measure their correlations. We observe that entanglement in TAM leads to a completely different structure of quantum correlations of photon pairs, compared with entanglement related to the two constituent angular momenta. This work paves the way for on-chip quantum information processing using the TAM of photons as the encoding property for quantum information.
GPT-4o mini: Non-social science research article
Transforming ceria into 2D clusters enhances catalytic activity
Konstantin Khivantsev, Hien Pham, Mark H. Engelhard, Hristiyan A. Aleksandrov, Libor Kovarik, Mark Bowden, Xiaohong Shari Li, Jinshu Tian, Iskra Z. Koleva, Inhak Song, Wenda Hu, Xinyi Wei, Yipeng Sun, Pascaline Tran, Trent R. Graham, Dong Jiang, David P. Dean, Christian J. Breckner, Jeffrey T. Miller, Georgi N. Vayssilov, JĂĄnos Szanyi, Abhaya Datye, Yong Wang
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Ceria nanoparticles supported on alumina are widely used in various catalytic reactions, particularly in conjunction with platinum group metals (PGMs)1,2,3,4,5,6,7,8,9. Here we found that treating these catalysts at temperatures between 750 and about 1,000 °C in the presence of CO and NO in steam (reactive treatment under reducing atmosphere) leads to the dispersion of ceria nanoparticles into high-density 2D (roughly one atomic layer thin) CexOy domains, as confirmed by microscopy, X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), infrared spectroscopy and density functional theory (DFT) calculations. These domains, which densely cover the alumina, exhibit substantially enhanced oxygen mobility and storage capacity, facilitating easier extraction of oxygen and the formation of Ce3+ sites and oxygen vacancies. As a result, these catalysts—whether with or without PGMs, such as Rh and Pt—show improved activity for several industrially important catalytic reactions, including NO and N2O reduction, as well as CO and NO oxidation, even after exposure to harsh ageing conditions. This study shows a catalyst architecture with superior redox properties under conditions that typically cause sintering, offering a pathway to more efficient metal–ceria catalysts for enhanced general catalysis.
GPT-4o mini: Non-social science research article
Mastering diverse control tasks through world models
Danijar Hafner, Jurgis Pasukonis, Jimmy Ba, Timothy Lillicrap
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Developing a general algorithm that learns to solve tasks across a wide range of applications has been a fundamental challenge in artificial intelligence. Although current reinforcement-learning algorithms can be readily applied to tasks similar to what they have been developed for, configuring them for new application domains requires substantial human expertise and experimentation 1,2 . Here we present the third generation of Dreamer, a general algorithm that outperforms specialized methods across over 150 diverse tasks, with a single configuration. Dreamer learns a model of the environment and improves its behaviour by imagining future scenarios. Robustness techniques based on normalization, balancing and transformations enable stable learning across domains. Applied out of the box, Dreamer is, to our knowledge, the first algorithm to collect diamonds in Minecraft from scratch without human data or curricula. This achievement has been posed as a substantial challenge in artificial intelligence that requires exploring farsighted strategies from pixels and sparse rewards in an open world 3 . Our work allows solving challenging control problems without extensive experimentation, making reinforcement learning broadly applicable.
GPT-4o mini: Non-social science research article
Global impoverishment of natural vegetation revealed by dark diversity
Meelis PĂ€rtel, Riin Tamme, Carlos P. Carmona, Kersti Riibak, Mari Moora, Jonathan A. Bennett, Alessandro Chiarucci, Milan ChytrĂœ, Francesco de Bello, Ove Eriksson, Susan Harrison, Robert John Lewis, Angela T. Moles, Maarja Öpik, Jodi N. Price, Vistorina Amputu, Diana Askarizadeh, Zohreh Atashgahi, Isabelle Aubin, Francisco M. AzcĂĄrate, Matthew D. Barrett, Maral Bashirzadeh, ZoltĂĄn BĂĄtori, Natalie Beenaerts, Kolja Bergholz, Kristine Birkeli, Idoia Biurrun, JosĂ© M. Blanco-Moreno, Kathryn J. Bloodworth, Laura Boisvert-Marsh, Bazartseren Boldgiv, Pedro H. S. Brancalion, Francis Q. Brearley, Charlotte Brown, C. Guillermo Bueno, Gabriella Buffa, James F. Cahill, Juan A. Campos, Giacomo Cangelmi, Michele Carbognani, Christopher Carcaillet, Bruno E. L. Cerabolini, Richard Chevalier, Jan S. Clavel, JosĂ© M. Costa, Sara A. O. Cousins, Jan Čuda, Mariana Dairel, Michele Dalle Fratte, Alena Danilova, John Davison, BalĂĄzs DeĂĄk, Silvia Del Vecchio, Iwona Dembicz, JĂŒrgen Dengler, Jiri Dolezal, Xavier Domene, Miroslav Dvorsky, Hamid Ejtehadi, Lucas Enrico, Dmitrii Epikhin, Anu Eskelinen, Franz Essl, Gaohua Fan, Edy Fantinato, Fatih Fazlioglu, Eduardo FernĂĄndez-Pascual, Arianna Ferrara, Alessandra Fidelis, Markus Fischer, Maren Flagmeier, T’ai G. W. Forte, Lauchlan H. Fraser, Junichi Fujinuma, Fernando F. Furquim, Berle Garris, Heath W. Garris, Melisa A. Giorgis, Gianpietro Giusso del Galdo, Ana GonzĂĄlez-Robles, Megan K. Good, MoisĂšs Guardiola, Riccardo Guarino, Irene Guerrero, JoannĂšs Guillemot, BehlĂŒl GĂŒler, Yinjie Guo, Stef Haesen, Martin Hejda, Ruben H. Heleno, Toke T. HĂžye, Richard HrivnĂĄk, Yingxin Huang, John T. Hunter, Dmytro Iakushenko, Ricardo Ibåñez, Nele Ingerpuu, Severin D. H. Irl, Eva JanĂ­kovĂĄ, Florian Jansen, Florian Jeltsch, Anke Jentsch, Borja JimĂ©nez-Alfaro, Madli JĂ”ks, Mohammad H. Jouri, Sahar Karami, Negin Katal, AndrĂĄs Kelemen, Bulat I. Khairullin, Anzar A. Khuroo, Kimberly J. Komatsu, Marie KonečnĂĄ, Ene Kook, Lotte Korell, Natalia Koroleva, Kirill A. Korznikov, Maria V. Kozhevnikova, Ɓukasz Kozub, Lauri Laanisto, Helena Lager, Vojtech Lanta, Romina G. Lasagno, Jonas J. Lembrechts, Liping Li, AleĆĄ Lisner, Houjia Liu, Kun Liu, Xuhe Liu, Manuel Esteban Lucas-Borja, Kristin Ludewig, Katalin LukĂĄcs, Jona Luther-Mosebach, Petr Macek, Michela Marignani, Richard Michalet, TamĂĄs MiglĂ©cz, Jesper Erenskjold Moeslund, Karlien Moeys, Daniel Montesinos, Eduardo Moreno-JimĂ©nez, Ivan Moysiyenko, Ladislav Mucina, Miriam Muñoz-Rojas, Raytha A. Murillo, Sylvia M. Nambahu, Lena Neuenkamp, Signe Normand, Arkadiusz Nowak, Paloma Nuche, Tatjana Oja, Vladimir G. Onipchenko, Kalina L. Pachedjieva, Bruno Paganeli, Begoña Peco, Ana M. L. Peralta, Aaron PĂ©rez-Haase, Pablo L. Peri, Alessandro Petraglia, Gwendolyn Peyre, Pedro Antonio Plaza-Álvarez, Jan Plue, Honor C. Prentice, Vadim E. Prokhorov, Dajana Radujković, Soroor Rahmanian, Triin Reitalu, Michael Ristow, AgnĂšs A. Robin, Ana BelĂ©n Robles, Daniel A. RodrĂ­guez Ginart, RaĂșl RomĂĄn, Ruben E. Roos, Leonardo Rosati, Jiƙí SĂĄdlo, Karina Salimbayeva, Rut SĂĄnchez de Dios, Khaliun Sanchir, Cornelia Sattler, John D. Scasta, Ute Schmiedel, Julian Schrader, Nick L. Schultz, Giacomo Sellan, Josep M. Serra-Diaz, Giulia Silan, Hana SkĂĄlovĂĄ, Nadiia Skobel, Judit Sonkoly, Kateƙina Ć tajerovĂĄ, Ivana SvitkovĂĄ, Sebastian ƚwierszcz, Andrew J. Tanentzap, Fallon M. Tanentzap, RubĂ©n Tarifa, Pablo Tejero, Dzhamal K. Tekeev, Michael Tholin, Ruben S. ThormodsĂŠter, Yichen Tian, Alla Tokaryuk, Csaba Tölgyesi, Marcello Tomaselli, Enrico Tordoni, PĂ©ter Török, BĂ©la TĂłthmĂ©rĂ©sz, AurĂšle Toussaint, Blaise Touzard, Diego P. F. Trindade, James L. Tsakalos, Sevda TĂŒrkiƟ, Enrique Valencia, Mercedes Valerio, Orsolya ValkĂł, Koenraad Van Meerbeek, Vigdis Vandvik, Jesus Villellas, Risto Virtanen, Michaela VĂ­tkovĂĄ, Martin VojĂ­k, Andreas von Hessberg, Jonathan von Oppen, Viktoria Wagner, Ji-Zhong Wan, Chun-Jing Wang, Sajad A. Wani, Lina Weiss, Tricia Wevill, Sa Xiao, Oscar ZĂĄrate MartĂ­nez, Martin Zobel
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Anthropogenic biodiversity decline threatens the functioning of ecosystems and the many benefits they provide to humanity1. As well as causing species losses in directly affected locations, human influence might also reduce biodiversity in relatively unmodified vegetation if far-reaching anthropogenic effects trigger local extinctions and hinder recolonization. Here we show that local plant diversity is globally negatively related to the level of anthropogenic activity in the surrounding region. Impoverishment of natural vegetation was evident only when we considered community completeness: the proportion of all suitable species in the region that are present at a site. To estimate community completeness, we compared the number of recorded species with the dark diversity—ecologically suitable species that are absent from a site but present in the surrounding region2. In the sampled regions with a minimal human footprint index, an average of 35% of suitable plant species were present locally, compared with less than 20% in highly affected regions. Besides having the potential to uncover overlooked threats to biodiversity, dark diversity also provides guidance for nature conservation. Species in the dark diversity remain regionally present, and their local populations might be restored through measures that improve connectivity between natural vegetation fragments and reduce threats to population persistence.
GPT-4o mini: Non-social science research article
Ancient DNA from the Green Sahara reveals ancestral North African lineage
Nada Salem, Marieke S. van de Loosdrecht, Arev Pelin SĂŒmer, Stefania Vai, Alexander HĂŒbner, Benjamin Peter, Raffaela A. Bianco, Martina Lari, Alessandra Modi, Mohamed Faraj Mohamed Al-Faloos, Mustafa Turjman, Abdeljalil Bouzouggar, Mary Anne Tafuri, Giorgio Manzi, Rocco Rotunno, Kay PrĂŒfer, Harald Ringbauer, David Caramelli, Savino di Lernia, Johannes Krause
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Although it is one of the most arid regions today, the Sahara Desert was a green savannah during the African Humid Period (AHP) between 14,500 and 5,000 years before present, with water bodies promoting human occupation and the spread of pastoralism in the middle Holocene epoch 1 . DNA rarely preserves well in this region, limiting knowledge of the Sahara’s genetic history and demographic past. Here we report ancient genomic data from the Central Sahara, obtained from two approximately 7,000-year-old Pastoral Neolithic female individuals buried in the Takarkori rock shelter in southwestern Libya. The majority of Takarkori individuals’ ancestry stems from a previously unknown North African genetic lineage that diverged from sub-Saharan African lineages around the same time as present-day humans outside Africa and remained isolated throughout most of its existence. Both Takarkori individuals are closely related to ancestry first documented in 15,000-year-old foragers from Taforalt Cave, Morocco 2 , associated with the Iberomaurusian lithic industry and predating the AHP. Takarkori and Iberomaurusian-associated individuals are equally distantly related to sub-Saharan lineages, suggesting limited gene flow from sub-Saharan to Northern Africa during the AHP. In contrast to Taforalt individuals, who have half the Neanderthal admixture of non-Africans, Takarkori shows ten times less Neanderthal ancestry than Levantine farmers, yet significantly more than contemporary sub-Saharan genomes. Our findings suggest that pastoralism spread through cultural diffusion into a deeply divergent, isolated North African lineage that had probably been widespread in Northern Africa during the late Pleistocene epoch.
GPT-4o mini: Non-social science research article
Leaf absorption contributes to accumulation of microplastics in plants
Ye Li, Junjie Zhang, Li Xu, Ruoqi Li, Rui Zhang, Mengxi Li, Chunmei Ran, Ziyu Rao, Xing Wei, Mingli Chen, Lu Wang, Zhiwanxin Li, Yining Xue, Chu Peng, Chunguang Liu, Hongwen Sun, Baoshan Xing, Lei Wang
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Plant absorption is important for the entry of many pollutants into food chains. Although terrestrial microplastics (MPs) can be absorbed by the roots1,2, their upward translocation is slow1. Meanwhile, atmospheric MPs are widely present3,4, but strong evidence on their direct absorption by plants is still lacking. Here, analyses using mass spectrometry detection show the widespread occurrence of polyethylene terephthalate (PET) and polystyrene (PS) polymers and oligomers in plant leaves, and identify that their levels increase with atmospheric concentrations and the leaf growth duration. The concentrations of PET and PS polymers can reach up to 104 ng per g dry weight in leaves at the high-pollution areas studied, such as the Dacron factory and a landfill site, and 102–103 ng per g dry weight of PET and PS can be detected in the open-air-grown leafy vegetables. Nano-sized PET and PS particles in the leaves were visually detected by hyperspectral imaging and atomic force microscopy–infrared spectroscopy. Absorption of the proactively exposed non-labelled, fluorescently labelled or europium-labelled plastic particles by maize (Zea mays L.) leaves through stomatal pathways, as well as their translocation to the vascular tissue through the apoplastic pathway, and accumulation in trichomes was identified using hyperspectral imaging, confocal microscopy and laser-ablation inductively coupled plasma mass spectrometry. Our results demonstrate that the absorption and accumulation of atmospheric MPs by plant leaves occur widely in the environment, and this should not be neglected when assessing the exposure of humans and other organisms to environmental MPs.
GPT-4o mini: Non-social science research article
Spatial multi-omics reveals cell-type-specific nuclear compartments
Yodai Takei, Yujing Yang, Jonathan White, Isabel N. Goronzy, Jina Yun, Meera Prasad, Lincoln J. Ombelets, Simone Schindler, Prashant Bhat, Mitchell Guttman, Long Cai
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The mammalian nucleus is compartmentalized by diverse subnuclear structures. These subnuclear structures, marked by nuclear bodies and histone modifications, are often cell-type specific and affect gene regulation and 3D genome organization1,2,3. Understanding their relationships rests on identifying the molecular constituents of subnuclear structures and mapping their associations with specific genomic loci and transcriptional levels in individual cells, all in complex tissues. Here, we introduce two-layer DNA seqFISH+, which enables simultaneous mapping of 100,049 genomic loci, together with the nascent transcriptome for 17,856 genes and subnuclear structures in single cells. These data enable imaging-based chromatin profiling of diverse subnuclear markers and can capture their changes at genomic scales ranging from 100–200 kilobases to approximately 1 megabase, depending on the marker and DNA locus. By using multi-omics datasets in the adult mouse cerebellum, we showed that repressive chromatin regions are more variable by cell type than are active regions across the genome. We also discovered that RNA polymerase II-enriched foci were locally associated with long, cell-type-specific genes (bigger than 200 kilobases) in a manner distinct from that of nuclear speckles. Furthermore, our analysis revealed that cell-type-specific regions of heterochromatin marked by histone H3 trimethylated at lysine 27 (H3K27me3) and histone H4 trimethylated at lysine 20 (H4K20me3) are enriched at specific genes and gene clusters, respectively, and shape radial chromosomal positioning and inter-chromosomal interactions in neurons and glial cells. Together, our results provide a single-cell high-resolution multi-omics view of subnuclear structures, associated genomic loci and their effects on gene regulation, directly within complex tissues.
GPT-4o mini: Non-social science research article
Ultra-broadband optical amplification using nonlinear integrated waveguides
Ping Zhao, Vijay Shekhawat, Marcello Girardi, Zonglong He, Victor Torres-Company, Peter A. Andrekson
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Four-wave mixing is a nonlinear optical phenomenon that can be used for wideband low-noise optical amplification and wavelength conversion. It has been extensively investigated for applications in communications 1 , computing 2 , metrology 3 , imaging 4 and quantum optics 5 . With its advantages of small footprint, large nonlinearity and dispersion-engineering capability, optical integrated waveguides are excellent candidates for realizing high-gain and large-bandwidth four-wave mixing for which anomalous dispersion is a key condition. Various waveguides based on, for example, silicon, aluminium gallium arsenide and nonlinear glass have been studied 6–10 , but suffer from considerable gain and bandwidth reductions, as conventional design approaches for anomalous dispersion result in multi-mode operation. We present a methodology for fabricating nonlinear waveguides with simultaneous single-mode operation and anomalous dispersion for ultra-broadband operation and high-efficiency four-wave mixing. Although we implemented this in silicon nitride waveguides, the design approach can be used with other platforms as well. By using higher-order dispersion, we achieved unprecedented amplification bandwidths of more than 300 nm in these ultra-low-loss integrated waveguides. Penalty-free all-optical wavelength conversion of 100 Gbit s −1 data in a single optical channel of over 200 nm was realized. These single-mode dispersion-engineered nonlinear waveguides could become practical building blocks in various nonlinear photonics applications.
GPT-4o mini: Non-social science research article
Translational genomics of osteoarthritis in 1,962,069 individuals
Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefansdottir, Cindy G. Boer, Merry-Lynn McDonald, J. Patrick Pett, Young-Chan Park, Margo Tuerlings, Rick Mulders, Andrei Barysenka, Ana Luiza Arruda, Vinicius Tragante, Alison Rocco, Norbert Bittner, Shibo Chen, Susanne Horn, Vinodh Srinivasasainagendra, Ken To, Georgia Katsoula, Peter Kreitmaier, Amabel M. M. Tenghe, Arthur Gilly, Liubov Arbeeva, Lane G. Chen, Agathe M. de Pins, Daniel Dochtermann, Cecilie Henkel, Jonas Höijer, Shuji Ito, Penelope A. Lind, Bitota Lukusa-Sawalena, Aye Ko Ko Minn, Marina Mola-Caminal, Akira Narita, Chelsea Nguyen, Ene Reimann, Micah D. Silberstein, Anne-Heidi Skogholt, Hemant K. Tiwari, Michelle S. Yau, Ming Yue, Wei Zhao, Jin J. Zhou, George Alexiadis, Karina Banasik, SÞren Brunak, Archie Campbell, Jackson T. S. Cheung, Joseph Dowsett, Tariq Faquih, Jessica D. Faul, Lijiang Fei, Anne Marie Fenstad, Takamitsu Funayama, Maiken E. Gabrielsen, Chinatsu Gocho, Kirill Gromov, Thomas Hansen, Georgi Hudjashov, Thorvaldur Ingvarsson, Jessica S. Johnson, Helgi Jonsson, Saori Kakehi, Juha Karjalainen, Elisa Kasbohm, Susanna LemmelÀ, Kuang Lin, Xiaoxi Liu, Marieke Loef, Massimo Mangino, Daniel McCartney, Iona Y. Millwood, Joshua Richman, Mary B. Roberts, Kathleen A. Ryan, Dino Samartzis, Manu Shivakumar, SÞren T. Skou, Sachiyo Sugimoto, Ken Suzuki, Hiroshi Takuwa, Maris Teder-Laving, Laurent Thomas, Kohei Tomizuka, Constance Turman, Stefan Weiss, Tian T. Wu, Eleni Zengini, Yanfei Zhang, character(0), character(0), George Babis, character(0), character(0), character(0), character(0), David A. van Heel, character(0), Bendik Winsvold, Maiken Gabrielsen, character(0), character(0), Manuel Allen Revez Ferreira, George Babis, Aris Baras, Tyler Barker, David J. Carey, Kathryn S. E. Cheah, Zhengming Chen, Jason Pui-Yin Cheung, Mark Daly, Renée de Mutsert, Charles B. Eaton, Christian Erikstrup, Ove Nord Furnes, Yvonne M. Golightly, Daniel F. Gudbjartsson, Nils P. Hailer, Caroline Hayward, Marc C. Hochberg, Georg Homuth, Laura M. Huckins, Kristian Hveem, Shiro Ikegawa, Muneaki Ishijima, Minoru Isomura, Marcus Jones, Jae H. Kang, Sharon L. R. Kardia, Margreet Kloppenburg, Peter Kraft, Nobuyuki Kumahashi, Suguru Kuwata, Ming Ta Michael Lee, Phil H. Lee, Robin Lerner, Liming Li, Steve A. Lietman, Luca Lotta, Michelle K. Lupton, Reedik MÀgi, Nicholas G. Martin, Timothy E. McAlindon, Sarah E. Medland, Karl Michaëlsson, Braxton D. Mitchell, Dennis O. Mook-Kanamori, Andrew P. Morris, Toru Nabika, Fuji Nagami, Amanda E. Nelson, Sisse Rye Ostrowski, Aarno Palotie, Ole Birger Pedersen, Frits R. Rosendaal, Mika Sakurai-Yageta, Carsten Oliver Schmidt, Pak Chung Sham, Jasvinder A. Singh, Diane T. Smelser, Jennifer A. Smith, You-qiang Song, Erik SÞrensen, Gen Tamiya, Yoshifumi Tamura, Chikashi Terao, Gudmar Thorleifsson, Anders Troelsen, Aspasia Tsezou, Yuji Uchio, A. G. Uitterlinden, Henrik Ullum, Ana M. Valdes, David A. van Heel, Robin G. Walters, David R. Weir, J. Mark Wilkinson, Bendik S. Winsvold, Masayuki Yamamoto, John-Anker Zwart, Kari Stefansson, Ingrid Meulenbelt, Sarah A. Teichmann, Joyce B. J. van Meurs, Unnur Styrkarsdottir, Eleftheria Zeggini
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Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes 1 . By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide 2 . As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFÎČ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.
GPT-4o mini: Non-social science research article
Multimodal cell maps as a foundation for structural and functional genomics
Leah V. Schaffer, Mengzhou Hu, Gege Qian, Kyung-Mee Moon, Abantika Pal, Neelesh Soni, Andrew P. Latham, Laura Pontano Vaites, Dorothy Tsai, Nicole M. Mattson, Katherine Licon, Robin Bachelder, Anthony Cesnik, Ishan Gaur, Trang Le, William Leineweber, Aji Palar, Ernst Pulido, Yue Qin, Xiaoyu Zhao, Christopher Churas, Joanna Lenkiewicz, Jing Chen, Keiichiro Ono, Dexter Pratt, Peter Zage, Ignacia Echeverria, Andrej Sali, J. Wade Harper, Steven P. Gygi, Leonard J. Foster, Edward L. Huttlin, Emma Lundberg, Trey Ideker
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Human cells consist of a complex hierarchy of components, many of which remain unexplored 1,2 . Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. Self-supervised multimodal data integration resolves 275 molecular assemblies spanning the range of 10 −8 to 10 −5 m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models 3 . We explore key applications in structural biology, yielding structures for 111 heterodimeric complexes and an expanded Rag–Ragulator assembly. The map assigns unexpected functions to 975 proteins, including roles for C18orf21 in RNA processing and DPP9 in interferon signalling, and identifies assemblies with multiple localizations or cell type specificity. It decodes paediatric cancer genomes 4 , identifying 21 recurrently mutated assemblies and implicating 102 validated new cancer proteins. The associated Cell Visualization Portal and Mapping Toolkit provide a reference platform for structural and functional cell biology.
GPT-4o mini: Non-social science research article
Millimetre-scale bioresorbable optoelectronic systems for electrotherapy
Yamin Zhang, Eric Rytkin, Liangsong Zeng, Jong Uk Kim, Lichao Tang, Haohui Zhang, Aleksei Mikhailov, Kaiyu Zhao, Yue Wang, Li Ding, Xinyue Lu, Anastasia Lantsova, Elena Aprea, Gengming Jiang, Shupeng Li, Seung Gi Seo, Tong Wang, Jin Wang, Jiayang Liu, Jianyu Gu, Fei Liu, Keith Bailey, Yat Fung Larry Li, Amy Burrell, Anna Pfenniger, Andrey Ardashev, Tianyu Yang, Naijia Liu, Zengyao Lv, Nathan S. Purwanto, Yue Ying, Yinsheng Lu, Claire Hoepfner, Altynai Melisova, Jiarui Gong, Jinheon Jeong, Junhwan Choi, Alex Hou, Rachel Nolander, Wubin Bai, Sung Hun Jin, Zhenqiang Ma, John M. Torkelson, Yonggang Huang, Wei Ouyang, Rishi K. Arora, Igor R. Efimov, John A. Rogers
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Temporary pacemakers are essential for the care of patients with short-lived bradycardia in post-operative and other settings1,2,3,4. Conventional devices require invasive open-heart surgery or less invasive endovascular surgery, both of which are challenging for paediatric and adult patients5,6,7,8. Other complications9,10,11 include risks of infections, lacerations and perforations of the myocardium, and of displacements of external power supplies and control systems. Here we introduce a millimetre-scale bioresorbable optoelectronic system with an onboard power supply and a wireless, optical control mechanism with generalized capabilities in electrotherapy and specific application opportunities in temporary cardiac pacing. The extremely small sizes of these devices enable minimally invasive implantation, including percutaneous injection and endovascular delivery. Experimental studies demonstrate effective pacing in mouse, rat, porcine, canine and human cardiac models at both single-site and multi-site locations. Pairing with a skin-interfaced wireless device allows autonomous, closed-loop operation upon detection of arrhythmias. Further work illustrates opportunities in combining these miniaturized devices with other medical implants, with an example of arrays of pacemakers for individual or collective use on the frames of transcatheter aortic valve replacement systems, to provide unique solutions that address risks for atrioventricular block following surgeries. This base technology can be readily adapted for a broad range of additional applications in electrotherapy, such as nerve and bone regeneration, wound therapy and pain management.
GPT-4o mini: Non-social science research article
Clinically relevant clot resolution via a thromboinflammation-on-a-chip
Yongzhi Qiu, Jessica Lin, Audrey Wang, Zhou Fang, Yumiko Sakurai, Hyoann Choi, Evelyn K. Williams, Elaissa T. Hardy, Kristin Maher, Ahmet F. Coskun, Gary Woods, Wilbur A. Lam
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Thromboinflammation occurs in various diseases, leading to life-threatening microvascular occlusion with resulting end-organ failure1,2,3,4. Importantly, how microvascular thromboinflammation resolves remains poorly understood due to the small size-scale of microvasculature and the long duration (weeks to months) of this process. Here we introduce a hydrogel-based thromboinflammation-on-a-chip model with long-term culture capabilities to model microvascular thromboinflammation and monitor clot resolution over clinically and physiologically relevant timescales (up to months). Using this system, we mapped out the distinct temporal phases of clot resolution in microvascular thromboinflammation. Using multiplexed RNA fluorescence in situ hybridization in combination with our thromboinflammation-on-a-chip model, we observed that inflammation shifts the endothelium fibrinolytic balance to favour thrombosis and pinpointed neutrophil elastase as a double-edged sword that induces clot resolution but also tissue damage. We then investigated the mechanisms of potential therapeutic agents that either prevent microvascular thrombosis or accelerate clot resolution. Specifically, we observed that, in thromboinflammation, (1) early tissue plasminogen activator administration within 3 h directly improves endothelial barrier function; (2) prophylactic defibrotide and enoxaparin suppress microvascular thromboinflammation through endothelium-mediated mechanisms; and (3) combining enoxaparin with crizanlizumab reduces microvascular occlusion and protects endothelial function in sickle cell disease. These data introduce a paradigm in investigating the underlying mechanisms of thromboinflammatory clot resolution and conducting drug discovery thereof.
GPT-4o mini: Non-social science research article
Haploid facultative parthenogenesis in sunflower sexual reproduction
Jian Lv, Dawei Liang, Eric Bumann, Virginie Mirleau Thebaud, Huaibing Jin, Changbao Li, Clemence Paris, Yinghui Dan, Chao Li, Ruijie Cui, Xianxia Chen, David Szwerdszarf, Peter Wittich, Bobby Clegg, Agustin Tassara, Hongmei Dan, Xiaolong Tian, Zhiqiang Liu, Wen Cai, Bin Sun, Jared Carter, Paul Drayton, Federico Bock, Timothy Kelliher
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Flowering plant sexual reproduction requires double fertilization, yielding embryo and endosperm seed compartments: the latter supports embryo growth and seed germination. In an experiment to generate haploid embryos through inhibition of pollen phospholipase activity in sunflower (Helianthus annus), we serendipitously discovered that emasculated sunflowers spontaneously form parthenogenic haploid seed. Exploration of genetic, chemical and environmental factors demonstrated that a specific genotype background enabled high parthenogenesis and that full spectrum high-intensity light supplementation boosted parthenogenesis, yielding hundreds of haploid seeds per head. Induction of doubled haploid plants can greatly accelerate plant breeding efficiency; however, despite successful engineering of haploid induction in many crops, few reported systems are commercially scalable1. Here we report efficient methods of chemical emasculation and genome doubling to produce fertile plants and enable a scalable sunflower doubled haploid system.
GPT-4o mini: Non-social science research article
Hidden states and dynamics of fractional fillings in twisted MoTe2 bilayers
Yiping Wang, Jeongheon Choe, Eric Anderson, Weijie Li, Julian Ingham, Eric A. Arsenault, Yiliu Li, Xiaodong Hu, Takashi Taniguchi, Kenji Watanabe, Xavier Roy, Dmitri Basov, Di Xiao, Raquel Queiroz, James C. Hone, Xiaodong Xu, X.-Y. Zhu
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The fractional quantum anomalous Hall (FQAH) effect was recently discovered in twisted MoTe2 bilayers (tMoTe2)1–4. Experiments to date have revealed Chern insulators from hole doping at Îœ = -1, -2/3, -3/5, and -4/7 (per moirĂ© unit cell) 1–6. In parallel, theories predict that, between v = -1 and -3, there exist exotic quantum phases 7–15, such as the coveted fractional topological insulators (FTI), fractional quantum spin Hall (FQSH) states, and non-abelian fractional states. Here we employ transient optical spectroscopy 16,17 on tMoTe2 to reveal nearly 20 hidden states at fractional fillings that are absent in static optical sensing or transport measurements. A pump pulse selectively excites charge across the correlated or pseudo gaps, leading to the disordering (melting) of correlated states 18. A probe pulse detects the subsequent melting and recovery dynamics via exciton and trion sensing 1,3,19–21. Besides the known states, we observe additional fractional fillings between Îœ = 0 and -1 and a large number of states on the electron doping side (Îœ > 0). Most importantly, we observe new states at fractional fillings of the Chern bands at Îœ = -4/3, -3/2, -5/3, -7/3, -5/2, and -8/3. These states are potential candidates for the predicted exotic topological phases 7–15. Moreover, we show that melting of correlated states occurs on two distinct time scales, 2-4 ps and 180-270 ps, attributed to electronic and phonon mechanisms, respectively. We discuss the differing dynamics of the electron and hole doped states from the distinct moirĂ© conduction and valence bands.
GPT-4o mini: Non-social science research article
Perisomatic ultrastructure efficiently classifies cells in mouse cortex
Leila Elabbady, Sharmishtaa Seshamani, Shang Mu, Gayathri Mahalingam, Casey M. Schneider-Mizell, Agnes L. Bodor, J. Alexander Bae, Derrick Brittain, JoAnn Buchanan, Daniel J. Bumbarger, Manuel A. Castro, Sven Dorkenwald, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Barak Nehoran, Sergiy Popovych, William Silversmith, Marc Takeno, Russel Torres, Nicholas L. Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-chieh Yu, H. Sebastian Seung, R. Clay Reid, Nuno Maçarico da Costa, Forrest Collman
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Mammalian neocortex contains a highly diverse set of cell types. These cell types have been mapped systematically using a variety of molecular, electrophysiological and morphological approaches 1–4 . Each modality offers new perspectives on the variation of biological processes underlying cell-type specialization. Cellular-scale electron microscopy provides dense ultrastructural examination and an unbiased perspective on the subcellular organization of brain cells, including their synaptic connectivity and nanometre-scale morphology. In data that contain tens of thousands of neurons, most of which have incomplete reconstructions, identifying cell types becomes a clear challenge for analysis 5 . Here, to address this challenge, we present a systematic survey of the somatic region of all cells in a cubic millimetre of cortex using quantitative features obtained from electron microscopy. This analysis demonstrates that the perisomatic region is sufficient to identify cell types, including types defined primarily on the basis of their connectivity patterns. We then describe how this classification facilitates cell-type-specific connectivity characterization and locating cells with rare connectivity patterns in the dataset.
GPT-4o mini: Non-social science research article
Foundation model of neural activity predicts response to new stimulus types
Eric Y. Wang, Paul G. Fahey, Zhuokun Ding, Stelios Papadopoulos, Kayla Ponder, Marissa A. Weis, Andersen Chang, Taliah Muhammad, Saumil Patel, Zhiwei Ding, Dat Tran, Jiakun Fu, Casey M. Schneider-Mizell, character(0), Nuno Maçarico da Costa, R. Clay Reid, Forrest Collman, Nuno Maçarico da Costa, Katrin Franke, Alexander S. Ecker, Jacob Reimer, Xaq Pitkow, Fabian H. Sinz, Andreas S. Tolias
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The complexity of neural circuits makes it challenging to decipher the brain’s algorithms of intelligence. Recent breakthroughs in deep learning have produced models that accurately simulate brain activity, enhancing our understanding of the brain’s computational objectives and neural coding. However, it is difficult for such models to generalize beyond their training distribution, limiting their utility. The emergence of foundation models 1 trained on vast datasets has introduced a new artificial intelligence paradigm with remarkable generalization capabilities. Here we collected large amounts of neural activity from visual cortices of multiple mice and trained a foundation model to accurately predict neuronal responses to arbitrary natural videos. This model generalized to new mice with minimal training and successfully predicted responses across various new stimulus domains, such as coherent motion and noise patterns. Beyond neural response prediction, the model also accurately predicted anatomical cell types, dendritic features and neuronal connectivity within the MICrONS functional connectomics dataset 2 . Our work is a crucial step towards building foundation models of the brain. As neuroscience accumulates larger, multimodal datasets, foundation models will reveal statistical regularities, enable rapid adaptation to new tasks and accelerate research.
GPT-4o mini: Non-social science research article
An integrated large-scale photonic accelerator with ultralow latency
Shiyue Hua, Erwan Divita, Shanshan Yu, Bo Peng, Charles Roques-Carmes, Zhan Su, Zhang Chen, Yanfei Bai, Jinghui Zou, Yunpeng Zhu, Yelong Xu, Cheng-kuan Lu, Yuemiao Di, Hui Chen, Lushan Jiang, Lijie Wang, Longwu Ou, Chaohong Zhang, Junjie Chen, Wen Zhang, Hongyan Zhu, Weijun Kuang, Long Wang, Huaiyu Meng, Maurice Steinman, Yichen Shen
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Integrated photonics, particularly silicon photonics, have emerged as cutting-edge technology driven by promising applications such as short-reach communications, autonomous driving, biosensing and photonic computing1,2,3,4. As advances in AI lead to growing computing demands, photonic computing has gained considerable attention as an appealing candidate. Nonetheless, there are substantial technical challenges in the scaling up of integrated photonics systems to realize these advantages, such as ensuring consistent performance gains in upscaled integrated device clusters, establishing standard designs and verification processes for complex circuits, as well as packaging large-scale systems. These obstacles arise primarily because of the relative immaturity of integrated photonics manufacturing and the scarcity of advanced packaging solutions involving photonics. Here we report a large-scale integrated photonic accelerator comprising more than 16,000 photonic components. The accelerator is designed to deliver standard linear matrix multiply–accumulate (MAC) functions, enabling computing with high speed up to 1 GHz frequency and low latency as small as 3 ns per cycle. Logic, memory and control functions that support photonic matrix MAC operations were designed into a cointegrated electronics chip. To seamlessly integrate the electronics and photonics chips at the commercial scale, we have made use of an innovative 2.5D hybrid advanced packaging approach. Through the development of this accelerator system, we demonstrate an ultralow computation latency for heuristic solvers of computationally hard Ising problems whose performance greatly relies on the computing latency.
GPT-4o mini: Non-social science research article
Evidence of star cluster migration and merger in dwarf galaxies
MĂ©lina Poulain, Rory Smith, Pierre-Alain Duc, Francine R. Marleau, Rebecca Habas, Patrick R. Durrell, JĂ©rĂ©my Fensch, Sungsoon Lim, Oliver MĂŒller, Sanjaya Paudel, RubĂ©n SĂĄnchez-Janssen
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Nuclear star clusters (NSCs) are the densest stellar systems in the Universe. These clusters can be found at the centre of all galaxy types but tend to favour galaxies of intermediate stellar mass around 10 9 M ⊙ (refs. 1,2 ). At present, two main processes are under debate to explain their formation: in situ star formation from gas infall 3 and migration and merging of globular clusters (GCs) caused by dynamical friction 4 . Studies 5–9 of NSC stellar populations suggest that the former predominates in massive galaxies, whereas the latter prevails in dwarf galaxies, and both contribute equally at intermediate mass. However, until now, no ongoing merger of GCs has been observed to confirm this scenario. Here we report the serendipitous discovery of five dwarf galaxies with complex nuclear regions, characterized by multiple nuclei and tidal tails, using high-resolution images from the Hubble Space Telescope. These structures have been reproduced in complementary N -body simulations, supporting the interpretation that they result from migrating and merging of star clusters. The small detection rate and short simulated timescales (below 100 Myr) of this process may explain why this has not been observed previously. This study highlights the need for large surveys with high resolution to fully map the migration scenario steps.
GPT-4o mini: Non-social science research article
Formation and composition of Earth’s Hadean protocrust
Simon Turner, Bernard Wood, Tim Johnson, Craig O’Neill, Bernard Bourdon
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Although Earth, together with other terrestrial planets, must have had an early-formed protocrust, the chemical composition of this crust has received little attention. The protocrust was extracted from an extensive magma ocean formed by accretion and melting of asteroidal bodies1. Both experimental and chronological data suggest that the silicate melt ascending from this magma ocean formed in equilibrium with, or after, metal was extracted to form Earth’s core. Here we show that a protocrust formed under these conditions would have had incompatible (with respect to silicate minerals) trace-element characteristics remarkably similar to those of the current average continental crust. This has major implications for subsequent planetary evolution. Many geochemical arguments for when and how plate tectonics began implicitly assume that subduction is required to produce the continental trace-element signature. These arguments are severely compromised if this signature was already a feature of the Hadean protocrust.
GPT-4o mini: Non-social science research article
The RAD52 double-ring remodels replication forks restricting fork reversal
Masayoshi Honda, Mortezaali Razzaghi, Paras Gaur, Eva Malacaria, Giorgia Marozzi, Ludovica Di Biagi, Francesca Antonella Aiello, Emeleeta A. Paintsil, Andrew J. Stanfield, Bailey J. Deppe, Lokesh Gakhar, Nicholas J. Schnicker, M. Ashley Spies, Pietro Pichierri, Maria Spies
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Human RAD52 is a multifunctional DNA repair protein involved in several cellular events that support genome stability, including protection of stalled DNA replication forks from excessive degradation1,2,3,4. In its gatekeeper role, RAD52 binds to and stabilizes stalled replication forks during replication stress, protecting them from reversal by SMARCAL1 motor3. The structural and molecular mechanism of the RAD52-mediated fork protection remains elusive. Here, using P1 nuclease sensitivity, biochemical and single-molecule analyses, we show that RAD52 dynamically remodels replication forks through its strand exchange activity. The presence of the single-stranded DNA binding protein RPA at the fork modulates the kinetics of the strand exchange without impeding the reaction outcome. Mass photometry and single-particle cryo-electron microscopy show that the replication fork promotes a unique nucleoprotein structure containing head-to-head arrangement of two undecameric RAD52 rings with an extended positively charged surface that accommodates all three arms of the replication fork. We propose that the formation and continuity of this surface is important for the strand exchange reaction and for competition with SMARCAL1.
GPT-4o mini: Non-social science research article
Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors
Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian, Neil K. Savalia, Quan Jiang, Cassandra Wojtasiewicz, Diran Tan, Jack D. Nothnagel, Rong-Jian Liu, Samuel C. Woodburn, Olesia M. Bilash, Hail Kim, Alicia Che, Alex C. Kwan
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Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1,2,3,4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells7,8,9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioural actions10. Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviourally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action.
GPT-4o mini: Non-social science research article
Human assembloid model of the ascending neural sensory pathway
Ji-il Kim, Kent Imaizumi, Ovidiu Jurjuț, Kevin W. Kelley, Dong Wang, Mayuri Vijay Thete, Zuzana Hudacova, Neal D. Amin, Rebecca J. Levy, GrĂ©gory Scherrer, Sergiu P. Pașca
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Somatosensory pathways convey crucial information about pain, touch, itch and body part movement from peripheral organs to the central nervous system1,2. Despite substantial needs to understand how these pathways assemble and to develop pain therapeutics, clinical translation remains challenging. This is probably related to species-specific features and the lack of in vitro models of the polysynaptic pathway. Here we established a human ascending somatosensory assembloid (hASA), a four-part assembloid generated from human pluripotent stem cells that integrates somatosensory, spinal, thalamic and cortical organoids to model the spinothalamic pathway. Transcriptomic profiling confirmed the presence of key cell types of this circuit. Rabies tracing and calcium imaging showed that sensory neurons connect to dorsal spinal cord neurons, which further connect to thalamic neurons. Following noxious chemical stimulation, calcium imaging of hASA demonstrated a coordinated response. In addition, extracellular recordings and imaging revealed synchronized activity across the assembloid. Notably, loss of the sodium channel NaV1.7, which causes pain insensitivity, disrupted synchrony across hASA. By contrast, a gain-of-function SCN9A variant associated with extreme pain disorder induced hypersynchrony. These experiments demonstrated the ability to functionally assemble the essential components of the human sensory pathway, which could accelerate our understanding of sensory circuits and facilitate therapeutic development.
GPT-4o mini: Non-social science research article
Inhibitory specificity from a connectomic census of mouse visual cortex
Casey M. Schneider-Mizell, Agnes L. Bodor, Derrick Brittain, JoAnn Buchanan, Daniel J. Bumbarger, Leila Elabbady, Clare Gamlin, Daniel Kapner, Sam Kinn, Gayathri Mahalingam, Sharmishtaa Seshamani, Shelby Suckow, Marc Takeno, Russel Torres, Wenjing Yin, Sven Dorkenwald, J. Alexander Bae, Manuel A. Castro, Akhilesh Halageri, Zhen Jia, Chris Jordan, Nico Kemnitz, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, William Silversmith, Nicholas L. Turner, William Wong, Jingpeng Wu, Jacob Reimer, Andreas S. Tolias, H. Sebastian Seung, R. Clay Reid, Forrest Collman, Nuno Maçarico da Costa
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Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties1. Synaptic connectivity shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here we used millimetre-scale volumetric electron microscopy2 to investigate the connectivity of all inhibitory neurons across a densely segmented neuronal population of 1,352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibition with more than 70,000 synapses. Inspired by classical neuroanatomy, we classified inhibitory neurons based on targeting of dendritic compartments and developed an excitatory neuron classification based on dendritic reconstructions with whole-cell maps of synaptic input. Single-cell connectivity showed a class of disinhibitory specialist that targets basket cells. Analysis of inhibitory connectivity onto excitatory neurons found widespread specificity, with many interneurons exhibiting differential targeting of spatially intermingled subpopulations. Inhibitory targeting was organized into ‘motif groups’, diverse sets of cells that collectively target both perisomatic and dendritic compartments of the same excitatory targets. Collectively, our analysis identified new organizing principles for cortical inhibition and will serve as a foundation for linking contemporary multimodal neuronal atlases with the cortical wiring diagram.
GPT-4o mini: Non-social science research article
Functional connectomics spanning multiple areas of mouse visual cortex
character(0), J. Alexander Bae, Mahaly Baptiste, Maya R. Baptiste, Caitlyn A. Bishop, Agnes L. Bodor, Derrick Brittain, Victoria Brooks, JoAnn Buchanan, Daniel J. Bumbarger, Manuel A. Castro, Brendan Celii, Erick Cobos, Forrest Collman, Nuno Maçarico da Costa, Bethanny Danskin, Sven Dorkenwald, Leila Elabbady, Paul G. Fahey, Tim Fliss, Emmanouil Froudarakis, Jay Gager, Clare Gamlin, William Gray-Roncal, Akhilesh Halageri, James Hebditch, Zhen Jia, Emily Joyce, Justin Ellis-Joyce, Chris Jordan, Daniel Kapner, Nico Kemnitz, Sam Kinn, Lindsey M. Kitchell, Selden Koolman, Kai Kuehner, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Jordan Matelsky, Sarah McReynolds, Elanine Miranda, Eric Mitchell, Shanka Subhra Mondal, Merlin Moore, Shang Mu, Taliah Muhammad, Barak Nehoran, Erika Neace, Oluwaseun Ogedengbe, Christos Papadopoulos, Stelios Papadopoulos, Saumil Patel, Guadalupe Jovita Yasmin Perez Vega, Xaq Pitkow, Sergiy Popovych, Anthony Ramos, R. Clay Reid, Jacob Reimer, Patricia K. Rivlin, Victoria Rose, Zachary M. Sauter, Casey M. Schneider-Mizell, H. Sebastian Seung, Ben Silverman, William Silversmith, Amy Sterling, Fabian H. Sinz, Cameron L. Smith, Rachael Swanstrom, Shelby Suckow, Marc Takeno, Zheng H. Tan, Andreas S. Tolias, Russel Torres, Nicholas L. Turner, Edgar Y. Walker, Tianyu Wang, Adrian Wanner, Brock A. Wester, Grace Williams, Sarah Williams, Kyle Willie, Ryan Willie, William Wong, Jingpeng Wu, Chris Xu, Runzhe Yang, Dimitri Yatsenko, Fei Ye, Wenjing Yin, Rob Young, Szi-chieh Yu, Daniel Xenes, Chi Zhang
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Understanding the brain requires understanding neurons’ functional responses to the circuit architecture shaping them. Here we introduce the MICrONS functional connectomics dataset with dense calcium imaging of around 75,000 neurons in primary visual cortex (VISp) and higher visual areas (VISrl, VISal and VISlm) in an awake mouse that is viewing natural and synthetic stimuli. These data are co-registered with an electron microscopy reconstruction containing more than 200,000 cells and 0.5 billion synapses. Proofreading of a subset of neurons yielded reconstructions that include complete dendritic trees as well the local and inter-areal axonal projections that map up to thousands of cell-to-cell connections per neuron. Released as an open-access resource, this dataset includes the tools for data retrieval and analysis 1,2 . Accompanying studies describe its use for comprehensive characterization of cell types 3–6 , a synaptic level connectivity diagram of a cortical column 4 , and uncovering cell-type-specific inhibitory connectivity that can be linked to gene expression data 4,7 . Functionally, we identify new computational principles of how information is integrated across visual space 8 , characterize novel types of neuronal invariances 9 and bring structure and function together to uncover a general principle for connectivity between excitatory neurons within and across areas 10,11 .
GPT-4o mini: Non-social science research article
Reprogramming site-specific retrotransposon activity to new DNA sites
Christopher W. Fell, Lukas Villiger, Justin Lim, Masahiro Hiraizumi, Dario Tagliaferri, Matthew T. N. Yarnall, Anderson Lee, Kaiyi Jiang, Alisan Kayabolen, Rohan N. Krajeski, Cian Schmitt-Ulms, Harsh Ramani, Sarah M. Yousef, Nathaniel Roberts, Christopher A. Vakulskas, Hiroshi Nishimasu, Omar O. Abudayyeh, Jonathan S. Gootenberg
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Retroelements have a critical role in shaping eukaryotic genomes. For instance, site-specific non-long terminal repeat retrotransposons have spread widely through preferential integration into repetitive genomic sequences, such as microsatellite regions and ribosomal DNA genes1,2,3,4,5,6. Despite the widespread occurrence of these systems, their targeting constraints remain unclear. Here we use a computational pipeline to discover multiple new site-specific retrotransposon families, profile members both biochemically and in mammalian cells, find previously undescribed insertion preferences and chart potential evolutionary paths for retrotransposon retargeting. We identify R2Tg, an R2 retrotransposon from the zebra finch, Taeniopygia guttata, as an orthologue that can be retargeted by payload engineering for target cleavage, reverse transcription and scarless insertion of heterologous payloads at new genomic sites. We enhance this activity by fusing R2Tg to CRISPR–Cas9 nickases for efficient insertion at new genomic sites. Through further screening of R2 orthologues, we select an orthologue, R2Tocc, with natural reprogrammability and minimal insertion at its natural 28S site, to engineer SpCas9H840A–R2Tocc, a system we name site-specific target-primed insertion through targeted CRISPR homing of retroelements (STITCHR). STITCHR enables the scarless, efficient installation of edits, ranging from a single base to 12.7 kilobases, gene replacement and use of in vitro transcribed or synthetic RNA templates. Inspired by the prevalence of nLTR retrotransposons across eukaryotic genomes, we anticipate that STITCHR will serve as a platform for scarless programmable integration in dividing and non-dividing cells, with both research and therapeutic applications.
GPT-4o mini: Non-social science research article
Comprehensive interrogation of synthetic lethality in the DNA damage response
John Fielden, Sebastian M. Siegner, Danielle N. Gallagher, Markus S. Schröder, Maria Rosaria Dello Stritto, Simon Lam, Lena Kobel, Moritz F. Schlapansky, Stephen P. Jackson, Petr Cejka, Marco Jost, Jacob E. Corn
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The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability 1,2 . Unravelling the complementary interplay between these pathways remains a challenge 3,4 . Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.
GPT-4o mini: Non-social science research article
Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease
Kimitoshi Kimura, Ayshwarya Subramanian, Zhuoran Yin, Ahad Khalilnezhad, Yufan Wu, Danyang He, Karen O. Dixon, Udbhav Kasyap Chitta, Xiaokai Ding, Niraj Adhikari, Isabell Guzchenko, Xiaoming Zhang, Ruihan Tang, Thomas Pertel, Samuel A. Myers, Aastha Aastha, Masashi Nomura, Ghazaleh Eskandari-Sedighi, Vasundhara Singh, Lei Liu, Conner Lambden, Kilian L. Kleemann, Neha Gupta, Jen-Li Barry, Ana Durao, Yiran Cheng, Sebastian Silveira, Huiyuan Zhang, Aamir Suhail, Toni Delorey, Orit Rozenblatt-Rosen, Gordon J. Freeman, Dennis J. Selkoe, Howard L. Weiner, Mathew Blurton-Jones, Carlos Cruchaga, Aviv Regev, Mario L. SuvĂ , Oleg Butovsky, Vijay K. Kuchroo
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Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFÎČ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFÎČ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-ÎČ pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFÎČ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.
GPT-4o mini: Non-social science research article
Phenotypic complexities of rare heterozygous neurexin-1 deletions
Michael B. Fernando, Yu Fan, Yanchun Zhang, Alex Tokolyi, Aleta N. Murphy, Sarah Kammourh, P. J. Michael Deans, Sadaf Ghorbani, Ryan Onatzevitch, Adriana Pero, Christopher Padilla, Sarah E. Williams, Erin K. Flaherty, Iya A. Prytkova, Lei Cao, David A. Knowles, Gang Fang, Paul A. Slesinger, Kristen J. Brennand
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Given the large number of genes significantly associated with risk for neuropsychiatric disorders, a critical unanswered question is the extent to which diverse mutations—sometimes affecting the same gene—will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1, which encodes a presynaptic cell-adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain and are differentially affected by unique (non-recurrent) deletions1. We contrast the cell-type-specific effect of patient-specific mutations in NRXN1 using human-induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Through distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1+/− deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Reciprocal isogenic manipulations causally demonstrate that aberrant splicing drives these changes in synaptic activity. For NRXN1 deletions, and perhaps more broadly, precision medicine will require stratifying patients based on whether their gene mutations act through LOF or GOF mechanisms, to achieve individualized restoration of NRXN1 isoform repertoires by increasing wild-type and/or ablating mutant isoforms. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disorders, our findings add nuance to future considerations of precision medicine.
GPT-4o mini: Non-social science research article
Stress dynamically modulates neuronal autophagy to gate depression onset
Liang Yang, Chen Guo, Zhiwei Zheng, Yiyan Dong, Qifeng Xie, Zijian Lv, Min Li, Yangyang Lu, Xiaonan Guo, Rongshan Deng, Yiqin Liu, Yirong Feng, Ruiqi Mu, Xuliang Zhang, Huan Ma, Zhong Chen, Zhijun Zhang, Zhaoqi Dong, Wei Yang, Xiangnan Zhang, Yihui Cui
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Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of brain homeostasis2, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.
GPT-4o mini: Non-social science research article
Strategic atom replacement enables regiocontrol in pyrazole alkylation
Alexander Fanourakis, Yahia Ali, Liao Chen, Patrick Q. Kelly, Abigail J. Bracken, Christopher B. Kelly, Mark D. Levin
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Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike.1,2 Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N-functionalization.3 This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity-determining bonds between poorly differentiated starting materials. To overcome this longstanding challenge, we here describe a prototypical example of an alternative conceptual approach, “Strategic Atom Replacement”, in which we synthesize N-alkyl pyrazoles from isothiazoles. The net forward transformation is a “swap” of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole.4,5 Linking the two azoles is an orphaned heterocycle class, 1,2,3-Thiadiazine-S-Oxides, whose synthetic potential has yet to be tapped.6 By proceeding via these unusual heterocycles, the typical selectivity and separation challenges associated with exclusively bond-based pyrazole preparations are circumvented, and even minimally differentiated peripheral substituents can be discriminated to afford isomerically pure products.
GPT-4o mini: Non-social science research article
A RISC-V 32-bit microprocessor based on two-dimensional semiconductors
Mingrui Ao, Xiucheng Zhou, Xinjie Kong, Saifei Gou, Sifan Chen, Xiangqi Dong, Yuxuan Zhu, Qicheng Sun, Zhejia Zhang, Jinshu Zhang, Qiran Zhang, Yan Hu, Chuming Sheng, Kaixuan Wang, Shuiyuan Wang, Jing Wan, Jun Han, Wenzhong Bao, Peng Zhou
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Recently the quest for post-silicon semiconductors has escalated owing to the inherent limitations of conventional bulk semiconductors, which are plagued by issues such as drain-induced barrier lowering, interfacial-scattering-induced mobility degradation and a constrained current on/off ratio determined by semiconductor bandwidth. These challenges have prompted the search for more advanced materials, with atomic-layer-thick two-dimensional (2D) semiconductors emerging as a potential solution. Following over a decade of research advances, recent developments1,2,3 in wafer-scale growth and device fabrication have led to breakthroughs in 2D semiconductor electronics. However, the level of integration remains constrained to a few hundred transistors. We describe a reduced instruction set computing architecture (RISC-V) microprocessor capable of executing standard 32-bit instructions on 5,900 MoS2 transistors and a complete standard cell library based on 2D semiconductor technology. The library contains 25 types of logic units. In alignment with advances in silicon integrated circuits, we also co-optimized the process flow and design of the 2D logic circuits. Our combined manufacturing and design methodology has overcome the significant challenges associated with wafer-scale integration of 2D circuits and enabled a pioneering prototype of an MoS2 microprocessor that exemplifies the potential of 2D integrated-circuit technology beyond silicon.
GPT-4o mini: Non-social science research article
DNA-guided transcription factor interactions extend human gene regulatory code
Zhiyuan Xie, Ilya Sokolov, Maria Osmala, Xue Yue, Grace Bower, J. Patrick Pett, Yinan Chen, Kai Wang, Ayse Derya Cavga, Alexander Popov, Sarah A. Teichmann, Ekaterina Morgunova, Evgeny Z. Kvon, Yimeng Yin, Jussi Taipale
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In the same way that the mRNA-binding specificities of transfer RNAs define the genetic code, the DNA-binding specificities of transcription factors (TFs) form the molecular basis of the gene regulatory code 1,2 . The human gene regulatory code is much more complex than the genetic code, in particular because there are more than 1,600 TFs that commonly interact with each other. TF–TF interactions are required for specifying cell fate and executing cell-type-specific transcriptional programs. Despite this, the landscape of interactions between DNA-bound TFs is poorly defined. Here we map the biochemical interactions between DNA-bound TFs using CAP-SELEX, a method that can simultaneously identify individual TF binding preferences, TF–TF interactions and the DNA sequences that are bound by the interacting complexes. A screen of more than 58,000 TF–TF pairs identified 2,198 interacting TF pairs, 1,329 of which preferentially bound to their motifs arranged in a distinct spacing and/or orientation. We also discovered 1,131 TF–TF composite motifs that were markedly different from the motifs of the individual TFs. In total, we estimate that the screen identified between 18% and 47% of all human TF–TF motifs. The novel composite motifs we found were enriched in cell-type-specific elements, active in vivo and more likely to be formed between developmentally co-expressed TFs. Furthermore, TFs that define embryonic axes commonly interacted with different TFs and bound to distinct motifs, explaining how TFs with a similar specificity can define distinct cell types along developmental axes.
GPT-4o mini: Non-social science research article
Swinging lever mechanism of myosin directly shown by time-resolved cryo-EM
David P. Klebl, Sean N. McMillan, Cristina Risi, Eva Forgacs, Betty Virok, Jennifer L. Atherton, Sarah A. Harris, Michele Stofella, Donald A. Winkelmann, Frank Sobott, Vitold E. Galkin, Peter J. Knight, Stephen P. Muench, Charlotte A. Scarff, Howard D. White
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Myosins produce force and movement in cells through interactions with F-actin 1 . Generation of movement is thought to arise through actin-catalysed conversion of myosin from an ATP-generated primed (pre-powerstroke) state to a post-powerstroke state, accompanied by myosin lever swing 2,3 . However, the initial, primed actomyosin state has never been observed, and the mechanism by which actin catalyses myosin ATPase activity is unclear. Here, to address these issues, we performed time-resolved cryogenic electron microscopy (cryo-EM) 4 of a myosin-5 mutant having slow hydrolysis product release 5,6 . Primed actomyosin was predominantly captured 10 ms after mixing primed myosin with F-actin, whereas post-powerstroke actomyosin predominated at 120 ms, with no abundant intermediate states detected. For detailed interpretation, cryo-EM maps were fitted with pseudo-atomic models. Small but critical changes accompany the primed motor binding to actin through its lower 50-kDa subdomain, with the actin-binding cleft open and phosphate release prohibited. Amino-terminal actin interactions with myosin promote rotation of the upper 50-kDa subdomain, closing the actin-binding cleft, and enabling phosphate release. The formation of interactions between the upper 50-kDa subdomain and actin creates the strong-binding interface needed for effective force production. The myosin-5 lever swings through 93°, predominantly along the actin axis, with little twisting. The magnitude of lever swing matches the typical step length of myosin-5 along actin 7 . These time-resolved structures demonstrate the swinging lever mechanism, elucidate structural transitions of the power stroke, and resolve decades of conjecture on how myosins generate movement.
GPT-4o mini: Non-social science research article
Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia
Aleksandra E. Kamizela, Daniel Leongamornlert, Nicholas Williams, Xin Wang, Kudzai Nyamondo, Kevin Dawson, Michael Spencer Chapman, Jing Guo, Joe Lee, Karim Mane, Kate Milne, Anthony R. Green, Timothy Chevassut, Peter J. Campbell, Patrick T. Ellinor, Brian J. P. Huntly, E. Joanna Baxter, Jyoti Nangalia
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Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer 1,2 . However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR , requiring exon skipping to derive BCR::ABL1 , were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3–14 years (confidence interval 2–16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.
GPT-4o mini: Non-social science research article
Author Correction: Traversable wormhole dynamics on a quantum processor
Daniel Jafferis, Alexander Zlokapa, Joseph D. Lykken, David K. Kolchmeyer, Samantha I. Davis, Nikolai Lauk, Hartmut Neven, Maria Spiropulu
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GPT-4o mini: Non-social science research article
Author Correction: Record sea surface temperature jump in 2023–2024 unlikely but not unexpected
Jens Terhaar, Friedrich A. Burger, Linus Vogt, Thomas L. Frölicher, Thomas F. Stocker
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GPT-4o mini: Non-social science research article
Photoinduced copper-catalysed deracemization of alkyl halides
Feng Zhong, Renhe Li, Binh Khanh Mai, Peng Liu, Gregory C. Fu
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Deracemization is an emerging strategy for generating enantioenriched compounds wherein the two enantiomers of a readily available racemic starting material are transformed into a single enantiomer, typically through the action of a light-induced catalyst1,2. Excellent proof of principle for this potentially powerful approach to asymmetric catalysis has been described3,4,5,6,7,8; nevertheless, substantial challenges have not yet been addressed, including the exploitation of carbon–heteroatom (rather than only carbon–hydrogen and carbon–carbon) bond cleavage to achieve deracemization, as well as the development of processes that provide broad classes of useful enantioenriched compounds and tetrasubstituted stereocentres. Here we describe a straightforward method that addresses these challenges, using a chiral copper catalyst, generated in situ from commercially available components, to achieve the photoinduced deracemization of tertiary (and secondary) alkyl halides through carbon–halogen bond cleavage. Mechanistic studies (including the independent synthesis of postulated intermediates, photophysical, spectroscopic and reactivity studies, and density functional theory calculations) provide support for the key steps and intermediates in our proposed catalytic cycle, as well as insight into the origin of enantioselectivity.
GPT-4o mini: Non-social science research article
Author Correction: Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome
Guang-Hui Liu, Basam Z. Barkho, Sergio Ruiz, Dinh Diep, Jing Qu, Sheng-Lian Yang, Athanasia D. Panopoulos, Keiichiro Suzuki, Leo Kurian, Christopher Walsh, James Thompson, Stephanie Boue, Ho Lim Fung, Ignacio Sancho-Martinez, Kun Zhang, John Yates III, Juan Carlos Izpisua Belmonte
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GPT-4o mini: Non-social science research article
Supramolecular docking structure determination of alkyl-bearing molecules
Yitao Wu, Le Shi, Lei Xu, Jiale Ying, Xiaohe Miao, Bin Hua, Zhijie Chen, Jonathan L. Sessler, Feihe Huang
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Numerous natural products and drugs contain flexible alkyl chains. The resulting conformational motion can create challenges in obtaining single crystals and thus determining their molecular structures by single-crystal X-ray diffraction (SCXRD)1,2,3,4,5,6,7,8,9,10,11. Here we demonstrate that by using pillar[5]arene-incorporated metal–organic frameworks (MOFs) and taking advantage of pillar[5]arene−alkyl chain host−guest recognition12,13,14,15, it is possible to reduce this motion and bring order to alkyl-chain-containing molecules as the result of docking within accessible pillar[5]arene units present in an overall MOF. This has allowed the single-crystal structures of 48 alkyl-chain-containing molecules, including 6 natural products, 2 approved drugs and 18 custom-made compounds collected from 16 research groups, to be determined using standard SCXRD instrumentation. The structures of alkyl-chain-containing molecules derived from crude reaction products can also be determined directly by SCXRD analyses without further purification. The simplicity, high efficiency and apparent generality of the present pillar[5]arene-incorporated MOF-based supramolecular docking approach suggest that it could emerge as a new tool for the analyses of natural products and drugs that might not be amenable to traditional SCXRD-based structure determination.
GPT-4o mini: Non-social science research article
A non-contact wearable device for monitoring epidermal molecular flux
Jaeho Shin, Joseph Woojin Song, Matthew Thomas Flavin, Seunghee Cho, Shupeng Li, Ansen Tan, Kyung Rok Pyun, Aaron G Huang, Huifeng Wang, Seongmin Jeong, Kenneth E. Madsen, Jacob Trueb, Mirae Kim, Katelynn Nguyen, Angela Yang, Yaching Hsu, Winnie Sung, Jiwon Lee, Sooyeol Phyo, Ji-Hoon Kim, Anthony Banks, Jan-Kai Chang, Amy S. Paller, Yonggang Huang, Guillermo A. Ameer, John A. Rogers
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Existing wearable technologies rely on physical coupling to the body to establish optical1,2, fluidic3,4, thermal5,6 and/or mechanical7,8 measurement interfaces. Here we present a class of wearable device platforms that instead relies on physical decoupling to define an enclosed chamber immediately adjacent to the skin surface. Streams of vapourized molecular substances that pass out of or into the skin alter the properties of the microclimate defined in this chamber in ways that can be precisely quantified using an integrated collection of wireless sensors. A programmable, bistable valve dynamically controls access to the surrounding environment, thereby creating a transient response that can be quantitatively related to the inward and outward fluxes of the targeted species by analysing the time-dependent readings from the sensors. The systems reported here offer unique capabilities in measuring the flux of water vapour, volatile organic compounds and carbon dioxide from various locations on the body, each with distinct relevance to clinical care and/or exposure to hazardous vapours. Studies of healing processes associated with dermal wounds in models of healthy and diabetic mice and of responses in models using infected wounds reveal characteristic flux variations that provide important insights, particularly in scenarios in which the non-contact operation of the devices avoids potential damage to fragile tissues.
GPT-4o mini: Non-social science research article
Functional connectomics reveals general wiring rule in mouse visual cortex
Zhuokun Ding, Paul G. Fahey, Stelios Papadopoulos, Eric Y. Wang, Brendan Celii, Christos Papadopoulos, Andersen Chang, Alexander B. Kunin, Dat Tran, Jiakun Fu, Zhiwei Ding, Saumil Patel, Lydia Ntanavara, Rachel Froebe, Kayla Ponder, Taliah Muhammad, J. Alexander Bae, Agnes L. Bodor, Derrick Brittain, JoAnn Buchanan, Daniel J. Bumbarger, Manuel A. Castro, Erick Cobos, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, Casey M. Schneider-Mizell, William Silversmith, Marc Takeno, Russel Torres, Nicholas L. Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-chieh Yu, Dimitri Yatsenko, Emmanouil Froudarakis, Fabian Sinz, Kreơimir Josić, Robert Rosenbaum, H. Sebastian Seung, Forrest Collman, Nuno Maçarico da Costa, R. Clay Reid, Edgar Y. Walker, Xaq Pitkow, Jacob Reimer, Andreas S. Tolias
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Understanding the relationship between circuit connectivity and function is crucial for uncovering how the brain computes. In mouse primary visual cortex, excitatory neurons with similar response properties are more likely to be synaptically connected 1–8 ; however, broader connectivity rules remain unknown. Here we leverage the millimetre-scale MICrONS dataset to analyse synaptic connectivity and functional properties of neurons across cortical layers and areas. Our results reveal that neurons with similar response properties are preferentially connected within and across layers and areas—including feedback connections—supporting the universality of ‘like-to-like’ connectivity across the visual hierarchy. Using a validated digital twin model, we separated neuronal tuning into feature (what neurons respond to) and spatial (receptive field location) components. We found that only the feature component predicts fine-scale synaptic connections beyond what could be explained by the proximity of axons and dendrites. We also discovered a higher-order rule whereby postsynaptic neuron cohorts downstream of presynaptic cells show greater functional similarity than predicted by a pairwise like-to-like rule. Recurrent neural networks trained on a simple classification task develop connectivity patterns that mirror both pairwise and higher-order rules, with magnitudes similar to those in MICrONS data. Ablation studies in these recurrent neural networks reveal that disrupting like-to-like connections impairs performance more than disrupting random connections. These findings suggest that these connectivity principles may have a functional role in sensory processing and learning, highlighting shared principles between biological and artificial systems.
GPT-4o mini: Non-social science research article
Connectomics of predicted Sst transcriptomic types in mouse visual cortex
Clare R. Gamlin, Casey M. Schneider-Mizell, Matthew Mallory, Leila Elabbady, Nathan Gouwens, Grace Williams, Alice Mukora, Rachel Dalley, Agnes L. Bodor, Derrick Brittain, JoAnn Buchanan, Daniel J. Bumbarger, Emily Joyce, Daniel Kapner, Sam Kinn, Gayathri Mahalingam, Sharmishtaa Seshamani, Marc Takeno, Russel Torres, Wenjing Yin, Philip R. Nicovich, J. Alexander Bae, Manuel A. Castro, Sven Dorkenwald, Akhilesh Halageri, Zhen Jia, Chris Jordan, Nico Kemnitz, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, William Silversmith, Nicholas L. Turner, William Wong, Jingpeng Wu, Szi-chieh Yu, Jim Berg, Tim Jarsky, Brian Lee, H. Sebastian Seung, Hongkui Zeng, R. Clay Reid, Forrest Collman, Nuno Maçarico da Costa, Staci A. Sorensen
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Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between them1. Neural cell types have previously been defined by morphology2,3, electrophysiology4, transcriptomic expression5,6, connectivity7,8,9 or a combination of such modalities10,11,12. The Patch-seq technique enables the characterization of morphology, electrophysiology and transcriptomic properties from individual cells13,14,15. These properties were integrated to define 28 inhibitory, morpho-electric-transcriptomic (MET) cell types in mouse visual cortex16, which do not include synaptic connectivity. Conversely, large-scale electron microscopy (EM) enables morphological reconstruction and a near-complete description of a neuron’s local synaptic connectivity, but does not include transcriptomic or electrophysiological information. Here, we leveraged morphological information from Patch-seq to predict the transcriptomically defined cell subclass and/or MET-type of inhibitory neurons within a large-scale EM dataset. We further analysed Martinotti cells—a somatostatin (Sst)-positive17 morphological cell type18,19—which were classified successfully into Sst MET-types with distinct axon myelination and synaptic output connectivity patterns. We demonstrate that morphological features can be used to link cell types across experimental modalities, enabling further comparison of connectivity to gene expression and electrophysiology. We observe unique connectivity rules for predicted Sst cell types.
GPT-4o mini: Non-social science research article
Towards accurate differential diagnosis with large language models
Daniel McDuff, Mike Schaekermann, Tao Tu, Anil Palepu, Amy Wang, Jake Garrison, Karan Singhal, Yash Sharma, Shekoofeh Azizi, Kavita Kulkarni, Le Hou, Yong Cheng, Yun Liu, S. Sara Mahdavi, Sushant Prakash, Anupam Pathak, Christopher Semturs, Shwetak Patel, Dale R. Webster, Ewa Dominowska, Juraj Gottweis, Joelle Barral, Katherine Chou, Greg S. Corrado, Yossi Matias, Jake Sunshine, Alan Karthikesalingam, Vivek Natarajan
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A comprehensive differential diagnosis is a cornerstone of medical care that is often reached through an iterative process of interpretation that combines clinical history, physical examination, investigations and procedures. Interactive interfaces powered by large language models present new opportunities to assist and automate aspects of this process 1 . Here we introduce the Articulate Medical Intelligence Explorer (AMIE), a large language model that is optimized for diagnostic reasoning, and evaluate its ability to generate a differential diagnosis alone or as an aid to clinicians. Twenty clinicians evaluated 302 challenging, real-world medical cases sourced from published case reports. Each case report was read by two clinicians, who were randomized to one of two assistive conditions: assistance from search engines and standard medical resources; or assistance from AMIE in addition to these tools. All clinicians provided a baseline, unassisted differential diagnosis prior to using the respective assistive tools. AMIE exhibited standalone performance that exceeded that of unassisted clinicians (top-10 accuracy 59.1% versus 33.6%, P = 0.04). Comparing the two assisted study arms, the differential diagnosis quality score was higher for clinicians assisted by AMIE (top-10 accuracy 51.7%) compared with clinicians without its assistance (36.1%; McNemar’s test: 45.7, P < 0.01) and clinicians with search (44.4%; McNemar’s test: 4.75, P = 0.03). Further, clinicians assisted by AMIE arrived at more comprehensive differential lists than those without assistance from AMIE. Our study suggests that AMIE has potential to improve clinicians’ diagnostic reasoning and accuracy in challenging cases, meriting further real-world evaluation for its ability to empower physicians and widen patients’ access to specialist-level expertise.
GPT-4o mini: Non-social science research article
Acoustic modes in M67 cluster stars trace deepening convective envelopes
Claudia Reyes, Dennis Stello, Joel Ong, Christopher Lindsay, Marc Hon, Timothy R. Bedding
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Acoustic oscillations in stars are sensitive to stellar interiors 1 . Frequency differences between overtone modes—large separations—probe stellar density 2 , whereas differences between low-degree modes—small separations—probe the sound-speed gradient in the energy-generating core of main-sequence Sun-like stars 3 , and hence their ages. At later phases of stellar evolution, characterized by inert cores, small separations are believed to lose much of their power to probe deep interiors and become proportional to large separations 4,5 . Here we present evidence of a rapidly evolving convective zone as stars evolve from the subgiant phase into red giants. By measuring acoustic oscillations in 27 stars from the open cluster M67, we observe deviations of proportionality between small and large separations, which are caused by the influence of the bottom of the convective envelope. These deviations become apparent as the convective envelope penetrates deep into the star during subgiant and red giant evolutions, eventually entering an ultradeep regime that leads to the red-giant-branch luminosity bump. The tight sequence of cluster stars, free of large spreads in ages and fundamental properties, is essential for revealing the connection between the observed small separations and the chemical discontinuities occurring at the bottom of the convective envelope. We use this sequence to show that combining large and small separations can improve estimations of the masses and ages of field stars well after the main sequence.
GPT-4o mini: Non-social science research article
Bifidobacteria support optimal infant vaccine responses
Feargal J. Ryan, Michelle Clarke, Miriam A. Lynn, Saoirse C. Benson, Sonia McAlister, Lynne C. Giles, Jocelyn M. Choo, Charné Rossouw, Yan Yung Ng, Evgeny A. Semchenko, Alyson Richard, Lex E. X. Leong, Steven L. Taylor, Stephen J. Blake, Joyce I. Mugabushaka, Mary Walker, Steve L. Wesselingh, Paul V. Licciardi, Kate L. Seib, Damon J. Tumes, Peter Richmond, Geraint B. Rogers, Helen S. Marshall, David J. Lynn
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Accumulating evidence indicates that antibiotic exposure may lead to impaired vaccine responses1,2,3,4; however, the mechanisms underlying this association remain poorly understood. Here we prospectively followed 191 healthy, vaginally born, term infants from birth to 15 months, using a systems vaccinology approach to assess the effects of antibiotic exposure on immune responses to vaccination. Exposure to direct neonatal but not intrapartum antibiotics was associated with significantly lower antibody titres against various polysaccharides in the 13-valent pneumococcal conjugate vaccine and the Haemophilus influenzae type b polyribosylribitol phosphate and diphtheria toxoid antigens in the combined 6-in-1 Infanrix Hexa vaccine at 7 months of age. Blood from infants exposed to neonatal antibiotics had an inflammatory transcriptional profile before vaccination; in addition, faecal metagenomics showed reduced abundance of Bifidobacterium species in these infants at the time of vaccination, which was correlated with reduced vaccine antibody titres 6 months later. In preclinical models, responses to the 13-valent pneumococcal conjugate vaccine were strongly dependent on an intact microbiota but could be restored in germ-free mice by administering a consortium of Bifidobacterium species or a probiotic already widely used in neonatal units. Our data suggest that microbiota-targeted interventions could mitigate the detrimental effects of early-life antibiotics on vaccine immunogenicity.
GPT-4o mini: Non-social science research article
Metal–support frontier orbital interactions in single-atom catalysis
Xianxian Shi, Zhilin Wen, Qingqing Gu, Long Jiao, Hai-Long Jiang, Haifeng Lv, Hengwei Wang, Jiani Ding, Mason P. Lyons, Alvin Chang, Zhenxing Feng, Si Chen, Yue Lin, Xiaoyan Xu, Pengfei Du, Wenlong Xu, Mei Sun, Yin Li, Bing Yang, Tao Zhang, Xiaojun Wu, Junling Lu
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Single-atom catalysts (SACs) with maximized metal use and discrete energy levels hold promise for broad applications in heterogeneous catalysis, energy conversion, environmental science and biomedicine1,2,3,4,5,6,7. The activity and stability of SACs are governed by the pair of metal–adsorbate and metal–support interactions8,9,10. However, the understanding of these interactions with their catalytic performance in nature is challenging. Correlations of activity with the charge state of metal atoms have frequently reached controversial conclusions11,12,13,14,15. Here we report that the activity of palladium (Pd1) SACs exhibits a linear scaling relationship with the positions of the lowest unoccupied molecular orbital (LUMO) of oxide supports across 14 types of semiconductor. Elevation of the LUMO position by reducing the support particle size to a few nanometres boosts a record high activity along with excellent stability in the semi-hydrogenation of acetylene. We show that the elevated LUMO of support reduces its energy gap with the highest occupied molecular orbital (HOMO) of Pd1 atoms, which promotes Pd1–support orbital hybridizations for high stability and further amends the LUMO of anchored Pd1 atoms to enhance Pd1–adsorbate interactions for high activity. These findings are consistent with the frontier molecular orbital theory and provide a general descriptor for the rational selection of metal–support pairs with predictable activity.
GPT-4o mini: Non-social science research article
NEURD offers automated proofreading and feature extraction for connectomics
Brendan Celii, Stelios Papadopoulos, Zhuokun Ding, Paul G. Fahey, Eric Wang, Christos Papadopoulos, Alexander B. Kunin, Saumil Patel, J. Alexander Bae, Agnes L. Bodor, Derrick Brittain, JoAnn Buchanan, Daniel J. Bumbarger, Manuel A. Castro, Erick Cobos, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, Casey M. Schneider-Mizell, William Silversmith, Marc Takeno, Russel Torres, Nicholas L. Turner, William Wong, Jingpeng Wu, Szi-chieh Yu, Wenjing Yin, Daniel Xenes, Lindsey M. Kitchell, Patricia K. Rivlin, Victoria A. Rose, Caitlyn A. Bishop, Brock Wester, Emmanouil Froudarakis, Edgar Y. Walker, Fabian Sinz, H. Sebastian Seung, Forrest Collman, Nuno Maçarico da Costa, R. Clay Reid, Xaq Pitkow, Andreas S. Tolias, Jacob Reimer
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We are in the era of millimetre-scale electron microscopy volumes collected at nanometre resolution 1,2 . Dense reconstruction of cellular compartments in these electron microscopy volumes has been enabled by recent advances in machine learning 3–6 . Automated segmentation methods produce exceptionally accurate reconstructions of cells, but post hoc proofreading is still required to generate large connectomes that are free of merge and split errors. The elaborate 3D meshes of neurons in these volumes contain detailed morphological information at multiple scales, from the diameter, shape and branching patterns of axons and dendrites, down to the fine-scale structure of dendritic spines. However, extracting these features can require substantial effort to piece together existing tools into custom workflows. Here, building on existing open source software for mesh manipulation, we present Neural Decomposition (NEURD), a software package that decomposes meshed neurons into compact and extensively annotated graph representations. With these feature-rich graphs, we automate a variety of tasks such as state-of-the-art automated proofreading of merge errors, cell classification, spine detection, axonal-dendritic proximities and other annotations. These features enable many downstream analyses of neural morphology and connectivity, making these massive and complex datasets more accessible to neuroscience researchers.
GPT-4o mini: Non-social science research article
Goal-specific hippocampal inhibition gates learning
Nuri Jeong, Xiao Zheng, Abigail L. Paulson, Stephanie M. Prince, Victor P. Nguyen, Sherina R. Thomas, Caroline E. Gilpin, Matthew C. Goodson, Annabelle C. Singer
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Goal-directed navigation in a new environment requires quickly identifying and exploiting important locations. Identifying new goal locations depends on neural computations that rapidly represent locations and connect location information to key outcomes such as food1. However, the mechanisms to trigger these computations at behaviourally relevant locations are not well understood. Here we show that parvalbumin (PV)-positive interneurons in the mouse hippocampal CA3 have a causal role in identifying and exploiting new food locations such that decreases in inhibitory activity around goals enable reactivation to bind goal locations to food outcomes. PV interneurons in the CA3 substantially reduce firing on approach to and at goal locations while food-deprived mice learn to find food. These inhibitory decreases anticipate reward locations as the mice learn and are more prominent on correct trials. Sparse optogenetic stimulation to prevent goal-related decreases in PV interneuron firing impaired learning of goal locations. Disrupting goal-related decreases in PV interneuron activity impaired the reactivation of new goal locations after receipt of food, a process that associates previous locations to food outcomes such that the mice know where to seek food later. These results reveal that goal-selective and goal-predictive decreases in inhibitory activity enable learning, representations and outcome associations of crucial locations.
GPT-4o mini: Non-social science research article
Recurrent humid phases in Arabia over the past 8 million years
Monika Markowska, Hubert B. Vonhof, Huw S. Groucutt, Paul S. Breeze, Nick Drake, Mathew Stewart, Richard Albert, Eric Andrieux, James Blinkhorn, Nicole Boivin, Alexander Budsky, Richard Clark-Wilson, Dominik Fleitmann, Axel Gerdes, Ashley N. Martin, Alfredo MartĂ­nez-GarcĂ­a, Samuel L. Nicholson, Gilbert J. Price, Eleanor M. L. Scerri, Denis Scholz, Nils Vanwezer, Michael Weber, Abdullah M. Alsharekh, Abdul Aziz Al Omari, Yahya S. A. Al-Mufarreh, Faisal Al-Jibreen, Mesfer Alqahtani, Mahmoud Al-Shanti, Iyad Zalmout, Michael D. Petraglia, Gerald H. Haug
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The Saharo-Arabian Desert is one of the largest biogeographical barriers on Earth, impeding dispersals between Africa and Eurasia, including movements of past hominins. Recent research suggests that this barrier has been in place since at least 11 million years ago 1 . In contrast, fossil evidence from the late Miocene epoch and the Pleistocene epoch suggests the episodic presence within the Saharo-Arabian Desert interior of water-dependent fauna (for example, crocodiles, equids, hippopotamids and proboscideans) 2–6 , sustained by rivers and lakes 7,8 that are largely absent from today’s arid landscape. Although numerous humid phases occurred in southern Arabia during the past 1.1 million years 9 , little is known about Arabia’s palaeoclimate before this time. Here, based on a climatic record from desert speleothems, we show recurrent humid intervals in the central Arabian interior over the past 8 million years. Precipitation during humid intervals decreased and became more variable over time, as the monsoon’s influence weakened, coinciding with enhanced Northern Hemisphere polar ice cover during the Pleistocene. Wetter conditions likely facilitated mammalian dispersals between Africa and Eurasia, with Arabia acting as a key crossroads for continental-scale biogeographic exchanges.
GPT-4o mini: Non-social science research article
A Jurassic acanthocephalan illuminates the origin of thorny-headed worms
Cihang Luo, Luke A. Parry, Brendon E. Boudinot, Shengyu Wang, Edmund A. Jarzembowski, Haichun Zhang, Bo Wang
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Acanthocephala (thorny-headed worms), characterized by the presence of an eversible proboscis with hooks, are a diverse endoparasitic group that infect a wide range of vertebrates and invertebrates1. Although long regarded as a separate phylum, they have several putative sister taxa based on morphological features, including Platyhelminthes (flatworms)2, Priapulida (penis worms)3 and Rotifera (wheel animals)4. Molecular phylogenies have instead recovered them within rotifers5,6,7,8,9,10, suggesting acanthocephalans are derived from free-living worms with a jaw apparatus (Gnathifera). Their only fossil record is Late Cretaceous eggs11, contributing limited palaeontological information to deciphering their early evolution. Here we describe an acanthocephalan body fossil, Juracanthocephalus daohugouensis gen. et. sp. nov., from the Middle Jurassic Daohugou biota of China. Juracanthocephalus shows unambiguous acanthocephalan characteristics, for example a hooked proboscis, a bursa, as well as a jaw apparatus with discrete elements that is typical of other gnathiferans. Juracanthocephalus shares features with Seisonidea (an epizoic member of Rotifera) and Acanthocephala, bridging the evolutionary gap between jawed rotifers and the obligate parasitic, jawless acanthocephalans. Our results reveal previously unrecognized ecological and morphological diversity in ancient Acanthocephala and highlight the significance of transitional fossils, revealing the origins of this highly enigmatic group of living organisms.
GPT-4o mini: Non-social science research article
Towards conversational diagnostic artificial intelligence
Tao Tu, Mike Schaekermann, Anil Palepu, Khaled Saab, Jan Freyberg, Ryutaro Tanno, Amy Wang, Brenna Li, Mohamed Amin, Yong Cheng, Elahe Vedadi, Nenad Tomasev, Shekoofeh Azizi, Karan Singhal, Le Hou, Albert Webson, Kavita Kulkarni, S. Sara Mahdavi, Christopher Semturs, Juraj Gottweis, Joelle Barral, Katherine Chou, Greg S. Corrado, Yossi Matias, Alan Karthikesalingam, Vivek Natarajan
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At the heart of medicine lies physician–patient dialogue, where skillful history-taking enables effective diagnosis, management and enduring trust 1,2 . Artificial intelligence (AI) systems capable of diagnostic dialogue could increase accessibility and quality of care. However, approximating clinicians’ expertise is an outstanding challenge. Here we introduce AMIE (Articulate Medical Intelligence Explorer), a large language model (LLM)-based AI system optimized for diagnostic dialogue. AMIE uses a self-play-based 3 simulated environment with automated feedback for scaling learning across disease conditions, specialties and contexts. We designed a framework for evaluating clinically meaningful axes of performance, including history-taking, diagnostic accuracy, management, communication skills and empathy. We compared AMIE’s performance to that of primary care physicians in a randomized, double-blind crossover study of text-based consultations with validated patient-actors similar to objective structured clinical examination 4,5 . The study included 159 case scenarios from providers in Canada, the United Kingdom and India, 20 primary care physicians compared to AMIE, and evaluations by specialist physicians and patient-actors. AMIE demonstrated greater diagnostic accuracy and superior performance on 30 out of 32 axes according to the specialist physicians and 25 out of 26 axes according to the patient-actors. Our research has several limitations and should be interpreted with caution. Clinicians used synchronous text chat, which permits large-scale LLM–patient interactions, but this is unfamiliar in clinical practice. While further research is required before AMIE could be translated to real-world settings, the results represent a milestone towards conversational diagnostic AI.
GPT-4o mini: Non-social science research article
Water abundance in the lunar farside mantle
Huicun He, Linxi Li, Sen Hu, Yubing Gao, Liang Gao, Zhan Zhou, Mengfan Qiu, Disheng Zhou, Huanxin Liu, Ruiying Li, Jialong Hao, Hejiu Hui, Yangting Lin
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The water contents of the lunar interior record important clues for understanding the formation and subsequent thermochemical evolution of the Moon1. The Chang’e-6 (CE6) mission returned samples from the South Pole–Aitken impact basin of the lunar farside2,3,4, providing an opportunity to study the water contents of the farside mantle. Here we report the water abundances and hydrogen isotope compositions of apatite and melt inclusions from CE6 mare basalt, derived from partial melting of the lunar mantle. The parent magma of CE6 mare basalt is estimated to have a water abundance of 15–168 Όg g−1 with a ÎŽD value of −123 ± 167‰. Our estimate of water abundance of 1–1.5 Όg g−1 for the mantle source indicates that the farside mantle is potentially drier than its nearside counterpart. This contrast thus suggests that the distribution of water in the interior of the Moon may exhibit a hemispheric dichotomy similar to numerous surface features5. The new estimate for the lunar farside mantle represents a landmark for estimating the water abundance of the bulk silicate Moon, providing critical constraints on the giant impact origin hypothesis6,7,8 and the subsequent evolution of the Moon for which the role of water is central1,9.
GPT-4o mini: Non-social science research article
Complete sequencing of ape genomes
DongAhn Yoo, Arang Rhie, Prajna Hebbar, Francesca Antonacci, Glennis A. Logsdon, Steven J. Solar, Dmitry Antipov, Brandon D. Pickett, Yana Safonova, Francesco Montinaro, Yanting Luo, Joanna Malukiewicz, Jessica M. Storer, Jiadong Lin, Abigail N. Sequeira, Riley J. Mangan, Glenn Hickey, Graciela Monfort Anez, Parithi Balachandran, Anton Bankevich, Christine R. Beck, Arjun Biddanda, Matthew Borchers, Gerard G. Bouffard, Emry Brannan, Shelise Y. Brooks, Lucia Carbone, Laura Carrel, Agnes P. Chan, Juyun Crawford, Mark Diekhans, Eric Engelbrecht, Cedric Feschotte, Giulio Formenti, Gage H. Garcia, Luciana de Gennaro, David Gilbert, Richard E. Green, Andrea Guarracino, Ishaan Gupta, Diana Haddad, Junmin Han, Robert S. Harris, Gabrielle A. Hartley, William T. Harvey, Michael Hiller, Kendra Hoekzema, Marlys L. Houck, Hyeonsoo Jeong, Kaivan Kamali, Manolis Kellis, Bryce Kille, Chul Lee, Youngho Lee, William Lees, Alexandra P. Lewis, Qiuhui Li, Mark Loftus, Yong Hwee Eddie Loh, Hailey Loucks, Jian Ma, Yafei Mao, Juan F. I. Martinez, Patrick Masterson, Rajiv C. McCoy, Barbara McGrath, Sean McKinney, Britta S. Meyer, Karen H. Miga, Saswat K. Mohanty, Katherine M. Munson, Karol Pal, Matt Pennell, Pavel A. Pevzner, David Porubsky, Tamara Potapova, Francisca R. Ringeling, Joana L. Rocha, Oliver A. Ryder, Samuel Sacco, Swati Saha, Takayo Sasaki, Michael C. Schatz, Nicholas J. Schork, Cole Shanks, LinnĂ©a Smeds, Dongmin R. Son, Cynthia Steiner, Alexander P. Sweeten, Michael G. Tassia, Françoise Thibaud-Nissen, Edmundo Torres-GonzĂĄlez, Mihir Trivedi, Wenjie Wei, Julie Wertz, Muyu Yang, Panpan Zhang, Shilong Zhang, Yang Zhang, Zhenmiao Zhang, Sarah A. Zhao, Yixin Zhu, Erich D. Jarvis, Jennifer L. Gerton, Iker Rivas-GonzĂĄlez, Benedict Paten, Zachary A. Szpiech, Christian D. Huber, Tobias L. Lenz, Miriam K. Konkel, Soojin V. Yi, Stefan Canzar, Corey T. Watson, Peter H. Sudmant, Erin Molloy, Erik Garrison, Craig B. Lowe, Mario Ventura, Rachel J. O’Neill, Sergey Koren, Kateryna D. Makova, Adam M. Phillippy, Evan E. Eichler
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The most dynamic and repetitive regions of great ape genomes have traditionally been excluded from comparative studies 1–3 . Consequently, our understanding of the evolution of our species is incomplete. Here we present haplotype-resolved reference genomes and comparative analyses of six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang. We achieve chromosome-level contiguity with substantial sequence accuracy (<1 error in 2.7 megabases) and completely sequence 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, to provide in-depth evolutionary insights. Comparative analyses enabled investigations of the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference genome. Such regions include newly minted gene families in lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes and subterminal heterochromatin. This resource serves as a comprehensive baseline for future evolutionary studies of humans and our closest living ape relatives.
GPT-4o mini: Non-social science research article
Active energy compression of a laser-plasma electron beam
P. Winkler, M. Trunk, L. HĂŒbner, A. Martinez de la Ossa, S. Jalas, M. Kirchen, I. Agapov, S. A. Antipov, R. Brinkmann, T. Eichner, A. Ferran Pousa, T. HĂŒlsenbusch, G. Palmer, M. Schnepp, K. Schubert, M. ThĂ©venet, P. A. Walker, C. Werle, W. P. Leemans, A. R. Maier
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Radio-frequency (RF) accelerators providing high-quality relativistic electron beams are an important resource enabling many areas of science, as well as industrial and medical applications. Two decades ago, laser-plasma accelerators 1 that support orders of magnitude higher electric fields than those provided by modern RF cavities produced quasi-monoenergetic electron beams for the first time 2–4 . Since then, high-brightness electron beams at gigaelectronvolt (GeV) beam energy and competitive beam properties have been demonstrated from only centimetre-long plasmas 5–9 , a substantial advantage over the hundreds of metres required by RF-cavity-based accelerators. However, despite the considerable progress, the comparably large energy spread and the fluctuation (jitter) in beam energy still effectively prevent laser-plasma accelerators from driving real-world applications. Here we report the generation of a laser-plasma electron beam using active energy compression, resulting in a performance so far only associated with modern RF-based accelerators. Using a magnetic chicane, the electron bunch is first stretched longitudinally to imprint an energy correlation, which is then removed with an active RF cavity. The resulting energy spread and energy jitter are reduced by more than an order of magnitude to below the permille level, meeting the acceptance criteria of a modern synchrotron, thereby opening the path to a compact storage ring injector and other applications.
GPT-4o mini: Non-social science research article
A natural experiment on the effect of herpes zoster vaccination on dementia
Markus Eyting, Min Xie, Felix Michalik, Simon Heß, Seunghun Chung, Pascal Geldsetzer
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Neurotropic herpesviruses may be implicated in the development of dementia 1–5 . Moreover, vaccines may have important off-target immunological effects 6–9 . Here we aim to determine the effect of live-attenuated herpes zoster vaccination on the occurrence of dementia diagnoses. To provide causal as opposed to correlational evidence, we take advantage of the fact that, in Wales, eligibility for the zoster vaccine was determined on the basis of an individual’s exact date of birth. Those born before 2 September 1933 were ineligible and remained ineligible for life, whereas those born on or after 2 September 1933 were eligible for at least 1 year to receive the vaccine. Using large-scale electronic health record data, we first show that the percentage of adults who received the vaccine increased from 0.01% among patients who were merely 1 week too old to be eligible, to 47.2% among those who were just 1 week younger. Apart from this large difference in the probability of ever receiving the zoster vaccine, individuals born just 1 week before 2 September 1933 are unlikely to differ systematically from those born 1 week later. Using these comparison groups in a regression discontinuity design, we show that receiving the zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of 7 years by 3.5 percentage points (95% confidence interval (CI) = 0.6–7.1, P = 0.019), corresponding to a 20.0% (95% CI = 6.5–33.4) relative reduction. This protective effect was stronger among women than men. We successfully confirm our findings in a different population (England and Wales’s combined population), with a different type of data (death certificates) and using an outcome (deaths with dementia as primary cause) that is closely related to dementia, but less reliant on a timely diagnosis of dementia by the healthcare system 10 . Through the use of a unique natural experiment, this study provides evidence of a dementia-preventing or dementia-delaying effect from zoster vaccination that is less vulnerable to confounding and bias than the existing associational evidence.
GPT-4o mini: Non-social science research article
A neural mechanism for learning from delayed postingestive feedback
Christopher A. Zimmerman, Scott S. Bolkan, Alejandro Pan-Vazquez, Bichan Wu, Emma F. Keppler, Jordan B. Meares-Garcia, Eartha Mae Guthman, Robert N. Fetcho, Brenna McMannon, Junuk Lee, Austin T. Hoag, Laura A. Lynch, Sanjeev R. Janarthanan, Juan F. LĂłpez Luna, Adrian G. Bondy, Annegret L. Falkner, Samuel S.-H. Wang, Ilana B. Witten
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Animals learn the value of foods on the basis of their postingestive effects and thereby develop aversions to foods that are toxic 1–10 and preferences to those that are nutritious 11–13 . However, it remains unclear how the brain is able to assign credit to flavours experienced during a meal with postingestive feedback signals that can arise after a substantial delay. Here we reveal an unexpected role for the postingestive reactivation of neural flavour representations in this temporal credit-assignment process. To begin, we leverage the fact that mice learn to associate novel 14,15 , but not familiar, flavours with delayed gastrointestinal malaise signals to investigate how the brain represents flavours that support aversive postingestive learning. Analyses of brain-wide activation patterns reveal that a network of amygdala regions is unique in being preferentially activated by novel flavours across every stage of learning (consumption, delayed malaise and memory retrieval). By combining high-density recordings in the amygdala with optogenetic stimulation of malaise-coding hindbrain neurons, we show that delayed malaise signals selectively reactivate flavour representations in the amygdala from a recent meal. The degree of malaise-driven reactivation of individual neurons predicts the strengthening of flavour responses upon memory retrieval, which in turn leads to stabilization of the population-level representation of the recently consumed flavour. By contrast, flavour representations in the amygdala degrade in the absence of unexpected postingestive consequences. Thus, we demonstrate that postingestive reactivation and plasticity of neural flavour representations may support learning from delayed feedback.
GPT-4o mini: Non-social science research article
Hunter-gatherer sea voyages extended to remotest Mediterranean islands
Eleanor M. L. Scerri, James Blinkhorn, Huw S. Groucutt, Mathew Stewart, Ian Candy, Ethel Allué, Aitor Burguet-Coca, Andrés Currås, W. Christopher Carleton, Susanne Lindauer, Robert Spengler, Kseniia Boxleitner, Gillian Asciak, Margherita Colucci, Ritienne Gauci, Amy Hatton, Johanna Kutowsky, Andreas Maier, Mario Mata-Gonzålez, Nicolette Mifsud, Khady Niang, Patrick Roberts, Joshua de Giorgio, Rochelle Xerri, Nicholas C. Vella
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The Maltese archipelago is a small island chain that is among the most remote in the Mediterranean. Humans were not thought to have reached and inhabited such small and isolated islands until the regional shift to Neolithic lifeways, around 7.5 thousand years ago (ka) 1 . In the standard view, the limited resources and ecological vulnerabilities of small islands, coupled with the technological challenges of long-distance seafaring, meant that hunter-gatherers were either unable or unwilling to make these journeys 2–4 . Here we describe chronological, archaeological, faunal and botanical data that support the presence of Holocene hunter-gatherers on the Maltese islands. At this time, Malta’s geographical configuration and sea levels approximated those of the present day, necessitating seafaring distances of around 100 km from Sicily, the closest landmass. Occupations began at around 8.5 ka and are likely to have lasted until around 7.5 ka. These hunter-gatherers exploited land animals, but were also able to take advantage of marine resources and avifauna, helping to sustain these groups on a small island. Our discoveries document the longest yet-known hunter-gatherer sea crossings in the Mediterranean, raising the possibility of unknown, precocious connections across the wider region.
Nature DOI suffix ≠ "/s...": Not a research article
Data centres will use twice as much energy by 2030 — driven by AI
Sophia Chen
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The electricity consumption of data centres is projected to more than double by 2030, according to a report from the International Energy Agency published today. The primary culprit? Artificial Intelligence (AI). The report covers the current energy footprint for data centres and forecasts their future needs, which could help governments, companies, and local communities to plan infrastructure and AI deployment. IEA’s models project that data centres will use 945 terawatt-hours (TWh) in 2030, roughly equivalent to the current annual electricity consumption of Japan. By comparison, data centres consumed 415 TWh in 2024, roughly 1.5% of the world’s total electricity consumption (see ‘Global electricity growth’). Source: IEA. CC BY 4.0 The projections largely focus on data centres, which also run computing tasks other than AI. Although the agency estimated the proportion of servers in data centres devoted to AI. They found that servers for AI accounted for 24% of server electricity demand and 15% of total data centre energy demand in 2024. Alex de Vries, a researcher at VU Amsterdam and the founder of Digiconomist, who was not involved with the report, thinks this is an underestimate. The report “is a bit vague when it comes to AI specifically,” he says. Even with these uncertainties, “we should be mindful about how much energy is ultimately being consumed by all these data centers,” says de Vries. “Regardless of the exact number, we're talking several percentage of our global electricity consumption.” More power needed The IEA report finds that the US, Europe, and China are collectively responsible for 85% of data centres’ current energy consumption. Of the predicted growth in consumption, developing economies will account for around 5% by 2030, while advanced economies will account for more than 20% (see ‘Data-centre energy growth’). Source: IEA. CC BY 4.0 Countries are building power plants and upgrading electricity grids to meet the forecasted energy demand for data centres. But the IEA estimates that 20% of planned centres could face delays being connected to the grid.
Nature DOI suffix ≠ "/s...": Not a research article
‘Now is not the time for despair’ — how scientists can take a stand against political interference
Fernando Tormos-Aponte
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Resistance is rising against the assault on science, the environment and marginalized communities by the administration of US President Donald Trump. Battles are starting to play out in courts, but these cannot be the only sites of resistance. A broader, more inclusive defence of science is needed. I have felt the impacts of political assaults. In 2017, after Hurricane Maria hit my homeland, Puerto Rico, and killed thousands of people, the first Trump administration denied the death toll and delayed the provision of US$20 billion in disaster aid. And, last month, a programme I run at the University of Pittsburgh in Pennsylvania — to help undergraduates from all backgrounds gain research experience — was among thousands of US National Science Foundation grants branded as promoting “woke” diversity propaganda by Republican Senator Ted Cruz (Texas). How Trump 2.0 is reshaping science My colleagues face similar challenges (see go.nature.com/42twbyb). The University of Pittsburgh is one of several that have paused or frozen graduate admissions, spending or hiring in response to the threat of losing millions in federal funding. Meanwhile, community environmental justice groups that I work with have been denied more than $50 million that was committed to them through the Inflation Reduction Act in 2022. The Environmental Protection Agency has paused all funding actions related to Biden-era climate and infrastructure laws. A rising chorus of voices in the scientific community is sending a clear message that researchers need to step up and defend our hard-won gains. But what is to be done? On climate change, for example, some researchers have proposed that compromise with moderate sectors, such as backing carbon-capture technologies, might be a way to keep up momentum. Yet such solutions fall short on environmental justice. They come from ‘top down’ and rely on big companies; surveys show that the public is unfamiliar with them; and their effectiveness at scale is yet to be demonstrated. Instead, policies to transition away from fossil-fuel dependence should emerge from democratic processes and deliberations that include and centre the needs of affected workers and communities. ‘Silence is complicity’ — universities must fight the anti-DEI crackdown Similarly, to protect the scientific enterprise itself, limiting ourselves to defence and elite-driven compromise will be a losing strategy. Those who believe in the importance of science for the public good should build power by boosting movements and coalitions and advocating for science and justice in the public arena. We can learn from successes, such as the mobilizations that helped to enhance research-integrity policies after Trump’s first administration attacked science by sidelining and censoring scientists, reducing data accessibility and halting studies. Leveraging diverse voices through transnational alliances also has a proven track record, such as enabling the United Nations Convention on the Elimination of All Forms of Discrimination Against Women.
Nature DOI suffix ≠ "/s...": Not a research article
Journal targeted by paper mill still grappling with the aftermath years later
Miryam Naddaf
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An analysis identified studies that contained duplicated images or tortured phrases.Credit: bernie_photo/Getty A biotechnology journal that was inundated with paper-mill submissions in 2021 — and claimed in 2023 that it had tackled the problem — still harbours hundreds of dubious papers, an analysis by research-integrity sleuths has found. At least 226 studies on rodents published in the open-access journal Bioengineered between 2010 and 2023 contain manipulated or duplicated images, says the analysis, which was posted on the arXiv preprint server on 28 March1. These are hallmarks of papers produced by paper mills — companies that churn out fake scientific manuscripts to order. Most of these 226 studies have not been retracted. Science’s fake-paper problem: high-profile effort will tackle paper mills Bioengineered and its publisher, Taylor & Francis, said in a 2023 blogpost that they became suspicious about paper-mill submissions in early 2021. In response, the publisher said, it had introduced policies to screen manuscripts more rigorously. However, the preprint’s authors say that efforts to clean up published papers have been too slow. “The problem isn’t that they were targeted by paper mills, because that can happen. It’s just the way that you solve the problem afterwards. And I think that this hasn’t happened correctly,” says RenĂ© Aquarius, a neurosurgery researcher at Radboud University Medical Center in the Netherlands and a co-author of the preprint. “It’s been two to four years since most of these bad papers have been published,” he adds. Taylor & Francis says that it is investigating “a large number of articles” in Bioengineered that it suspects were produced by paper mills. “We will cross-check that list with papers of concern identified by the preprint’s authors,” a spokesperson for the UK-based publisher told Nature. “Alongside this work, we have made a range of editorial and process changes to the journal, which, as noted in the preprint, have prevented the publication of further paper-mill content.” The spokesperson declined to answer specific questions about the preprint’s findings. Suspicious activity From its launch in 2010 until 2019, Bioengineered published around 70 papers a year. This rose to 131 papers in 2020, then soared to more than 1,000 per year in 2021 and 2022. “Our previous experience on other journals that had been targeted by paper mills signaled the need for a thorough investigation,” said Todd Hummel, a global publishing director at Taylor & Francis, in the 2023 blogpost. He added that the journal had brought in measures to root out fraudulent submissions. These included asking authors to provide raw data with their manuscripts, training editors on how to spot paper-mill submissions and applying closer scrutiny to requests to change author lists. In 2023, the number of papers the journal published dropped back down to 64. Science journals crack down on image manipulation “I think it’s admirable that they have been transparent about this,” says Aquarius. “It’s great that [they] stopped the influx of paper-mill papers, or at least the acceptance of them.” “But why leave some of those papers for multiple years?” he adds. “I think cleaning up the literature is also an important task.” Jana Christopher, an image-integrity analyst at FEBS Press, who is based in Heidelberg, Germany, agrees. “It’s important that the effort of correcting the literature takes place efficiently, effectively, thoroughly and at a reasonable pace,” she says. Manipulated images In their analysis, Aquarius and his colleagues decided to screen studies that mentioned mice or rats in their titles or abstracts. The number of articles that met these criteria had increased sharply in 2021 — before 2019, they made up less than 15% of Bioengineered papers, but in 2021 and 2022, they accounted for more than 35%.
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Countries must consider their global footprint when using natural resources
Éva Plagányi
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The article ‘Global biodiversity loss from outsourced deforestation’ (R. A. Wiebe and D. S. Wilcove Nature 639, 389–394; 2025) shows that the resource needs of rich nations are responsible for “much greater cumulative range loss to species outside their own borders than within them”.
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Creating an ‘all comers’ research group in quantitative history
Rachel Crowell
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Changemakers This Nature Q&A series celebrates people who fight racism in science and who champion inclusion. It also highlights initiatives that could be applied to other scientific workplaces. Inclusion — not gatekeeping — is a theme in mathematician Nathan Alexander’s laboratory at Howard University in Washington DC. His quantitative-histories workshop is a computational and community hub for studying social problems, such as housing insecurity and homelessness. He founded that lab while in a previous post at Morehouse College in Atlanta, Georgia, and has now expanded it to include Howard and another site at the Institute for Racial Justice in Chicago, Illinois. “We have anyone and everyone come together,” he says. “Our youngest member is in high school, and our oldest is someone who, in their late 60s, was interested in returning to mathematics. We have members from the community, including formerly incarcerated persons,” he adds. Undergraduate and graduate students, along with collaborators from outside academia, all have a place at the table. By adopting a community-centred mindset, the team approaches problems with a blend of academic training and real-world experience. As a result, team members learn from each other, broaden their views on the problems they are studying and obtain better results than could be achieved without that diversity of perspectives. The financial shackling of historically Black universities in the United States For instance, Alexander’s lab is in the early stages of a project to use the US Census Bureau’s community resilience estimates (CRE) — a metric of how vulnerable neighbourhoods are to disasters — to probe housing insecurity and homelessness. “Each member of our group is taking on an area of the United States that they are familiar with and conducting a local analysis to help us make sense of the different features across geographical contexts, and by state,” Alexander says. The team is also building a set of statistical models that can be used to compare relationships between the CRE and measures of segregation. Alexander, who is also assistant graduate director of the Center for Applied Data Science and Analytics at Howard, notes that it’s a common mistake to view mathematics as a universal pursuit that everyone approaches in the same way. Instead, as he tells Nature’s careers team, his team members each approach data-driven problems with their own unique lens. What is the great passion that has driven you as a mathematician? Solving problems. At some point in studying mathematics, you learn a method to solve a problem. And then, as you learn more, you realize that there are many different ways to approach a problem. That has been the impetus for my interdisciplinary work — the idea that we can ‘patchwork’ our way to solutions and think about different fields and what they offer. Is there one thing in your career that you wish you could revisit? My knee-jerk reaction is that things have really worked out in a way that has been beautifully scary. So I'm content with my choices. Collection: Changemakers in science If I could go back and change one thing, I would spend a little more time in graduate school and do more exploring. At the time, I was broke, and wanted to be done with my studies, so I rushed through; I said to myself, let me get my dissertation taken care of and then I can begin my actual academic career. But now, I think it’s all about investigating and solving problems, and as a graduate student, I didn’t do enough of that. Now I’ve found more time to just do that and learn with my students and our community members. What is the coolest discovery to come out of your work? We have found some really abstract connections between mathematical fields — such as graph theory, number theory, probability, game theory — and real-world problems. The CRE census analysis is one example of our attempts to model real-world factors by taking a numerical analytic approach initially. Our goal is to consider mathematical insights, using probability and statistics, before moving forward with a single methodological model. Mathematics is often viewed as being universal, but the field of ethnomathematics reveals that mathematical practices look different across cultures, communities and their histories. For the sake of universality, we would want to steer clear of a single frame of reference or method. Indeed, what we see among mathematicians today are attempts to make sense of a diverse set of problems across a diverse set of disciplines which give attention to the different cultural foundations of mathematics. People use mathematics differently, and they have done so throughout history. Our lab’s goal is to learn how to balance a focus on deep theoretical aspects with the need to quantify things. Often when we quantify, or mathematize, things, you want to get down to their essence, to their core. We have been working hard all these years to maintain those theoretical, critical foundations that contribute to intersections between maths and society. For example, we can quantify changes in demographics over time in a specific community, such as the effects of gentrification, but we see that these processes play out differently in cities such as Atlanta and Washington DC. We want to understand those nuances in both our theory and quantification. If he could be a graduate student again, Alexander says he would spend more time simply exploring ideas.Credit: Cheriss May for Nature Why is running an inclusive research group important to you? Anyone who visits our lab understands clearly that we try to get rid of hierarchy as much as possible. So, although I’m the principal investigator, founder and leader of the lab, I think that empowering everyone in our space — other faculty members, students and also our elders — to give us that context, that intuition, has been our greatest asset. We call this a near-peer model. For example, a younger team member might have experience of recently released computational tools, whereas a more experienced member might discuss the different tools used over the course of their lifetime. Implementing this near-peer model has been a learning process. As faculty members, we’re often told to be the expert. I’ve tried to do the opposite of that by saying, “Here’s what I’m able to contribute. What do other people think?” That has led to this explosion of ideas. I want to ensure that Africans take part in the AI revolution It also opens up space for all lab members to play around with ideas in a way that is not always possible in a conventional classroom setting. This ultimately leads to a ripple effect in which conventional lines of inquiry can be supplemented by, at times, abstract inquiries that result in many more ideas. We try our best to avoid a top-down model and collect regular feedback from lab members.
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Obesity-drug pioneers and 13,508 physicists win US$3-million Breakthrough Prizes
Zeeya Merali
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The Breakthrough prize trophy’s design is inspired by imagery from science, including black holes, seashells and the structure of DNA.Credit: The Breakthrough Prizes Five scientists who contributed to the development of the blockbuster weight-loss drugs Ozempic and Wegovy have picked up one of this year’s US$3-million Breakthrough prizes — the most lucrative awards in science. Originally developed to treat diabetes, these drugs work by mimicking a hormone called glucagon-like peptide 1 (GLP-1) that controls blood sugar levels and helps to curb appetite. “This class of drugs truly saves lives, changes lives and brings joy back to people’s lives,” says Ziyad Al-Aly, a physician-scientist at the Veterans Affairs St. Louis Health Care System in Missouri, who recently led a massive study analysing data from almost two million people to evaluate the effects of such medication1. The ‘breakthrough’ obesity drugs that have stunned researchers This life-sciences prize is shared between the four researchers who discovered and characterized GLP-1 – endocrinologist Daniel Drucker at the University of Toronto, Canada; physician-researchers Joel Habener at Harvard Medical School in Boston, Massachusetts and Jens Juul Holst at the University of Copenhagen; and chemist Svetlana Mojsov at The Rockefeller University in New York City — along with Lotte Bjerre Knudsen of pharmaceutical company Novo Nordisk in Bagsvérd, Denmark, who spearheaded the development of drugs based on these discoveries2,3. In the 1990s, Drucker and his colleagues realized that GLP-1 caused animals to eat less and lose weight. Knudsen stablized the drug by adding fatty-acid chains, enabling it to bind to proteins in the blood, which prevents it from breaking down rapidly once injected. “It’s a tremendous honour to receive this prestigious award,” says Drucker. “But the most amazing gratification is when someone comes to my office and says, ‘I lost 40 pounds [18 kg] and I feel healthy’.” Everyone’s a winner The award is one of six Breakthrough prizes to be awarded this year in life sciences, physics and mathematics. Unusually for a major award, one of the fundamental-physics prizes was awarded to a grand total of 13,508 physicists spanning four collaborations at CERN, Europe’s particle physics laboratory near Geneva in Switzerland. Through experiments using the Large Hadron Collider (LHC), these researchers have taken multiple precision measurements over the past decade to probe, and so far confirm, the standard model of particle physics. “We’re honoured the award was made to the entire collaboration because without all those people we could not have made these advances,” says Patricia McBride, a spokesperson for CERN’s CMS collaboration. The prize money will be used to fund international students to visit CERN, she adds. CERN’s Compact Muon Solenoid (CMS) detector, one of the collaborations whose scientists share a Breakthrough prize in fundamental physics.Credit: Harold Cunningham/Getty The award is well deserved, says Brian Rebel, a particle physicist at the University of Wisconsin–Madison. “Finding the Higgs [boson] in 2012 was a once-in-lifetime event, but it was only the first step,” Rebel says. Since then, LHC scientists have been pinning down the mass of the Higgs and its interactions, as well as discovering 72 new particles, investigating antimatter and probing the nature of the ‘quark–gluon plasma’ that existed soon after the Big Bang. “It takes a small army to create the tools to test and validate these results,” says Rebel. Another Breakthrough prize in fundamental physics was awarded to one of the architects of the standard model, theoretical physicist Gerard ’t Hooft at Utrecht University in the Netherlands, who also won a share of the 1999 Nobel prize in physics for his work on the weak nuclear force, and contributed to understanding the strong nuclear force. “A beautiful synthesis emerges when one’s mathematics is linked to particles actually seen in the world,” says ’t Hooft, adding that he is “honoured” to win the prize. A theory of everything
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Does US science have a future in Antarctica? Trump cuts threaten to cancel fieldwork and more
Alexandra Witze
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McMurdo Station in Antarctica, which is operated by the US National Science Foundation, has been in need of repairs and upgrades for decades.Credit: U.S. National Science Foundation/Associated Press/Alamy US President Donald Trump’s massive government cuts are threatening the nation’s leadership at the ends of the Earth, say scientists who work in Antarctica. By presidential directives stretching back decades, the United States maintains three research stations in Antarctica. Each summer, scientists descend on them keen to make discoveries, and each winter small crews maintain the bases as a key national presence. US research in Antarctica has yielded groundbreaking insights into our planet, and the research stations aren’t just science hubs. They are also a proxy for geopolitical power; without them, the United States might cede soft power in Antarctica to other nations. Trump’s bid for Greenland threatens to destabilize Arctic research Much of that research and clout is now in danger, many scientists say. US Antarctic research is run by the National Science Foundation (NSF), which Trump has threatened with drastic budget and staff cuts. He has already withdrawn construction funds previously set aside to update the biggest US Antarctic station, and his administration has fired and — under court order — rehired several crucial programme officers for Antarctic research. Uncertainty about what might happen next is undermining plans for research from penguin surveys to studies of the Universe. “People are looking over their shoulders,” says Sridhar Anandakrishnan, a glaciologist at Pennsylvania State University in University Park. “They don’t know whether the science that they have been doing for decades is of interest to NSF any more.” “What’s really unhelpful is the timing,” says Gary Wilson, a geoscientist at the University of Waikato in Hamilton, New Zealand, and president of the international Scientific Committee on Antarctic Research. “The global issues we face are urgent.” Urgent work on the ice Of all the science done in Antarctica, none is more urgent than that seeking to understand the continent’s melting ice, which is fuelling sea-level rise that will displace millions of people in the coming decades. The NSF has supported many projects to study ice loss, coordinating the complex logistics of getting people and equipment to remote areas using icebreakers, ski-equipped planes and other polar infrastructure. New Antarctic island spotted as mammoth glacier retreats Such work has included a US–UK project allotted US$25 million over five years to study how quickly Antarctica’s Thwaites Glacier is losing ice. “That’s a very small amount of money relative to the cost of not understanding what’s happening,” says Brent Minchew, a geophysicist at the Massachusetts Institute of Technology in Cambridge who studies glacier melting. In one of the agency’s biggest investments in facilities, the NSF’s Office of Polar Programs spends more than $200 million each year to maintain civilian infrastructure at the three US bases: the small Palmer Station on an island off the Antarctic peninsula, the large McMurdo Station near the Ross ice shelf and the remote Amundsen–Scott South Pole Station. Even before Trump took office in January, the NSF had been struggling to fund Antarctic work. Stagnant budgets led to programme cutbacks in the late 2010s, and COVID-19 derailed years of fieldwork. On top of that, the NSF has been trying to rebuild the crumbling infrastructure at McMurdo, but has not had enough money to do so. Fieldwork fears But last month, Trump cancelled the NSF’s construction budget for the current fiscal year ― which includes work on the McMurdo rebuild ― overriding Congress’s spending priorities. Scientists fear that he will also seek to slash the agency’s budget for the fiscal year 2026: one preliminary document leaked to The Washington Post suggested a 28% cut. Trump will release his budget request in the next few months, although the agency’s final budget for next year, to be decided by Congress, could differ substantially from that request. If support for the Antarctic programme is slashed, then the NSF might not be able to fund substantial field research for at least a couple of years. “It feels like a complete exercise in blind hope to be writing scientific proposals and submitting them,” says a US scientist who asked not to be named for fear of reprisals. In a worst-case scenario, the NSF could be faced with winding down research at the bases. “Keeping the stations alive is the first imperative,” says Michael Jackson, a geophysicist who worked at the NSF as an Antarctic programme officer until December. “Keeping the stations viable for science is the second, and doing science is the third.”
Nature DOI suffix ≠ "/s...": Not a research article
Sleep is essential — researchers are trying to work out why
Tammy Worth
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Nature DOI suffix ≠ "/s...": Not a research article
The great brain clearance and dementia debate
Benjamin Plackett
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New treatments to put insomnia to bed
Rachel Nuwer
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Research round-up: sleep
Bianca Nogrady
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How do I explain the publication gap I ended up with after a hostile manager?
Bianca Nogrady
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The problem Dear Nature, I’m a biogeochemist from the United States. I experienced bullying in a previous workplace, where I wasn’t given opportunities to participate in academic activities such as applying for grants, teaching students and publishing papers. I have since learnt that others have been similarly victimized, but at the time I was encouraged not to take any formal action. Three years of no opportunities means I have very little to show from that crucial time in my career, and I have no reference from my manager. How do I explain this career gap to prospective employers or represent this in my CV? — A struggling biogeochemist The advice Nature’s careers section spoke to three academics who study academic bullying and its impacts. All expressed their sympathy for any researcher — particularly those in science, technology, engineering, mathematics and medicine (STEMM) — caught in such a situation. “I’ve seen scholars who are in the social sciences and the liberal arts who can work their way around the mentor, and I think it’s harder in STEMM subjects because so much emphasis is put on the head of your lab: your adviser,” says Leah Hollis, associate dean of access, equity and inclusion at Pennsylvania State University in University Park. Hollis notes that a gap in a publication record isn’t unusual, and can come from any number of life events, such as serious illness or caring responsibilities. However, she notes, “I know those stories are much more palatable than ‘my adviser was a jerk’.” Loraleigh Keashly, a communications scholar at Wayne State University in Detroit, Michigan, agrees that it is OK to have a break in your career record, because “we already have mechanisms in place that say that there are extraordinary circumstances in one’s life that draw people’s attention away”. The challenge is how to frame this particular circumstance. Having been on interview panels, Keashly says she might be curious enough to ask about a gap. Her advice is to address that question simply — saying, for example, that ‘there was a challenging environment, and it wasn’t a good fit’, or ‘the principal investigator (PI) wanted to move in one direction, I wanted to move in another’ — and move on to talk about other things, to avoid drawing extra attention to the experience. Both Hollis and Keashly also suggested seeking out other researchers and academics in the field who could serve as references in place of the difficult supervisor. “Access professional networks, other people in the discipline,” Keashly says — maybe people you’ve worked with before, or you’ve met at conferences and “had positive, constructive conversations” about your work. Hollis also suggests contacting the Academic Parity Movement — a non-profit organization in Brookline, Massachusetts, working to address academic bullying, discrimination and violence — which she is on the advisory board for. “Perhaps we can get you connected with somebody,” she says, such as other senior scientists in the field who might be familiar with your work and the situation. An ‘agony aunt’ for working scientists
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How Trump 2.0 is slashing NIH-backed research — in charts
Max Kozlov, Chris Ryan
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Scientists and others have been protesting the massive cuts to research at the US National Institutes of Health being made by the administration of US President Donald Trump.Credit: Dominic Gwinn/Middle East Images/AFP via Getty The US National Institutes of Health (NIH) has terminated nearly 800 research projects at a breakneck pace, wiping out significant chunks of funding to entire scientific fields, finds a Nature analysis of the unprecedented cuts. The administration of US President Donald Trump began purging NIH-funded studies on topics that it deems problematic less than 50 days ago, continuously expanding its list to include research on topics ranging from COVID-19 to misinformation. Hundreds of the 30,000-plus scientists funded by the NIH yearly have been forced to halt their work after receiving notices that their research “no longer effectuates agency priorities”, and some have had to fire personnel or even shut down their laboratories. These US labs risk imminent closure after Trump cuts To understand the extent and breadth of these actions, which have so far clawed back more than US$2.3 billion allocated to US researchers, Nature tapped into a scientist-led effort to track these cuts (see ‘How Nature analysed NIH’s grant terminations’ in supplemental info). Our analysis reveals the project topics, NIH institutes and US states affected the most. The cancellations of projects, despite scientists scoring them highly during review, “tears the long-standing fabric of the government’s contract to pursue medical research that seeks to better the healthspan and lifespan for all Americans”, says Francis Collins, a geneticist who led the NIH, based in Bethesda, Maryland, for 12 years under 3 US presidents, including Trump. The NIH and its parent organization, the US Department of Health and Human Services (HHS) based in Washington DC, did not respond to Nature’s queries about the terminations or scientists’ concerns about them. Grant assessment The NIH is by far the world’s largest public funder of biomedical research, with an annual budget of US$47 billion paying for more than 60,000 grants. This size means that the agency’s funding is irreplaceable for science, says Shirley Tilghman, a molecular biologist and former president of Princeton University in New Jersey. Source: Nature analysis of NIH Grant Terminations in 2025 database Nature’s analysis shows that, looking at just the projects terminated so far, 17% are related to COVID-19, and 29% to HIV/AIDS (see ‘Terminated grant tally’) — although this represents less than 4% of all the grants awarded to each of those topics that the agency funded in 2024. One reason for the focus of these cuts is that the Trump administration has said that the COVID-19 pandemic is over and people in the United States have moved on from it. Another potential reason is that HIV/AIDS disproportionately affects sexual and gender minorities (LGBT+); Trump signed an executive order on his first day in office on 20 January, directing the US government to stop acknowledging the fact that a person’s gender can differ from their sex at birth. The scientific fields hit hardest by the NIH’s cuts are those related to the health of transgender people, and the broader LGBT+ community, where around half of grants have been cut compared with what the NIH funded in 2024 (see ‘Fields under fire’). Source: Nature analysis of NIH Grant Terminations in 2025 database These actions deny “a small but real percentage of the population answers to critically important questions about their health”, Tilghman says. “You cannot eliminate a segment of the population by executive order, but you can harm them greatly.” The NIH institutes that fund a lot of research in these now-disfavoured topic areas — for instance, the US National Institute on Minority Health and Health Disparities — have been hammered by the cuts (see ‘US NIH institutes losing the most’). Five of six of the directors of the NIH’s institutes and centres affected the most by these grant cancellations were placed on administrative leave last week, amid a glut of lay-offs and restructuring at the HHS. Source: Nature analysis of NIH Grant Terminations in 2025 database Geographical impacts Trump and his Republican allies have said that they want to rein in ‘woke’ left-wing, elite universities. The grant terminations are now damaging the scientific enterprise at research institutions in both ‘red’ states that voted for Trump in 2024 and ‘blue’ states that didn’t (see ‘Grant cuts by state’). Washington state, a blue state in 2024, has been hit hardest by the grant terminations, relative to how much NIH funding it typically receives in a year, with North Carolina, a red state in 2024, being a close second. But the administration isn’t just cutting NIH grants at the wealthiest universities: many cuts are also happening at small state schools and historically Black colleges and universities, says Scott Delaney, an epidemiologist at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts, who co-runs the database that Nature used for its analysis. To create the database, Delaney and his collaborator, Noam Ross, executive director of the data-science non-profit organization rOpenSci, based in Berkeley, California, have been asking scientists to submit information about their grant terminations and scraping from a list of cancelled projects that the HHS posts on its website weekly. Source: Nature analysis of NIH Grant Terminations in 2025 database Biomedical-research heavyweight states Massachusetts, California, Maryland and Texas have lost some of the largest absolute amounts of research funding, but because they receive so much from the NIH, the impact has been less than for other states. New York state is an exception — it registers in the top five states affected, according to Nature’s analysis, because it is home to Columbia University in New York City. Trump’s team has targeted research grants at Columbia, cancelling $400 million to the university because, the administration has said, it failed to protect Jewish students from harassment during campus protests over Israel’s war in Gaza. Exclusive: NIH to cut grants for COVID research, documents reveal
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Tariffs hit science labs: Trump’s levies raise cost of supplies
Celeste Biever
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Increased tariffs on imports into the United States are affecting the global trade in laboratory supplies.Credit: Allen J. Schaben/Los Angeles Times via Getty The Trump administration’s sweeping tariffs on all imports into the United States — which range from 10% on products from some countries up to 54% on goods from China — are increasing the costs of labware and specialist scientific instruments in the country. The price increases come as research budgets for US laboratories are stretched thin by unprecedented grant cancellations and cuts to university funding introduced since Donald Trump’s second presidency began in January. “We’re already doing quotes today that are 20% more than they were yesterday,” says Drew Kevorkian, chief executive of ARES Scientific in Miami Beach, Florida, which supplies research equipment to scientific laboratories, including those at many universities. “I think almost everybody is going to see a price increase of some sort.” The latest round of tariffs comes into effect on 5 April for all countries, to be followed by steeper hikes for some on 9 April. It represents “systemic changes to the cost structure of doing science — and they’re landing at a time when research institutions are already under acute financial stress”, says Tinglong Dai, who researches global supply chains and health care at Johns Hopkins University in Baltimore, Maryland. “This isn’t just about belt-tightening. It could be the last straw — and risks causing lasting damage.” Source: TrendEconomy The United States imports billions of dollars’ worth of lab equipment and reagents each year, says Dai (see ‘Global trade in reagents’). Many of these products come from countries about to be hit by tariff rises, including China, Switzerland, Japan, the United Kingdom and European Union countries; others come from Mexico and Canada, on which the Trump administration imposed tariffs earlier this year. Announcing the latest tariffs on 2 April, Trump said they will save the United States from a “national emergency”, boost a hollowed-out manufacturing base and reduce the country’s dependence on “foreign adversaries”. The news prompted global financial turmoil: stocks tumbled, and the International Monetary Fund is warning of a significant risk to the global economy. Microscopes, glassware, DNA sequencers Researchers told Nature that the prices of many scientific products could be affected. China supplies basic lab equipment, such as glass tubes, and reagents to the United States, they say, as well as advanced electronic equipment including computer chips, liquid-crystal displays and incubators. Germany (whose imports, like those from the rest of the EU, will be hit with a 20% tariff) and Japan (24%) supply high-end lab instruments such as microscopes or precision analytical devices, whereas Switzerland (32%) and the United Kingdom (10%) are major exporters of diagnostic tools, antibodies and specialty chemicals. Mexico supplies plasticware and Canada provides specialized equipment including DNA sequencers and cell counters. Sterilizers, centrifuges and glassware washers used in US labs often come from Europe. ‘Does anyone have any of these?’: Lab-supply shortages strike amid global pandemic “These aren’t luxury items,” says Dai. “They’re the core infrastructure of modern science.” Mikhail Kats, a physicist at the University of Wisconsin–Madison, says it’s not clear how tariffs will apply to items already budgeted for in a grant. “Do we budget the price or the price with the tariff?” he asks. Kevorkian says around 60% of the products his company supplies are made in the United States, and 40% are imported. But even US-made products often rely on imported components. “A DNA sequencer built in California might still depend on optics from Germany and semiconductors from China,” says Dai. Switching to US-based suppliers doesn’t always reduce costs, says Kevorkian. “Believe it or not, some of the products that we’re buying overseas, even when you put the tariffs on them, they’re still less expensive than buying them from the US.” Supply-chain complexity
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Science’s big problem is a loss of influence, not a loss of trust
Heidi J. Larson, David M. Bersoff
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People who have high trust in their health-care system are more likely to be fully vaccinated against COVID-19.Credit: Anshuman Poyrekar/Hindustan Times via Getty Science has a trust problem — at least, that is the common perception. If only, the argument goes, we could get people to ‘trust’ or ‘follow’ the science, we, as a society, would be doing more about climate change, childhood vaccination rates would be increasing rather than decreasing and fewer people would have died during the COVID-19 pandemic. Characterizing the problem as ‘science denialism’, however, is misleading and wrongly suggests that the solution is to build greater trust between scientists and the public. Indeed, the research produced by our organizations — the Edelman Trust Institute think tank and the Global Listening Project non-profit organization — suggests that trust in science and scientists remains high globally. But scientists and scientific information exist in an increasingly complex ecosystem in which people’s perception of what counts as reliable evidence or proof is influenced by myriad other people and factors, including politics, religion, culture and personal belief. In the face of this complexity, the public are turning to friends, family, journalists and others to help them filter and interpret the vast amounts of information available. Our work suggests that the crux of science’s current challenge is not lost trust, but rather misplaced trust in untrustworthy sources. High trust levels can be dangerous when they are invested in institutions and individuals that are misinformed or not well-intentioned. In this regard, it is especially problematic when societal institutions become politicized and advocate policies and behaviours that are at odds with scientific consensus. Misplaced trust can drive behaviours that put people’s lives at risk1,2. For example, during the COVID-19 pandemic, cases and deaths were higher in nations, such as the United States and Brazil, that had political leaders who dismissed the severity or even existence of the pandemic, undermined the need for masks and questioned the safety of the vaccines2–4. In what follows, we share data on trust in science and strategies to help scientists compete with non-credentialed sources for influence. Unpacking the real challenges Trust in science is generally high. A survey, conducted in 68 countries between November 2022 and August 2023, found that 75% of respondents said that they trusted scientists5. In a separate study across 70 countries, conducted by the Global Listening Project between July and September 2023, 71% of respondents said that they had high trust in science (see go.nature.com/3qyawpb). And the 2024 Edelman Trust Barometer, an annual online survey of 28 countries conducted by the Edelman Trust Institute in November 2023, found that 74% of respondents trust scientists to tell the truth about new innovations and technologies6. By contrast, our research revealed concern over the sanctity and independence of science, especially for certain topics, such as COVID-19 and climate change. More than half of Trust Barometer respondents (53%) said that science had become politicized in their country, and 59% said that governments and other large funding organizations have too much influence on how science is done6. One by-product of these perceptions has been an increase in aggression towards scientists7. Another damaging consequence of this politicization is that it makes people more open to alternative narratives that might not be evidence-based and are often rooted in political ideologies, on topics such as climate and vaccines. This ideological schism is not defined by a pro-science versus anti-science antipathy but by a ‘my science’ versus ‘your science’ or a ‘my evidence’ versus ‘your evidence’ polarization. People in some countries put more trust in community leaders than scientists.Credit: Jorge Mantilla/NurPhoto/Shutterstock Often, this tension stems from the fact that scientists seek truth in experiments and data analyses, and focus on effects that manifest across large numbers of people. By contrast, the public is often focused on, and driven by, the experiences of people they know personally or vicariously. These experiences are taken as evidence and often carry more weight than peer-reviewed research. All sides claim respect for science and evidence, hence the generally high numbers for trust in scientists across ideological groups; but each side has its own version of the ‘truth’ based on its own evidence and its own interpretation of what actions the evidence dictates6. For example, parental concerns about the potential of vaccines to cause autism have been refuted by many scientific studies8; nevertheless, a parent’s experience with their own child or witnessing what has happened to others can be taken as direct and compelling evidence of a causal rather than a coincidental link between the timing of a measles, mumps and rubella vaccine and the onset of autism. Sometimes a sample of one, when you know that person, is more powerful emotionally, if not statistically, than a sample of 10,000. Competing narratives around topics such as vaccines or climate change can also breed confusion, which manifests as doubt or misguided beliefs about the best actions to take, for oneself and for wider society. Doubt can weaken people’s resolve to support and follow scientific advice, especially when doing so requires effort, risk and sacrifice. Misguided beliefs, meanwhile, can lead people to act against their own or society’s best interests. Another challenge is that many people trust non-scientists to tell them the truth about scientific matters. According to the 2024 Edelman Trust Barometer report, those with most influence include ‘someone like me’ (74%) and ‘friends and family’ (78%). Even celebrities (39%) and religious leaders (43%) enjoy substantial amounts of trust on technology and innovation matters6. Participants in the Global Listening Project study ranked family members higher than scientists when it came to who they would go to for truthful information in a crisis (see go.nature.com/3qyawpb and ‘Local influences’). Source: Global Listening Project Although these other sources generally lack scientific credentials, they exhibit other characteristics that people associate with legitimacy. In particular, respondents to the 2025 Edelman Trust Barometer survey conducted between October and November last year indicated that relevant personal experience (70%) is more strongly associated with source legitimacy than are formal training and academic credentials (65%; see go.nature.com/4jpparb). Although this might not affect the world of theoretical physics, it does matter in domains such as health and climate. Legitimacy based on personal experience is something that people extend to themselves. The 2024 Edelman Trust Barometer Special Report: Trust and Health survey9, which involved 16 countries and was conducted in March last year, found that 65% of people are confident in their own judgement, information acumen and personal efficacy when it comes to health matters (see ‘Trust in health’). Of these ‘high health self-confidence’ individuals, 43% have relatively low trust in the health-care system9. High health self-confidence coupled with trust in health-care systems generally drives better health outcomes, but when there is a high level of self-confidence accompanied by low levels of trust, things can be problematic. Source: Ref. 9 This is especially true when it comes to complying with public-health mandates, acceptance of medical-care innovations and being a positive influence on the health decisions of others. In the case of vaccines, those who reported themselves as being self-confident with high trust in the health-care system were more likely to be fully vaccinated (including all boosters) against COVID-19 (54%) than were those who felt equally self-confident but had lower trust (40%)9. The threat posed by high levels of trust in non-credentialed sources is exacerbated by where and how people get their scientific information. Most often, it is through online searches, which return a mix of credentialed and non-credentialed information. Because of how people judge credibility, it cannot be assumed that they will discount non-credentialed information in favour of evidence-based, peer-reviewed findings. In fact, those with high self-confidence and little trust in official sources are often drawn to non-credentialed voices and sources8. Because the information ecosystem contains misinformation disseminated by sources who lack scientific training but are trusted at similar levels to those who have had training, scientists need to communicate better — with more relevance, emotional resonance and empathy — if they are going to compete with other sources that are increasingly influential. Three strategies to build trust We recommend three strategies for scientists to enhance the influence of evidence-based, peer-reviewed information. First, work with locally trusted sources to disseminate information. Beyond their credibility, respected individuals such as physicians and religious leaders are often in the best position to make information relevant to people’s lives and their values. Public-health authorities that issue scientific information, as well as academic and research institutions, should identify and work with such partners, and provide them with training to become trusted sources of information armed with accurate and compelling arguments to address misconceptions. Finland is consistently recognized for having one of the best science-literacy programmes.Credit: Jonathan Nackstrand/AFP via Getty For example, people trust family physicians more than they do scientists in some settings, and religious leaders are more influential than scientists in many countries. Employers are another potential partner: 68% of respondents said they trust their employer to do what is right when it comes to addressing their health-related needs and concerns9. This trust was higher than for government, media, business and non-governmental organizations.
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An animal source of mpox emerges — and it’s a squirrel
Jane Qiu
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Researchers think that the fire-footed rope squirrel could be a reservoir host for the monkeypox virus.Credit: ANT Photo Library/Science Source One of the great mysteries of the monkeypox virus has been pinpointing its ‘reservoir’ hosts — the animals that carry and spread the virus without becoming sick from it. Now, an international team of scientists suggests that it has an answer: the fire-footed rope squirrel (Funisciurus pyrropus), a forest-dwelling rodent found in West and Central Africa1. Monkeypox in Africa: the science the world ignored Although the name ‘monkeypox’ comes from the virus’s discovery in laboratory monkeys in 1958, researchers have long suspected rodents and other small mammals in Africa of being reservoir hosts. And studies published in the past year2,3 have demonstrated that African outbreaks of mpox, the disease caused by the virus, have been fuelled by several transmission events from animals to humans. Pinpointing viral reservoirs is crucial to breaking the vicious cycle of transmission, says Placide Mbala, an epidemiologist at the National Institute of Biomedical Research in Kinshasa, Democratic Republic of the Congo. By identifying the sources, scientists could work with local communities to design strategies to shield people from infection — for instance, safe handling of wild-animal meat. The identification of the squirrel is “exceptional” detective work and provides compelling evidence, says Alexandre Hassanin, who studies the evolution of monkeypox at Sorbonne University in Paris. He and others who spoke to Nature, however, aren’t sure that the study definitively establishes F. pyrropus as a monkeypox reservoir, but they applaud the long-term wildlife-surveillance work. The report was posted as a preprint, ahead of peer review, to the Research Square server on 8 April. (Research Square is owned by Springer Nature, Nature’s publisher.) Disease ecologist Carme Riutord-Fe observes a sooty mangabey in the Taï National Park in Cîte d’Ivoire.Credit: TCP/Constant Kaye Long-term surveillance Although mpox has affected Africa for decades, it captured headlines worldwide in 2022 when the virus sparked a global outbreak, fuelled by human-to-human transmission. Last August, the World Health Organization declared another global emergency after a worrisome strain of the virus spread to previously unaffected African countries. Growing mpox outbreak prompts WHO to declare global health emergency As these outbreaks have become more common, one question on researchers’ minds has been their animal sources. A clue emerged in 2023 in Taï National Park in Cîte d’Ivoire, where a team of researchers has been monitoring a group of sooty mangabeys (Cercocebus atys) for many years. In late January that year, Carme Riutord-Fe, a disease ecologist at the Swiss Centre of Scientific Research in Abidjan, noticed an infant mangabey with red skin lesions on its forehead, chest and legs. The fluid-filled lesions, characteristic of mpox, quickly spread across its body, and it died two days later. Within two months, the disease had spread to nearly one-third of the group of 80 mangabeys; 4 of them died. The team identified the monkeypox virus as causing the outbreak and successfully sequenced the full viral genome from two of the infected animals. They were identical, suggesting that the outbreak originated from a single source, says Livia Patrono, a disease ecologist at the Helmholtz Institute for One Health in Greifswald, Germany, and a study author. But what was the source? For most outbreak investigations, scientists begin collecting animal samples weeks or months after the first reported cases. Animals don’t always carry detectable levels of the virus, and those responsible for the outbreak might have left the “crime scene” by the time researchers arrive, says Fabian Leendertz, leader of the work and founding director of the Helmholtz Institute. This makes it difficult to pinpoint disease origins, he says. Leendertz and his team surveil a group of sooty mangabeys to study pathogens, such as the monkeypox virus, that are relevant to humans.Credit: TCP/Ane Lopez-Morales In the case of the mangabey outbreak, however, “we were there when it happened”, Leendertz says. His team has been monitoring several populations of free-living, non-human primates in the Taï forest on a daily basis since 2001 to better understand pathogens relevant to humans4. When mpox struck in 2023, archived samples of the mangabeys’ urine and faeces, as well as tissues and swabs from dead animals found in the forest, proved invaluable. Monkeypox virus showed up in faecal samples collected as early as 6 December 2022 from a mangabey called Bako — the mother of the infant that first drew researchers’ attention. Three pieces of evidence then led the researchers to conclude that Bako, who survived the infection without developing symptoms, had caught the virus after eating a fire-footed rope squirrel. The first was that they observed mangabeys hunt and eat F. pyrropus. The second was that they found an F. pyrropus carcass teeming with a virus identical to the one infecting the mangabeys one month before Bako’s faecal samples turned positive. And finally, they identified F. pyrropus DNA in the earliest positive faecal sample from Bako.
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Losing weight through better sleep
Tammy Worth
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Nature DOI suffix ≠ "/s...": Not a research article
What makes us human? Milestone ape genomes promise clues
Humberto Basilio
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Conservation of critically endangered Bornean orangutans could be aided by the sequencing of the creature’s genome.Credit: Fiona Rogers/Nature Picture Library After more than two decades of work, researchers have achieved a genetics milestone: they have successfully sequenced the complete genomes of six ape species, a feat that seemed impossible just a few years ago1. The results, published today in Nature by a team of 123 researchers spread across multiple nations, are expected to aid ape conservation efforts and advance scientists’ understanding of how humans differ from other apes. Podcast: Long-awaited ape genomes give new insights into their evolution — and ours “I’ve never thought that this would be accomplished in my lifetime,” says Kateryna Makova, an evolutionary geneticist at the Pennsylvania State University in University Park, and a co-author of the study, who has been working to assemble complete sequences of ape genomes for almost 25 years. Close human relatives A genome is the complete set of DNA instructions found in a cell, and sequencing it means determining the identity and order of the building blocks in each molecule of DNA. After scientists succeeded in sequencing the human genome in 20012, they quickly began working on the genomes of other apes — the closest genetic relatives to humans. Understanding the genomes of non-human apes is crucial because it gives geneticists insights into human evolution and the genetic factors that differentiate us from other apes, says Makova. In medicine, for instance, scientists frequently study the variations in ape DNA that make the animals resistant to certain diseases, such as AIDS. In the past, scientists had deciphered segments of non-human apes’ genomes, but they had never managed to assemble a complete sequence for any species. In the current study, however, Makova and her collaborators used advanced sequencing techniques and algorithms that allowed them to read long segments of DNA and assemble them into a sequence that stretched from one end of each chromosome to the other, without any gaps. “This has never been done before,” says Makova. The chimpanzee is one of humanity’s closest living relatives, and its genome promises to shed light on human evolution.Credit: Fiona Rogers/Nature Picture Library Using these techniques, the authors decoded the genomes of six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang gibbon. The scientists discovered between 770 and 1,482 possible new genes for each species. They also found unusual DNA structures lurking in previously inaccessible regions of the genome.
Nature DOI suffix ≠ "/s...": Not a research article
Skin wound healing measured remotely through molecular flux
Kellen Chen, Geoffrey C. Gurtner
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The skin is the largest organ of the human body, maintaining internal homeostasis – for example by releasing heat through sweating on a hot day – and providing a barrier that protects the body from external threats such as bacteria and other microorganisms. But skin is also highly vulnerable to injury. Chronic, non-healing wounds can increase the susceptibility of the body to infection, increase the complications of elective surgical procedures and greatly add to health-care costs1. In a paper in Nature, Shin et al.2 present details of a non-contact wearable device that can continuously monitor wounds and wound healing by measuring the flux of molecules into and out of the skin, potentially decreasing treatment costs and improving patient outcomes.
Nature DOI suffix ≠ "/s...": Not a research article
Biggest brain map ever details huge number of neurons and their activity
Miryam Naddaf
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A rendering of more than 1,000 brain cells out of the those reconstructed from analysis of a cubic millimetre of brain tissue from a mouse. Credit: Allen Institute Researchers have created the largest and most detailed wiring diagram of a mammalian brain to date, by mapping cells in a cubic millimetre of a mouse’s brain tissue1. In a landmark achievement, the diagram also details the activity of individual neurons on a large scale ― a neuroscience first. The high-resolution 3D map contains more than 200,000 brain cells, around 82,000 of which are neurons. It also includes more than 500 million of the neuronal connection points called synapses and more than 4 kilometres of neuronal wiring, all found in a tiny block of tissue in a brain region involved in vision. The only brain map of comparable scale is that of a cubic millimetre of human brain, which included 16,000 neurons and 150 million synapses2. The new map also captured the activity of tens of thousands of neurons firing signals and interacting with each other to process visual information. Read more on the MICrONS project This brain-activity map, combined with the wiring diagram, marks a milestone in connectomics, a field that aims to show how brains process and organize information. Behind the massive efforts are more than 150 researchers in the Machine Intelligence from Cortical Networks (MICrONS) project, who described their work in a package of eight papers published today in Nature and Nature Methods. The MICrONS project has made its resources available for the neuroscience community online, and other teams are already exploring them in different studies. “They managed to do something that we haven’t done as a neuroscience community in basically all of our history, which is to be able to map the activity of neurons onto the wiring on a very large population of neurons,” says Mariela Petkova, a neuroscientist at Harvard University in Cambridge, Massachusetts, who is not involved with the project. “We have never seen it at this scale.” The data “are really stunningly beautiful,” says Forrest Collman, a neuroscientist at the Allen Institute for Brain Science in Seattle, Washington, who co-authored the studies. “Looking at it really gives you an awe about the sense of complexity in the brain that is very much akin to looking up at the stars of night.” Mouse in a matrix To create the breakthrough map, researchers first recorded the firing of almost 76,000 neurons in the visual cortex of a mouse as the animal watched various videos, including clips from The Matrix, for two hours. Then they sliced up a cubic millimetre of the mouse’s brain into thousands of tissue slices, each about one four-hundredth the width of a human hair. Cubic millimetre of brain mapped in spectacular detail The scientists imaged each slice and assembled the images into a 3D map. Finally, they used artificial intelligence and machine-learning algorithms to annotate the neurons, their branching projections and their synapses. The team also matched the neurons in the map with their recordings of brain cells in action. Moritz Helmstaedter, a neuroscientist at the Max Planck Institute for Brain Research in Frankfurt, Germany, says “the combination of function and structure at that scale” is unprecedented. It’s “a very impressive endeavour and success”.
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AI is transforming peer review — and many scientists are worried
Miryam Naddaf
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This February, ecologist TimothĂ©e Poisot was surprised when he read through the peer reviews of a manuscript he had submitted for publication. One of the referee reports seemed to have been written with, or perhaps entirely by, artificial intelligence (AI). It contained the telltale sentence, “Here is a revised version of your review with improved clarity and structure”, a strong indication that the text was generated by large language models (LLMs). Poisot hasn’t yet told the journal editor of his suspicions; he asked that the journal involved — which bans the use of LLMs in peer reviews — not be revealed in this article. But in a blogpost about the incident, he argued strongly against automated peer review. “I submit a manuscript for review in the hope of getting comments from my peers. If this assumption is not met, the entire social contract of peer review is gone,” wrote Poisot, who works at the University of Montreal in Canada. AI systems are already transforming peer review — sometimes with publishers’ encouragement, and at other times in violation of their rules. Publishers and researchers alike are testing out AI products to flag errors in the text, data, code and references of manuscripts, to guide reviewers toward more-constructive feedback, and to polish their prose. Some new websites even offer entire AI-created reviews with one click. But with these innovations come concerns. Although today’s AI products are cast in the role of assistants, AI might eventually come to dominate the peer-review process, with the human reviewer’s role reduced or cut out altogether. Some enthusiasts see the automation of peer review as an inevitability — but many researchers, such as Poisot, as well as journal publishers, view it as a disaster. My other editor is AI Even before the appearance of ChatGPT and other AI tools based on LLMs, publishers had been using a variety of AI applications to ease the peer-review process for more than half a decade — including for tasks such as checking statistics, summarizing findings and easing the selection of peer reviewers. But the advent of LLMs, which mimic fluent human writing, has changed the game. In a survey of nearly 5,000 researchers, some 19% said they had already tried using LLMs to ‘increase the speed and ease’ of their review. But the survey, by publisher Wiley, headquartered in Hoboken, New Jersey, didn’t interrogate the balance between using LLMs to touch up prose, and relying on the AI to generate the review. Three AI-powered steps to faster, smarter peer review One study1 of peer-review reports for papers submitted to AI conferences in 2023 and 2024 found that between 7% and 17% of these reports contained signs that they had been ‘substantially modified’ by LLMs — meaning changes beyond spell-checking or minor updates to the text. Many funders and publishers currently forbid reviewers of grants or papers from using AI, citing concerns about leaking confidential information if researchers load material into chatbot websites. But if researchers host offline LLMs on their own computers, then data aren’t fed back into the cloud, says Sebastian Porsdam Mann at the University of Copenhagen, who studies the practicalities and ethics of using generative AI in research. Using offline LLMs to rephrase one’s notes can speed up and sharpen the process of writing reviews, so long as the LLMs don’t “crank out a full review on your behalf”, wrote Dritjon Gruda, an organizational-behaviour researcher at the Catholic University of Portugal in Lisbon, in a Nature careers column. But “taking superficial notes and having an LLM synthesize them falls far, far short of writing an adequate peer review”, counters Carl Bergstrom, an evolutionary biologist at the University of Washington in Seattle. If reviewers start relying on AI so that they can skip most of the process of writing reviews, they risk providing shallow analysis. “Writing is thinking,” Bergstrom says. LLMs can certainly improve some reviewers’ style, says Porsdam Mann: this is unsurprising, given that some peer reviews are slapdash or poorly written. However, LLM output almost always contains errors, because the tools work by producing text that seems statistically likely on the basis of their training data and inputs — although researchers are finding ways to dampen error rates. In many cases, the gap between humans and LLMs isn’t so great, according to a study that provided more than 300 US computational biologists and AI researchers with reviews of their own papers — some produced by human reviewers and others by GPT-4, one of the leading LLMs at the time2. Some 40% of respondents said the AI was either more helpful than the human reviews, or as helpful; and a further 42% that the AI was less helpful than many, but more helpful than some (see ‘Comparing AI and human peer review’). Source: Ref. 2 AI that goes beyond editing The team behind the study that compared AI and human reviews, led by James Zou, a computational biologist at Stanford University, California, is now developing a reviewer ‘feedback agent’. It evaluates human review reports against a checklist of common issues — such as vague or inappropriate feedback — and, in turn, suggests how reviewers can improve their comments. At a publisher innovation fair in London last December, many AI developers lined up to pitch products to improve peer review that do more than mere editing. One tool, called Eliza, launched last year by the firm World Brain Scholar (WBS) in Amsterdam, the Netherlands, makes suggestions to improve reviewer feedback, recommends relevant references and translates reviews written in other languages into English. The tool is not meant to replace human peer reviewers, says WBS founder Zeger Karssen. “The tool will just analyse what the peer reviewer has written down,” he says. A similar tool is Review Assistant, developed by multinational publishing-services firm Enago and Charlesworth. Initially, the tool used an LLM system to answer structured queries about a manuscript, which reviewers could then check or verify. But after talking to publishers, developers added a ‘human first’ mode, in which reviewers answer the queries and then have an AI tool look at their answers. The tool can “support reviewers to do what they may already be doing illegitimately, in a legitimate way”, says co-developer Mary Miskin, global operations director at Charlesworth, who is based in Huddersfield, UK. Another AI approach aims to free reviewers from the laborious parts of peer review. A start-up firm called Grounded AI, in Stevenage, UK, has developed a tool called Veracity, which checks whether cited papers in manuscripts exist, and then — using an LLM — analyses whether the cited work corresponds to the author’s claims. It functions like “the workflow that a motivated, rigorous human fact checker would go through if they had all the time in the world”, says co-founder Nick Morley. What are the best AI tools for research? Nature’s guide And a host of efforts have sprung up to apply LLM-assisted tools to existing papers — from software to spot image duplications, to statistics-checking programs. But researchers have expressed concerns that LLMs can be unreliable and that some apparent errors could be false positives. One AI review tool that’s already in trials with publishers is Alchemist Review, developed by Grounded AI and a company called Hum in Charlottesville, Virginia. The software’s creators say that it can summarize core findings and methods and assess the novelty of research, as well as validate citations. They also say that reviewers can use the tool in a secure environment that protects the confidentiality of manuscripts and authors’ intellectual property. AIP Publishing, the publishing arm of the American Institute of Physics, headquartered in Melville, New York, is piloting a version of this software in two journals, says chief transformation officer Ann Michael. Journal editors will test a prototype of the tool and, at their discretion, allow some peer reviewers to try it. However, the publisher will not test the tool’s ability to judge novelty, because internal surveys suggested editors didn’t rate that as being as helpful as other features, Michael says. “We’re trying to learn how to responsibly apply AI to peer review,” she says, emphasizing that the tool is being used before human review, not to replace it. Other publishers also told Nature that they were exploring developing in-house AI tools for peer review, but didn’t say exactly what they were working on. Wiley, for instance, is “looking into various potential use cases for AI to strengthen peer review, including at the editor and reviewer levels”, a spokesperson said. A December 2024 study of guidelines at top medical journals3 found that among large publishers, Elsevier currently bans reviewers from using generative AI or AI-assisted review, whereas Wiley and Springer Nature permit “limited use”. Both Springer Nature and Wiley require the disclosure of any use of AI to support review, and forbid online uploading of manuscripts. (Nature’s news team is editorially independent of its publisher.) The study noted that 59% of the 78 top medical journals with guidance on the matter ban AI use in peer review. The rest allow it, with varying requirements. AI-led review? The most radical applications of AI in peer reviewing are tools that directly provide automated reviews of manuscripts. One example is Paper-Wizard, which generates full-fledged multi-page reviews when a paper is uploaded, and checks for detailed aspects of methodological designs, such as statistical rigour. Its co-creator, cognitive neuroscientist Shane Ehrhardt in Brisbane, Australia, says that it is a ‘pre-peer-review’ product, intended to help authors with their own work.
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Microbial warfare brought us CRISPR. What big breakthroughs could be next?
Amber Dance
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All around the world — in the oceans, the soil, your body — an invisible battle is raging. Earth’s vast population of roughly 1030 bacteria faces an unending onslaught from an even larger army of viruses, known as bacteriophages. The bacteria have a variety of defences at their disposal: they chop up viral components, deny the invaders key ingredients for replication and even shut down their own biological systems to halt infections, sacrificing themselves to protect nearby kin. The viruses, in turn, evolve counter-defence mechanisms, resulting in an ever-escalating arms race. Although microbiologists are just beginning to understand the extent of this eternal contest, microbial immune mechanisms have already inspired technologies that have revolutionized biology. The discovery of restriction enzymes, bacterial proteins that slice DNA at specific sites, sparked the field of molecular biology in the 1970s, enabling everything from the development of genetically modified organisms to DNA forensics. CRISPR–Cas, a bacterial defence system that recognizes and slashes specific sequences in viral genomes, gave scientists the power to delete or edit genes with remarkable precision. Developed in the early 2010s, CRISPR-based gene editing has attracted billion-dollar investments and earned its key discoverers the 2020 Nobel Prize in Chemistry. Credit: Nik Spencer/Nature CRISPR–Cas and other breakthroughs have spurred an explosion of interest and discoveries in microbial defence systems. Thanks to advances in computational biology and genomic sequencing, scientists have identified a slew of immune mechanisms that bacteria and the other prokaryotic form of life on Earth, archaea, use in their ongoing existential struggle with viruses (see ‘The many sides of microbial immunity’). “I would venture to say that bacteria and archaea use everything that you can imagine for the purpose of defence — and then, some that you cannot,” says Eugene Koonin, an evolutionary biologist at the National Library of Medicine in Bethesda, Maryland. The discoveries have already led to improvements in gene editing and other laboratory processes. And these defences — some of which have relatives in the human immune system — are likely to inspire new treatments, particularly in the area of phage therapies, which kill pathogenic bacteria but are harmless to humans, and antibiotics. And although no single technology seems poised to dethrone CRISPR–Cas as one of the most transformative biological discoveries of the century, the excitement is palpable. “To do better than CRISPR is a very tall order,” says Koonin, but “there are some of these systems that have very significant applications”. A strong defence Although bacteria and archaea and their phages have been locked in competition for billions of years, microbiologists were oblivious to the panoply of defence systems until the past decade or so. In part, that’s because there was no easy way to search for them, says Rotem Sorek, a microbiologist at the Weizmann Institute of Science in Rehovot, Israel. That changed in 2011, when Koonin, evolutionary biologist Kira Makarova and their colleagues showed that immunity genes in the microbial genome tend to cluster together in ‘defence islands’1. This discovery meant that scientists could use known defence genes to find likely suspects nearby. Biggest-ever AI biology model writes DNA on demand Candidates were soon pouring in. In the years that followed, Sorek’s group and others reported hundreds of potential defence genes2,3. Most of the research so far has focused on bacteria, for which scientists have ample tools to tinker with genes. To verify a defence system, scientists can select a candidate, insert the genes into a standard strain of laboratory bacteria and test whether they allow the microbes to resist phages that they couldn’t fend off before. The discoveries are coming fast, says Artem Isaev, a microbial immunologist at the Center for Molecular and Cellular Biology in Moscow. “Right now, we are discussing in our journal club five papers a week, and we don’t have time to discuss everything.” Studies have yielded surprising immune mechanisms, such as the one biochemist Philip Kranzusch encountered while he was a postdoctoral researcher in Jennifer Doudna’s lab at the University of California, Berkeley. Kranzusch was not a microbiologist: he trained in human virology. In the early 2010s, he was interested in a human immune protein called cGAS. It detects foreign DNA and produces a signalling molecule that kick-starts part of the immune system known as the interferon response. Bacteria contain enzymes that produce a similar signalling molecule, so Kranzusch wondered whether studying those enzymes would provide insights into cGAS function. Remarkably, the bacterial proteins had a very similar structure to cGAS. “I remember running into Jennifer’s office,” Kranzusch recalls. “The same machine, found in human cells, is found in bacteria as well.” ‘Dark proteins’ hiding in our cells could hold clues to cancer and other diseases Kranzusch, at his own lab at Harvard Medical School in Boston, Massachusetts, continued to investigate the system. Sorek was also studying the bacterial cGAS counterpart, called CBASS. Their groups showed that CBASS is a bona fide microbial defence system that even uses the same signalling molecule receptor, called STING, as the human immune system4,5. Kranzusch and Sorek also discovered bacterial counterparts of eukaryotic immune proteins called gasdermins, which create pores in the cell membrane to kill infected cells and block viral replication6. And microbiologist Aude Bernheim, then a postdoc in Sorek’s lab, and her colleagues described prokaryotic versions of eukaryotic viperins: these proteins produce molecules that halt the transcription of viral genes into RNAs7. Sorek’s team also described a microbial immune mechanism called Thoeris that has close parallels with plant defences2. “From an evolutionary perspective, this is highly unexpected,” says Bernheim, who is now at the Pasteur Institute in Paris. Scientists had presumed that immune systems would evolve rapidly in the face of ongoing viral assaults, leading to vast divergence between prokaryotic and eukaryotic defences. Instead, at least in some cases, a system that evolved in the precursor of prokaryotes and eukaryotes has persisted over billions of years of evolution, creating parallel biology in microbes and humans or plants. Building tools Now, biotechnologists are adapting these ancient innovations into lab or clinical tools. At a basic level, they can protect valuable microbial cultures, says Owen Tuck, a graduate student in Doudna’s lab who is working on a DNA-chomping defence system called Hachiman. For instance, if a bioreactor became infected with phages, scientists could activate defences in the bacteria to vanquish the invaders, Tuck says. Researchers are also creating bespoke tools. Consider the Argonaute system, an immune response initially identified in eukaryotes — first in plants, then in animals. It uses small RNA guides to target other RNAs, such as viral RNAs, for destruction. In microbes, Argonaute systems work in more variable ways, says Daan Swarts, a biochemist at Wageningen University & Research in the Netherlands. Argonaute sensors might notice loose DNA ends, he speculates, or an excess of circular DNA molecules. In response to infection, Argonaute-associated mechanisms might then damage pathogen genes or deplete the cell of crucial metabolites such as NAD+ and NADP+, which are involved in energy generation and other processes. Researchers have used microbial Argonautes to edit bacterial genomes and cut precise DNA sequences in test tubes. In experiments seeking specific, rare sequences, scientists have also used Argonautes to eliminate common but undesired sequences so that the rare ones are easier to detect. And Swarts and his team have designed diagnostics to identify sequences of interest. To do so, they adapted the NAD+/NADP+-depleting system, called SPARTA, to create a test that changes colour or fluoresces once the target sequence is captured8. “Basically, any type of sequence can be detected with these Argonautes,” says Swarts. “We’ve not run into any limitations yet.” Many of these tasks can be performed by CRISPR–Cas, but Argonautes offer some different features. Both systems require a guide RNA to find target sequences, and the Cas enzyme also needs an extra bit of sequence, called a PAM, that helps Cas to bind to and unwind the DNA double helix. Argonaute works without a PAM and the guide RNA sequence can be shorter, making the system simpler to manufacture. Furthermore, Swarts notes, it is easier to submit patent applications for Argonautes than to obtain patents for ideas in the saturated CRISPR–Cas field. Feng Zhang, a molecular biologist at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, has discovered9 another efficient CRISPR-like system. He and his colleagues sought molecules with genetic sequences and protein structures similar to CRISPR–Cas and found a DNA-binding system they called TIGR–Tas (for tandem interspaced guide RNA–TIGR-associated protein). Like CRISPR, it’s a two-part system that detects specific DNA sequences and can be programmed to cut at desired locations. But TIGR–Tas requires no PAM, and the components are physically smaller than those for CRISPR, which could be useful in applications such as gene therapy, in which only a limited amount of molecular cargo can be delivered to tissues. Another bacterial defence system primed for innovation involves genetic elements called retrons. These were discovered in the 1980s, when scientists noticed hundreds of copies of short, single-stranded DNAs in samples of the soil bacterium Myxococcus xanthus. They determined that these single-stranded DNAs were produced by a reverse transcriptase enzyme — which creates DNA from an RNA template — and this type of system became known as a retron. Seth Shipman, a bioengineer at the Gladstone Institutes and the University of California, San Francisco, came across retrons in the scientific literature in the early 2010s as he sought a way to manufacture specific DNA sequences in cells. “They were just the perfect tool,” he says. Bacterial immune-system components can be used to alter genes in other organisms, such as the yeast Saccharomyces cerevisiae.Credit: Michael Short/Gladstone Institutes It wasn’t until 2020 that Sorek and others reported that retrons were actually involved in microbial immunity3,10. They fall into a common category of defensive methods known as toxin–antitoxin, in which an antiviral toxin — which can vary from system to system — remains caged by a corresponding antitoxin until an invader is sensed.
Nature DOI suffix ≠ "/s...": Not a research article
NSF slashes prestigious PhD fellowship awards by half
Dan Garisto
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Young researchers in the United States can benefit from the National Science Foundation’s Graduate Research Fellowship Program, which awards students a stipend and pays for their tuition.Credit: Rob Felt, Georgia Tech Each April, the US National Science Foundation (NSF) offers around 2,000 promising young researchers prestigious fellowships to support their careers in science. Yesterday, the agency, which is a major funder of basic science, announced that it is awarding only 1,000 fellowships — slashing the cohort by half. ‘My career is over’: Columbia University scientists hit hard by Trump team’s cuts The NSF Graduate Research Fellowship Program (GRFP) selectively offers five-year awards to students pursuing master’s and PhD degrees in the sciences. Only about 16% of the more than 13,000 applicants are usually successful. Fellows receive an annual stipend of US$37,000 for three years, plus coverage of their tuition fees. The GRFP is one of the longest-running programmes to fill the global pipeline of science talent: since 1952, it has funded more than 75,000 young researchers. The programme’s goal, according to its website before US President Donald Trump took office, was to “ensure the quality, vitality, and diversity of the scientific and engineering workforce”. A new version of the website replaces “diversity” — a priority the Trump administration has sought to eradicate — with “strength”. This cut to the GRFP is “a heartbreaker”, says Rob Denton, a biologist at Marian University in Indianapolis, Indiana, who has previously reviewed GRFP applications. Many of the applicants are vulnerable because they’re just starting their careers, he says, and receiving this award “could be the difference between them staying in science or finding another career”. 75% of US scientists who answered Nature poll consider leaving The cuts to the GRFP add to the headwinds that the Trump administration has been stirring up for young scientists. Under Trump, US funding agencies have been cutting active research grants — many of them training grants for students and postdocs — as the US government seeks to reduce its spending. In response to funding uncertainty, some universities have curtailed PhD admissions, and the National Institutes of Health, the world’s largest biomedical research funder, has also cancelled a summer programme for undergraduate students. The NSF’s ability to administer awards could soon be diminished — a possible reason for slashing the fellowships. The Washington Post reported in March that an internal White House document indicated the agency would soon face a 28% reduction in its staff headcount. But cutting the GRFP to save money is “boneheaded”, says Kenny Evans, a science-policy specialist at Rice University in Houston, Texas. “GRFPs are one of the most cost-effective ways for NSF to give out money,” he says, because the outcome is a trained, promising young scientist and it’s relatively inexpensive. An NSF spokesperson declined to comment on the cuts to the GRFP, but said that the agency is committed to preserving funding at levels promised to new and existing GRFP recipients. “A subsequent announcement of additional awardees is possible, subject to future resourcing considerations,” the spokesperson also noted. Application ambiguity The cuts to the programme mark a sharp decline from a record high 2,555 fellowship offers in 2023. For 15 years, the number of scientists selected for fellowships has remained relatively stable; the last time the NSF made fewer than 1,000 offers was in 2008 (see ‘Early-career cuts’). In addition to this year’s 1,000 fellowship offers, the NSF also gave a record 3,018 applicants honourable mentions — an award that does not provide funding but that young researchers can put on their CVs to boost their standing. The high number of honourable mentions is a sign that the number of worthy candidates far outstripped the number of fellowships that could be awarded, Evans says. Source: NSF
Nature DOI suffix ≠ "/s...": Not a research article
From Hippocrates to COVID-19: the scientific fight to prove diseases can be airborne
Benjamin Thompson
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Nature DOI suffix ≠ "/s...": Not a research article
Neck deep in overdiagnosis: Books in brief
Andrew Robinson
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The Age of Diagnosis Suzanne O’Sullivan Thesis (2025) In 2019, the UK health secretary praised a direct-to-consumer genetic test that revealed his 15% risk of prostate cancer, and planned its widespread use. This diagnosis was not significant — the average lifetime risk for men is 18%, notes neurologist Suzanne O’Sullivan. Her riveting book argues that new technologies often lead to overdiagnosis, which both doctors and patients often welcome. “New diagnostic criteria need to be measured more by their ability to make quality of life better — not by how many patients they can find.” Mother Animal Helen Jukes Elliott & Thompson (2025) Her first pregnancy and childbirth inspired Helen Jukes to investigate motherhood in a variety of other species, from polar bears to burying beetles. In her intimate and personal second book, the leader of creative-writing workshops warns that “if there are grounds for alarm” in the book, “I hope there is also much to inspire wonder”. For example, labour in humans takes many hours longer than in other primates, requiring the baby to rotate so that its head can — just — pass safely through its mother’s tilted pelvis. Not all babies fit through. The Neck Kent Dunlap Univ. California Press (2025) The human neck is the “ultimate multitasker”, writes biologist Kent Dunlap. “It flexes, senses, vibrates, transports, and secretes every second of our lives”, using bones, muscles, cartilages, cords, tubes, nerves, glands and nodes. Ironically, he researches the neurobiology and behaviour of (neckless) fishes. The book shows Dunlap’s fascination with the neck, ranging from anatomy to Indian dancing, opening with a medical drawing from Henry Gray’s classic Anatomy (1858), showing the neck’s tortuous inner complexity. Waste Wars Alexander Clapp Little, Brown and Company (2025)
Nature DOI suffix ≠ "/s...": Not a research article
The infuriating, expensive road to a good night’s sleep
Rachel Nuwer
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Nature DOI suffix ≠ "/s...": Not a research article
AI race in 2025 is tighter than ever before
Nicola Jones
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Top AI models’ performance is improving quickly, and the competition between them is growing ever fiercer.Credit: Adapted from Olivier Morin/AFP/Getty The artificial intelligence (AI) race is heating up: the number and quality of high-performing Chinese AI models is rising to challenge the US lead, and the performance edge between top models is shrinking, according to an annual state of the industry report. The report highlights that as AI continues to improve quickly, no one firm is pulling ahead. On the Chatbot Arena Leaderboard, which asks users to vote on the performance of various bots, the top-ranked model scored about 12% higher than the tenth-ranked model in early 2024, but only 5% higher in early 2025 (see ‘All together now’). “The frontier is increasingly competitive — and increasingly crowded,” the report says. The Artificial Intelligence Index Report 2025 was released today by the Institute for Human Centered AI at Stanford University in California. Source: AI Index Report 2025 The index shows that notable generative AI models are, on average, still getting bigger, by using more decision-making variables, more computing power and bigger training data sets. But developers are also proving that smaller, sleeker models are capable of great things. Thanks to better algorithms, a modern model can now match the performance that could be achieved by a model 100 times larger two years ago. “2024 was a breakthrough year for smaller AI models,” the index says. Bart Selman, a computer scientist at Cornell University in Ithaca, New York, who was not involved in writing the Index report, says it’s good to see relatively small, cheap efforts such as China’s DeepSeek proving they can be competitive. “I’m predicting we’ll see some individual teams with five people, two people, that come up with some new algorithmic ideas that will shake things up,” he says. “Which is all good. We don’t want the world just to be run by some big companies.” Neck and neck The report shows that the vast majority of notable AI models are now developed by industry rather than academia: a reversal of the situation in the early 2000s, when neural nets and generative AI had not yet taken off. Industry produced fewer than 20% of notable AI models before 2006, but 60% of them in 2023 and nearly 90% in 2024, the report says. The United States continues to be the top producer of notable models, releasing 40 in 2024, compared with China’s 15 and Europe’s 3. But plenty of other regions are joining the race, including the Middle East, Latin America and southeast Asia. Meta AI creates speech-to-speech translator that works in dozens of languages And the previous US lead in terms of model quality has disappeared, the report adds. China, which produces the most AI publications and patents, is now developing models that match their US competition in performance. In 2023, the leading Chinese models lagged behind the top US model by nearly 20 percentage points on the Massive Multitask Language Understanding test (MMLU), a common benchmark for large language models. However, as of the end of 2024, the US lead had shrunk to 0.3 percentage points. “Around 2015, China put itself on the path to be a top player in AI, and they did it through investments in education,” says Selman. “We’re seeing that’s starting to pay off.” The field has also seen a surprising surge in the number and performance of ‘open weight’ models such as DeepSeek and Facebook’s LLaMa. Users can freely view the parameters that these models learn during training and use to make predictions, although other details, such as the training code, might remain secret. Originally, closed systems, in which none of these factors are disclosed, were markedly superior, but the performance gap between top contenders in these categories narrowed to 8% in early 2024, and to just 1.7% in early 2025. “It’s certainly good for anyone who can’t afford to build a model from scratch, which is a lot of little companies and academics,” says Ray Perrault, a computer scientist at SRI, a non-profit research institute in Menlo Park, California, and co-director of the report. OpenAI in San Francisco, California, which developed the chatbot ChatGPT, plans to release an open-weight model in the next few months. Better, smaller, cheaper
Nature DOI suffix ≠ "/s...": Not a research article
154 million lives and counting: 5 charts reveal the power of vaccines
Heidi Ledford
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Vaccines have made several deadly diseases a thing of the past.Credit: Christina House/Los Angeles Times/Getty A second unvaccinated child in Texas has died from measles, amplifying fears that the outbreak there could be wider than reported. The death, announced on 6 April, also harkens back to a pre-vaccine past that many Americans have forgotten, when hundreds of children died each year of measles. Generations ago, a child swimming in a community pool could become paralysed by polio. Pregnant individuals who contracted rubella (also called German measles) were at risk of their babies being born deaf, intellectually disabled or stillborn. Vaccines have granted families in wealthy countries the luxury of forgetting this history, says Anne Schuchat, a former deputy director of the US Centers for Disease Control and Prevention in Atlanta, Georgia. “Many doctors have never seen these diseases because our vaccines have been so successful,” she says. But public-health specialists fear that vaccination is under threat. Around the world, funds for vaccination drives are in jeopardy as the United States scales back foreign aid, and other countries and public-health organizations juggle competing demands. Robert F. Kennedy Jr, a prominent anti-vaccine campaigner, has risen to head the US Department of Health and Human Services, which has the power to shape the country’s approach to public health. Misinformation about vaccine safety and efficacy is rampant in the United States and beyond. “It can be very confusing for parents right now with the flood of information they get,” says Schuchat. To illustrate the impact of vaccines, Nature examines the millions of lives that they have saved. The most contagious of them all An alarming outbreak of measles is raging in the United States. It has infected more than 500 people and hospitalized dozens. In addition to the two Texas children, measles is thought to have killed an adult in New Mexico — the first measles deaths in the country in the past decade. Source: US CDC Before the introduction of the measles vaccine in 1963, the country saw hundreds of thousands of measles infections each year. Within a decade of the vaccine’s roll-out, infections in the United States plummeted from about 450,000 a year to fewer than 50,000 (see ‘Measles cases in the United States’). Measles kills up to 3 out of every 1,000 infected people. In 2000, the World Health Organization declared that measles had been eliminated from the United States. But measles is so contagious that at least 95% of a population must be immunized to prevent transmission. US vaccination has dropped to 93% among children starting school, with pockets of the country falling even lower. If the measles virus circulates in the country for more than a year, the virus will no longer be considered eliminated. “We can’t take for granted the progress that we’ve made,” says Schuchat. About 55 countries were reporting large measles outbreaks at the end last year, and an outbreak in Vietnam is thought to have infected tens of thousands of people. A bumpy road to eradication The world is teetering on the edge of eradicating polio, thanks to a global vaccination campaign that has eliminated the virus in every country except Afghanistan and Pakistan. The only virus to ever have been eradicated globally is smallpox in 1980. Eradicating polio would be an enormous victory against a virus that once killed or paralysed more than half a million people every year in the middle of the twentieth century, before vaccines were introduced (see ‘Severe polio’). Source: Badizadegan/The Journal of Infectious Diseases Polio is not nearly as contagious as the measles, but it is still important to maintain high vaccination rates, says Neil Maniar, a public-health researcher at Northeastern University in Boston, Massachusetts. “If we start to see a consistent decline around the world in polio vaccination rates, all it takes is a couple of outbreaks for infections to start to expand more rapidly,” he says. Lives saved by childhood vaccinations In total, childhood vaccinations have saved about 154 million lives over the past 50 years. Most of these are thanks to the measles vaccine, which has saved more lives than vaccines against tetanus, whooping cough (pertussis) and tuberculosis combined (see ‘Childhood vaccines save lives’). Source: Shattock/The Lancet That figure doesn’t include lives saved by the eradication of smallpox. Obidimma Ezezika, who studies vaccine implementation at the University of Western Ontario in London, Canada, estimates that the world would lose at least five million people each year to smallpox, had vaccines not been used to stamp out the virus entirely. Even without the development of new vaccines, just getting existing ones to more people would save another one to two million lives each year, Ezezika estimates. “As I think about the great public-health success stories of the past century, vaccinations are at the top of that list,” says Maniar. Infant deaths spared by vaccines
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Cells are swapping their mitochondria. What does this mean for our health?
Gemma Conroy
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There’s unexpected movement in the world of cell biology — specifically, with the energy factories known as mitochondria. Ever since they were discovered in the mid-nineteenth century, mitochondria have been known as organelles that reside inside cells. But that textbook picture now seems to be wrong. An explosion of research is challenging mitochondria’s long-standing image as exclusively cellular organelles. “They may be a multicellular organelle,” says Jonathan Brestoff, an immunologist who studies metabolism at Washington University in St. Louis, Missouri. In other words, the supposedly static energy factories now seem to be expert travellers, skipping from one cell to another on demand. Cancer cells ‘poison’ the immune system with tainted mitochondria This ‘mitochondrial transfer’ has been observed in a wide variety of cells and in organisms as diverse as yeast, molluscs and rodents. “It’s really exciting to see,” says Jeffrey Spees, a stem-cell biologist at the University of Vermont in Burlington. It’s not yet clear why mitochondria are so mobile. Some studies have hinted that cells donate their mitochondria to their neighbours during times of need. In cellular emergencies, newly arrived mitochondria might kick-start tissue repair, fire up the immune system or rescue distressed cells from death. Other research suggests that mitochondrial transfer can be a lethal weapon that cancer cells deploy to gain an advantage. But what this means for human health is still a mystery. Researchers haven’t yet captured the process inside the human body and so don’t know for sure if it happens in people, says Daniel Davis, an immunologist at Imperial College London. “We don’t have the technology yet to witness this happening,” he says. That fact hasn’t stopped researchers from exploring how to leverage mitochondrial transfer to treat a variety of diseases, including cancer and stroke. A borrowed bacterium Over the past three decades, research has revealed that mitochondria are much more than cellular powerhouses that turn nutrients from food into energy. They’re key players in multiple processes in the body: they guide the chatter that keeps cells functioning and contribute to the immune response against harmful invaders. They’re also unexpectedly diverse. Last year, researchers found that mitochondria divide themselves into two distinct forms to help cells survive nutrient starvation1. Another study, published in March, modelled the density and type of mitochondria throughout the human brain2. All mitochondria — in whatever organism, in whatever part of the body — are thought to have sprung from the same ancient bacterium. Around 1.5 billion years ago, this drifting bacterium was swallowed up by the microbe that eventually gave rise to eukaryotes — the large group of organisms, including us, whose cells have an enclosed nucleus. Scientists make precise gene edits to mitochondrial DNA for first time After several evolutionary twists and turns, this borrowed bacterium became the organelle that drives metabolism. Mitochondria’s microbial origins probably help to explain why they are more dynamic than they first appear, says Kazuhide Hayakawa, a neuroscientist at Massachusetts General Hospital in Boston, who studies how mitochondrial transfer could help to treat stroke. “It is possible that mitochondria retain the ancient ability to spread from cell to cell, like bacteria,” he says. In 2006, Spees and his colleagues captured the first glimpse of mitochondria skipping from one cell to another3. The team had been trying to understand a perplexing behaviour of stem cells in laboratory dishes. These cells seemed to be sharing some kind of physical information that told them how to differentiate, and mitochondria were thought to be involved. To investigate mitochondria’s role, the researchers cultured human lung cancer cells, which lacked the organelles, with stem cells sourced from bone marrow. With the stem cells’ mitochondria tagged with fluorescent proteins, the team shot a time-lapse video of what happened next. The grainy black and white footage showed the stem cells shooting out their mitochondria, which were then taken up by the defective lung cells. After the donation, the lung cells quickly recovered their ability to divide and transform glucose into energy. “Watching it was like a miracle,” says Spees. Since then, researchers have observed mitochondria zipping between several types of cell — lung, heart, brain, fat, bone and more. Sometimes the mitochondria are travelling down ephemeral highways known as tunnelling nanotubes that form between cells and transport other cellular cargo. In other cases, the mitochondria take their journey in bubble-shaped vesicles or float freely in blood4 (see ‘Three ways to go’). How mitochondria are getting around is largely settled, but what’s less clear is why. Researchers are learning that the process is often a form of cellular damage control, says Clair Crewe, a cell biologist at Washington University. Some studies suggest, for example, that mitochondrial transfer might help cells to weather neurological storms. In 2016, Hayakawa and his colleagues found that in mice that have had a stroke, support cells called astrocytes deliver their mitochondria to faltering neurons. With this mitochondrial boost, neurons grew branches and restarted their metabolic processes, which improved their chances of survival. When the researchers inhibited mitochondrial transfer, fewer neurons survived, suggesting the donated organelles were key to the cells’ recovery5. But which part of the mitochondria’s structure or function protected the cells remains unknown, says Hayakawa. Lung cells might also benefit from a mitochondrial boost during a crisis, says Jahar Bhattacharya at Columbia University in New York City, who specializes in a severe inflammatory condition known as acute lung injury. He and his colleagues have found that in mice with this inflammation, stromal cells — which make up connective tissues that support organs — transfer their mitochondria to lung cells6. Cells with loaned organelles had higher concentrations of the cellular fuel ATP, which ended up being distributed to nearby cells that did not receive new mitochondria. These diseased lungs showed more signs of recovery than did diseased lungs that didn’t receive outside mitochondria. Bhattacharya was amazed when he and his team witnessed mitochondrial transfer in action. “I don’t think we slept for the next few nights, it was so exciting,” he says. Other research hints that transferred mitochondria might supercharge wound healing. In 2021, Anne-Marie Rodriguez, a cell biologist at Sorbonne University in Paris, and her colleagues found that platelets isolated from human blood shuttled their mitochondria to stem cells when researchers put the two cell types into a dish together. After taking up the mitochondria, the stem cells released molecules that play a part in forming new blood vessels. When the cells were placed onto skin wounds in mice, those injuries healed faster than did injuries in rodents that had received either stem cells or platelets alone7. Researchers suspect that cells with dysfunctional mitochondria might even have ways to request healthy mitochondria from their neighbours, although the exact mechanisms underlying this process remain murky. “We’re only beginning to understand the signalling that’s involved,” says Crewe. Everyday operations Beyond its role in recovery, researchers want to know whether mitochondrial transfer is an essential part of everyday biology. Initial evidence suggests it might help to maintain healthy tissues. Last year, Minghao Zheng, a regenerative biologist at the University of Western Australia in Perth, and his colleagues discovered that some types of astrocyte donate their mitochondria to cells that line blood vessels in the mouse brain8. When the researchers disrupted this process, the blood–brain barrier became leaky, suggesting that mitochondrial transfer helps to maintain this protective membrane shield. Zheng and his team had already reported that mitochondrial transfer in the bones of mice can accelerate the formation of new blood vessels9. In healthy mice, Brestoff and his colleagues reported, white fat cells transfer their mitochondria to macrophages — white blood cells that hoover up cellular debris. The number of shuttled organelles was reduced in obese mice. The obese mice also burnt less energy than their healthy counterparts10. These organelles might help macrophages to function when their metabolism is disrupted, says Brestoff. In the labyrinthine world of the immune system, donated mitochondria might have an anti-inflammatory effect, especially when they are taken up by T cells — white blood cells that stave off infections and disease. In studies in cell cultures, Patricia Alejandra Luz-Crawford, an immunologist at the University of the Andes in Santiago, Chile, and her colleagues found that some types of T cell that receive mitochondria from stem cells produce fewer inflammatory molecules. Stem cells cultured from people with rheumatoid arthritis pass fewer mitochondria along to T cells than do stem cells from healthy individuals, which she says might contribute to the chronic inflammation associated with the disease11. Mitochondria, visible in red, travel through a tunnelling nanotube from a type of bone marrow cell (top left) to a T cell that fights infections and cancer (bottom right).Credit: Jeremy Baldwin But there are many unanswered questions about mitochondrial transfer, including what the organelles might be doing after they enter cells and how long they last, says Luz-Crawford. “There’s still a lot of mystery.” The lack of detail about why cells transfer their mitochondria makes it hard to know what specific role these cellular exchanges might have in conditions such as cardiovascular disease and obesity, says Rodriguez. In vivo studies have tracked mitochondria in only a handful of tissue types, making it difficult to build a bigger picture of the wider impacts these transfers have on health.
Nature DOI suffix ≠ "/s...": Not a research article
World’s tiniest pacemaker could revolutionize heart surgery
Noah Baker, Shamini Bundell
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Nature DOI suffix ≠ "/s...": Not a research article
A wetter ancient Arabia could have enabled easier intercontinental species dispersal
Faysal Bibi
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The Saharo-Arabian belt is the largest sand desert on Earth. Viewed from space, it is a conspicuous sea of yellow stretching from the Atlantic Ocean eastwards across northern Africa and into the Arabian Peninsula. Today, few species — human or otherwise — can survive its stony barrenness and arid extremes, and it forms a formidable barrier to the dispersal of animals and plants between Africa and Eurasia (Fig. 1). Writing in Nature, however, Markowska et al.1 present evidence for multiple humid phases in Arabia over the past seven million years or so. Their findings challenge the idea of Arabia as enduringly hyper-arid, and suggest that the region could have acted recurrently as a bridge for intercontinental species dispersal, including of ancient hominins.
Nature DOI suffix ≠ "/s...": Not a research article
A map of neural signals and circuits traces the logic of brain computation
Mariela D. Petkova, Gregor F. P. Schuhknecht
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Millions of years of evolution have endowed animals with cognitive abilities that can surpass modern artificial intelligence. Machine learning requires extensive data sets for training, whereas a mouse that explores an unfamiliar maze and randomly stumbles upon a reward can remember the location of the prize after a handful of successful journeys1. To shine a light on the computational circuitry of the mouse brain, researchers from institutes across the United States have led the collaborative MICrONS (Machine Intelligence from Cortical Networks) project and created the most comprehensive data set ever assembled that links mammalian brain structure to neuronal function in an active animal2.
Nature DOI suffix ≠ "/s...": Not a research article
Complete ape genomes offer a close-up view of human evolution
Lukas Kuderna
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Apes, the group of primates that includes humans, are our closest evolutionary relatives. Comparisons between the genomes of humans and those of other apes have been crucial for understanding the function of the human genome and our own evolutionary history. But, because ape genomes are large and contain repetitive sequences, many genomic regions have been difficult to sequence and reconstruct accurately, which has so far resulted in incomplete representations that preclude full comparisons. Writing in Nature, Yoo et al.1 report essentially complete genome sequences for six ape species that represent all of the main ape lineages: chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla), Bornean orangutan (Pongo pygmaeus), Sumatran orangutan (Pongo abelii) and siamang (Symphalangus syndactylus).
Nature DOI suffix ≠ "/s...": Not a research article
Long-awaited ape genomes give new insights into their evolution — and ours
Benjamin Thompson, Shamini Bundell
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Nature DOI suffix ≠ "/s...": Not a research article
Long COVID activists fought Trump team’s research cuts and won ― for now
Heidi Ledford, Max Kozlov
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Long COVID advocates attend a budget hearing in the US Senate.Credit: Tom Williams/CQ-Roll Call, Inc/Getty Long COVID advocates and researchers in the United States have done the extraordinary. After a bruising battle, they managed to revive some of the research grants cancelled by the administration of President Donald Trump ― a rare victory for science as Trump’s team slashes funding and fires federal scientific staff. The crisis began in late March, when the US National Institutes of Health (NIH) terminated the funding for dozens of long-COVID projects. Activists and researchers – including many with long COVID — began a dogged advocacy campaign, including an eleventh-hour effort to sway a sympathetic member of Congress to intervene, according to an employee of the US Department of Health and Human Services (HHS), which oversees the NIH. (The employee requested anonymity because they were not authorized to speak to the press.) Within days, the cuts had been reversed. But the administration’s termination of an array of infectious-diseases research suggests a rocky path ahead for long-COVID research. Now activists and scientists are both anxious and hopeful as they brace themselves for the potential of future cuts to federal support. “The long COVID patient community is reeling and flabbergasted by what they’re seeing,” says Emily Taylor, president of the Solve ME/CFS Initiative and based in Glendale, California. “We’ve been telling congresspeople, ‘Stop cutting, first thing. Stop hurting us. Stop the pain.’” The HHS, which includes the NIH and other health agencies, did not respond to a request for comment. Long COVID’s reach Over the past two months, US President Donald Trump’s new administration has cancelled or delayed thousands of biomedical research grants, including those for research on COVID-19. When asked about the COVID-19 cuts, a spokesperson for HHS told Nature on 26 March, “HHS will no longer waste billions of taxpayer dollars responding to a non-existent pandemic that Americans moved on from years ago.” That response appalled some long COVID advocates and researchers. “It’s totally shocking and really incorrect,” says Serena Spudich, an infectious disease neuroscientist at the Yale School of Medicine in New Haven, Connecticut. “The aftermath of the COVID pandemic is absolutely affecting millions of people, the economy, people’s ability to work and attend school.” A 2024 study estimated that 11 million people in the United States currently have long COVID, and that the condition costs the country more than $152.6 billion in lost work hours each year. Closed doors HHS is run by longtime anti-vaccine advocate Robert F. Kennedy Jr, who said during his confirmation hearing on 29 January that he’d commit to funding long COVID research. That gave Ian Simon, who was at the time the director of HHS’s Office of Long COVID Research and Practice, a “glimmer of hope”, he says, because it seemed “a full-throated endorsement of serious government action.” But the grant cancellations “make me question what a full-throated endorsement in front of Congress means these days”. Long COVID still has no cure — so these patients are turning to research Under Kennedy, the HHS shuttered its long COVID office and laid off Simon and another employee in the office. An executive order signed by Trump dismantled the only federal advisory committee on long COVID, and the US Department of Labor stripped mention of long COVID from its websites. The NIH cut not only research on long COVID but also other work that could affect people with the condition. For example, the NIH has terminated several disability studies, says David Putrino, a physical therapist and neuroscientist at the Icahn School of Medicine at Mount Sinai in New York City. Many people with severe long COVID live with disabilities. Despite this, some advocates had hoped that a US$1.8 billion NIH long COVID research initiative, called RECOVER, might be safe because Congress had funded the programme directly in 2020. Then, in late March, the NIH cancelled a wave of RECOVER grants. “We were completely shocked,” says Megan Fitzgerald, a neuroscientist in Philadelphia, Pennsylvania who has long COVID and works with the advocacy group Patient-Led Research Collaborative. “And that’s when we started mobilizing.” Wasted investment Fitzgerald’s detective work revealed dozens of cancelled projects, most of them studies of either the biology underlying long COVID, or of long COVID in children. The loss of the paediatric studies would have been particularly painful, says Fitzgerald, because the study of long COVID in children has lagged research in adults. The biology studies included a project on dysautonomia, a condition sometimes seen in people with long COVID that affects the body’s ability to control heart rate and blood pressure. Another terminated project aimed to characterize antibodies made against the body’s own proteins. Such “autoantibodies” are thought to contribute to some cases of long COVID and could become targets for medicines to treat the condition. Exclusive: NIH to cut grants for COVID research, documents reveal
Nature DOI suffix ≠ "/s...": Not a research article
Why more AI researchers should collaborate with governments
Mohamed Ibrahim
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Artificial intelligence (AI) is beginning to transform many industries, yet its use to improve public services remains limited globally. AI-based tools could streamline access to government benefits through online chatbots or automate systems by which citizens report problems such as potholes. Currently, scholarly advances in AI are mostly confined to academic papers and conferences, rarely translating into actionable government policies or products. This means that the expertise at universities is not used to solve real-world problems. As a No10 Innovation Fellow with the UK government and a lecturer in spatial data science, I have explored the potential of AI-driven rapid prototyping in public policy. Take Street.AI, a prototype smartphone app that I developed, which lets citizens report issues including potholes, street violence or illegal litter dumping by simply taking a picture through the app. The AI model classifies the problem automatically and alerts the relevant local authority, passing on the location and details of the issue. A key feature of the app is its on-device processing, which ensures privacy and reduces operational costs. Similar tools were tested as an early-warning system during the riots that swept the United Kingdom in July and August 2024. AI models can also aid complex decision-making — for instance, that involved in determining where to build houses. The UK government plans to construct 1.5 million homes in the next 5 years, but planning laws require that several parameters be considered — such as proximity to schools, noise levels, the neighbourhoods’ built-up ratio and flood risk. The current strategy is to compile voluminous academic reports on viable locations, but an online dashboard powered by AI that can optimize across parameters would be much more useful to policymakers. How to track the economic impact of public investments in AI This is the key insight from my stint in government: public officials are often interested in deliverable products or demonstrable solutions, whereas academics are trained to funnel new knowledge into papers. Existing mechanisms to bring academic expertise into government, such as secondment opportunities and exchange programmes, do not adequately address the factors that limit collaboration. A more effective approach would be to frame research in practical, solution-oriented terms. There are several measures that could strengthen collaboration between academia and public institutions, particularly in emerging domains such as AI, to enhance the delivery of public services. Academics can ease into a product-focused mindset through prototyping, where the risk is low. The aim is to go beyond conventional research-dissemination practices to ensure that findings are accessible and can be applied in government settings. This involves translating complex data, models and insights into user-friendly digital tools. For instance, imagine that a university research team has developed an AI model capable of predicting which areas are at high risk of flooding. As well as publishing the findings in academic journals, the team could create a digital tool — an interactive platform — to display the AI insights for government officials in a way that makes them actionable.
Nature DOI suffix ≠ "/s...": Not a research article
AI for research: the ultimate guide to choosing the right tool
Amanda Heidt
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When Mohammed Shafi, a PhD student in civil engineering at the Indian Institute of Technology Guwahati, first saw his friends testing out artificial intelligence (AI) tools back in late 2022, he didn’t immediately see the appeal. Mostly, people seemed to be using generative AI platforms such as OpenAI’s ChatGPT as a replacement for Google, or as a novelty for drumming up ideas for practical jokes and pet names. “They were fun to play around with, but I didn’t necessarily sense any relevance to my own coursework or my research,” he says. He quickly came around, however, when he started seeing more AI tools being built to meet the needs of students and scientists. Now a daily user of AI, Shafi has pieced together an entire pipeline of AI-powered platforms that feed into one another. These update him on new research, break down complex topics, troubleshoot experiments, organize his writing and citations, and help him to navigate the demands of classes and research. Shafi now says that the arrival of AI has been “a revolution for research”, a sentiment seemingly shared by others. Surveys show that many university students and scientists are using AI in their work, often on a weekly or even daily basis. And whereas many educators and academic institutions initially responded with wariness, academia seems increasingly willing to allow students to use AI, albeit in controlled ways. Although it wouldn’t be impossible to go back to the way he did things before, Shafi says, “it’s hard to imagine wanting to”. Here, Nature explores how academics and students can harness AI to streamline various parts of the research process. Sharpen your literature review Daniel Weld, chief scientist at the academic search engine Semantic Scholar, who is based in Seattle, Washington, says that many popular AI platforms have “advanced enormously” in an area called active learning — a method that mimics how a person would approach a research question. Programs such as Google’s Gemini Deep Research and OpenAI’s Deep Research offer the most powerful tools in this regard, and many companies are launching similar products. Students can enter a query, supported by their own data or documents, and then step away as these advanced models conduct in-depth searches over 30 minutes or so. The final report might include text, figures and visualizations, and all output is thoroughly referenced — another jump over past iterations, says Isa Fulford, a technical staff researcher at OpenAI in San Francisco, California, who helped to develop Deep Research. “Especially in the context of scientific research, we recognize that veracity is critical, and we think this model is better at including the proper citations than any other model we’ve released,” she says. Chuck Downing, a PhD student in accounting at the Massachusetts Institute of Technology (MIT) in Cambridge, says that these deep-research tools have been especially useful when digging into unfamiliar topics. During one project, Downing used OpenAI’s Deep Research to create a report ranking various approaches for reducing emissions at manufacturing plants. “I didn’t know much going in, but I learnt quite a bit, and so I use these deep dives all the time now,” he says. “It’s better than anything else I’ve used so far at finding good papers and in presenting the information in a way that I can easily understand.” Other programs enable students to delve more deeply into a single document or small collection of papers. The student-focused AI platform SciSpace , for example, has a ‘Chat with PDF’ function. Users can upload a paper and ask questions about its content — a feature shared by other platforms, such as Claude, NotebookLM and PDF.ai. For David Tompkins, a PhD student in human development at Cornell University in Ithaca, New York, this approach has helped him to stay on top of the burgeoning scientific literature. Tompkins often goes to journal-club meetings having used Claude to generate a summary of a chosen paper, which he then follows up with more-targeted questions based on the group’s discussion. “I’m still a big believer in actually reading papers to fully understand them, but it’s become much easier to do my prep when I’m feeling stretched,” he says. “In some ways, I feel I’m engaging more with the material through these tools than I did before them.” Create your hypothesis The ability of AI to pull together many threads of information has seemingly made it easier to identify research gaps and connect ideas — although a recent survey suggests that an over-reliance on generative AI could dampen a person’s critical-thinking skills. Weld, who is also an AI researcher at the Allen Institute for AI in Seattle, says there has been so much demand for tools that assist with ideation that he and his team are developing hypothesis-generation and detection products that attempt to combine ideas across papers into something new. “We have them running internally, but we’re trying to make sure that they’re working robustly,” he says, adding that his Allen Institute group hopes to release them publicly in the next few months. Shafi turned to programs such as the visualization tool Research Rabbit when working on his dissertation, which focuses on how microplastics are transported through soil and into groundwater. Research Rabbit takes a single ‘seed paper’ and generates an interconnected web of research linked by topic, author, methodology or other key features. By piping its results into a chatbot such as ChatGPT, “it’s possible to query the body of work for hidden links or new ideas”, Shafi says. MarĂ­a Mercedes HincapiĂ©-Otero.Credit: Jayson J. Ricamara AI-powered programs are also proving increasingly capable as experimental assistants. As a PhD student at MIT, Zhichu Ren created the software Copilot for Real-world Experimental Scientist (CRESt), which combines several AI technologies into an enhanced chatbot (Z. Ren et al. Preprint at ChemRxiv https://doi.org/pdwv; 2023). Users can chat with CRESt as they would with a colleague, and it can help to craft and run experiments by retrieving and analysing data, turning equipment on and off using digital switches, powering robotic arms, documenting findings and alerting scientists by e-mail when issues arise or protocols end. In a 2023 conference paper, CRESt assisted researchers by prioritizing candidate alloys for a new fuel cell, and suggested experiments that the group might run to test them. “I wanted to create a tool that can continue to help even as your needs change,” says Ren, who now works at the AI start-up firm Labig in Cambridge, Massachusetts. “AI can do that in a way that static, written documentation cannot.” But even for students who do not have access to something as advanced as CRESt, AI can still function as a helpful colleague. Gemini Deep Research, for example, can generate a “personalized multi-point research plan” among other features, and resources such as Scite and Elicit are billed as research assistants. Users can give these programs a handful of papers or a working hypothesis, for example, and ask for a set of experiments to test the theory. Joseph Fernandez, a PhD student in biomedical engineering at the University of Colorado Anschutz Medical Campus in Aurora, says he continues to use ChatGPT for most things, including troubleshooting his experiments. In the past, the bot has helped him to brainstorm explanations when one of his assays was returning unusual values, and to calculate serial dilutions to avoid wasting expensive reagents. ChatGPT has also served as a stand-in for his committee, generating pointed questions to test his research proposal before his exams. “I think you’re really only limited by your imagination, even if some uses are more mundane than others,” he says. “Nowadays, if a question or task pops into my mind, I’m generally wondering if ChatGPT can help with it.” Streamline your statistics Code editors including GitHub’s Copilot, Amazon CodeWhisperer (now Amazon Q Developer) and Anysphere’s Cursor aim to make it easy for beginners to use coding to organize data, create analysis pipelines, run descriptive statistics and generate visualizations. Such tools, researchers note, have also largely overtaken websites such as GitHub and Stack Exchange as the main resources for troubleshooting. Rather than spending hours looking for answers, users can simply highlight a section of code and ask a chatbot to fix it, Downing says. “Thinking about what a PhD student primarily does, the largest tasks are increasingly coding and data analysis, at least for computational fields, so anything that helps there is just disproportionately useful,” he says. Although he already considered himself an adequate coder, he says that his preferred tool, Cursor, has made him better by removing the more tedious aspects and making it easier to probe specific aspects of a data set. Instead of spending all of his time debugging (cleaning the code), he says, he is “putting more effort into really getting to know the underlying data and engaging with my code in ways that help me learn. If I get curious about something, it’s very easy to generate descriptive statistics, something like a chart.” Tompkins has likewise found tools such as Claude to be essential for writing code for compelling, dynamic visualizations. Creating a good graph, particularly if it’s interactive, can require hundreds of lines of code, and Tompkins says that, in the past, that level of effort had put him off. “But once I started using Claude, I was able to have it write out those literal hundreds of lines of code,” he says. The resulting visualizations have gone a long way towards helping others to understand his research, which describes how small changes in the way in which people experience information can drive their reactions to it. Researcher Zhichu Ren created an AI-based system called CRESt to run experiments.Credit: Jason Sparapani/MIT Department of Materials Science and Engineering He adds, however, that he still always writes his own code for statistical analyses: “I want to make sure that whatever I’m reporting is something that I fully understand and can stand behind when I submit a paper.” These AI programs focus on generating new code, but Gaurav Ragtah, who founded a platform called CatalyzeX, saw an opportunity to repurpose existing code. If researchers write a new analysis pipeline for each experiment, for example, it can make it more challenging for others to reproduce their work, particularly if the documentation is poor or a developer stops updating their code. Instead, Ragtah, who is based in San Francisco, wanted to make it easier to locate and share code that others have published. CatalyzeX uses a web platform and browser extension to flag open-source code shared in papers indexed on websites such as Google Scholar or PubMed, and researchers can search for code through the platform using keywords. Someone interested in using machine learning to aid in cancer detection, for example, could search for a modified data-processing pipeline that helps to address the fact that publicly available data often involve small sample sizes. “As amazing as some of these code generators are, we don’t need to reinvent the wheel every time when there are excellent examples of what you’re trying to do,” Ragtah says. “Open source keeps people from having to start from scratch and gives them a scaffold on which to build and improve, while making research more easily comparable.”
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Daily briefing: Drug makes people’s blood poisonous to mosquitoes
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
A mental-health crisis plagues PhDs — these evidence-led initiatives offer help
Fred Schwaller
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Researchers have found that sharing experiences of mental-health struggles reduces stigma.Credit: Tempura/Getty In 2019, at a conference in Germany, Wendy Ingram spoke about a grass-roots project aimed at raising awareness of mental-health issues among US researchers. Talking to other attendees, she realized that the problems were “systemic in academia: in every field, in every country”. Studies of researchers globally suggest there is a mental-health crisis in academia. Depression and anxiety are particularly acute for early-career researchers, who uproot their lives every few years, have few long-term job prospects and must cope with the relentless pressures of science’s ‘publish or perish’ culture. Do smartphones and social media really harm teens’ mental health? Driven by a lack of support at their institutions, graduate students and postdocs have begun building their own movements to find solutions. Now, many research centres offer evidence-based mental-health services to assist researchers, often through workshops and providing access to clinical support. Importantly, say researchers, initiatives are beginning to challenge the fundamental structures that reinforce what manycall the toxic culture of research. “Not only are there evidence-based tactics that work, but they are being deployed, and everyone can take advantage of them,” says Ingram, the founder and chief executive of Dragonfly Mental Health, a global non-profit advocacy group based in Bradenton, Florida. “Culture change is the big challenge, and the question is how we move away from the narrative of surviving in academia to one of thriving. The only way it will happen is from the collective actions of many,” says Karin Jensen, a researcher in engineering education who conducts research to support faculty members’ mental health and well-being at the University of Michigan in Ann Arbor. Connecting efforts At the 2019 conference, Ingram realized that grass-roots initiatives trying to help were disconnected. “Engineers and cell biologists were trying to muddle their way through the psychology research. They were constantly reinventing the wheel,” she says. The huge toll of PhDs on mental health: data reveal stark effects So Ingram co-foundedDragonflyto join “wisdom from all the grass-roots things going on in siloed institutes” into formalized structures. The organization has grown into a coalition of more than 450 volunteer academics worldwide who offer workshops, training schemes and campaigns to raise awareness of mental-health provisions in academia. It has delivered more than 375 programmes to some 60,000 academics in 32 countries — “with 96% of participants recommending our programmes to colleagues”, says Ingram. The efforts focus on five areas: reducing stigma, improving mental-health literacy, improving supportive skills, encouraging peer-support networks, and creating structures across the research enterprise to take responsibility for mental health. In addition to working with individual research centres such as the University of California (UC), Berkeley, Dragonfly has delivered workshops to fellows of science-funding agencies such as the Alfred P. Sloan Foundation in New York City and the Pew Charitable Trusts in Philadelphia, Pennsylvania. Grounded in research Dragonfly’s programmes are evidence-led, says Ingram. “We have studies; nothing hand-wavy or surface level. We provide actions that can and should be taken.” And where evidence is lacking, the organization collaborates on research to investigate solutions. Ingram co-published a 2024 study1that found viewing a short film about mental-health challenges in academia reduced stigma around the topic for 92% of the 149 academics who participated. How PhD students and other academics are fighting the mental-health crisis in science The film shows senior faculty members talking about their experiences of mental-health conditions or neurodiversity. Kevin Mark, who watched the film during his postdoctoral studies at UC Berkeley, says it was the first time he’d seen senior researchers disclose their personal struggles.
Nature DOI suffix ≠ "/s...": Not a research article
Norway set to scrap mandatory language training for foreign postdocs and PhD students
Linda Nordling
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The government has backed off its requirement for PhD students and postdocs, but learning to speak Norwegian is a ‘key component’ of an enjoyable stay in the country, say some.Credit: Izusek/Getty Norway’s new research minister has signalled that the government will axe a controversial law that requires PhD students and postdoctoral researchers from other countries to undertake mandatory Norwegian language training. The move follows a backlash from scientists, who argued that the language stipulation — which was introduced in August last year with a year’s implementation delay — would create substantial barriers to recruiting international talent to their labs. Under the law, PhD students and postdocs who do not speak Norwegian, Danish or Swedish must complete 15 study points of Norwegian language training — around 3 months of study — during the period covered by their contracts. But on 21 March, Sigrun Aasland of Norway’s Labour party, who was appointed minister for research and higher education in February, announced the intention to reverse it, in a white paper setting out the government’s plan to enhance Norway’s research competitiveness and bolster its national security through science. The proposed U-turn has been sent out for fast-tracked public consultation — a necessary step for such amendments. “Norway is a small country; we must collaborate more,” said Aasland. She also highlighted the need to create more attractive conditions for international researchers, and said the government might review its work-permit rules for scientists to make it easier for them to leave, to arrive and to stay. “I am grateful that the Norwegian government listened to us so quickly,” says Olga Lehmann, a psychology researcher from Colombia, who has lived in Norway for 11 years and is based at the University of Stavanger. “Norwegian academia needs to strive for balance between local and global needs.” She is optimistic that this is a step in the right direction. ‘Enormous relief’ “It’s an enormous relief,” adds Nobel laureate Edvard Moser, who leads the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology in Trondheim. But he warns that the policy could be reversed if the country’s Centre Party rejoins the government in September’s parliamentary elections. Moser joined more than two dozen Norwegian researchers who backed a complaint made to the European Free Trade Association Surveillance Authority in December last year. They argued that the language requirement contravened European Economic Area rules on the free movement of workers. That legal challenge will be withdrawn when the minister’s policy change is completed, says Pierre Lison, an artificial-intelligence researcher at the Norwegian Computing Center in Oslo, and one of the instigators of the complaint. “Right now, the ministry has only indicated its intention to drop the requirement, but it’s not yet official,” he adds. It’s unclear whether the reversal will also apply to another stipulation around Norwegian language competency, which affects permanent academic staff who don’t speak Norwegian, Danish or Swedish. Under the current rules, they must reach a B2 language proficiency level within three years — a higher standard than that required for Norwegian citizenship. “This is a key point still to be clarified, but hopefully, [it will also be] scrapped to support Norway’s goals to attract top international talent,” says Simon Roussanaly, an energy researcher at SINTEF, an independent research institute in Trondheim. Roussanaly is originally from France, and has lived in Norway since 2011. Although many universities had similar rules as part of their policies previously, there was some flexibility in those arrangements, which the law has removed, Roussanaly says. “This is a significant burden and work for academics and researchers.”
Nature DOI suffix ≠ "/s...": Not a research article
Mysterious human fossil found in Taiwan was a Denisovan
Dyani Lewis
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An artist's illustration of an ancient human male, who belonged to the Denisovans.Credit: Cheng-Han Sun A fossilized jawbone found off the coast of Taiwan more than 20 years ago belonged to a group of ancient humans, called the Denisovans, first identified in a Siberian cave. The finding, published today in Science1, is the result of time-consuming work to extract ancient proteins from the fossil. It also expands the known geographical range of the group, from colder, high-altitude regions to warmer climates. “I’m very excited to see this,” says Janet Kelso, a computational biologist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. The lower jawbone, with four teeth intact, is called Penghu 1 and was dredged up by fishing crews from the Penghu channel, 25 kilometres off the west coast of Taiwan. Penghu 1 was donated to Taiwan’s National Museum of Natural Science in Taichung after researchers recognized its significance as coming from an ancient human relative2. But the identity of that unknown relative remained a mystery, until now. Ancient proteins Researchers spent more than two years carefully refining techniques for extracting ancient proteins from animal bones taken from the channel. They then used acid to isolate protein fragments from the surface of a Penghu 1 molar tooth and enzymes to extract them from the jawbone. The team identified several degraded fragments, two of which bore specific amino-acid sequence variations matching those seen in the genetic sequences of a Denisovan finger bone3 found in the Denisova Cave in southern Siberia in 2008. The researchers could also tell that the jawbone came from a male Denisovan. It’s the second location that molecular evidence from ancient proteins has definitively linked fossil remains to the Denisovans. The first was in a cave in Xiahe, Tibet where proteins from a jawbone4 and then a rib bone were determined to be from Denisovans. Pinning down an exact age for the Penghu fossil is challenging because scientists do not have samples of the sediment it was buried in. “One can only say it’s older than 50,000” years, says Rainer GrĂŒn, a geochronologist at the Australian National University in Canberra, who dated the fossil in 2015 and subsequently reanalysed the data5. The Xiahe 1 mandible is at least 160,000 years old, and material from the Denisova cave indicates that Denisovans lived in Siberia between 200,000 and 50,000 years ago. At that time, sea levels were lower and the Chinese mainland was connected to Taiwan. Multiple populations
Nature DOI suffix ≠ "/s...": Not a research article
Trump team removes senior NIH chiefs in shock move
Benjamin Thompson, Max Kozlov
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Nature DOI suffix ≠ "/s...": Not a research article
International PhD students make emergency plans in fear of US immigration raids
Jeff Tollefson
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The US Immigration and Customs Enforcement agency has been tracking down and detaining international scholars across the United States.Credit: Raquel Natalicchio/Houston Chronicle via Getty A wave of shock and fear has spread among university researchers as US immigration officials have moved to detain and deport international students and scholars. The officials allege, in many instances, that the detainees’ involvement in protests against Israel’s war in Gaza constitutes a threat to national security. ‘Anxiety is palpable’: detention of researchers at US border spurs travel worries Multiple organizations representing university faculty members filed a lawsuit on 25 March challenging the actions, which include high-profile cases that have landed several student researchers in jail and sent others into hiding. Professors and students who spoke to Nature say they have already begun brushing up on their legal rights and taking precautions. “People are living in fear, if not for their lives, then certainly for their liberty and safety,” says Michael Thaddeus, a mathematician at Columbia University in New York City. He stresses that the detentions are just one part of a broader attack by the government of US President Donald Trump on scientists and academics that includes the cancellation of hundreds of millions of dollars in research grants at Columbia and other universities. One graduate student who studies public health tells Nature that they are crafting contingency plans for reuniting with their children and spouse if they are detained while returning from a pending research trip abroad. “These are insane things to be thinking about in the United States,” says the scientist, who has had their primary research grant terminated by the Trump team and who asked for anonymity out of fear that they would be targeted by the administration. The Trump White House and the US Department of State did not respond to Nature’s requests for comment. Taking away visas Trump set the stage for the current detentions when, on 30 January, he signed an executive order that called on US immigration officials to deport alleged student “sympathizers” of Hamas, the organization that governs the Gaza Strip. Hamas attacked Israel in October 2023 and is designated as a terrorist group by the United States. Many students and professors reject the charge that they support Hamas, arguing that they — and most protestors — instead oppose Israel’s subsequent war in Gaza, which has killed tens of thousands of Palestinians, according to Gaza’s health ministry. Protests over Israel–Hamas war have torn US universities apart: what’s next? Marco Rubio, head of the US Department of State, confirmed at a press event last week that his agency has revoked visas for at least 300 students, with more to come. “Every time I find one of these lunatics, I take away their visa,” Rubio said. In nearly a dozen cases that have attracted media attention, officials with the US Immigration and Customs Enforcement (ICE) agency have detained or sought to detain students and scholars who have been living legally in the United States either on visas or on ‘green cards’ that provide permanent-residency status. The list includes several well-known pro-Palestinian activists, such as Mahmoud Khalil, a graduate of Columbia’s School of International and Public Affairs, and RĂŒmeysa ÖztĂŒrk, a PhD student studying social-media use among young people at Tufts University in Medford, Massachusetts. Both are being detained in Louisiana. Although the US state department has broad latitude over visas and green cards, the lawsuit filed by faculty organizations in a federal court in Boston, Massachusetts, last week alleges that, in many instances, these actions violate students’ constitutional right to free speech, which scholars say applies to everybody in the United States, not just US citizens. Signs decorate a tree in Somerville, Massachusetts, where immigration agents arrested Tufts University PhD student RĂŒmeysa ÖztĂŒrk.Credit: Scott Eisen/Getty “This is ideological deportation,” says Ramya Krishnan, an attorney at Columbia University’s Knight First Amendment Institute and counsel on the lawsuit. She raises particular concern about the Trump administration’s argument that many of the arrested scholars pose a threat to US foreign policy because of the opinions they have voiced about the war in Gaza. She asks: what’s to stop the administration from saying that opinions on climate policy or other issues are threats? “There really is no limit to the government’s theory here, and that is part of what is so disturbing.” Already, multiple cases seem to hinge on issues other than students’ involvement in the Gaza war protests. For instance, on 16 February, Kseniia Petrova, a bioinformatician from Russia at Harvard Medical School in Boston, was arrested at the US border after failing to declare that she was bringing frog embryos to her laboratory from France. She is also being detained in Louisiana. The White House and the state department did not respond to questions from Nature about the reasons for various detentions.
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The US is against the world on sustainable development
Guillaume Lafortune, Jeffrey D. Sachs
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The US government has long dragged its feet on implementing the Sustainable Development Goals (SDGs). Since these goals were adopted in 2015, 190 of the 193 United Nations member states have put forward Voluntary National Reviews of their SDG programmes. The United States has not.
Nature DOI suffix ≠ "/s...": Not a research article
Europe needs to step up on epidemic preparedness
Jonathan Ewbank
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The cuts to funding (see Nature https://doi.org/pcxr; 2025) and changes in governance of biomedical research in the United States (see Nature https://doi.org/pcxt; 2025) could presage a severe reduction in global preparedness for infectious-disease outbreaks.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Mass layoffs across US health agencies
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Why an overreliance on AI-driven modelling is bad for science
Arvind Narayanan, Sayash Kapoor
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The use of artificial intelligence (AI) is exploding across many branches of science. Between 2012 and 2022, the average proportion of scientific papers engaging with AI, across 20 fields, quadrupled (see ‘AI’s rise in research’), including economics, geology, political science and psychology1. Hopes are high that AI can accelerate scientific discovery, because the rate at which fundamental advances are made seems to be slowing down: despite there being more funding, publications and personnel, we are making advances at a slower pace. But the rush to adopt AI has consequences. As its use proliferates — in forecasting disease outbreaks, predicting people’s life outcomes and anticipating civil wars — some degree of caution and introspection is warranted. Whereas statistical methods in general carry a risk of being used erroneously, AI carries even greater risks owing to its complexity and black-box nature. And errors are becoming increasingly common, especially when off-the-shelf tools are used by researchers who have limited expertise in computer science. It is easy for researchers to overestimate the predictive capabilities of an AI model, thereby creating the illusion of progress while stalling real advancements. Here, we discuss the dangers and suggest a set of remedies. Establishing clear scientific guidelines on how to use these tools and techniques is urgent. There are many ways in which AI can be deployed in science. It can be used to effectively comb through previous work, or to search a problem space (of, say, drug candidates) for a solution that can then be verified through conventional means. Another use of AI is to build a machine-learning model of a phenomenon of interest, and interrogate it to gain knowledge about the world. Researchers call this machine-learning-based science; it can be seen as an upgrade of conventional statistical modelling. Machine-learning modelling is the chainsaw to the hand axe of statistics — powerful and more automated, but dangerous if used incorrectly. SOURCE: Ref. 1 Our concern is mainly about these modelling-based approaches, in which AI is used to make predictions or test hypotheses about how a system functions. One common source of error is ‘leakage’, an issue that arises when information from a model’s evaluation data improperly influences its training process. When this happens, a machine-learning model might simply memorize patterns in the evaluation data instead of capturing the meaningful patterns behind the phenomenon of interest. This limits the real-world applicability of such models and produces little in terms of scientific knowledge. Through our investigations and compiling existing evidence, we have found that papers across at least 30 scientific fields — ranging from psychiatry and molecular biology to computer security — that use machine learning are plagued with leakage2 (see go.nature.com/4ieawbk). It is a type of ‘teaching to the test’, or, worse, giving the answers away before the exam. For example, during the COVID-19 pandemic, hundreds of studies stated that AI could diagnose the disease using just chest X-rays or CT scans. A systematic review of 415 such studies found that only 62 met basic quality standards3. Even among them, flaws were widespread, including poor evaluation methods, duplicate data and lack of clarity on whether ‘positive’ cases were from people with a confirmed medical diagnosis. In more than a dozen studies, the researchers had used a training data set in which all COVID-positive cases were in adults, and the negatives were in children aged between one and five. As a result, the AI model had merely learnt to distinguish between adults and children, but the researchers mistakenly concluded that they had developed a COVID-19 detector. It’s hard to systematically catch errors such as these because evaluating predictive accuracy is notoriously tricky and, as yet, lacks standardization. Computer codebases can be thousands of lines long. Errors can be hard to spot, and a single error can be costly. Thus, we think that the reproducibility crisis in machine-learning-based science is still in its early days. With some studies now using large language models in research — for instance, by using them as surrogates for human participants in psychological experiments — there are even more ways in which research might be irreproducible. These models are sensitive to inputs; small changes in the wording of prompts can cause notable changes to outputs. And because the models are often owned and operated by private companies, access to them can be restricted at any point, making such studies difficult to replicate. Fooling ourselves A greater risk from the hasty adoption of AI and machine learning lies in the fact that the torrent of findings, even if error-free, might not result in true scientific progress. To understand that risk, consider the impact of an enormously influential paper from 2001, in which statistician Leo Breiman astutely described the cultural and methodological differences between the fields of statistics and machine learning4. Will AI jeopardize science photography? There’s still time to create an ethical code of conduct He strongly advocated the latter, including the adoption of machine-learning models over simpler statistical models, with predictive accuracy prioritized over questions of how faithfully the model represents nature. In our view, this advocacy did not mention the known limitations of the machine-learning approach. The paper doesn’t make enough of a distinction between the use of machine-learning models in engineering and in the natural sciences. Although Breiman found that such black-box models can work well in engineering, such as by classifying submarines using sonar data, they are harder to use in natural science, in which explaining nature (say, the principles behind the propagation of sound waves in water) is the whole point. This confusion is still widespread, and too many researchers are seduced by the commercial success of AI. But just because a modelling approach is good for engineering, it doesn’t mean that it’s good for science. There is an old maxim that ‘every model is wrong, but some models are useful’. It takes a lot of work to translate outputs from models to claims about the world. The toolbox of machine learning makes it easier to build models, but it doesn’t necessarily make it easier to extract knowledge about the world, and might well make it harder. As a result, we run the risk of producing more but understanding less5. Science is not merely a collection of facts or findings. Actual scientific progress happens through theories, which explain a collection of findings, and paradigms, which are conceptual tools for understanding and investigating a domain. As we move from findings to theories to paradigms, things get more abstract, broader and less amenable to automation. We suspect that the rapid proliferation of scientific findings based on AI has not accelerated — and might even have inhibited — these higher levels of progress. If researchers in a field are concerned about flaws in individual papers, we can measure their prevalence by analysing a sample of papers. But it is hard to find smoking-gun evidence that scientific communities as a whole are overemphasizing predictive accuracy at the expense of understanding, because it is not possible to access the counterfactual world. That said, historically, there have been many examples of fields getting stuck in a rut even as they excelled at producing individual findings. Among them are alchemy before chemistry, astronomy before the Copernican revolution and geology before plate tectonics. A shout-out for AI studies that don’t make the headlines The story of astronomy is particularly relevant to AI. The model of the Universe with Earth at its centre was extremely accurate at predicting planetary motions, because of tricks such as ‘epicycles’ — the assumption that planets move in circles whose centres revolve around Earth along a larger circular path. In fact, many modern planetarium projectors use this method to compute trajectories. Today, AI excels at producing the equivalent of epicycles. All else being equal, being able to squeeze more predictive juice out of flawed theories and inadequate paradigms will help them to stick around for longer, impeding true scientific progress. The paths forward We have pointed out two main problems with the use of AI in science: flaws in individual studies and epistemological issues with the broad adoption of AI. The following are tentative ideas to improve the credibility of machine-learning-based scientific studies and avoid illusions of progress. We offer these as starting points for discussion, rather than proven solutions.
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Photonic chips provide a processing boost for AI
Anthony Rizzo
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Systems based on artificial intelligence (AI) are becoming ever more widely used for tasks from decoding genetic data to driving cars. But as the size of AI models and the extent of their use grows, both a performance ceiling and an energy wall are looming. With the performance of transistors in computer chips set to plateau, the computing power needed to support AI models will push today’s electronic hardware to its breaking point. Meanwhile, AI’s overall energy demand is soaring1, increasing carbon emissions and putting strain on local electricity grids around data centres. In September last year, technology firm Microsoft signed up for exclusive rights to the output of an entire US nuclear-power station to help to fuel its AI ambitions.
Nature DOI suffix ≠ "/s...": Not a research article
The life aquatic: this board game lets you dip into marine ecology
Angela Chuang, Orlando Schwery
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Finspan Designers: David Gordon & Michael O’Connell; Artists: Ana María Martínez, Catalina Martínez & Mesa Schumacher Stonemaier Games (2025)
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Docking stations in porous crystals unlock elusive molecular structures
Hongyi Xu
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Writing in Nature, Wu et al.1 report a groundbreaking method for determining previously elusive molecular structures. The researchers developed a crystalline porous material containing molecular ‘docking stations’ that securely capture flexible molecules that have long alkyl chains (hydrocarbon groups that contain chains of carbon atoms). By fixing the conformation of these otherwise highly flexible molecules in the host material’s rigid crystal lattice, the X-ray structures of the molecules can be determined at atomic resolution. This advance addresses a long-standing challenge that has hindered drug developers, materials scientists and chemists who study compounds isolated from natural sources, all of whom need precise insight into the structures of alkyl-bearing compounds that resist analysis by conventional crystallography.
Nature DOI suffix ≠ "/s...": Not a research article
Airborne microplastics enter plant leaves and end up in our food
Willie Peijnenburg
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Plastic production is increasing sharply. This has raised concerns about the effects of microplastics (typically defined as plastic particles smaller than 5 millimetres in diameter) and nanoplastics (smaller plastic particles that are less than 1,000 nanometres in diameter) on human health. These concerns are partly influenced by alarming findings of the presence of microplastics in various human tissues, including the brain and placenta1–3. Continuing research is examining pathways of human exposure to microplastics, including through food sources. Most attention is focused on soil and water as common sources of plastics that enter the food chain. However, writing in Nature, Li et al.4 provide strong evidence supporting the air as being a major route for plastics to enter plants.
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Will AI improve your life? Here’s what 4,000 researchers think
Fred Schwaller
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Credit: Andrey Rudakov/Bloomberg via Getty Researchers working at the forefront of artificial intelligence (AI) are much more optimistic than members of the public about the future of AI, reveals a survey of 4,260 scientists in the field: 54% think that the technology will bring more benefits than risks, compared with 13% of the UK public (see ‘Views on AI risks vary by country’). But the researchers share the public’s concerns about the technology’s role in disinformation, data use and cybercrime. In the survey, 77% of researchers and 68% of the public said that AI makes misinformation a problem, and 65% of researchers and 71% of the public expressed issues with tech companies using people’s personal data without consent. Source: Ref. 1 That means researchers’ opinions run counter to some governments’ plans to implement a mechanism for people to opt out of having their data used for AI training, says Cian O’Donovan, the study’s lead author and an innovation specialist at University College London. For instance, the UK government is proposing such a policy for copyright holders. What are the best AI tools for research? Nature’s guide To regulate effectively, “we need to do an enormous amount of research, for instance to understand how AI systems can be applied to make cyberdefences and information ecosystems more robust”, says Robert Trager, director of the Oxford Martin AI Governance Initiative at the University of Oxford, UK. The study, published1 on 1 April on the preprint server Zenodo, surveyed researchers globally, including in the United States, India and China, and compared their answers with responses from the UK public previously collected by the UK Office of National Statistics. Source: Ref. 1 Risks versus benefits When asked how AI could have a positive impact on people’s lives, 75% of researchers think the technology will increase people’s access to learning, and 57% think it will improve access to health care (see ‘How will AI change your life?‘). The most striking finding is that fewer than one-third of AI scientists think that the technologies should be developed as quickly as possible, says Trager. “They seem to want a more considered approach to development to mitigate risks.” How people’s personal data are used to train AI models particularly concerns researchers. Millions of people’s books and scientific papers have been pirated and used to train AI models, raising concerns about intellectual property. Only 25% of AI researchers say that firms should be allowed train their models on publicly available data. And almost half say that people should give explicit permission for AI companies to use their data in training — a higher proportion than members of the public (see ‘Data concerns’). Source: Ref. 1 Public involvement
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Hunter-gatherers journeyed by sea to Malta
Dylan Gaffney
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The emergence of seafaring in various archipelagos is a phenomenon that sheds light on many aspects of the evolution of human behaviour. Although early hominins reached offshore islands more than one million years ago, strategic and planned water crossings to visit these places seem to be limited to our own species1. In the central Mediterranean Sea, evidence has pointed to late island settlement compared with other parts of the world2. Around 7,400 years ago, agricultural populations arrived in the archipelago of Malta and, some 5,800 years ago, began to construct a complex array of enormous stone monuments unlike anything found on the European mainland3. Until now, it has been assumed that these enigmatic groups of farmers were the first humans on the islands. Writing in Nature, Scerri et al.4 reveal an earlier phase of seafaring activity, by hunter-gatherers, that pushes back the human settlement of these Mediterranean islands by more than 1,000 years.
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How does the brain control consciousness? This deep-brain structure
Smriti Mallapaty
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The inner structures of the brain are difficult to investigate without surgery.Credit: K H Fung/Science Photo Library Neuroscientists have observed for the first time how structures deep in the brain are activated when the brain becomes aware of its own thoughts, known as conscious perception1. The brain is constantly bombarded with sights, sounds and other stimuli, but people are only ever aware of a sliver of the world around them — the taste of a piece of chocolate or the sound of someone’s voice, for example. Researchers have long known that the outer layer of the brain, called the cerebral cortex, plays a part in this experience of being aware of specific thoughts. The involvement of deeper brain structures has been much harder to elucidate, because they can be accessed only with invasive surgery. Designing experiments to test the concept in animals is also tricky. But studying these regions would allow researchers to broaden their theories of consciousness beyond the brain’s outer wrapping, say researchers. “The field of consciousness studies has evoked a lot of criticism and scepticism because this is a phenomenon that is so hard to study,” says Liad Mudrik, a neuroscientist at Tel Aviv University in Israel. But scientists have increasingly been using systematic and rigorous methods to investigate consciousness, she says. Aware or not In a study published in Science today1, Mingsha Zhang, a neuroscientist at Beijing Normal University, focused on the thalamus. This region at the centre of the brain is involved in processing sensory information and working memory, and is thought to have a role in conscious perception. Participants were already undergoing therapy for severe and persistent headaches, for which they had thin electrodes injected deep into their brains. This allowed Zhang and his colleagues to study their brain signals and measure conscious awareness. The participants were asked to move their eyes in a particular way depending on whether they noticed an icon flash onto a screen in front of them. The icon was designed so that the participants would be aware of its appearance only about half of the time. During the tasks, the researchers recorded neural activity in multiple regions of the brain, including the thalamus and the cortex. This is the first time that such simultaneous recordings have been made in people doing a task that is relevant to consciousness science, says Christopher Whyte, a systems neuroscientist at the University of Sydney in Australia. The work “is really pretty remarkable”, he says, because it allowed the team to look at how the timing of neural activity in different regions varied. Gatekeeper
Nature DOI suffix ≠ "/s...": Not a research article
Exclusive: Trump White House directs NIH to study ‘regret’ after transgender people transition
Max Kozlov
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Activists rally for the rights of transgender people at the National Mall in Washington DC last month.Credit: Kayla Bartkowski/Getty As the US National Institutes of Health (NIH) continues to defund nearly every research project on transgender health, the White House has directed the agency to focus on studying “regret” after a person transitions to align their body with their gender identity. Several NIH employees, who were granted anonymity because they are not authorized to speak to the press, confirmed the directive to Nature. ‘Mind-boggling’: US CDC orders gender-related terms cut from scientific papers Two weeks ago, Matthew Memoli, who was acting NIH director at the time, sent an e-mail to the directors of several NIH institutes. It said that the Department of Health and Human Services (HHS), which is the NIH’s parent agency, “has been directed to fund research on a few specific areas” related to what it calls “chemical and surgical mutilation” of children and adults — a reference to gender-affirming care and surgery. “This is very important to the President and the Secretary” of the HHS, Robert F. Kennedy Jr, the e-mail added. Based on its priorities, the White House sometimes directs the NIH — the world’s largest public funder of biomedical science — to study certain broad topics, such as cancer or women’s health, but the latest directive’s specificity, inflammatory language and focus on a hyper-polarizing topic are unprecedented, the NIH employees say. Although the White House can sometimes “push us on various different things, we normally get to chart out the approach”, a staff member says. Many scientists, reeling from the abrupt cancellation of more than US$180 million in NIH funding for research on transgender health, slammed the proposed studies as ideologically driven. “It’s really pigeonholing trans people into this medical lens where the only thing important to know about them is that they seek medical transition” and regret it, says Harry Barbee, who studies the health of people from gender and sexual minorities (LGBT+) at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, and identifies as non-binary and queer. “When ideology is prioritized over scientific merit, that threatens the entire scientific enterprise.” The NIH and the White House did not respond to Nature’s queries about the new research priorities or scientists’ concerns with their apparent ideological bent. The HHS said that the “NIH is prioritizing research that serves the best interests of public health, not ideological agendas, and will continue to support studies that provide clear, objective data — particularly regarding the long-term effects of gender transitions.” Shifting focus Estimates suggest that 1.6 million people in the United States identify as transgender, and about one-quarter of them obtain gender-affirming surgeries. Research suggests1 that access to these procedures can reduce anxiety, depression and suicidal ideation in transgender people. Exclusive: NIH to cut grants for COVID research, documents reveal US President Donald Trump signed an executive order on his first day in office on 20 January that directed the US government to stop acknowledging that gender can differ from sex at birth. The cancellation of many trans-health research grants quickly followed, and now the agency seems to be shifting the type of research it funds. The e-mail from Memoli, obtained by Nature, specifies two areas of research that the Trump administration wishes to fund about “social transition”, which is when a person changes how they express their gender to others — for example, by changing their name or appearance. These include “regret and detransition following social transition as well as chemical and surgical mutilation of children and adults” and “outcomes from children who have undergone social transition and/or chemical and surgical mutilation”, the e-mail says. More research on the experience of trans people — including understanding reasons for dissatisfaction after transition — is direly needed, Barbee says. But they worry that the sole focus on negative consequences is misplaced: fewer than 1% of transgender people who undergo gender-affirming surgery regret it, according to an analysis published by Barbee and their colleagues2. By comparison, 14.4% of the broader population reports regret after any kind of surgery3. So far, about 187 NIH grants funding trans-health research have been terminated, according to an online effort to track the Trump team’s research cuts by Brittany Charlton, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, who studies LGBT+ health, and her colleagues. In 2023, the NIH funded about 180 projects in this field, according to another NIH employee. If these proposed studies move forwards, it will create a “a distorted research ecosystem where only politically favourable findings are permitted to exist” and an “evidence vacuum for clinicians who are trying to do right by their patients”, Barbee says.
Nature DOI suffix ≠ "/s...": Not a research article
Europe must grasp chance to become a scientific powerhouse
Oskar MacGregor, Maurice Lamb
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The Second World War sparked an exodus of scientific talent from Europe to the United States. Simultaneously, Vannevar Bush, who directed the US Office of Scientific Research and Development from 1941 to 1947, helped to foster enormous investments in basic research (V. Bush Trans. Kans. Acad. Sci. 48, 231–264; 1945).
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Daily briefing: The physicist behind baseball’s new ‘torpedo’ bat
Flora Graham
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Tiger turnaround as populations grow in India
William F. Laurance, Uma Ramakrishnan
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Until a few tens of thousands of years ago, Earth harboured a remarkable collection of large animals1, including giant ground sloths (Megatherium), woolly mammoths (Mammuthus primigenius) and elephant birds (Mullerornis and Aepyornis). Most of these iconic beasts are now extinct, and many large mammals are vanishingly rare following widespread human persecution and habitat disruption. Yet in India, a nation with a burgeoning human population, good news is reverberating about the population of wild tigers (Panthera tigris). Writing in Science, Jhala et al.2 present findings about tigers that provide key lessons for conserving imperilled large animals elsewhere in the world.
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Where do proteins go in cells? Next-generation methods map the molecules’ hidden lives
Ariana Remmel
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The average human cell contains roughly 10,000 different proteins. Existing as several to millions of copies in each cell, proteins mediate all manner of tasks, including chemical transformations, communication and intracellular trafficking. To execute these crucial functions, each protein must cosy up with designated partners, says Emma Lundberg, a bioengineer at Stanford University in California. If you want to understand how cells function, you have to work out what proteins interact with — and where. To coordinate the mass of moving parts, eukaryotic cells evolved membrane-bound organelles and other subcellular compartments that gather protein networks together in controlled environments, each with a distinct function. By working out the sites at which a protein operates, researchers can infer something about its job. “It’s like a person in a house: if you are in the kitchen or in your laundry room, I can make a pretty good guess of what you’re doing,” says Lundberg. But, like people, proteins aren’t restricted to one place; as researchers such as Lundberg in the fast-growing field of spatial proteomics have discovered, more than half of our proteins have more than one hangout spot. Many have multiple functions and moonlight in different roles depending on their position. By the same token, cellular processes falter when proteins show up to the wrong job site. “It really shows that this notion of ‘one gene, one protein, one function’ is really not correct,” Lundberg says. With advances in high-resolution imaging, mass spectrometry and machine-learning-assisted data analysis, spatial-proteomics researchers are mapping and tracking proteins with increasing detail at multiple scales, from subcellular compartments to tissues. The work is challenging and data-intensive, but findings have yielded insights into cellular biology and disease progression — not to mention, potential therapeutic strategies. Cellular cartography Proteomics is to proteins what transcriptomics is to RNA. By counting the RNA-based messages that the cell writes to direct its protein-making machinery, transcriptomics practitioners hope to deduce what the cell is doing. But the expression level of a given transcript doesn’t necessarily match the abundance of its corresponding protein. And cells often edit their transcripts and modify proteins after translation to create different variants, called proteoforms. Enter proteomics, which provides concrete data to explain how the ‘parts list’ of possible proteins in our genes is assembled to build the cell types in the body. By mapping protein abundances to their physical locations, spatial proteomics highlights how those proteins — and cells — are organized in tissues. There are two basic approaches: the imaging method fluorescence microscopy and quantitative mass spectrometry. The methods are complementary, and two large-scale atlas projects demonstrate the power of using them together. A tissue sample is prepared for highly multiplexed proteoform imaging.Credit: Lisa La Vallee In 2017, Lundberg and her collaborators used a mix of both methods to build a subcellular atlas of more than 12,000 proteins in 22 cell types called the Cell Atlas, which is part of the Sweden-based Human Protein Atlas project1. The team stained a library of cells with fluorescently labelled antibodies for each target protein alongside markers for notable structures, such as the nucleus and mitochondria. These cellular landmarks helped the researchers to assign each protein to one or more of 30 subcellular locations, from major organelles to more esoteric options, such as cell junctions and lipid droplets. Immunofluorescence works well when researchers know what proteins they are looking for and have suitable antibodies that can tag them, says Kathryn Lilley, a biochemist at the University of Cambridge, UK. Newer methods that combine repeated cycles of staining and imaging — such as co-detection by indexing (CODEX) and iterative bleaching extends multiplexity (IBEX) — can visualize tens to hundreds of labelled proteins in a single sample. But even these multiplexed methods overlook most of the proteome. Mass spectrometry can help to complete the picture, Lilley says. Lilley and her colleagues developed a suite of mass-spectrometry-based techniques for subcellular mapping that are broadly called ‘localization of organelle proteins by isotope tagging’ (LOPIT). To validate the Cell Atlas’s image-based assignments, the researchers applied a variant called hyperLOPIT that works by carefully breaking cells open, separating their contents across a density gradient and digesting the proteins from each sample using enzymes. Next, they label each sample with a different isotope tag, recombine them and analyse the resulting mixture using tandem mass spectrometry — a quantitative approach that allows them to identify, quantify and assign thousands of proteins back to their original subcellular compartments. The team used these and other methods to demonstrate that more than half of the proteins in human cells could be found in more than one location, and a subset could be found in at least three. About one-third of the proteins were present in every cell type, suggesting that they have generic ‘housekeeping’ roles that keep our cells running. In 2022, Manuel Leonetti at the Chan Zuckerberg Biohub in San Francisco, California, working with Matthias Mann at the Max Planck Institute of Biochemistry in Munich, Germany, and their colleagues on the OpenCell project generated a library of 1,310 lines of human embryonic kidney cells, each of which fused a genetically encoded fluorescent protein tag to a different protein target. The team then used fluorescence microscopy to manually annotate the distribution of the tagged protein in living cells of each type and to train a machine-learning algorithm to carry out the same assignments. At the same time, the genetically encoded tags provided an antigen with which Mann’s team could perform immunoprecipitation-coupled mass spectrometry experiments. These allow the researchers to grab hold of a protein and its interaction partners and then train a second machine-learning algorithm to systematically build up a ‘social network’ for these proteins. Users can explore each protein’s whereabouts and known associates on the OpenCell web portal. Take, for example, FAM241A, an ‘orphan’ protein of previously unknown function. When Leonetti and his colleagues looked at cells engineered to express FAM241A with a fluorescent tag, they found it in the endoplasmic reticulum, an organelle that, among other things, affixes chemical modifications to proteins. From those snapshots, the project’s machine-learning algorithm predicted that FAM241A might interact with two enzymes from the OpenCell library that add a specific type of sugar molecule to proteins. Further investigation confirmed that FAM241A is part of the same pathway, revealing its function2. Moving molecules Living cells are dynamic, ceaselessly building and breaking biomolecules, and shuffling them from one location to another. Detailed descriptions of where proteins typically congregate — and how they move from place to place — can help researchers to understand the significance of protein movements when cells are stressed or during disease. In one study3, for instance, Lilley and her colleagues measured how the proteome of lung cancer cells responds to radiotherapy — a common treatment for this disease. Using a LOPIT-based workflow, the team measured the proteomes of cultured lung cancer cells exposed to X-rays and those of untreated controls. Of the several hundred proteins that differed between the two conditions, most changed in either abundance or location, but rarely in both, Lilley says. Focusing on those proteins that seemed to migrate after exposure to radiation, the researchers identified several key players in an iron-dependent cell-death pathway called ferroptosis that might contribute to radiotherapy resistance in some cancers. Although the work is preliminary, the pathway is a potential therapeutic target, Lilley says. Method of the year 2024: spatial proteomics Similarly, Mikko Taipale, a functional geneticist at the University of Toronto in Canada, and his colleagues coaxed human cell cultures to produce 3,448 fluorescently tagged proteins in which a single-letter alteration to the coding sequence changes one amino acid for another. Such ‘missense mutations’ can sometimes disable a protein, he notes; at other times, “it leads to this rewiring of cellular networks so that the protein ends up in the wrong place and interacts with the wrong partners”. In this case, manual analysis of the microscopy data showed that 16% of variants that were known or likely to be pathogenic also congregated in the wrong place in cells, suggesting a link between protein location and disease4. “I don’t think I would have guessed that it’s that common,”Taipale says. In fact, misplaced proteins in cancer and neurodegenerative disease “seems sufficiently widespread that an approach to fixing that mislocalization would be quite powerful”, says Stanford chemical biologist Steven Banik. Scientists have developed tools to study these processes either by reuniting estranged interaction partners5 or by sequestering crucial components in distant parts of the cell6. Now, they are attempting to exploit this information for therapeutic benefit. Banik and his colleagues, for instance, have created a chemical ‘tow hitch’ called targeted relocalization-activating molecules (TRAMs) that latch on to a shuttle protein at one end and a designated cargo on the other7. In one demonstration of this technology, Banik’s team used an RNA-binding protein called FUS as cargo. This protein is normally present in the nucleus but can form toxic granules in the cytoplasm of neurons in some cases of the neurodegenerative condition motor neuron disease (amyotrophic lateral sclerosis). In cells that are manipulated to express both the faulty form of FUS and a protein that shuttles cargo from the cytoplasm to the nucleus, treatment with the matching TRAM effectively dissolved the troublesome granules by carting away the errant variants. With further development, Banik is hopeful that such molecular tools will uncover the rules that govern logistical networks in cells and even serve as medicinal compounds themselves. Spatial conundrum Despite these advances, significant knowledge gaps remain — even to seemingly obvious questions. For instance, just how big is the human proteome? Between variations in gene splicing, post-translational modification and folding, every protein-coding gene can give rise to multiple proteoforms, each of which might have a different function and location, says Neil Kelleher, a protein biochemist at Northwestern University in Evanston, Illinois. To survey the proteoform landscape of cells and tissues, Kelleher and his collaborators combined an existing imaging system called nanospray desorption electrospray ionization (nano-DESI) and a new instrument for individual ion mass spectrometry, which is being commercialized by biotechnology company Thermo Fisher Scientific. Kelleher and his collaborators call the resulting platform ‘proteoform imaging mass spectrometry’ (PiMS); it can measure hundreds of proteoforms at the tissue level with a resolution of the order of a few cells. In one analysis of ovarian cancer biopsies, Kelleher and his colleagues identified 303 proteoforms that were expressed differently in healthy tissue and tumours8. Now, they are drilling down to the scale of isolated organelles such as nuclei. A section of brain hippocampus from an individual with Alzheimer’s disease highlights proteins in different cell types: neurons (orange, magenta and green), astrocytes (cyan) and microglia (yellow). Amyloid-ÎČ plaques are in red and nuclei are in blue.Credit: Emma Lundberg Lab
Nature DOI suffix ≠ "/s...": Not a research article
Studying seabirds with a cactus as a research assistant
Ugo Mellone
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“This century-old cactus that stands on the uninhabited Isla Espíritu Santo, in the Gulf of California, Mexico, is like my very own field technician: the device that we’ve attached to it automatically collects data from tagged magnificent frigatebirds (Fregata magnificens) whenever they come within a 500-metre range. Every month, my team and I come by boat to retrieve the data, as I am doing in this picture with my student Joel Lopez (I’m on the right). In this project, we tagged 30 individual birds with GPS data-loggers, including 10 that live in the local mangrove trees, which host around 500 breeding pairs. Catching these birds is tricky, so we do it at night when they’re less active; we can dazzle an individual with a light and avoid disturbing others. The GPS tracking revealed that frigatebirds cross the Baja California Peninsula up to three times per day, an unusual behaviour for a seabird. On average, foraging trips last 14 hours and birds fly about 30 kilometres from the colony, with males venturing farther than females. One male even reached Clipperton Island in the Pacific Ocean, more than 1,500 km away, returning after a few days. Then he did it again exactly one year later.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: This brain structure filters which thoughts we become aware of
Flora Graham
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Unlocking the secrets of sleep
Herb Brody
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Nature DOI suffix ≠ "/s...": Not a research article
Relics
C. B. Stuckey
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The heart is one long muscle, coiled in a tight fist. When it stops beating, the blood does not run out. ***** The surgeon folds the model of the electric heart in your hands. You squeeze it, feel the matt silver flex, soft as flower petals, and you consider the weakening walls of your own heart. You twist the model apart to inspect the core and the leads that weave into the chambers. You’re told that it will work like a casing with the new core implanted. When it’s your time — or what would be your time — your heart will tilt, and the tissue will wither until only the new heart is left. You look up to ask, “How long does it live?” ***** If your heart beats an average of 72 beats per minute, that means 4,320 per hour, 103,680 per day. Read more science fiction from Nature Futures You hold your breath long enough to feel the soft timpani in your chest. So you continue to hold it, longer and longer. Your chest burns as you swallow another breath, chirrup with each inhale, each one smaller and smaller as you fill and fill. You swell until your pulse becomes one body of vibration, until you hang on one great breath held too long, on the swell of a breath that waits. When you press your palms to your chest to hold each beat, you wonder how many fewer you already have, how many are left. ***** You cannot feel the metal casing or the leads that tendril through the muscle into the new walls. Yet you know your flesh trembles within the implant that pulses in what the surgeon calls pericardial whir, each beat perfect, rhythmic, stable. Although you live another six years, two months, three days, four minutes without feeling anything but your own body, the moment comes when gravity shifts and all within you seems to slant into collapse. The part that was perhaps the most you simply ceases to be, preceded in death by two billion beats. Yet here you are, upright and breathing, with a palm to your chest, the little hummingbird of hearts beating on. You begin counting heartbeats in reverse, all that survive you. Minus 1 
 minus 2 
 minus 65 
 minus 143 
 You breathe a little deeper, lengthen your stride, fold your hands behind your head to open your chest and expand your lungs as you step across the line of demarcation into your own living afterlife. If shimmer was a sound, the new heartbeat sings in this high voice. ***** The surface of the water ripples as you lower yourself into the warm bathtub and let the water slip up, over your ears. You close your eyes, float, let all air seep from your lungs, until the only sound is the pattern of small whooshes, like an unborn child on an ultrasound. The soft pulse grows into a heavy gallop, reverberating, pounding until it feels as though it might split your bones. And you wonder how to be, without being, how to be, while being, a body. ***** Hours lean into days as the all-consuming pulse throbs within your ears, and you search for something calm, reach for the earth to still you. You walk in bare feet, palm the base of a tree, trace the corrugations of bark down to the tops of the roots. You turn to press your back into the trunk, nestle into the tangle of grass, as you watch the birds overhead, beaks opening and closing without a sound. You hold onto the calm, the pulse unspooling from you until birdsong and breeze uncoil from the branches above. And you can hear again. The thrum fades as sound returns from each feathered voice, from wind that lifts and catches through the leaves in whispers.
Intersectional analysis for science and technology
Mathias Wullum Nielsen, Elena Gissi, Shirin Heidari, Richard Horton, Kari C. Nadeau, Dorothy Ngila, Safiya Umoja Noble, Hee Young Paik, Girmaw Abebe Tadesse, Eddy Y. Zeng, James Zou, Londa Schiebinger
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Intersectionality describes interdependent systems of inequality related to sex, gender, race, age, class and other socio-political dimensions. By focusing on the compounded effects of social categories, intersectional analysis can enhance the accuracy and experimental efficiency of science. Here we extend intersectional approaches that were predominantly developed in the humanities, social sciences and public health to the fields of natural science and technology, where this type of analysis is less established. Informed by diverse global and disciplinary examples—from enhancing facial recognition for diverse user bases to mitigating the disproportionate impact of climate change on marginalized populations—we extract methods to demonstrate how quantitative intersectional analysis functions throughout the research process, from strategic considerations for establishing research priorities to formulating research questions, collecting and analysing data and interpreting results. Our goal is to offer a set of guidelines for researchers, peer-reviewed journals and funding agencies that facilitate systematic integration of intersectional analysis into relevant domains of science and technology. Precision in research best guides effective social and environmental policy aimed at achieving global equity and sustainability.

Nature Human Behaviour

GPT-4o mini: Non-social science research article
Human motor cortex encodes complex handwriting through a sequence of stable neural states
Yu Qi, Xinyun Zhu, Xinzhu Xiong, Xiaomeng Yang, Nai Ding, Hemmings Wu, Kedi Xu, Junming Zhu, Jianmin Zhang, Yueming Wang
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How the human motor cortex (MC) orchestrates sophisticated sequences of fine movements such as handwriting remains a puzzle. Here we investigate this question through Utah array recordings from human MC during attempted handwriting of Chinese characters (n = 306, each consisting of 6.3 ± 2.0 strokes). We find that MC activity evolves through a sequence of states corresponding to the writing of stroke fragments during complicated handwriting. The directional tuning curve of MC neurons remains stable within states, but its gain or preferred direction strongly varies across states. By building models that can automatically infer the neural states and implement state-dependent directional tuning, we can significantly better explain the firing pattern of individual neurons and reconstruct recognizable handwriting trajectories with 69% improvement compared with baseline models. Our findings unveil that skilled and sophisticated movements are encoded through state-specific neural configurations.
Nationwide demonstration of improved COVID-19 vaccination uptake through behavioural reminders
Hannah Behrendt, Giulia Tagliaferri, Lev Tankelevitch, Yihan Xu, Hugo Harper, Natalie Gold, Dale Weston, Rachel Rosen, Robert Scott
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Here we report the results of two nationwide randomized controlled trials. By refining behavioural-science-informed text messages notifying patients of their vaccine eligibility, we observed improvements in vaccination rates. The randomized controlled trials involved adults aged 40–44 years (n = 1,825,937) and 24–29 years (n = 2,174,064) in England. Messages emphasizing ‘Top of queue’ status led to small, but policy-relevant, increases in vaccination rates in both the 40–44 age group (odds ratio 1.02, 95% confidence interval 1.01–1.03) and the 24–29 age group (odds ratio 1.02, 95% confidence interval 1.01–1.04). Consequently, the ‘Top of queue’ message was nationally rolled out to other age groups. These findings demonstrate the potential of ‘queue’ framing in relevant contexts and the value of rigorous testing of public health messaging.
Health is the landing zone for climate change adaptation
John S. Ji
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Effective climate action rests on two key strategies: mitigation and adaptation. Mitigation focuses on reducing greenhouse gas emissions through measurable targets, including tonnes of carbon dioxide equivalent, net carbon balance and carbon intensity. The goal is to limit global temperature rise to well below 2 °C, ideally to 1.5 °C, above preindustrial levels. Without effective mitigation, average global temperature increases will push beyond 3 °C (ref. 4). Adaptation is the process of preparing for and adjusting to the effects of climate change. It is inherently multidimensional, and spans diverse sectors such as health, infrastructure, agriculture and ecosystems, without a singular, quantifiable metric. Adaptation is especially context-specific, so quantifying adaptation indicators remains a challenge. The global stocktake, a process designed to assess adaptation and resilience-building efforts, continues to grapple with defining and evaluating success.
South Korea’s landmark ruling on climate justice
Kil Won Lee, Tae Jung Park
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This case is the first of its kind in Asia, and the complainants included children and young people. The part of the ‘Carbon Neutrality Act’ (the Framework Act on Carbon Neutrality and Green Growth for Climate Crisis Response; hereafter, the Act) that was declared unconstitutional is Article 8.1, the part that set national targets for reductions in greenhouse gas emissions. The court ruled that Article 8.1 failed to uphold constitutional environmental rights by omitting quantitative reduction targets for 2031–2049. These missing targets undermine the long-term consistency and ambition necessary to address the escalating climate crisis. Although this provision remains temporarily valid until 28 February 2026 (to allow time for legislative amendments), the decision highlights notable deficiencies in South Korea’s climate governance.

Proceedings of the National Academy of Sciences

GPT-4o mini: Non-social science research article
Whole-brain white matter variation across childhood environments
Sofia Carozza, Isaiah Kletenik, Duncan Astle, Lee Schwamm, Amar Dhand
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White matter develops over the course of childhood in an experience-dependent manner. However, its role in the relationship between the early environment and later cognition is unclear, in part due to focus on changes in specific gray matter regions. This study examines white matter differences across adolescents from diverse environments, evaluating both their extent throughout the brain and their contribution to cognitive outcomes. Using data from the Adolescent Brain Cognitive Development (ABCD) study (N = 9,082, female = 4,327), we found extensive cross-sectional associations with lower white matter fractional anisotropy (FA) and streamline count in the brains of 9- and 10-y-old children exposed to a range of experiences, including prenatal risk factors, interpersonal adversity, household economic deprivation, and neighborhood adversity. Lower values of FA were associated with later difficulties with mental arithmetic and receptive language. Furthermore, white matter FA partially mediated the detrimental relationship between adversity and cognition later in adolescence. These findings advance a white matter-based account of the neural and cognitive effects of adversity, which supports leading developmental theories that place interregional connectivity prior to gray matter maturation.
GPT-4o mini: Non-social science research article
Tetrathienylethene-based porous framework composites for boosting photocatalytic antibacterial activity
Si Ma, Yintung Lam, Le Shi, Jian Yang, Kun Wang, Bo Yu, Chiwai Kan, Bin Fei, John H. Xin, Kaikai Ma, J. Fraser Stoddart, Zhijie Chen
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In order to reduce the risk of high-threat pathogens, a photocatalytic antibacterial method with a reputation for high efficiency and sustainability has attracted widespread attention. Recently, metal-organic frameworks (MOFs) have emerged as desirable platforms for photocatalytic applications by virtue of their structural diversity and functional adjustability. Herein, we report that we have synthesized a stable and photosensitive zirconium-based MOF (Zr-MOF) with a photoactive tetrathienylethene-based organic linker, Zr-TSS-1. Compared with all-carbocyclic Zr-MOF counterparts, Zr-TSS-1 shows a substantial improvement in visible-light harvesting and free-carrier generation, enabling it to be a promising candidate for photocatalytic antibacterial applications. In order to validate the advantages of this framework as an antibacterial protective material, a composite was fabricated by incorporating robust Zr-TSS-1 onto sustainably accessible bacterial cellulose (BC) using an in situ growth method. This composite exhibits near-complete lethality toward typical Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus within 1 h under mild irradiation and preserves outstanding antibacterial capability after five cycles of reutilization. In addition, the high biocompatibility is confirmed by the low cytotoxicity toward human skin fibroblast, suggesting its potential for biomedical and healthcare applications. This research demonstrates the efficacious integration of a purposely designed photosensitive porous framework onto a sustainable substrate for synergistic functionality, paving a practical way for the development of the next-generation high-efficiency antimicrobial technology.
GPT-4o mini: Non-social science research article
Emergent gauge fields in band insulators
Zhaoyu Han, Steven A. Kivelson
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By explicit microscopic construction involving a mapping to a quantum vertex model subject to the “ice rule,” we show that an electronically “trivial” band insulator with suitable vibrational (phonon) degrees of freedom can host a “resonating valence-bond” state—a quantum phase with emergent gauge fields. This type of band insulator is identifiable by the existence of emergent gapless “photon” modes and deconfined excitations, the latter of which carry nonquantized mobile charges. We suggest that such phases may exist in the quantum regimes of various nearly ferroelectric materials.
GPT-4o mini: Non-social science research article
SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss
Xinqi Xi, Ling Liu, Natasha Tuano, Julien Tailhades, Dmitri Mouradov, Jason Steen, Oliver Sieber, Max Cryle, Tu Nguyen-Dumont, Eva Segelov, Joseph Rosenbluh
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Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli ( APC ) is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify SRP19 and the protein secretion machinery as a unique vulnerability in cancers with heterozygous APC loss. SRP19 is located 15 kb from APC and is almost always codeleted in these tumors. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19 . Moreover, we show that SRP19 is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous SRP19 loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with APC deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.
GPT-4o mini: Non-social science research article
Breaking the mobility–stability dichotomy in organic semiconductors through adaptive surface doping
Zhaofeng Wang, Xianshuo Wu, Siyuan Zhang, Shuyuan Yang, Pichao Gao, Panhui Huang, Yanling Xiao, Xianfeng Shen, Ximeng Yao, Dong Zeng, Jiansheng Jie, Yecheng Zhou, Fangxu Yang, Rongjin Li, Wenping Hu
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Organic semiconductors (OSCs) are pivotal for next-generation flexible electronics but are limited by an intrinsic trade-off between mobility and stability. We introduce adaptive surface doping (ASD), an innovative strategy to overcome this dichotomy in OSCs. ASD's adaptive mechanism accommodates a broad range of dopant concentrations, optimally passivating trap states as needed. This approach significantly lowers the trap energy level from 84 meV to 14 meV above the valence band edge, promoting a transition from hopping to band-like transport mechanisms. ASD boosts carrier mobility by over 60%, reaching up to 30.7 cm 2 V −1 s −1 , while extending the extrapolated operational lifetime of treated devices beyond 57.5 y. This breakthrough sets a standard in organic electronics, positioning ASD as a powerful method for simultaneously enhancing performance and stability in OSC devices.
GPT-4o mini: Non-social science research article
An unusual potassium conductance protects Caenorhabditis elegans pharyngeal muscle rhythms against environmental noise
Max Kenngott, Piali Sengupta, Shawn Lockery, Eve Marder
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The nematode Caenorhabditis elegans feeds by rhythmic contraction and relaxation of a neuromuscular organ called the pharynx, which draws in and filters water and bacterial food. This behavior is driven by myogenic plateau potentials, long-lasting depolarizations of the pharyngeal muscle, which are timed by neuronal input from a dedicated pharyngeal nervous system. While the timing of these plateaus’ initiation has received significant attention, their mechanisms of termination remain incompletely understood. In particular, it is unclear how plateaus resist early termination by hyperpolarizing current noise. Here, we present a computational model of pharyngeal plateaus against a noisy background. We propose that an unusual, rapidly inactivating potassium conductance confers exceptional noise robustness on the system. We further investigate the possibility that a similar mechanism in other systems permits switching between plateau and spiking behavior under noisy conditions.
GPT-4o mini: Non-social science research article
Critical dynamics predicts cognitive performance and provides a common framework for heterogeneous mechanisms impacting cognition
Paul Manuel MĂŒller, Gadi Miron, Martin Holtkamp, Christian Meisel
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The brain criticality hypothesis postulates that brain dynamics are set at a phase transition where information processing is optimized. Long-range temporal correlations (TCs) characterizing the dissipation of information within a signal have been shown to be a hallmark of brain criticality. However, the experimental link between cognitive performance, criticality, and thus TCs has remained elusive due to limitations in recording length and spatial and temporal resolution. In this study, we investigate multiday invasive EEG recordings of 104 persons with epilepsy (PwE) together with an extensive cognitive test battery. We show that short TCs predict cognitive impairment. Further, we show that heterogeneous factors, including interictal epileptiform discharges (IEDs), antiseizure medications (ASMs), and intermittent periods with slow-wave activity (SWSs), all act directly to perturb critical dynamics and thus cognition. Our work suggests critical dynamics to be the setpoint to measure optimal network function, thereby providing a unifying framework for the heterogeneous mechanisms impacting cognition in conditions like epilepsy.
GPT-4o mini: Non-social science research article
Colony pattern multistability emerges from a bistable switch
Pan Chu, Jingwen Zhu, Zhixin Ma, Xiongfei Fu
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Microbial colony development hinges upon a myriad of factors, including mechanical, biochemical, and environmental niches, which collectively shape spatial patterns governed by intricate gene regulatory networks. The inherent complexity of this phenomenon necessitates innovative approaches to comprehend and compare the mechanisms driving pattern formation. Here, we unveil the multistability of bacterial colony patterns, where bacterial colony patterns can stabilize into multiple distinct types including ring-like patterns and sector-like patterns on hard agar, orchestrated by a simple synthetic bistable switch. Utilizing quantitative imaging and spatially resolved transcriptome approaches, we explore the deterministic process of a ring-like colony pattern formation from a single cell. This process is primarily driven by bifurcation events programmed by the gene regulatory network and microenvironmental cues. Additionally, we observe a noise-induced process amplified by the founder effect, leading to patterns of symmetry-break during range expansion. The degrees of asymmetry are profoundly influenced by the initial conditions of single progenitor cells during the nascent stages of colony development. These findings underscore how the process of range expansion enables individual cells, exposed to a uniform growth-promoting environment, to exhibit inherent capabilities in generating emergent, self-organized behavior.
GPT-4o mini: Non-social science research article
Roquin exhibits opposing effects on RNA stem-loop stability through its two ROQ domain binding sites
Jan-Niklas Tants, Andreas Walbrun, Lucas Kollwitz, Katharina Friedrich, Matthias Rief, Andreas Schlundt
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The interaction of mRNA and regulatory proteins is critical for posttranscriptional control. For proper function, these interactions, as well as the involved protein and RNA structures, are highly dynamic, and thus, mechanistic insights from structural biology are challenging to obtain. In this study, we employ a multifaceted approach combining single-molecule force spectroscopy (SMFS) with NMR spectroscopy to analyze the concerted interaction of the two RNA-binding interfaces (A-site and B-site) of the immunoregulatory protein Roquin’s ROQ domain with the 3’ untranslated region (UTR) of the Ox40 mRNA. This 3’UTR contains two specific hairpin structures termed constitutive and alternative decay elements (CDE, ADE), which mediate mRNA degradation through Roquin binding. Our single-molecule experiments reveal that the CDE folds cooperatively, while ADE folding involves at least three on-pathway and three off-pathway intermediates. Using an integrated microfluidics setup, we extract binding kinetics to Roquin in real time. Supported by NMR data, we find opposing effects of the two Roquin subdomains on distinct regions of the ADE: While the A-site interacts strongly with the folded apical stem-loop, we find that the B-site has a distinct destabilizing effect on the central stem of the ADE owed to single-strand RNA binding. We propose that RNA-motif nature and Roquin A- and B-sites jointly steer mRNA decay with context-encoded specificity, and we suggest plasticity of stem structures as key determinant for Roquin–RNA complex formation. The unique combination of NMR and SMFS uncovers a mechanism of a dual-function RNA-binding domain, offering a model for target RNA recognition by Roquin.
GPT-4o mini: Non-social science research article
A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis
Rosella Mechelli, Renato Umeton, Gianmarco Bellucci, Rachele Bigi, Virginia Rinaldi, Daniela F. Angelini, Gisella Guerrera, Francesca C. Pignalosa, Sara Ilari, Marco Patrone, Sundararajan Srinivasan, Gabriel Cerono, Silvia Romano, Maria C. Buscarinu, Serena Martire, Simona Malucchi, Doriana Landi, Lorena Lorefice, Raffaella Pizzolato Umeton, Eleni Anastasiadou, Pankaj Trivedi, Arianna Fornasiero, Michela Ferraldeschi, character(0), Alessia Di Sapio, Gerolama Marfia, Eleonora Cocco, Diego Centonze, Antonio Uccelli, Dario Di Silvestre, Pierluigi Mauri, Paola de Candia, Sandra D’Alfonso, Luca Battistini, Cinthia Farina, Roberta Magliozzi, Richard Reynolds, Sergio E. Baranzini, Giuseppe Matarese, Marco Salvetti, Giovanni Ristori, Lars Alfredsson, Helle Bach SĂžndergaard, Sergio E. Baranzini, Lisa F. Barcellos, Luisa Bernardinelli, David Booth, Manuel Comabella, Alastair Compston, Chris Cotsapas, Sandra D’Alfonso, Efthimios Dardiotis, Philip L De Jager, BĂ©nĂ©dicte Dubois, Federica Esposito, Betrand Fontaine, An Goris, Pierre-Antoine Gourraud, Giorgos Hadjigeorgiou, David A. Hafler, Jonathan L. Haines, Hanne F. Harbo, Stephen L. Hauser, Bernhard Hemmer, Roland Henry, Hillert, Rogier Hintzen, Noriko Isobe, Adrian J. Ivinson, Seema Kalra, Michael Khalil, Ingrid Kockum, Jeanette Lechner-Scott, Roland Martin, Filippo Martinelli-Boneschi, Jacob L. McCauley, Gil McVean, Jorge R. Oksenberg, Tomas Olsson, Annette Oturai, Grant P. Parnell, Nikolaos A. Patsopoulos, Margaret A. Pericak-Vance, Neil Robertson, Janna Saarela, Stephen J. Sawcer, Joost Smolders, Graeme J. Stewart, Bruce Taylor, V. Wee Yong, Frauke Zipp, Ines Barroso, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Mark Caulfield, David Clayton, Aiden Corvin, Nick Craddock, Panos Deloukas, Peter Donnelly, Audrey Duncanson, Martin Farrall, Alistair Hall, Andrew Hattersley, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Mark McCarthy, Colin N.A. Palmer, Miles Parkes, Robert Plomin, Anna Rautanen, Nilesh Samani, Stephen Sawcer, John Todd, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Jane Worthington, Chris C.A. Spencer, Gavin Band, CĂ©line Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E. Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Rathi Ravindrarajah, Michelle Ricketts, Matthew J. Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Alexander Dilthey, Stephen Leslie, Loukas Moutsianas, Marc L. Perez, Gil McVean
Full text
Recent sero-epidemiological studies have strengthened the hypothesis that Epstein–Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV–host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.
GPT-4o mini: Non-social science research article
The histone variant H2A.W restricts heterochromatic crossovers in Arabidopsis
Namil Son, Heejin Kim, Jaeil Kim, Jihye Park, Dohwan Byun, Sang-jun Park, Hyein Kim, Yeong Mi Park, Pierre Bourguet, Frédéric Berger, Kyuha Choi
Full text
Meiotic crossovers rearrange allele combinations and create offspring diversity. Crossovers occur nonrandomly along chromosomes, predominantly in distal euchromatin and less in pericentromeric heterochromatin marked with histone H3 lysine 9 dimethylation (H3K9me2) and the H2A variant H2A.W in Arabidopsis thaliana . Loss of H3K9me2 increases heterochromatic crossovers, but how H2A.W affects crossover formation in pericentromeric regions is unknown. Here, we report that H2A.W is required to restrict heterochromatic crossovers in Arabidopsis . Using meiosis-specific microRNA-induced gene silencing (meiMIGS) and fluorescence-tagged recombination reporters, we show that meiotic knockdown of H2A.W.6 , H2A.W.7 , and H2A.W.12 ( meiMIGS-H2A.W.6/7/12 ) increases pericentromeric crossovers. High-resolution genomic maps of crossovers show that meiMIGS-H2A.W.6/7/12 enhances heterochromatic crossovers, similar to meiMIGS plants silencing the H3K9me2 pathway. Consistently, genome-wide crossover maps show that the mutants h2a.w.6 , h2a.w.7 , h2a.w.6 h2a.w.7 , and h2a.w.6 h2a.w.7 h2a.w.12, but not h2a.w.12, exhibit a similar increase in heterochromatic crossovers to meiMIGS-H2A.W.6/7/12 , demonstrating that H2A.W.6 and H2A.W.7 limit heterochromatic crossovers. Profiling of genome-wide nucleosome density using micrococcal nuclease sequencing reveals that h2a.w mutants with increased heterochromatic crossovers have increased heterochromatin accessibility, with lower H3K9me2 levels during meiosis. Our findings shed light on the role of H2A.W variants as heterochromatin compaction factors that suppress meiotic crossovers within the pericentromeric regions.
GPT-4o mini: Non-social science research article
Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development
Sara Formichetti, Joana B. Serrano, Urvashi Chitnavis, Agnieszka Sadowska, Na Liu, Ana Boskovic, Matthieu Boulard
Full text
The main form of intracellular protein glycosylation (O-GlcNAc) is reversible and has been mapped on thousands of cytoplasmic and nuclear proteins, including RNA polymerase II, transcription factors, and chromatin modifiers. The O-GlcNAc modification is catalyzed by a single enzyme known as O-GlcNAc Transferase, that is required for mammalian early development. Yet, neither the regulatory function of protein O-GlcNAcylation in the embryo nor the embryonic O-GlcNAc proteome have been documented. Here, we devised a strategy to enzymatically remove O-GlcNAc from preimplantation embryonic nuclei, where this modification accumulates coincidently with embryonic genome activation (EGA). Unexpectedly, the depletion of nuclear O-GlcNAc to undetectable levels has no impact on EGA, but dampens the transcriptional upregulation of the translational machinery, and triggers a spindle checkpoint response. These molecular alterations were phenotypically associated with a developmental delay starting from early cleavage stages and persisting after embryo implantation, establishing a link between nuclear glycosylation and the pace of embryonic development.
GPT-4o mini: Non-social science research article
Host ZAP activity correlates with the levels of CpG suppression in primate lentiviruses
Rayhane Nchioua, Dorota Kmiec, Veronika Krchlikova, Sarah Mattes, Sabrina Noettger, Frederic Bibollet-Ruche, Ronnie M. Russell, Konstantin M. J. Sparrer, Thomas Charpentier, Frédéric Tardy, Steven E. Bosinger, Daniel Sauter, Beatrice H. Hahn, Frank Kirchhoff
Full text
Zinc-finger antiviral protein (ZAP) is thought to drive the suppression of CpG dinucleotides in many viruses to mimic the composition of their host genomes. However, in vivo evidence is sparse. Here, we investigated the reasons for unusually high CpG levels in SIVmus and SIVmon from mustached and mona monkeys, descendants of one of the precursors of HIV-1. We show that SIVmus is not resistant to ZAP inhibition. Instead, these Cercopithecus monkey hosts differ from other primate species by a splice site mutation and express the poorly active extralarge XL rather than the highly active L isoform of ZAP. Similarly, higher CpG levels in endogenous prosimian lentiviruses were associated with low activity of the corresponding host lemur ZAPs. In addition, lemur genes also show lower CpG suppression than other primates. Thus, the antiviral activity of ZAP not only affects suppression of CpG dinucleotides in viral transcripts but possibly also host genomes.
GPT-4o mini: Non-social science research article
Dual genetic tracing demonstrates the heterogeneous differentiation and function of neuromesodermal progenitors in vivo
Hengwei Jin, Zixin Liu, Jialing Mou, Muxue Tang, Xiuzhen Huang, Kuo Liu, Qianyu Zhang, Kathy O. Lui, Bin Zhou
Full text
In recent decades, the traditional paradigm of three distinct germ layers formed during gastrulation has been revised with the identification of neuromesodermal progenitors (NMPs). These progenitors emerge during gastrulation and contribute to both the neural ectoderm, particularly the spinal cord, and the adjacent paraxial mesoderm [D. Henrique et al. , Development 142 , 2864–2875 (2015); R. J. Garriock et al. , Development 142 , 1628–1638 (2015); E. Tzouanacou et al. , Dev. Cell 17 , 365–376 (2009)]. However, effective genetic tools for lineage tracing and functional assessments of NMPs in vivo are currently lacking. Here, we developed a dual recombinase–mediated genetic system to specifically trace and ablate Brachyury + Sox2 + NMPs. Our genetic tracing and single-cell RNA sequencing analyses revealed that NMPs consist of three distinct unipotent and bipotent progenitor populations that progressively differentiate into neural and mesodermal fates. Genetic depletion of NMPs demonstrated their critical role in trunk and tail formation. This study provides in vivo genetic evidence supporting the heterogeneity of NMPs in terms of cell fate determination and their functional roles in the developing embryo.
GPT-4o mini: Non-social science research article
AcrIE7 inhibits the CRISPR-Cas system by directly binding to the R-loop single-stranded DNA
Do Yeon Kim, So Yeon Lee, Hyun Ji Ha, Hyun Ho Park
Full text
The CRISPR-Cas system is a well-known adaptive immune system in bacteria, and a prominent mechanism for evading this immunity involves anti-CRISPR (Acr) proteins, which employ various methods to neutralize the CRISPR-Cas system. In this study, using structural and biochemical analyses, we revealed that AcrIE7 binds to the single-stranded DNA in the R-loop formed when Cascade encounters the target DNA, thereby preventing Cas3 from cleaving the DNA. This represents a different inhibition strategy distinct from previously reported Acr mechanisms and offers insights into CRISPR-Cas inhibition.
GPT-4o mini: Non-social science research article
Activity of spinal RORÎČ neurons is related to functional improvements following combination treatment after complete SCI
Nicholas J. Stachowski, Jaimena H. Wheel, Shayna Singh, Sebastian J. Atoche, Lihua Yao, D. Leonardo Garcia-Ramirez, Simon F. Giszter, Kimberly J. Dougherty
Full text
Various strategies targeting spinal locomotor circuitry have been associated with functional improvements after spinal cord injury (SCI). However, the neuronal populations mediating beneficial effects remain largely unknown. Using a combination therapy in a mouse model of complete SCI, we show that virally delivered brain-derived neurotrophic factor (BDNF) (AAV-BDNF) activates hindlimb stepping and causes hyperreflexia, whereas submotor threshold epidural stimulation (ES) reduces BDNF-induced hyperreflexia. Given their role in gating proprioceptive afferents and as a potential convergence point of BDNF and ES, we hypothesized that an enhanced excitability of inhibitory RORÎČ neurons would be associated with locomotor improvements. Ex vivo spinal slice recordings from mice with a range of locomotor and hyperreflexia scores revealed that the excitability of RORÎČ neurons was related to functional outcome post-SCI. Mice with poor locomotor function after SCI had less excitable RORÎČ neurons, but the excitability of RORÎČ neurons was similar between the uninjured and “best stepping” SCI groups. Further, chemogenetic activation of RORÎČ neurons reduced BDNF-induced hyperreflexia and improved stepping, similar to ES. Our findings identify inhibitory RORÎČ neurons as a target population to limit hyperreflexia and enhance locomotor function after SCI.
GPT-4o mini: Non-social science research article
Alpha-tubulin tails regulate axoneme differentiation
Ming Li, Zhe Chen, Zhengyang Guo, Yang Wang, Yongping Chai, Wei Li, Guangshuo Ou
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The tubulin tail is a key element for microtubule (MT) functionality, but the functional redundancy of tubulin genes complicates the genetic determination of their physiological functions. Here, we removed the C-terminal tail of five alpha- and four beta-tubulin genes in the C. elegans genome. Sensory cilia typically exhibit an axoneme that longitudinally differentiates into a middle segment with doublet MTs and a distal segment with singlet MTs. However, the excision of the alpha-tubulin tail, but not the beta-tubulin tail, resulted in the ectopic formation of doublet MTs in the distal segments. Molecular dynamics simulations suggest that the alpha-tubulin tail could prevent the B-tubule from docking on the surface of A-tubule. Using recombinant tubulins, we demonstrated that removing the alpha-tubulin tail efficiently promoted doublet MTs formation in vitro. These results reveal the vital and unique contributions of tubulin tails to the structural integrity and accuracy of axoneme MT organization.
GPT-4o mini: Non-social science research article
FLIP L permits apoptotic and inflammatory signaling and inhibits necroptosis in mice without Caspase-8 oligomerization
Jeremy J. P. Shaw, Cliff Guy, Bart Tummers, Douglas R. Green
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Caspase-8 signaling has proapoptotic, antinecroptotic, and proinflammatory signaling roles dependent on interaction with the adapter molecule FADD, oligomerization, and autocleavage. Previously, a Caspase-8 binding partner cFLIP L (FLIP, encoded by Cflar ) was shown to prevent Caspase-8-dependent apoptosis, but permit Caspase-8-dependent inhibition of necroptosis. We sought to explore the role of FLIP in Caspase-8-dependent apoptosis induction, necroptosis inhibition, and inflammatory signaling inhibition in vitro and in vivo. We provide evidence that in mice with a mutation that prevents Caspase-8 oligomerization ( Casp8 FGLG/FGLG ), FLIP is necessary to inhibit necroptosis, promote apoptosis, regulate inflammation, and control lymphoproliferative disease. Unlike Casp8 FGLG/FGLG mice, Casp8 FGLG/FGLG ,Cflar −/− mice do not survive embryogenesis, but ablation of Mlkl , required for necroptosis, allows their survival to adulthood. Further, unlike Casp8 FGLG/FGLG ,Mlkl −/− mice, Casp8 FGLG/FGLG ,Cflar −/− ,Mlkl −/− mice display lymphoproliferative disease. We analyzed apoptosis, necroptosis, and inflammatory signaling in Casp8 FGLG/FGLG mice with or without FLIP, gaining insights into the functions of the Caspase-8–FLIP heterodimer in vitro and in vivo.
GPT-4o mini: Non-social science research article
Two transcription factors play critical roles in mediating epigenetic regulation of fruit ripening in tomato
Qingfeng Niu, Yaping Xu, Huan Huang, Linzhu Li, Dengguo Tang, Siqun Wu, Ping Liu, Ruie Liu, Yu Ma, Bo Zhang, Jian-Kang Zhu, Zhaobo Lang
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DNA methylation regulates fruit ripening in tomato, and disruption of the DNA demethylase DEMETER-LIKE 2 (DML2) results in genome-wide DNA hypermethylation and impaired ripening. We report here that the transcription factors Ripening Inhibitor (RIN) and FRUITFULL 1 (FUL1) play critical roles in mediating the effect of DNA methylation on tomato fruit ripening. RIN and FUL1 are silenced in dml2 mutant plants, and the defective ripening phenotype of dml2 is mimicked by the rin/ful1 double mutant. Restoration of RIN expression in dml2 partially rescues its ripening defects. DNA methylation controls ripening not only by regulating the expression of RIN and FUL1 but also by interfering with the genomic binding of RIN. In dml2 mutant plants, RIN cannot bind to some of its targets in vivo even though DNA methylation does not interfere with RIN binding in vitro; this inhibited binding in vivo is correlated with increased DNA methylation and histone H3 enrichment within 100 bp of the binding site. Our work uncovers the molecular mechanisms underlying DNA methylation control of fruit ripening in tomato.
GPT-4o mini: Non-social science research article
Chemically active wetting
Susanne Liese, Xueping Zhao, Christoph A. Weber, Frank JĂŒlicher
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Wetting of liquid droplets on passive surfaces is ubiquitous in our daily lives, and the governing physical laws are well understood. When surfaces become active, however, the governing laws of wetting remain elusive. Here, we propose chemically active wetting as a class of active systems where the surface is active due to a binding process that is maintained away from equilibrium. We derive the corresponding nonequilibrium thermodynamic theory and show that active binding fundamentally changes the wetting behavior, leading to steady, nonequilibrium states with droplet shapes reminiscent of a pancake or a mushroom. The origin of such anomalous shapes can be explained by mapping to electrostatics, where pairs of binding sinks and sources correspond to electrostatic dipoles along the triple line. This is an example of a more general analogy, where localized chemical activity gives rise to a multipole field of the chemical potential. The underlying physics is relevant for cells, where droplet-forming proteins can bind to membranes accompanied by the turnover of biological fuels.
GPT-4o mini: Non-social science research article
Monomers and short oligomers of human RAD52 promote single-strand annealing
Maria A. Kharlamova, Manish S. Kushwah, Tobias J. Jachowski, Sivaraman Subramaniam, Viktor Schiff, A. Francis Stewart, Philipp Kukura, Erik SchÀffer
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Genome maintenance and stability rely on the repair of DNA double-strand breaks. Breaks can be repaired via the single-strand-annealing pathway mediated by the protein RAD52. RAD52 oligomerizes to rings that are thought to promote annealing. However, rings have only been observed at micromolar concentrations at which annealing activity is impaired. Thus, it is unclear which oligomeric form is responsible for annealing. We combined single-molecule mass photometry with biochemical assays to determine the in vitro oligomeric states of human RAD52. We found that RAD52 was mostly monomeric at lower nanomolar concentrations. With increasing concentration, RAD52 oligomerized and formed rings with a variable stoichiometry from heptamers to tridecamers consistent with an oligomerization model of noncooperative assembly coupled with preferential cyclization. Under conditions where hardly any rings were present, RAD52 already promoted single-strand annealing in vitro. Our findings indicate that in vitro single-strand annealing can be mediated by monomers and short oligomers of RAD52. The oligomerization model suggests that ring formation is similar to a phase transition whereby rings are a reservoir to replenish the monomer and short oligomer pool. This pool has a nearly constant concentration which may be optimal for annealing and would be independent, for example, of the amount of DNA damage, protein upregulation, or the cell cycle.
GPT-4o mini: Non-social science research article
HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion
Masashi Arakawa, Keiya Uriu, Koki Saito, Mai Hirose, Kaoru Katoh, Krisana Asano, Akio Nakane, Tatsuya Saitoh, Tamotsu Yoshimori, Eiji Morita
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Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella , and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3–LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.
GPT-4o mini: Non-social science research article
Unbalanced growth and land overvaluation
Tomohiro Hirano, Alexis Akira Toda
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Historical trends suggest the decline in the importance of land as a production factor, as evidenced by the decline in the employment and gross domestic product (GDP) shares of land-intensive industries. However, land continues to be a prominent store of value, as over half of household wealth in major countries is real estate. To explain this apparent disconnection between land output and land value, in a plausible economic model with land and aggregate risk, we theoretically study the long-run behavior of land prices and identify economic conditions under which land becomes overvalued relative to the fundamentals defined by the present value of land rents. Unbalanced growth together with the elasticity of substitution between production factors plays a critical role. We establish the Land Overvaluation Theorem: When the elasticity of substitution between land and nonland factors exceeds 1 (which is natural because we can create more space by constructing taller buildings with fixed land) and technological progress is faster in nonland sectors, land overvaluation necessarily emerges. As applications of the Theorem, we present three examples: i) land overvaluation emerges along the long-run transition from the Malthusian agricultural economy to the modern knowledge- and service-based economy; ii) with aggregate uncertainty, land prices exhibit recurrent stochastic fluctuations around the trend, with expansions and contractions in the size of land overvaluation; and iii) in modern economies, land use is also changing and urban land has high value. We present a model of urban land prices and show that land overvaluation emerges in the process of urban formation characterized by unbalanced growth.
GPT-4o mini: Non-social science research article
The Hippo pathway and p27 Kip1 cooperate to suppress mitotic regeneration in the organ of Corti and the retina
Eva Jahanshir, Juan Llamas, Yeeun Kim, Kevin Biju, Sanyukta Oak, Ksenia Gnedeva
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The mature mammalian auditory sensory organ, the organ of Corti (OC), lacks the capacity for regenerating hair cells, leading to permanent hearing impairment. In contrast, the vestibular system has a limited capacity for hair cell regeneration, which we have shown to be further enhanced by inhibiting the Hippo pathway. Here, we demonstrate that, despite similar transcriptional responses, only vestibular and not auditory supporting cells proliferate as a result of Yap activation following Hippo inhibition. Mechanistically, we identify p27 Kip1 , a cell cycle kinase inhibitor encoded by Cdkn1b , as an additional barrier preventing cell cycle reentry specifically in the OC. We show that while in both systems Yap stimulates p27 Kip1 degradation through activation of its direct target gene Skp2 , this protein-level control is antagonized by an unusually high level of Cdkn1b transcription in the cochlea. Consequently, p27 Kip1 activity is maintained in the OC even in the presence of constitutively active Yap5SA, counteracting its mitogenic effects. Supporting this model, inactivation of the Hippo pathway in the Cdkn1b -deficient background is sufficient to induce adult auditory supporting cell proliferation in vivo. Furthermore, we show that the synergistic interaction between Hippo and p27 Kip1 is conserved in the retina where inhibition of both pathways potently induces MĂŒller glia proliferation and initiates neuronal regeneration. Our work uncovers the molecular mechanism preventing quiescent adult sensory progenitor cells, supporting cells in the ear and MĂŒller glia in the eye, from reentering the cell cycle after damage—the key step toward sensory receptor regeneration blocked in mammals.
GPT-4o mini: Non-social science research article
Reply to Vanunu and Newell: The frequent-winner effect is necessary to explain experience-based decisions
Sebastian Olschewski, Mikhail S. Spektor, Gaël Le Mens
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GPT-4o mini: Non-social science research article
Motion artifact–controlled micro–brain sensors between hair follicles for persistent augmented reality brain–computer interfaces
Hodam Kim, Ju Hyeon Kim, Yoon Jae Lee, Jimin Lee, Hyojeong Han, Hoon Yi, Hyeonseok Kim, Hojoong Kim, Tae Woog Kang, Suyeong Chung, Seunghyeb Ban, Byeongjun Lee, Haran Lee, Chang-Hwan Im, Seong J. Cho, Jung Woo Sohn, Ki Jun Yu, Tae June Kang, Woon-Hong Yeo
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Modern brain–computer interfaces (BCI), utilizing electroencephalograms for bidirectional human–machine communication, face significant limitations from movement-vulnerable rigid sensors, inconsistent skin–electrode impedance, and bulky electronics, diminishing the system’s continuous use and portability. Here, we introduce motion artifact–controlled micro–brain sensors between hair strands, enabling ultralow impedance density on skin contact for long-term usable, persistent BCI with augmented reality (AR). An array of low-profile microstructured electrodes with a highly conductive polymer is seamlessly inserted into the space between hair follicles, offering high-fidelity neural signal capture for up to 12 h while maintaining the lowest contact impedance density (0.03 kΩ·cm −2 ) among reported articles. Implemented wireless BCI, detecting steady-state visually evoked potentials, offers 96.4% accuracy in signal classification with a train-free algorithm even during the subject’s excessive motions, including standing, walking, and running. A demonstration captures this system’s capability, showing AR-based video calling with hands-free controls using brain signals, transforming digital communication. Collectively, this research highlights the pivotal role of integrated sensors and flexible electronics technology in advancing BCI’s applications for interactive digital environments.
GPT-4o mini: Non-social science research article
Bispecific antibodies against the hepatitis C virus E1E2 envelope glycoprotein
Laura Radić, Anna Offersgaard, Tereza Kadavá, Ian Zon, Joan Capella-Pujol, Fabian Mulder, Sylvie Koekkoek, Vera Spek, Ana Chumbe, Jens Bukh, Marit J. van Gils, Rogier W. Sanders, Victor C. Yin, Albert J. R. Heck, Judith M. Gottwein, Kwinten Sliepen, Janke Schinkel
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Hepatitis C virus (HCV) currently causes about one million infections and 240,000 deaths worldwide each year. To reach the goal set by the World Health Organization of global HCV elimination by 2030, it is critical to develop a prophylactic vaccine. Broadly neutralizing antibodies (bNAbs) target the E1E2 envelope glycoproteins on the viral surface, can neutralize a broad range of the highly diverse circulating HCV strains, and are essential tools to inform vaccine design. However, bNAbs targeting a single E1E2 epitope might be limited in neutralization breadth, which can be enhanced by using combinations of bNAbs that target different envelope epitopes. We have generated 60 immunoglobulin G (IgG)-like bispecific antibodies (bsAbs) that can simultaneously target two distinct epitopes on E1E2. We combine non- or partially overlapping E1E2 specificities into three types of bsAbs, each containing a different hinge length. The majority of bsAbs shows retained or increased potency and breadth against a diverse panel of HCV pseudoparticles and HCV produced in cell culture compared to monospecific and cocktail controls. Additionally, we demonstrate that changes in the hinge length of bsAbs can alter the binding stoichiometry to E1E2. These results provide insights into the binding modes and the role of avidity in bivalent targeting of diverse E1E2 epitopes.This study illustrates how potential cooperative effects of HCV bNAbs can be utilized by strategically designing bispecific constructs. These HCV bsAbs can guide vaccine development and unlock novel therapeutic and prophylactic strategies against HCV and other (flavi)viruses.
GPT-4o mini: Non-social science research article
Structural basis for immune cell binding of Fusobacterium nucleatum via the trimeric autotransporter adhesin CbpF
Gian Luca Marongiu, Uwe Fink, Felix Schöpf, Andreas Oder, Jens Peter von Kries, Daniel Roderer
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Fusobacterium nucleatum (Fn), a commensal in the human oral cavity, is overrepresented in the colon microbiota of colorectal cancer (CRC) patients and is linked to tumor chemoresistance, metastasis, and a poor therapeutic prognosis. Fn produces numerous adhesins that mediate tumor colonization and downregulation of the host’s antitumor immune response. One of these, the trimeric autotransporter adhesin (TAA) CEACAM binding protein of Fusobacterium (CbpF), targets CEACAM1 on T-cells and has been associated with immune evasion of Fn-colonized tumors. Whereas the role of CEACAM1 in homophilic and heterophilic cell interactions and immune evasion is well described, the mechanistic details of its interaction with fusobacterial CbpF remain unknown due to the lack of a high-resolution structure of the adhesin–receptor complex. Here, we present two structures of CbpF alone and in complex with CEACAM1, obtained by cryogenic electron microscopy and single particle analysis. They reveal that CbpF forms a stable homotrimeric complex whose N-terminal part of the extracellular domain comprises a 64 Å long ÎČ roll domain with a unique lateral loop extension. CEACAM1 binds to this loop with high affinity via its N-terminal IgV-like domain with a nanomolar dissociation constant as determined by surface plasmon resonance. This study provides a comprehensive structural description of a fusobacterial TAA, illustrates a yet undescribed CEACAM1 binding mode, and paves the way for rational drug design targeting Fn in CRC.
GPT-4o mini: Non-social science research article
Seismic fault slip at depths simulated by high-velocity friction experiments under hydrothermal conditions
Lu Yao, Wei Feng, Chiara Cornelio, Toshihiko Shimamoto, Shengli Ma, Giulio Di Toro
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Seismic fault slip and rupture propagation often occur at crustal depths in the presence of hot and pressurized aqueous fluids (i.e., hydrothermal conditions). Previous experiments investigated fault frictional properties under hydrothermal conditions, but at imposed subseismic fault slip velocities ( V ~Όm/s). Here, using a rotary-shear apparatus equipped with a hydrothermal pressure vessel, we study friction at seismic slip velocities ( V = 1.5 m/s) of gabbro- and marble-built faults under temperatures of 40 to 400 °C and pore water pressure of 30 MPa. We find that with increasing initial water temperature ( T amb ), the dynamic friction during initial slip acceleration and subsequent high-velocity sliding decreases for both gabbro- and marble-built faults, while the slip-weakening distance decreases for gabbro but increases for marble. Then, during rapid deceleration at the end of sliding, frictional strength recovery decreases for gabbro with increasing T amb and increases for marble independently of T amb . As in previous experiments performed at room T amb , the mechanical and microstructural data, plus numerical modeling, suggest that the seismic fault weakening mechanisms shift from flash heating to bulk melting for gabbro, and from flash heating to grain boundary sliding accommodated by diffusion creep for marble, with their activation processes depending on T amb . Our results demonstrate the effects of ambient temperature on seismic fault friction, which contribute to changes in fault strength and dynamic weakening processes at crustal depths and should be considered in earthquake rupture modeling.
GPT-4o mini: Non-social science research article
Transferring climate change physical knowledge
Francesco Immorlano, Veronika Eyring, Thomas le Monnier de Gouville, Gabriele Accarino, Donatello Elia, Stephan Mandt, Giovanni Aloisio, Pierre Gentine
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Precise and reliable climate projections are required for climate adaptation and mitigation, but Earth system models still exhibit great uncertainties. Several approaches have been developed to reduce the spread of climate projections and feedbacks, yet those methods cannot capture the nonlinear complexity inherent in the climate system. Using a Transfer Learning approach, we show that Machine Learning can be used to optimally leverage and merge the knowledge gained from global temperature maps simulated by Earth system models and observed in the historical period to reduce the spread of global surface air temperature fields projected in the 21st century. We reach an uncertainty reduction of more than 50% with respect to state-of-the-art approaches while giving evidence that our method provides improved regional temperature patterns together with narrower projections uncertainty, urgently required for climate adaptation.
GPT-4o mini: Non-social science research article
In situ generated hydrogen-bonding microenvironment in functionalized MOF nanosheets for enhanced CO 2 electroreduction
Ge Yang, Jiajia Huang, Weizhi Gu, Zhongyuan Lin, Qingyu Wang, Rong Kang, Jing-Yao Liu, Zhihu Sun, Xusheng Zheng, Long Jiao, Hai-Long Jiang
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The microenvironment around catalytic sites plays crucial roles in enzymatic catalysis while its precise control in heterogeneous catalysts remains challenging. Herein, the coordinatively unsaturated metal nodes of Hf-based metal-organic framework nanosheets are simultaneously codecorated with catalytically active Co(salen) units and adjacent pyridyl-substituted alkyl carboxylic acids via a post modification route. By varying pyridyl-substituted alkyl carboxylic acids, the spatial positioning of the N atom in pyridine group relative to adjacent Co(salen) can be precisely controlled. Notably, the 3-(pyridin-4-yl)propionic acid, with para -position pyridine N atom, maximally improves the electrocatalytic CO 2 reduction performance of Co(salen) unit, far superior to other counterparts. Mechanism investigations reveal that the pyridine unit of 3-(pyridin-4-yl)propionic acid is optimally positioned relative to Co(salen) and undergoes in situ reduction to pyridinyl radical under working potentials. This greatly facilitates the stabilization of *COOH intermediate via hydrogen-bonding interaction, lowering the formation energy barrier of *COOH and therefore boosting CO 2 electroreduction.
GPT-4o mini: Non-social science research article
Arf1 and ARFGEF2/Sec71 control neuroblast polarity by anchoring nonmuscle myosin II
Mahekta R. Gujar, Ye Sing Tan, Yang Gao, Hongyan Wang
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Neural stem cells (NSCs) can self-renew and undergo differentiation via asymmetric division. Dysregulation in the balance between self-renewal and differentiation can lead to tumor formation or neurodevelopmental disorders. However, the regulation of phosphatidylinositol transfer protein (PITP)-dependent PI(4)P pools and myosin localization during asymmetric division in dividing cells is not well established. Here, we show that the Golgi proteins Arf1 and ARFGEF2/Sec71 control asymmetric division of Drosophila NSCs by facilitating the localization of myosin II regulatory light chain, Sqh, to the NSC cortex. Arf1 can physically associate with Sqh and Vibrator, a type I PITP that stimulates phospholipid PI4K activity for PI(4)P production. Further, Arf1 and Sec71 facilitate PI(4)P localization to the cell cortex of neuroblasts. Our data provide evidence that the Golgi proteins Arf1 and its GEF Sec71 facilitate neuroblast polarity through phospholipid-dependent nonmuscle myosin II cortical localization.
GPT-4o mini: Non-social science research article
The Beholder’s Share: Bridging art and neuroscience to study individual differences in subjective experience
Celia Durkin, Marc Apicella, Christopher Baldassano, Eric Kandel, Daphna Shohamy
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Our experience of the world is inherently subjective, shaped by individual history, knowledge, and perspective. Art offers a framework within which this subjectivity is practiced and promoted, inviting viewers to engage in interpretation. According to art theory, different forms of art—ranging from the representational to the abstract—challenge these interpretive processes in different ways. Yet, much remains unknown about how art is subjectively interpreted. In this study, we sought to elucidate the neural and cognitive mechanisms that underlie the subjective interpretation of art. Using brain imaging and written descriptions, we quantified individual variability in responses to paintings by the same artists, contrasting figurative and abstract paintings. Our findings revealed that abstract art elicited greater interindividual variability in activity within higher-order, associative brain areas, particularly those comprising the default-mode network. By contrast, no such differences were found in early visual areas, suggesting that subjective variability arises from higher cognitive processes rather than differences in sensory processing. These findings provide insight into how the brain engages with and perceives different forms of art and imbues it with subjective interpretation.
GPT-4o mini: Non-social science research article
Uniform elementary fibrils in diverse plant cell walls
Kazuho Daicho, Shuji Fujisawa, Yoshinori Doi, Michio Suzuki, Junichiro Shiomi, Tsuguyuki Saito
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Plant cell walls are composed of skeletal cellulose and a filling matrix of hemicelluloses and lignin. Cellulose has slender crystallite units referred to as microfibrils or elementary fibrils, and these crystallites form a dense network skeleton in the cell walls. In this study, we assessed the morphology and crystallinity of individually dispersed microfibrils isolated from the cell walls of wood, cotton, and ramie celluloses. It is well known that microfibrils in higher plants exhibit structural diversity, and these three plants, in particular, have distinct differences in the morphology and crystallinity of microfibrils. Our structural analyses combining atomic force microscopy (AFM), wide-angle X-ray diffraction (WAXD), small-angle X-ray scattering (SAXS), solid-state 13 C NMR spectroscopy, and all-atom molecular dynamics (MD) simulations revealed the uniformity in the cross-sectional dimensions and crystallinity of the dispersed microfibrils, irrespective of the plant species. The majority of the microfibrils were dispersed as structural units with widths of approximately 2 to 3 nm, and their crystallite sizes and crystallinity degrees were approximately 2 nm and 20%, respectively. These structural profiles were in agreement with the simulation results; here, the model assumed that a single microfibril consisted of 18 cellulose molecules. These results from the direct dimensional assessments support a recent hypothesis in biophysics that a single biosynthesis system of cellulose, referred to as the terminal complex (TC), consisted of 18 synthases. Some of the dispersed microfibrils had bundled sizes of two or three microfibrils. We also demonstrated that this bundling was stabilized by the fusion of several crystallites.
GPT-4o mini: Non-social science research article
Cortical scaling of the neonatal brain in typical and altered development
Alexandra F. Bonthrone, Daniel Cromb, Andrew Chew, Barat Gal-Er, Christopher Kelly, Shona Falconer, Tomoki Arichi, Kuberan Pushparajah, John Simpson, Mary A. Rutherford, Joseph V. Hajnal, Chiara Nosarti, A. David Edwards, Jonathan O’Muircheartaigh, Serena J. Counsell
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Theoretically derived scaling laws capture the nonlinear relationships between rapidly expanding brain volume and cortical gyrification across mammalian species and in adult humans. However, the preservation of these laws has not been comprehensively assessed in typical or pathological brain development. Here, we assessed the scaling laws governing cortical thickness (CT), surface area (SA), and cortical folding in the neonatal brain. We also assessed multivariate morphological terms that capture brain size, shape, and folding processes. The sample consisted of 345 typically developing infants, 73 preterm infants, and 107 infants with congenital heart disease (CHD) who underwent brain MRI. Our results show that typically developing neonates and those with CHD follow the cortical folding scaling law obtained from mammalian brains, children, and adults which captures the relationship between exposed SA, total SA, and CT. Cortical folding scaling was not affected by gestational age at birth, postmenstrual age at scan, sex, or multiple birth in these populations. CHD was characterized by a unique reduction in the multivariate morphological term capturing size, suggesting that CHD affects cortical growth overall but not cortical folding processes. In contrast, preterm birth was characterized by altered cortical folding scaling and altered shape, suggesting that the developmentally programmed processes of cortical folding are disrupted in this population. The degree of altered shape was associated with cognitive abilities in early childhood in preterm infants.
GPT-4o mini: Non-social science research article
Multiplexing of cognitive encoding by oculomotor networks leads to incidental gaze shifts
Matthew C. Rosen, David J. Freedman
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Humans and other animals are adept at learning to perform cognitively demanding behavioral tasks. Neurophysiological recordings in nonhuman primates during such tasks find that the requisite cognitive variables are encoded strongly in core oculomotor brain regions. Here, we assembled a large dataset—11 monkeys performing an abstract visual categorization task, surveyed across more than 1,000 neural recording sessions—to reveal that this produces a robust but uninstructed behavioral “tell,” observed in all subjects and experiments: small, cognitively modulated eye movements. We find that these eye movements are causally linked to activity in SC but not LIP, and that they occur following transient alignment of cognitive and saccadic population coding subspaces in SC. This behavioral signature of oculomotor engagement is absent during a similar task that does not require rule-based categorization, suggesting that abstract task behaviors recruit primate oculomotor networks more strongly than previously understood.
GPT-4o mini: Non-social science research article
Probing ultraweak in-plane magnetic anisotropy within a two-dimensional layered antiferromagnet
Yijie Fan, Yihong Xu, Renji Bian, Ruan Zhang, Junning Mei, Jiaxin Wu, Binghe Xie, Shuangxing Zhu, Yu Chen, Feifan Gu, Ying Liu, Takashi Taniguchi, Kenji Watanabe, Fucai Liu, Xinghan Cai
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Magnetic anisotropy plays a crucial role in determining the critical behavior and phase transitions in two-dimensional magnetic systems. It is also required for the design of thin-film spintronic devices. Despite its significance, sensing extremely weak anisotropy has proven challenging in van der Waals antiferromagnetic/ferrimagnetic materials. Here, we first employ simulations of micromagnetic energy function in few-layer easy-plane antiferromagnetic systems with a weak additional uniaxial anisotropy and unveil an intriguing even–odd effect closely linked to low-field spin–flop behaviors. We further perform tunneling magneto-conductance measurements on a model 2D antiferromagnetic insulator, CrCl 3 , exhibiting near-ideal easy-plane anisotropy. The magnetic field-controlled tunneling current at low temperature aligns well with simulated in-plane anisotropic spin-configuration, providing direct experimental evidence for detecting magnetic anisotropy field around 1 mT. Our work creates opportunities for finely characterizing magnetic structures and behaviors in 2D antiferromagnetic/ferrimagnetic systems, with potential applications in spintronics such as data storage and magnetic sensing.
GPT-4o mini: Non-social science research article
Disease resistance is more costly at younger ages: An explanation for the maintenance of juvenile susceptibility in a wild plant
Samuel P. Slowinski, Allyson K. Kido, Laura W. Alexander, Andrea H. Shirdon, Emily L. Bruns
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High juvenile susceptibility drives infectious disease epidemics across kingdoms, yet the evolutionary mechanisms that maintain this susceptibility are unclear. We tested the hypothesis that juvenile susceptibility is maintained by high costs of resistance by quantifying the genetic correlation between host fitness and age-specific innate resistance to a fungal pathogen in a wild plant. We separately measured the resistance of 45 genetic families of the wild plant, Silene latifolia, to its endemic fungal pathogen, Microbotryum lychnidis-dioicae, at four ages in a controlled inoculation experiment. We then grew these same families in a field common garden and tracked survival and fecundity over a 2-y period and quantified the correlation between age-specific resistance and fitness in the field. We found significant fitness costs associated with disease resistance at juvenile but not at adult host stages. We then used an age-structured compartmental model to show that the magnitude of these costs is sufficient to prevent the evolution of higher juvenile resistance in models, allowing the disease to persist. Taken together, our results show that costs of resistance vary across host lifespan, providing an evolutionary explanation for the maintenance of juvenile susceptibility.
GPT-4o mini: Non-social science research article
Glassy ionogels with high compressibility and strength for impact protection
Jiayu Wang, Shilong Zhang, Lingling Li, Xiaoliang Wang, Jiaofeng Xiong, Qingning Li, Weizheng Li, Feng Yan
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Solvents within gels enhance the mobility of polymer chain segments while concurrently diminishing interchain interactions, thereby facilitating the ductility of glassy polymers at the cost of their mechanical strength. Here, we develop a solvent toughening strategy for the preparation of highly compressible and high-strength ionogels in the glassy state. This approach leverages the synergistic effects of the slow dissociation-shift kinetics of solvent ionic liquids and polymer crystallization. Ionogels exhibit an ultimate compressive stress of 2.3 GPa (at 98% compressive strain), toughness of 1219.3 MJ m −3 , and energy dissipation rate of 81.9% (at 70% compression strain). The highly interacting ionic bonds of solvent and the fast crystallization of polymers under load toughen the ionogels and confer impact hardening and efficient energy dissipation behavior under fast impact. A 500-ÎŒm-thick ionogel coating can protect fragile items, such as glass, from impact damage. Ionogels, renowned for their impact resistance, hold promise for various applications across industries including human body implants, equipment, transportation, and aerospace.
GPT-4o mini: Non-social science research article
On the hidden transient interphase in metal anodes: Dynamic precipitation controls electrochemical interfaces in batteries
Stephen T. Fuller, J.-X. Kent Zheng
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The solid–electrolyte interphase (SEI) formed on a battery electrode has been a central area of research for decades. This structurally complex layer profoundly impacts the electrochemical deposition morphology and stability of metal anodes. Departing from conventional approaches, we investigate metal dissolution—the reverse reaction of deposition—in battery environments using a state-of-the-art electroanalytical system combining a rotating-disk electrode and operando visualization. Our key finding is the presence of a transient SEI (T-SEI) that forms during fast discharging at high dissolution rates. We attribute T-SEI formation to local supersaturation and resultant electrolyte salt deposition. The T-SEI fundamentally alters the dissolution kinetics at the electrochemical interface, yielding a flat, clean surface. Unlike a classical SEI formed due to electrolyte decomposition, the T-SEI is “relaxable” upon removal of the enforced dissolution current; that is, the T-SEI dissolves back into the electrolyte when rested. The formation of T-SEI plays an unexpected critical role in the subsequent electrodeposition. When the metal is redeposited on a fully relaxed T-SEI surface, the morphology is remarkably different from that deposited on pristine or low-rate-discharged metal electrodes. Electron backscatter diffraction analysis suggests that the deposition occurs via growth of the original grains; this is in stark contrast to the isolated, new nuclei seen on standard metal electrodes without T-SEI formation. Using 3D profilometry, we observe a 42% reduction in surface roughness due to T-SEI formation. Our findings provide important insights into the kinetics at ion-producing electrochemical interfaces, and suggest a new dimension for engineering next generation batteries.
GPT-4o mini: Non-social science research article
ID3 enhances PD-L1 expression by restructuring MYC to promote colorectal cancer immune evasion
Chuanzhong Huang, Ling Wang, Changhua Zhuo, Wenxin Chen, Hongmei Fan, Yilin Hong, Yu Zhang, Dongmei Zhou, Wansong Lin, Lingyu Zhang, Jingjing Zhao, Shuping Chen, Chundong Yu, Yunbin Ye
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The inhibitor of DNA binding protein ID3 has been associated with the progression of colorectal cancer (CRC). Despite its significance, its specific role in the immune evasion strategies utilized by CRC remains unclear. RNA-seq analysis revealed that ID3 was positively associated with the PD-L1 immune checkpoint. We further demonstrated that tumor cell–expressed ID3 enhanced PD-L1 expression, suppressed the infiltration and activation of CD8 + T cells, and facilitated the immune evasion of CRC cells. Additionally, we found that knockdown of ID3 significantly enhanced the effectiveness of PD-L1 antibody blockade treatment in combating CRC, reduced the upregulation of PD-L1 induced by the antibody, and altered the immune microenvironment within CRC. Mechanistically, ID3 interacted with the transcription factor MYC and reconstructed the four-dimensional structure of MYC, thereby enhancing its binding affinity to the PD-L1 promoter and augmenting PD-L1 transcriptional activity. By integrating analysis of ChIP-seq, RNA-seq, and ImmPort gene sets, we found that ID3’s DNA-assisted binding function was widespread and could either enhance or suppress gene transcription, not only affecting tumor immune escape through immune checkpoints but also regulating various cytokines and immune cells involved in tumor immunity. In conclusion, our study uncovers a mechanism by which ID3 promotes immune evasion in CRC and implicates that targeting ID3 may improve the efficacy of anti-PD-1/PD-L1 immunotherapy.
GPT-4o mini: Non-social science research article
On Hodge polynomials for nonalgebraic complex manifolds
Ludmil Katzarkov, Kyoung-Seog Lee, Ernesto Lupercio, Laurent Meersseman
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Hodge theory is pivotal in studying algebraic varieties’ intricate geometry and topology: it provides essential insights into their structure. The Hodge decomposition theorem establishes a profound link between the geometry of varieties and their cohomology groups, helping to understand their underlying properties. Moreover, Hodge theory was crucial at the inception of the field of mirror symmetry, revealing deep connections among seemingly disparate algebraic varieties. It also sheds light on studying algebraic cycles and motives, crucial objects in algebraic geometry. This article explores Hodge polynomials and their properties, specifically focusing on non-KĂ€hler complex manifolds. We investigate a diverse range of such manifolds, including (quasi-)Hopf, (quasi-)Calabi–Eckmann, and LVM manifolds, alongside a class of definable complex manifolds encompassing both algebraic varieties and the aforementioned special cases. Our research establishes the preservation of the motivic nature of Hodge polynomials inside this broader context. Through explicit calculations and thorough analyses, this work contributes to a deeper understanding of complex manifold geometry beyond the realm of algebraic varieties. The outcomes of this study have potential applications in various areas of mathematics and physics where complex manifolds play a significant role.
GPT-4o mini: Non-social science research article
Compositional and topological determinants of a physiological Ashwell–Morell receptor ligand
John Hintze, Robert Fraumeni, Noortje de Haan, Rebecca L. Miller, Mayank Saraswat, Zhang Yang, Henrik Clausen, Jamey D. Marth
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The hepatocyte Ashwell–Morell receptor (AMR) is the prototypical mammalian lectin and the first cell receptor isolated. This recycling endocytic receptor of the plasma membrane determines the concentrations of hundreds of circulating glycoproteins in the blood and plays important roles in host responses to and outcomes of infection. The compositional and topological determinants of a physiological AMR ligand have remained unclear with contradictory findings reported. Previous studies established that the AMR binds multivalent galactose on desialylated triantennary or higher-branched N-glycans with little to no binding to galactose on biantennary forms. However, the vast majority of circulating blood glycoproteins are modified by biantennary N-glycans, rendering them unlikely to be ligands bound and eliminated by the AMR. Separately, other studies reported that AMR ligands include sialylated N-glycans, and specifically α2-6, but not α2-3, sialic acid linkages. Herein, we investigated the composition and topology of AMR ligands using a known physiological AMR ligand, intestinal alkaline phosphatase (IAP). Recombinant active IAP was produced in glycoengineered cells with either biantennary or higher valency triantennary and tetra-antennary N-glycan structures, and further with and without either α2-6 or α2-3 sialic acid linkages. These closely homogenous IAP monomer glycoforms assemble as dimers with similar enzymatic activity and were compared in AMR binding and clearance assays. Our results indicate that the AMR does not significantly bind IAP when its N-glycans are predominantly sialylated with either α2-6 or α2-3 sialic acid linkages. Multivalent desialylated AMR ligands may, however, appear when IAP monomers dimerize, resulting in the close proximation of biantennary N-glycans.
GPT-4o mini: Non-social science research article
Neddylation modification stabilizes LC3B by antagonizing its ubiquitin-mediated degradation and promoting autophagy in skin
Linlin Xu, Xinxing Lyu, Yibo Wang, Li Ni, Pin Li, Piao Zeng, Qixia Wang, Yunhao Chang, Chenglong Pan, Qingxia Hu, Shuhong Huang, Ningning Dang
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The Atg8-family proteins, including LC3B (microtubule-associated protein 1 light chain 3 beta), are pivotal for key steps in the autophagy process. Proper regulation of LC3B homeostasis is essential for its function. Although LC3B is modulated by various posttranslational modifications (PTMs), the impact of these modifications on LC3B protein homeostasis remains unclear. Neddylation, a recently identified ubiquitin-like modification, plays diverse biological roles. Here, we identify LC3B as a specific target for neddylation. This modification weakens LC3B’s interaction with the ubiquitin E3 ligases VHL and BIRC6, thereby reducing LC3B ubiquitination. Depletion of ubiquitin-conjugating enzyme E2M (UBE2M), the primary E2 enzyme in the neddylation pathway, destabilizes LC3B and suppresses autophagy activity. Heterozygous Ube2m knockout ( Ube2m +/− ) mice exhibit pronounced aging-like phenotypes, with reduced LC3B expression and impaired autophagy in skin tissues. Our findings demonstrate that LC3B neddylation is vital for maintaining its stability and regulating autophagy flux, offering a potential therapeutic avenue to mitigate aging-related processes.
GPT-4o mini: Non-social science research article
Proximity-activated DNA scanning encoded sequencing for massive access to membrane proteins nanoscale organization
Xueqi Zhao, Yue Zhao, Zhu Li, Huan Liu, Wenhao Fu, Feng Chen, Ying Sun, Daqian Song, Chunhai Fan, Yongxi Zhao
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Cellular structure maintenance and function regulation critically depend on the composition and spatial distribution of numerous membrane proteins. However, current methods face limitations in spatial coverage and data scalability, hindering the comprehensive analysis of protein interactions in complex cellular nanoenvironment. Herein, we introduce p roximity- a ctivated D NA s canning e ncoded sequencing (PADSE-seq), an innovative technique that utilizes flexible DNA probes with adjustable lengths. These dynamic probes are anchored at a single end, enabling free swings within a nanoscale range to perform global scanning, recording, and accumulating of information on diverse proximal proteins in random directions along unrestricted paths. PADSE-seq leverages the autonomous cyclic cleavage of single-stranded DNA to sequentially activate encoded probes distributed throughout the local area. This process triggers strand displacement amplification and bidirectional extension reactions, linking proteins barcodes with molecular barcodes in tandem and further generating millions to billions of amplicons embedded with the combinatorial identifiers for next-generation sequencing analysis. As a proof of concept, we validated PADSE-seq for mapping the distribution of over a dozen kinds of proteins, including HER1, EpCAM, and PDL1, in proximity to HER2 in breast cancer cell lines, demonstrating its ability to decode multiplexed protein proximities at the nanoscale. Notably, we observed that the spatial distribution of proximal proteins around low-abundance target proteins exhibited greater diversity across regions with variable proximity ranges. This method offers a massive access for high-resolution and comprehensive mapping of cellular molecular interactions, paving the way for deeper insights into complex biological processes and advancing the field of precision medicine.
GPT-4o mini: Non-social science research article
ZmGCT1/2 negatively regulate drought tolerance in maize by inhibiting ZmSLAC1 to maintain guard cell turgor
Zhenkai Feng, Huiying Li, Zhihui Sun, Jinkui Cheng, Deping Hua, Yu Wang, Junsheng Qi, Shuhua Yang, Zhizhong Gong
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Stomata, which are essential for the exchange of CO 2 and water vapor between plant leaves and the atmosphere, are regulated by a variety of environmental and internal factors. In this study, we identified and characterized two genes, Guard Cell Turgor Maintaining 1 ( GCT1 ) and its closest homolog GCT2 , which encode rapidly accelerated fibrosarcoma (RAF)-like protein kinases that play a critical role in maintaining guard cell turgor in Zea mays . We found that overexpression of ZmGCT1 and ZmGCT2 confers resistance to abscisic acid (ABA)-promoted stomatal closure, whereas the zmgct1 zmgct2 double loss-of-function mutants exhibit a loss of guard cell turgor, resulting in nearly closed stomata even under favorable growth conditions. A dominant mutation, zmgct1-9D , which lacks nine amino acids including T80, retains its kinase activity and plasma membrane localization but displays insensitive to ABA-, CO 2 -, Ca 2+ -, or H 2 O 2 -promoted stomatal closure. ABA-activated ZmSnRK2.8/9 phosphorylates ZmGCT1 at T80, reducing its plasma membrane localization. Intriguingly, the ZmSnRK2.10 or ZmSLAC1 mutant can suppress the reduced turgor phenotype in guard cells of the zmgct1 mutant. Furthermore, ZmGCT1 phosphorylates the penultimate threonine residue (T573) of ZmSLAC1, inhibiting both the constitutively active ZmSLAC1 and ZmSnRK2.8-activated ZmSLAC1 in Xenopus laevis oocytes, a process dependent on ZmGCT1 kinase activity. These findings suggest that ZmGCT1 and ZmGCT2 directly inhibit ZmSLAC1 to maintain guard cell turgor under favorable growth conditions, while ABA treatment alleviates this inhibition primarily by reducing ZmGCT1’s plasma membrane localization. This study provides mechanistic insights into the regulation of stomatal movement by ZmGCT1/2 kinases under both favorable and stress conditions.
GPT-4o mini: Non-social science research article
Downregulation of Nesprin1 by Runx2 deficiency is critical for the development of skeletal laminopathy-like pathology
Akiko Saito, Kazuaki Nagayama, Hiroyuki Okada, Shoko Onodera, Natsuko Aida, Takashi Nakamura, Takashi Sawada, Hironori Hojo, Shigeaki Kato, Toshifumi Azuma
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Runx2 is a master regulator of bone formation, and its dysfunction causes cleidocranial dysplasia (CCD) in humans. When iPS cells were generated from patients with CCD and Runx2-deficient iPS cells were generated using gene-editing techniques, abnormal laminopathy-like nuclei were observed. Runx2-deficient cells showed reduced Lamin A/C expression, but not protein levels. However, in Runx2-deficient cells, both the gene expression and protein levels of Nesprin1 were reduced, perinuclear actin fibers were sparser, and nuclear stiffness was reduced. Forced expression of Lamin A/C increased nuclear stiffness but did not improve nuclear morphology. In contrast, the induction of Nesprin1 expression alone normalized nuclear stiffness and restored nuclear morphology and perinuclear actin distribution. In Runx2-null cells, mechanical stress-induced phosphorylation of emerin was not observed. In contrast, forced expression of Nesprin1 in Runx2-null cells resulted in phosphorylation of emerin, indicating the restoration of intracellular tension. These observations were confirmed by atomic force microscopy. Therefore, the intracellular tension was inferred to pull the nuclear membrane into its normal shape. CUT&RUN assay and single RNA-seq analysis showed that an aberrant nuclear membrane caused loss of nuclear lamina gene regulation machinery, making the progression of normal osteogenic differentiation impossible; however, supplementation with Nesprin1 restored gene regulation mechanisms and promoted preosteoblast formation with normal nuclear morphology. Nesprin1 expression induced by Runx2 is essential for epigenetic regulation of the nuclear lamina. We propose CCD as a type of laminopathy involving defective expression of Nesprin1 regulated by Runx2.
GPT-4o mini: Non-social science research article
Degenerate domain walls in supersymmetric theories
Shi Chen, Evgenii Ievlev, Mikhail Shifman
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In supersymmetric Yang–Mills theories tension-degenerate domain walls are typical. Adding matter fields in fundamental representation, we arrive at supersymmetric quantum chromodynamics (SQCD) supporting similar walls. We demonstrate that the degenerate domain walls can belong to one of two classes: i) locally distinguishable, i.e. those which differ from each other locally (which could be detected in local measurements); and ii) those which have identical local structure and are differentiated only topologically, through a judicially chosen compactification of R 4 . Depending on the number of flavors F and the pattern of Higgsing, both classes can coexist among SQCD k walls interpolating between the vacua n and n + k . We prove that the overall multiplicity of the domain walls obtained after accounting for both classes is Îœ N , k walls = N ! / [ ( N − k ) ! k ! ] , as was discovered previously in limiting cases. (Here, N is the number of colors.) Thus, Îœ N , k walls is a peculiar index. For the locally distinguishable degenerate domain walls, we observe two-wall junctions, a phenomenon specific for supersymmetry with central extensions. This phenomenon does not exist for topological replicas.
GPT-4o mini: Non-social science research article
Astrocytic Ryk signaling coordinates scarring and wound healing after spinal cord injury
Zhe Shen, Bo Feng, Wei Ling Lim, Timothy Woo, Yanlin Liu, Silvia Vicenzi, Jingyi Wang, Brian K. Kwon, Yimin Zou
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Wound healing after spinal cord injury involves highly coordinated interactions among multiple cell types, which are poorly understood. Astrocytes play a central role in creating a border against the non-neural lesion core. To do so, astrocytes undergo dramatic morphological changes by first thickening and elongating their processes and then overlapping them to form a physical barrier. We show here that the expression of a cell-surface receptor, Ryk, is induced in astrocytes after injury in both rodent and human spinal cords. Astrocyte-specific knockout of Ryk dramatically elongated the reactive astrocytes, accelerated the formation of the border, and reduced the size of the scar. Astrocyte-specific knockout of Ryk also accelerated the injury responses of multiple cell types. Single-cell transcriptomics analyses revealed a broad range of changes in cell signaling among astrocytes, microglia, fibroblasts, and endothelial cells after astrocyte-specific Ryk knockout, suggesting that Ryk not only regulates injury responses of astrocytes but may also regulate signals emanating from astrocytes and coordinate the responses of these cell types. The elongation of astrocyte processes is mediated by NrCAM, a cell adhesion molecule induced by astrocyte-specific conditional knockout of Ryk after spinal cord injury. Our findings suggest that Ryk is a promising therapeutic target to accelerate wound healing, promote neuronal survival, and enhance functional recovery.
GPT-4o mini: Non-social science research article
Biallelic variants in the conserved ribosomal protein chaperone gene PDCD2 are associated with hydrops fetalis and early pregnancy loss
Anne-Marie Landry-Voyer, Tess Holling, Emily K. Mis, Zabih Mir Hassani, Malik Alawi, Weizhen Ji, Lauren Jeffries, Kerstin Kutsche, François Bachand, Saquib A. Lakhani
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Pregnancy loss is a major problem in clinical medicine with devastating consequences for families. Next generation sequencing has improved our ability to identify underlying molecular causes, though over half of all cases lack a clear etiology. Here, we began with clinical evaluation combined with exome sequencing across independent families to identify bi-allelic candidate genetic variants in the Programmed Cell Death 2 (PDCD2) gene in multiple fetuses with nonimmune hydrops fetalis (NIHF). PDCD2 is an evolutionarily conserved protein with no prior association with monogenic disorders. PDCD2 is known to act as a molecular chaperone for the ribosomal protein uS5, and this complex formation is important for incorporation of uS5 into the 40S subunit, a crucial step in ribosome biogenesis. Primary fibroblasts from an affected fetus and cell lines expressing PDCD2 patient variants demonstrated reduced levels of PDCD2, reduced PDCD2 binding to uS5, and altered ribosomal RNA processing. Xenopus tadpoles with Pdcd2 knockdown demonstrated developmental defects and edema, reminiscent of the NIHF seen in affected fetuses, and showed altered ribosomal RNA processing. Through genetic, biochemical, and in vivo approaches, we provide evidence that bi-allelic PDCD2 variants cause an autosomal recessive ribosomal biogenesis disorder resulting in pregnancy loss.
GPT-4o mini: Non-social science research article
Richardson’s law and the origins of alcohol research
Snigdha Mukerjee, Cody A. Siciliano
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Interest in the biological actions of alcohols, ethanol in particular, dates back to the earliest historical texts. Alcohol research is now a highly active field with roots in physiology, pharmacology, toxicology, and neuroscience. But at what point did interest and speculation evolve into bona fide science? Here, we set out to identify the earliest systematic empirical investigations into the biological actions of alcohols and unearthed a surprisingly rigorous literature which included a fundamental insight with significant implications for modern research and policy. Through manual backward citation mapping of archived texts, much of which was digitally inaccessible, we outline the origins of alcohol research beginning with a transcribed lecture from Benjamin Ward Richardson in 1869. In the years immediately following, the field of alcohol research was legitimized around what came to be briefly known as “Richardson’s law.” Richardson’s law states that the acute toxicity of straight-chain monohydroxy alcohols is directly proportional to the carbon chain length of the molecule. This law was recognized only briefly not because it was disproven, but rather because it was simply forgotten during the decades that passed between its inception and the advent of systematic bibliographic databases which paved the way for digital archiving. Quantitative analysis of studies spanning a century revealed that across monohydroxy alcohols with one (methanol) to thirteen (tridecanol) carbons, there is a near-deterministic relationship between chain-length and lethal dose (R 2 = 0.96). Richardson’s law of alcohol potency has silently stood the test of time and is among functional biology’s oldest and least challenged scientific laws.
GPT-4o mini: Non-social science research article
Mixing microbiomes in vitro reveals rules of community assembly
Alyssa H. Mitchell, Tami D. Lieberman
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GPT-4o mini: Non-social science research article
Stability of the cnidarian–dinoflagellate symbiosis is primarily determined by symbiont cell-cycle arrest
Lucy M. Gorman, Trevor R. Tivey, Evan H. Raymond, Immy A. Ashley, Clinton A. Oakley, Arthur R. Grossman, Virginia M. Weis, Simon K. Davy
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The cnidarian–dinoflagellate symbiosis relies on the regulation of resident symbiont populations to maintain biomass stability; however, the relative importance of host regulatory mechanisms [cell-cycle arrest (CC), apoptosis (AP), autophagy (AU), and expulsion (EX)] during symbiosis onset and maintenance is largely unknown. Here, we inoculated a symbiont-free (aposymbiotic) model cnidarian ( Exaiptasia diaphana : “Aiptasia”) with either its native symbiont Breviolum minutum or one of three non-native symbionts: Symbiodinium microadriaticum , Cladocopium goreaui, and Durusdinium trenchii . We then measured and compared host AP, host AU, symbiont EX, and symbiont cell-cycle phase for up to a year with these different symbionts and used these discrete measurements to inform comparative models of symbiont population regulation. Our models showed a general pattern, where regulation through AP and AU is reduced after onset, followed by an overshoot of the symbiont population that requires a strong regulatory response, dealt with by strong CC and increased EX. As colonization progresses into symbiosis maintenance, CC remains crucial for achieving steady-state symbiont populations, with our models estimating that CC regulates 10-fold more cells (60 to 90%) relative to the other mechanisms. Notably though, our models also revealed that D. trenchii is less tightly regulated than B. minutum , consistent with D. trenchii’s reputation as a suboptimal partner for this cnidarian. Overall, our models suggest that single regulatory mechanisms do not accurately replicate observed symbiont colonization patterns, reflecting the importance of all mechanisms working concomitantly. This ultimately sheds light on the cell biology underpinning the stability of this ecologically significant symbiosis.
GPT-4o mini: Non-social science research article
DNA bending mediated by ORC is essential for replication licensing in budding yeast
Wai Hei Lam, Daqi Yu, Qiongdan Zhang, Yuhan Lin, Ningning Li, Jian Li, Yue Wu, Yingyi Zhang, Ning Gao, Bik Kwoon Tye, Yuanliang Zhai, Shangyu Dang
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In eukaryotes, the origin recognition complex (ORC) promotes the assembly of minichromosome maintenance 2 to 7 complexes into a head-to-head double hexamer at origin DNA in a process known as replication licensing. In this study, we present a series of cryoelectron microscopy structures of yeast ORC mutants in complex with origin DNA. We show that Orc6, the smallest subunit of ORC, utilizes its transcription factor II B-B domain to orchestrate the sequential binding of ORC to origin DNA. In addition, Orc6 plays the role of a scaffold by stabilizing the basic patch (BP) of Orc5 for ORC to capture and bend origin DNA. Importantly, disrupting DNA bending through mutating three key residues in Orc5-BP impairs ORC’s ability to promote replication initiation at two points during the pre-RC assembly process. This study dissects the multifaceted role of Orc6 in orchestrating ORC’s activities on DNA and underscores the vital role of DNA bending by ORC in replication licensing.
GPT-4o mini: Non-social science research article
Maximizing underwater energy harvesting efficiency using flexible solar cells: A pathway to sustainable ocean power
Haoliang Bai, Tonghui Lu, Wenzhuo Liu, Xianglin Li, Wenhao Lv, Song Lv
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Photovoltaic technology has emerged as a key candidate for powering underwater devices. However, traditional solar cells face limitations in real marine environments. Flexible solar cells offer new possibilities for underwater energy harvesting. This study identifies the optimal bandgap and depth for flexible underwater solar cells through detailed balance calculations and experiments. We also established an optical model for underwater flexible solar cells, determining the ideal curvature through outdoor testing. The flexible a-Si solar cell achieves an impressive maximum efficiency of 59.7% at 2 m, generating up to 15.9% more energy throughout the day compared to planar solar cells. Theoretical results surpass the fundamental limits of seabed solar collection, outperforming all existing underwater photovoltaic solutions. Building on this foundation, we demonstrated their all-day capabilities in powering unmanned underwater vehicles (UUVs) and LED light beacons. Furthermore, we explored the global power generation potential of flexible solar cells at typical depths, identifying the optimal operating ranges during different seasons and analyzing the power generation costs for typical water bodies. This study highlights the immense potential of flexible solar cells in advancing marine energy generation.
GPT-4o mini: Non-social science research article
Structural and functional characterization of the brain-specific dynamin superfamily member RNF112
Ya-Ting Zhong, Li-Li Huang, Kangning Li, Bingke Yang, Xueting Ye, Hao-Ran Zhong, Bing Yu, Menghan Ma, Yuerong Yuan, Yang Meng, Runfeng Pan, Haiqing Zhang, Lijun Shi, Yunyun Wang, Ruijun Tian, Song Gao, Xin Bian
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Most members of the dynamin superfamily of large guanosine triphophatases (GTPases) have an ability to remodel membranes in response to guanosine triphosphate (GTP) hydrolysis. Ring Finger Protein 112 (RNF112) (ZNF179/neurolastin) is a recently identified brain-specific dynamin-like protein possessing a really interesting new gene (RING) finger domain. Despite its essential role as an E3 ligase in neuron development, the architecture of RNF112 and the exact role of its GTPase activity remain unknown. Here, we determined the crystal structure of truncated RNF112 (RNF112 T ) containing a GTPase domain (GD) and three-helical middle domain (MD) at different nucleotide-loading states. In the nucleotide-free (apo) state, the monomeric RNF112 T remained in a unique self-restraint conformation characterized by docking of the proximal end of the MD to a groove in the GD. At the transition state of GTP hydrolysis, the MD was released from the GD and stretched aside to form an intertwined RNF112 T homodimer. Engineered RNF112 equipped with the C-terminal elements of ATL1 or the two transmembrane domains of yeast Sac1p relocated to the endoplasmic reticulum and was capable of mediating membrane remodeling. Taken together, our results offer necessary understandings of RNF112 as a dynamin-like large GTPase in its cellular function and provide insights into the functional mechanisms of dynamin superfamily proteins.
GPT-4o mini: Non-social science research article
Structure of a Gcn2 dimer in complex with the large 60S ribosomal subunit
Helge Paternoga, Lu Xia, Lyudmila Dimitrova-Paternoga, Sihan Li, Liewei L. Yan, Malte Oestereich, Sergo Kasvandik, Ankanahalli N. Nanjaraj Urs, Bertrand Beckert, Tanel Tenson, Hani Zaher, Toshifumi Inada, Daniel N. Wilson
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The integrated stress response (ISR) is a central signaling network that enables eukaryotic cells to respond to a variety of different environmental stresses. Such stresses cause ribosome collisions that lead to activation of the kinase Gcn2, resulting in the phosphorylation and inactivation of eukaryotic initiation factor 2 and thereby promoting selective translation of mRNAs to restore homeostasis. Despite the importance of the ISR and intensive study over the past decades, structural insight into how Gcn2 interacts with ribosomal particles has been lacking. Using ex vivo affinity purification approaches, we have obtained a cryoelectron microscopy structure of a yeast Gcn2 dimer in complex with the ribosomal 60S subunit. The Gcn2 dimer is formed by dimerization of the histidine tRNA synthetase-like domains, which establish extensive interactions with the stalk-base and sarcin–ricin loop of the 60S subunit. The C-terminal domain of Gcn2 is also dimerized and occupies the A- and P-site tRNA binding sites at the peptidyl-transferase center of the 60S subunit. Complementary functional studies indicate that binding of Gcn2 to the 60S subunit does not require the coactivators Gcn1 or Gcn20, nor does it lead to phosphorylation of eIF2α. Instead, upon stress, we observe a shift of Gcn2 from the 60S subunit into the colliding ribosome fraction, suggesting that the Gcn2–60S complex represents an inactive stand-by state to enable a rapid redistribution to collided ribosomes, and thereby facilitating a quick and efficient response to stress.
GPT-4o mini: Non-social science research article
The fruit fly, Drosophila melanogaster , as a microrobotics platform
Kenichi Iwasaki, Charles Neuhauser, Chris Stokes, Aleksandr Rayshubskiy
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Engineering small autonomous agents capable of operating in the microscale environment remains a key challenge, with current systems still evolving. Our study explores the fruit fly, Drosophila melanogaster , a classic model system in biology and a species adept at microscale interaction, as a biological platform for microrobotics. Initially, we focus on remotely directing the walking paths of fruit flies in an experimental arena. We accomplish this through two distinct approaches: harnessing the fruit flies’ optomotor response and optogenetic modulation of its olfactory system. These techniques facilitate reliable and repeated guidance of flies between arbitrary spatial locations. We guide flies along predetermined trajectories, enabling them to scribe patterns resembling textual characters through their locomotion. We enhance olfactory-guided navigation through additional optogenetic activation of attraction-inducing mushroom body output neurons. We extend this control to collective behaviors in shared spaces and navigation through constrained maze-like environments. We further use our guidance technique to enable flies to carry a load across designated points in space, establishing the upper bound on their weight-carrying capabilities. Additionally, we demonstrate that visual guidance can facilitate novel interactions between flies and objects, showing that flies can consistently relocate a small spherical object over significant distances. Last, we demonstrate multiagent formation control, with flies alternating between distinct spatial patterns. Beyond expanding tools available for microrobotics, these behavioral contexts can provide insights into the neurological basis of behavior in fruit flies.
GPT-4o mini: Non-social science research article
Ultra narrowband geometric-phase resonant metasurfaces
Xu Ouyang, Yixuan Zeng, Zi Wang, Baichuan Bo, Fangxing Lai, Chi Zhang, Cheng-wei Qiu, Qinghai Song, Shaohua Yu, Yuri Kivshar, Shumin Xiao
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The concept of a geometric phase has sparked a revolution in photonics. Conventional space-variant polarization manipulation in optical systems only results in broadband geometric phases. Recently emerged nonlocal metasurfaces show an ability to compress the operating bandwidth through modulations of wavelength-dependent amplitudes. However, their geometric phases are still broadband and not linear, posing severe challenges to realize ultra narrowband metadevices. Here, we propose and demonstrate the generation of ultra narrowband and spatially variable geometric phases in resonant metasurfaces. We find that an array of perturbed Mie resonators is able to simultaneously preserve its global symmetry and local transformation. Local transformation provides a pixel-level geometric phase, whereas global symmetry yields an ultranarrow operation bandwidth. We further reveal that this geometric phase can be well pinned to the resonant mode by introducing additional perturbations to individually define the phase at nonresonant wavelengths. Consequently, we realize experimentally pixelated phase-gradient metasurfaces and metalenses with record-breaking Q factors and high confidentiality. We believe that our general approach and demonstrated results will open a paradigm of multiplexed metasurfaces and information encryption.
GPT-4o mini: Non-social science research article
Pulsatile basal gene expression as a fitness determinant in bacteria
K. Jain, R. Hauschild, O. O. Bochkareva, R. Roemhild, G. Tkačik, C. C. Guet
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Active regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of the mar operon, the main regulator of intrinsic multiple antibiotic resistance in Escherichia coli , and link its dynamic properties to the noncanonical, yet highly conserved start codon of marR across Enterobacteriaceae . Real-time, single-cell measurements across tens of generations reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of the mar operon has likely been evolutionarily maintained for its role in growth homeostasis of Enterobacteria within the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g., control of costly-to-induce multidrug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multidrug resistance is crucial for effective public health measures.
GPT-4o mini: Non-social science research article
A monoclonal anti-hemagglutinin stem antibody modified with zanamivir protects against both influenza A and B viruses
Xin Liu, Thomas Balligand, Camille Le Gall, Hidde L. Ploegh
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Influenza remains a significant public health threat. Both monoclonal antibodies and small-molecule inhibitors can target the influenza surface glycoproteins hemagglutinin (HA) or neuraminidase (NA) for prevention and treatment of influenza. Here, we combine the strengths of anti-influenza antibodies and small molecules by site-specific conjugation of the NA inhibitor zanamivir to MEDI8852, an HA-specific fully human monoclonal antibody. MEDI8852 targets the conserved stem region of HA and inhibits HA-mediated fusion of the viral and host cell membranes. Elimination of virus-infected cells involves Fcγ receptor–mediated effector functions. The efficacy of MEDI8852 is limited to influenza A viruses. Zanamivir, on the other hand, binds to the active site of NA in both influenza A and B viruses to inhibit NA activity and virus release. However, because of its small size, zanamivir has a short half-life and requires repeated dosing at high concentrations. We produced a MEDI8852–zanamivir antibody–drug conjugate (ADC) that engages Fc-mediated effector functions and benefits from neonatal Fc receptor (FcRn)-mediated recycling. The MEDI8852–zanamivir conjugate extends the circulatory half-life of zanamivir, targets both influenza HA and NA, and shows enhanced antibody-dependent cellular cytotoxicity (ADCC) compared to MEDI8852 alone. The MEDI8852–zanamivir conjugate protected mice from a lethal (10 × LD 50 ) challenge with influenza A and B viruses at a dose similar to that required for broadly neutralizing anti-NA antibodies, with the added advantage of simultaneously targeting NA (influenza A and B) and HA (influenza A).
GPT-4o mini: Non-social science research article
Enhanced polymorph metastability drives glycine nucleation in aqueous salt solutions
Ruiyu Wang, Pratyush Tiwary
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GPT-4o mini: Non-social science research article
Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4
Mengting Jiang, Youwei Xu, Xiaodong Luan, Kai Wu, Zhen Li, H. Eric Xu, Shuyang Zhang, Yi Jiang, Wanchao Yin
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The G protein–coupled cysteinyl leukotriene receptor CysLT2R plays intricate roles in the physiology and pathogenesis of inflammation-related processes. It has garnered increasing attention as a potential therapeutic target for atopic asthma, brain injury, central nervous system disorders, and various types of cancer. In this study, we present the cryo-electron microscopy structure of the cysteinyl leukotriene D4 (LTD4)-bound human CysLT2R in complex with a Gα q protein, adopting an active conformation at a resolution of 3.15 Å. The structure elucidates a spacious polar pocket designed to accommodate the two branched negative ends of LTD4 and reveals a lateral ligand access route into the orthosteric pocket located on transmembrane domain helix (TM) 4 and 5. Furthermore, our findings highlight the crucial role of transmembrane domain helix 3 in sensing agonist moieties, representing the pivotal mechanism of receptor activation for both CysLT1R and CysLT2R. Collectively, the insights derived from our structural investigation establish a foundation for comprehending CysLT2R activation by its endogenous ligand LTD4, offering a rational basis for the design of drugs targeting CysLT2R.
GPT-4o mini: Non-social science research article
MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis
Lucky Sarkar, GuanQun Liu, Dhiraj Acharya, Junji Zhu, Zuberwasim Sayyad, Michaela U. Gack
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The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5 K23R/K43R ) in which the two major ISGylation sites, K23 and K43, in MDA5, were mutated. Primary cells derived from MDA5 K23R/K43R mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies, leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying MDA5 −/− mice, the MDA5 K23R/K43R mice infected with EMCV displayed increased myocardial injury and mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.
GPT-4o mini: Non-social science research article
Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia
Frank Charbonier, Junqin Zhu, Raleigh Slyman, Cole Allan, Ovijit Chaudhuri
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Collective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large-scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell–substrate interactions at the tissue scale.
GPT-4o mini: Non-social science research article
Evolutionary divergent kinetoplast genome structure and RNA editing patterns in the trypanosomatid Vickermania
Evgeny S. Gerasimov, Dmitry A. Afonin, Ingrid Ć kodovĂĄ-SverĂĄkovĂĄ, Andreu Saura, NatĂĄlia Trusina, Ondƙej Gahura, Alexandra Zakharova, Anzhelika Butenko, Peter BarĂĄth, Anton HorvĂĄth, Fred R. Opperdoes, David PĂ©rez-Morga, Sara L. Zimmer, Julius LukeĆĄ, Vyacheslav Yurchenko
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The trypanosomatid flagellates possess in their single mitochondrion a highly complex kinetoplast (k)DNA, which is composed of interlocked circular molecules of two types. Dozens of maxicircles represent a classical mitochondrial genome, and thousands of minicircles encode guide (g)RNAs, which direct the processive and essential uridine insertion/deletion messenger RNA (mRNA) editing of maxicircle transcripts. While the details of kDNA structure and this type of RNA editing are well established, our knowledge mostly relies on a narrow foray of intensely studied human parasites of the genera Leishmania and Trypanosoma . Here, we analyzed kDNA, its expression, and RNA editing of two members of the poorly characterized genus Vickermania with very different cultivation histories. In both Vickermania species, the gRNA-containing heterogeneous large (HL)-circles are atypically large with multiple gRNAs each. Examination of Vickermania spadyakhi HL-circle loci revealed a massive redundancy of gRNAs relative to the editing needs. In comparison, the HL-circle repertoire of extensively cultivated Vickermania ingenoplastis is greatly reduced. It correlates with V. ingenoplastis -specific loss of productive editing of transcripts encoding subunits of respiratory chain complex I and corresponding lack of complex I activity. This loss in a parasite already lacking genes for subunits of complexes III and IV suggests an apparent requirement for its mitochondrial adenosine triphosphate (ATP) synthase to work in reverse to maintain membrane potential. In contrast, V. spadyakhi retains a functional complex I that allows ATP synthase to work in its standard direction.
GPT-4o mini: Non-social science research article
Exploring RNA destabilization mechanisms in biomolecular condensates through atomistic simulations
Matteo Boccalini, Yelyzaveta Berezovska, Giovanni Bussi, Matteo Paloni, Alessandro Barducci
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Biomolecular condensates are currently recognized to play a key role in organizing cellular space and in orchestrating biochemical processes. Despite an increasing interest in characterizing their internal organization at the molecular scale, not much is known about how the densely crowded environment within these condensates affects the structural properties of recruited macromolecules. Here, we adopted explicit-solvent all-atom simulations based on a combination of enhanced sampling approaches to investigate how the conformational ensemble of an RNA hairpin is reshaped in a highly concentrated peptide solution that mimics the interior of a biomolecular condensate. Our simulations indicate that RNA structure is greatly perturbed by this distinctive physico-chemical environment, which weakens RNA secondary structure and promotes extended nonnative conformations. The resulting high-resolution picture reveals that RNA unfolding is driven by the effective solvation of nucleobases through hydrogen bonding and stacking interactions with surrounding peptides. This solvent effect can be modulated by the amino acid composition of the model condensate as proven by the differential RNA behavior observed in the case of arginine-rich and lysine-rich peptides.
GPT-4o mini: Non-social science research article
NAL1 forms a molecular cage to regulate FZP phase separation
Ling-Yun Huang, Ting-Ting Wang, Peng-Tao Shi, Ze-Yu Song, Wei-Fei Chen, Na-Nv Liu, Xia Ai, Hai-Hong Li, Xi-Miao Hou, Li-Bing Wang, Kun-Ming Chen, Stephane Rety, Xu-Guang Xi
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NARROW LEAF 1 ( NAL1 ), originally identified for its role in shaping leaf morphology, plant architecture, and various agronomic traits in rice, has remained enigmatic in terms of the molecular mechanisms governing its multifaceted functions. In this study, we present a comprehensive structural analysis of NAL1 proteins, shedding light on how NAL1 regulates the phase separation of its physiological substrate, FRIZZY PANICLE (FZP), a transcription factor. We determined that NAL1 assembles as a hexamer and forms a molecular cage with a wide central channel and three narrower lateral channels, which could discriminate its different substrates into the catalytic sites. Most notably, our investigation unveils that FZP readily forms molecular condensates via phase separation both in vitro and in vivo. NAL1 fine-tunes FZP condensation, maintaining optimal concentrations to enhance transcriptional activity. While phase separation roles include sequestration and suppression of transcriptional or enzymatic activity, our study highlights its context-dependent contribution to transcriptional regulation. NAL1 assumes a pivotal role in regulating the states of these molecular condensates through its proteolytic activity, subsequently enhancing transcriptional cascades. Our findings offer insights into comprehending the molecular mechanisms underpinning NAL1’s diverse functions, with far-reaching implications for the field of plant biology. Additionally, these insights provide valuable guidance for the development of rational breeding strategies aimed at enhancing crop productivity.
GPT-4o mini: Non-social science research article
Conformational signatures induced by ubiquitin modification in the amyloid-forming tau repeat domain
Giovanna Viola, Daniele Trivellato, Mikko Laitaoja, Janne JĂ€nis, Isabella C. Felli, Mariapina D’Onofrio, Luca Mollica, Gabriele Giachin, Michael Assfalg
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Posttranslational modifications can critically affect conformational changes of amyloid-forming proteins. Ubiquitination of the microtubule-associated tau protein, an intrinsically disordered biomolecule, has been proposed to influence the formation of filamentous deposits in neurodegenerative conditions. Given the reported link between aggregation propensity and intrinsic structural preferences (e.g., transient extended structural motifs or tertiary contacts) in disordered proteins, we sought to explore the conformational landscape of ubiquitinated tau. Exploiting selective conjugation reactions, we produced single- and double-monoubiquitinated protein samples. Next, we examined the ubiquitinated species from different standpoints using NMR spectroscopy, small-angle X-ray scattering experiments, and native ion mobility–mass spectrometry (IM–MS). Moreover, we obtained atomistic representations of the conformational ensembles via scaled MD calculations, consistent with the experimental data. Modifying the repeat domain of tau with ubiquitin had a limited effect on secondary structure propensities and local mobility of distal regions. Instead, ubiquitination enhanced the compaction of the conformational ensemble, with the effect modulated by the site and the number of modifications. Native IM–MS patterns pinpointed similarities and differences between distinct tau proteoforms. It emerges that ubiquitination exerts a position-specific influence on the conformational distribution of tau molecules. This study reveals the unique conformational features of ubiquitinated forms of tau and points to their potential impact on aggregation and phase separation propensities, offering clues for a better understanding of disease-related structural alterations.
GPT-4o mini: Non-social science research article
The cryo-EM structure and physical basis for anesthetic inhibition of the THIK1 K2P channel
Elena B. Riel, Weiming Bu, Thomas T. Joseph, Leila Khajoueinejad, Roderic G. Eckenhoff, Paul M. Riegelhaupt
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THIK1 tandem pore domain (K2P) potassium channels regulate microglial surveillance of the central nervous system and responsiveness to inflammatory insults. With microglia recognized as critical to the pathogenesis of neurodegenerative diseases, THIK1 channels are putative therapeutic targets to control microglia dysfunction. While THIK channels can principally be distinguished from other K2Ps by their distinctive inhibitory response to volatile anesthetics (VAs), molecular details governing THIK channel gating remain largely unexplored. Here, we report a 3.2 Å cryo-electron microscopy structure of the THIK1 channel in a closed conformation. A central pore gate located directly below the THIK1 selectivity filter is formed by inward-facing TM4 helix tyrosine residues that occlude the ion conduction pathway. VA inhibition of THIK requires closure of this central pore gate. Using a combination of anesthetic photolabeling, electrophysiology, and molecular dynamics simulation, we identify a functionally critical THIK1 VA binding site positioned between the central gate and a structured section of the THIK1 TM2/TM3 loop. Our results demonstrate the molecular architecture of the THIK1 channel and elucidate critical structural features involved in regulation of THIK1 channel gating and anesthetic inhibition.
GPT-4o mini: Non-social science research article
Searching permutations for constructing uniformly distributed point sets
François Clément, Carola Doerr, Kathrin Klamroth, Luís Paquete
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Uniformly distributed point sets of low discrepancy are heavily used in experimental design and across a very wide range of applications such as numerical integration, computer graphics, and finance. Recent methods based on Graph Neural Networks [T. K. Rusch, N. Kirk, M. M. Bronstein, C. Lemieux, D. Rus, Proc. Natl. Acad. Sci. U.S.A. 121, e2409913121 (2024).] and solver-based optimization identified point sets having much lower discrepancy than previously known constructions. We show in this note that further substantial improvements are possible by separating the construction of low-discrepancy point sets into i) the relative position of the points, and ii) the optimal placement respecting these relationships. Using tailored permutations, we construct point sets that are of 20% smaller discrepancy on average than those proposed by Rusch et al. In terms of inverse discrepancy, our sets reduce the number of points in dimension 2 needed to obtain a discrepancy of 0.005 from more than 500 points to less than 350. For applications where the sets are used to query time-consuming models, this is a significant reduction.
GPT-4o mini: Non-social science research article
RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa
Laurel C. Chandler, Apolonia Gardner, Constance L. Cepko
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Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration worldwide. It is characterized by the sequential death of rod and cone photoreceptors, the cells responsible for night and daylight vision, respectively. Although the expression of most RP genes occurs only in rods, there is a secondary degeneration of cones. One possible mechanism of cone death is metabolic dysregulation. Photoreceptors are highly metabolically active, consuming large quantities of glucose and producing substantial amounts of lactate. The retinal pigment epithelium (RPE) mediates the transport of glucose from the blood to photoreceptors and, in turn, removes lactate, which can influence the rate of consumption of glucose by the RPE. One model for metabolic dysregulation in RP suggests that following the death of rods, lactate levels are substantially diminished causing the RPE to withhold glucose, resulting in nutrient deprivation for cones. Here, we present adeno-associated viral vector-mediated delivery of monocarboxylate transporter 2 (MCT2, Slc16a7 ) into the eye, with expression limited to RPE cells, with the aim of promoting lactate uptake from the blood and encouraging the passage of glucose to cones. We demonstrate prolonged survival and function of cones in rat and mouse RP models, revealing a possible gene-agnostic therapy for preserving vision in RP. We also present the use of fluorescence lifetime imaging-based biosensors for lactate and glucose within the eye. Using this technology, we show changes to lactate and glucose levels within MCT2-expressing RPE, suggesting that cone survival is impacted by changes in RPE metabolism.
GPT-4o mini: Non-social science research article
Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis
Xiaoyi Mo, Keyu Meng, Bohan Xu, Zehui Li, Shanwei Lan, Zhengda Ren, Xin Xiang, Peiqian Zou, Zesen Chen, Zhongming Lai, Xiang Ao, Zhongyuan Liu, Wanjing Shang, Bingyang Dai, Li Luo, Jiajia Xu, Zhizhang Wang, Zhongmin Zhang
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Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.
GPT-4o mini: Non-social science research article
Coupling between the lever arm and active site via an N-terminal extension tunes force sensitivity in the myosin-1 family
Harry W. Rathbone, Anne Houdusse
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GPT-4o mini: Non-social science research article
An integrated AI knowledge graph framework of bacterial enzymology and metabolism
Norman R. Spencer, Mathusan Gunabalasingam, Keshav Dial, Xiaxia Di, Tonya Malcolm, Nathan A. Magarvey
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The study of bacterial metabolism holds immense significance for improving human health and advancing agricultural practices. The prospective applications of genomically encoded bacterial metabolism present a compelling opportunity, particularly in the light of the rapid expansion of genomic sequencing data. Current metabolic inference tools face challenges in scaling with large datasets, leading to increased computational demands, and often exhibit limited inter-relatability and interoperability. Here, we introduce the Integrated Biosynthetic Inference Suite (IBIS), which employs deep learning models and a knowledge graph to facilitate rapid, scalable bacterial metabolic inference. This system leverages a series of Transformer based models to generate high quality, meaningful embeddings for individual enzymes, biosynthetic domains, and metabolic pathways. These embedded representations enable rapid, large-scale comparisons of metabolic proteins and pathways, surpassing the capabilities of conventional methodologies. The examination of evolutionary and functionally conserved metabolites across diverse bacterial species is facilitated by integrating the predictive capabilities of IBIS into a graph database enriched with comprehensive metadata. The consideration of both primary and specialized metabolism, combined with an embedding logic for enzyme discovery, uniquely positions IBIS to identify potential novel metabolic pathways. With the expansion of genomic data necessitating transformative approaches to advance molecular metabolism research, IBIS delivers an AI-driven holistic investigation of bacterial metabolism.
GPT-4o mini: Non-social science research article
The genetic legacy of a global marine invader
Erik E. Sotka, Ryan B. Carnegie, James T. Carlton, Lucia Couceiro, Jeffrey A. Crooks, Hikaru Endo, Hilary Hayford, Masakazu Hori, Mitsunobu Kamiya, Gen Kanaya, Judith Kochmann, Kun-Seop Lee, Lauren Lees, Hannah Miller, Masahiro Nakaoka, Eric Pante, Jennifer L. Ruesink, Evangelina Schwindt, Åsa Strand, Richard B. Taylor, Ryuta Terada, Martin Thiel, Takefumi Yorisue, Danielle Zacherl, Allan E. Strand
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The massive geographic expansion of terrestrial plant crops, livestock, and marine aquacultured species during the 19th and 20th centuries provided local economic benefits, stabilized food demands, and altered local ecosystems. The invasion history of these translocations remains uncertain for most species, limiting our understanding of their future adaptive potential and historical roles as vectors for coinvaded species. We provide a framework for filling this gap in invasion biology using the widely transplanted Pacific oyster as a case study. A two-dimensional summary of population-level variation in single nucleotide polymorphisms in native Japan reflected the geographical map of Japan and allowed identification of the source regions for the worldwide expansion. Pacific oysters proliferate in nonnative areas with environmental temperatures similar to those areas where native lineages evolved. Using Approximate Bayesian Computation, we ranked the likelihood of historical oyster or shipping vectors to explain current-day distribution of genotypes in 14 coinvaded algal and animal species. Oyster transplants were a more likely vector than shipping for six species, shipping activity was more likely for five species, and a vector was ambiguous for three species. Applying this approach to other translocated species should reveal similar legacy effects, especially for economically important foundation species that also served as vectors for nonnative species.
GPT-4o mini: Non-social science research article
A continental view of climate effects on lakes
Stephen R. Carpenter
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GPT-4o mini: Non-social science research article
Inactivation of microglial LXRÎČ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction
Keyi Lv, Yi Luo, Tianyao Liu, Meiling Xia, Hong Gong, Dandan Zhang, Xuan Chen, Xin Jiang, Yulong Liu, Jiayin Liu, Yulong Cai, Per Antonson, Margaret Warner, Haiwei Xu, Jan-Åke Gustafsson, Xiaotang Fan
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Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris and in cognition by pruning synapses. Since liver X receptor ÎČ (LXRÎČ) has been identified as a regulator of microglial homeostasis, this study examined whether its removal from microglia affects neuroinflammation and cognitive function. We used a cell-specific tamoxifen-inducible Cre-loxP-mediated recombination to remove LXRÎČ from microglia specifically. We now report that ablation of LXRÎČ in microglia in early postnatal life led to a reduction in microglial numbers, distinct morphological changes indicative of microglial activation, and enhanced synapse engulfment accompanied by cognitive deficits. Removal of LXRÎČ from microglia in adult mice caused no cognitive defects. RNAseq analysis of microglia revealed that loss of LXRÎČ led to reduced expression of SAll1, a master regulator of microglial homeostasis, while increasing expression of genes associated with microglial activation and CNS disease. This study demonstrates distinctly different functions of microglial LXRÎČ in developing and adult mice and points to long-term consequences of defective LXRÎČ signaling in microglia in early life.
A computational analysis of lexical elaboration across languages
Temuulen Khishigsuren, Terry Regier, Ekaterina Vylomova, Charles Kemp
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Claims about lexical elaboration (e.g. Mongolian has many horse-related terms) are widespread in the scholarly and popular literature. Here, we show that computational analyses of bilingual dictionaries can be used to test claims about lexical elaboration at scale. We validate our approach by introducing BILA, a dataset including 1,574 bilingual dictionaries, and showing that it confirms 147 out of 163 previous claims from the literature. We then identify previously unreported examples of lexical elaboration, and analyze how lexical elaboration is influenced by ecological and cultural variables. Claims about lexical elaboration are sometimes dismissed as either obvious or fanciful, but our work suggests that large-scale computational approaches to the topic can produce nonobvious and well-grounded insights into language and culture.
Indigenous Knowledge as a sole data source in habitat selection functions
Rowenna Gryba, Andrew Von Duyke, Henry P. Huntington, Billy Adams, Brower Frantz, Justin Gatten, Qaiyaan Harcharek, Robert Sarren, Greg Henry, Marie Auger-Méthé
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While Indigenous Knowledge (IK) contains a wealth of information on the behavior and habitat use of species, it is rarely included in the species–habitat models frequently used by Western species management authorities. As decisions from these authorities can limit access to species that are important culturally and for subsistence, exclusion of IK in conservation and management frameworks can negatively impact both species and Indigenous communities. In partnership with Iñupiat hunters, we developed methods to statistically characterize IK of species–habitat relationships and developed models that rely solely on IK to identify species habitat use and important areas. We provide methods for different types of IK documentation and for dynamic habitat types (e.g., ice concentration). We apply the method to ringed seals (natchiq in Iñupiaq) in Alaskan waters, a stock for which the designated critical habitat has been debated in part due to minimal inclusion of IK. Our work demonstrates that IK of species–habitat relationships, with the inclusion of dynamic habitat types, expands on existing mapping approaches and provides another method to identify species habitat use and important areas. The results of this work provide a straightforward and meaningful approach to include IK in species management, especially through comanagement processes.
The impact of sampling bias on preferences for skewed distributions in decisions from experience
Yonatan Vanunu, Ben R. Newell
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Transparency by Chinese cities reduces pollution violations and improves air quality
Mengdi Liu, Mark T. Buntaine, Sarah E. Anderson, Bing Zhang
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We provide national-scale experimental evidence from China showing that transparency by local governments improves the management of air pollution. Governments that perform better have more reasons to be transparent, making the causal relationship between transparency and policy outcomes difficult to disentangle. In 2015, we randomly assigned municipal governments in China to a high-visibility, public rating of their adherence to national requirements for transparency about their regulation of pollution. By 2016, this treatment significantly boosted transparency in treated cities relative to control cities, allowing us to observe the effect of randomly increasing transparency in the years that followed. Subsequently, high-polluting firms in treated cities cut their violations by 37% compared to similar firms in control cities. Inspections by local governments increased by about 90% in treated cities relative to control cities. Ambient air pollution decreased between 8 and 10% in treated cities relative to control cities, which likely generated significant health benefits. This study provides strong evidence that governmental transparency causes improved environmental quality, at least in a setting where the public and higher governments want to hold local governments accountable.
The importance of playing the long game when it comes to pandemic surveillance
Freya M. Shearer, Marc Lipsitch
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Academic achievement helps coordination on mutually advantageous outcomes
Isabelle Brocas, Juan D. Carrillo
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This study examines the relationship between academic achievement and strategic ability to coordinate among middle school students. We designed an experimental framework using repeated asymmetric Battle of the Sexes and Hawk–Dove games, to explore how cognitive and social skills related to academic success influence behavior. A total of 132 students participated, divided into groups of high and low academic achievers based on their performance at school. Our results show that, on average, high achievers coordinate better on equilibrium outcomes with simple but effective strategies and obtain higher payoffs compared to low achievers. However, we notice also substantial heterogeneity within groups. Finally, performance in pairs with one high and one low achiever is intermediate but closer to the level of high achievers, suggesting potential peer learning effects and the educational value of mixed groups to promote guidance and joint improvements. These findings suggest that academic success may reflect broader cognitive abilities–such as strategic thinking, anticipation of others’ choices, and cooperation–crucial for navigating real-world interactions in complex environments.
New Advanced Placement course designed to broaden access promotes participation and demographic diversity in computer science education
Daniela Ganelin, Thomas S. Dee
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Advanced Placement (AP) provides college-level courses to over 1 million US secondary students annually. Black, Hispanic, and female students have historically been underrepresented in AP Computer Science (CS). A new, broadly focused course—AP CS Principles—launched nationally in 2016–17 with the goal of increasing student participation and diversity. We examine its effects on AP CS participation. Combining publicly available sources, we assemble a panel dataset of annual AP exam-taking and course offerings from 2006–07 to 2020–21 at Massachusetts high schools. Using synthetic difference-in-differences, we estimate that offering the new course led to 16 additional yearly AP Computer Science exams per school, more than tripling baseline exam counts for the average adopting school. Exam counts among female and Black or Hispanic students more than quadrupled. The new exams were concentrated in AP Computer Science Principles, with no statistically significant reduction in exam counts for the preexisting AP CS course. We also estimate that offering the new course increased schools’ probability of having any AP CS exam participation by 29 percentage points, with larger gains for female and Black or Hispanic students. We find some evidence of positive spillover effects on several other AP courses. The results suggest the promise of course design and availability in promoting engagement and diversity in advanced STEM education.

Science

GPT-4o mini: Non-social science research article
AI drug development’s data problem
E. Richard Gold, Robert Cook-Deegan
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The future of drug discovery may be artificial intelligence (AI), but its present is not. AI is in its infancy in the field. To help AI mature, developers need nonproprietary, open, large, high-quality datasets to train and validate models, managed by independent organizations.
GPT-4o mini: Non-social science research article
A self-regenerating Pt/Ge-MFI zeolite for propane dehydrogenation with high endurance
Huizhen Hong, Zhikang Xu, Bingbao Mei, Wende Hu, Paolo Fornasiero, Chuanming Wang, Tinghai Wang, Yuanyuan Yue, Tiesen Li, Chen Yang, Qingyan Cui, Haibo Zhu, Xiaojun Bao
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Supported noble metal cluster catalysts are typically operated under severe conditions involving switches between reducing and oxidizing atmospheres, causing irreversible transformation of catalyst structure and thereby leading to permanent deactivation. We discovered that various Pt precursors spontaneously disperse in Ge-MFI zeolite, which opposes the Ostwald ripening phenomenon, producing self-regenerating Pt/Ge-MFI catalysts for propane dehydrogenation. These catalysts reversibly switch between Pt clusters and Pt single-atoms in response to reducing reaction and oxidizing regeneration conditions. This environmental adaptability allows them to completely self-regenerate over 110 reaction-regeneration cycles in propane dehydrogenation. They exhibited unprecedented sintering-resistance when exposed to air at 800 °C for 10 days. Such spontaneous metal dispersion in Ge-zeolites is a robust and versatile methodology for fabricating various Rh, Ru, Ir and Pd cluster catalysts.
GPT-4o mini: Non-social science research article
Integrating multiple evidence streams to understand insect biodiversity change
Rob Cooke, Charlotte L. Outhwaite, Andrew J. Bladon, Joseph Millard, James G. Rodger, Zhaoke Dong, Ellie E. Dyer, Siobhan Edney, John F. Murphy, Lynn V. Dicks, Cang Hui, J. Iwan Jones, Tim Newbold, Andy Purvis, Helen E. Roy, Ben A. Woodcock, Nick J. B. Isaac
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Insects dominate animal species diversity yet face many threats from anthropogenic drivers of change. Many features of insect ecology make them a challenging group, and the fragmented state of knowledge compromises our ability to make general statements about their status. In this Review, we discuss the challenges of assessing insect biodiversity change. We describe how multiple lines of evidence—time series, spatial comparisons, experiments, and expert opinion—can be integrated to provide a synthesis overview of how insect biodiversity responds to drivers. Applying this approach will generate testable predictions of insect biodiversity across space, time, and changing drivers. Given the urgency of accelerating human impacts across the environment, this approach could yield a much-needed rapid assessment of insect biodiversity change.
GPT-4o mini: Non-social science research article
Meningeal regulatory T cells inhibit nociception in female mice
Élora Midavaine, Beatriz C. Moraes, Jorge Benitez, Sian R. Rodriguez, Joao M. Braz, Nathan P. Kochhar, Walter L. Eckalbar, Lin Tian, Ana I. Domingos, John E. Pintar, Allan I. Basbaum, Sakeen W. Kashem
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T cells have emerged as orchestrators of pain amplification, but the mechanism by which T cells control pain processing is unresolved. We found that regulatory T cells (T reg cells) could inhibit nociception through a mechanism that was not dependent on their ability to regulate immune activation and tissue repair. Site-specific depletion or expansion of meningeal T reg cells (mT reg cells) in mice led to female-specific and sex hormone–dependent modulation of mechanical sensitivity. Specifically, mT reg cells produced the endogenous opioid enkephalin that exerted an antinociceptive action through the delta opioid receptor expressed by MrgprD + sensory neurons. Although enkephalin restrains nociceptive processing, it was dispensable for T reg cell–mediated immunosuppression. Thus, our findings uncovered a sexually dimorphic immunological circuit that restrains nociception, establishing T reg cells as sentinels of pain homeostasis.
GPT-4o mini: Non-social science research article
Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling
Yuanheng Yang, Cong Hao, Tingying Jiao, Zidan Yang, Hui Li, Yuqing Zhang, Weiya Zhang, Michael Doherty, Chuying Sun, Tuo Yang, Jiatian Li, Jing Wu, Mengjiao Zhang, Yilun Wang, Dongxing Xie, Tingjian Wang, Ning Wang, Xi Huang, Changjun Li, Frank J. Gonzalez, Jie Wei, Cen Xie, Chao Zeng, Guanghua Lei
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Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)—the receptor of GUDCA—alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of Clostridium bolteae , which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with C. bolteae and Food and Drug Administration–approved UDCA alleviated osteoarthritis through the gut FXR–joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota–GUDCA–intestinal FXR–GLP-1–joint pathway offers a potential strategy for osteoarthritis treatment.
GPT-4o mini: Non-social science research article
Extensive compositionality in the vocal system of bonobos
M. Berthet, M. Surbeck, S. W. Townsend
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Compositionality, the capacity to combine meaningful elements into larger meaningful structures, is a hallmark of human language. Compositionality can be trivial (the combination’s meaning is the sum of the meaning of its parts) or nontrivial (one element modifies the meaning of the other element). Recent studies have suggested that animals lack nontrivial compositionality, representing a key discontinuity with language. In this work, using methods borrowed from distributional semantics, we investigated compositionality in wild bonobos and found that not only does each call type of their repertoire occur in at least one compositional combination, but three of these compositional combinations also exhibit nontrivial compositionality. These findings suggest that compositionality is a prominent feature of the bonobo vocal system, revealing stronger parallels with human language than previously thought.
GPT-4o mini: Non-social science research article
A distinct priming phase regulates CD8 T cell immunity by orchestrating paracrine IL-2 signals
Katarzyna Jobin, Deeksha Seetharama, Lennart RĂŒttger, Chloe Fenton, Ekaterina Kharybina, Annerose Wirsching, Anfei Huang, Konrad Knöpper, Tsuneyasu Kaisho, Dirk H. Busch, Martin Vaeth, Antoine-Emmanuel Saliba, Frederik Graw, Alain Pulfer, Santiago F. GonzĂĄlez, Dietmar Zehn, Yinming Liang, Milas Ugur, Georg Gasteiger, Wolfgang KastenmĂŒller
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T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.
GPT-4o mini: Non-social science research article
Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk
Georgia Minakaki, Nathaniel Safren, Bernabe I. Bustos, Steven J. Lubbe, NiccolĂČ E. Mencacci, Dimitri Krainc
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Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain–containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain–containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk. Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.
GPT-4o mini: Non-social science research article
Direct neutrino-mass measurement based on 259 days of KATRIN data
character(0), Max Aker, Dominic Batzler, Armen Beglarian, Jan Behrens, Justus Beisenkötter, Matteo Biassoni, Benedikt Bieringer, Yanina Biondi, Fabian Block, Steffen Bobien, Matthias Böttcher, Beate Bornschein, Lutz Bornschein, Tom S. Caldwell, Marco Carminati, Auttakit Chatrabhuti, Suren Chilingaryan, Byron A. Daniel, Karol Debowski, Martin Descher, Deseada DĂ­az Barrero, Peter J. Doe, Otokar Dragoun, Guido Drexlin, Frank Edzards, Klaus Eitel, Enrico Ellinger, Ralph Engel, Sanshiro Enomoto, Arne Felden, Caroline Fengler, Carlo Fiorini, Joseph A. Formaggio, Christian Forstner, Florian M. FrĂ€nkle, Kevin Gauda, Andrew S. Gavin, Woosik Gil, Ferenc GlĂŒck, Steffen Grohmann, Robin Grössle, Rainer Gumbsheimer, Nathanael Gutknecht, Volker Hannen, Leonard Hasselmann, Norman Haußmann, Klaus Helbing, Hanna Henke, Svenja Heyns, Stephanie Hickford, Roman Hiller, David Hillesheimer, Dominic Hinz, Thomas Höhn, Anton Huber, Alexander Jansen, Christian Karl, Jonas Kellerer, Khanchai Khosonthongkee, Matthias Kleifges, Manuel Klein, Joshua Kohpeiß, Christoph Köhler, Leonard Köllenberger, Andreas Kopmann, Neven Kovač, Alojz KovalĂ­k, Holger Krause, Luisa La Cascio, Thierry Lasserre, Joscha Lauer, Thanh-Long Le, Ondƙej Lebeda, Bjoern Lehnert, Gen Li, Alexey Lokhov, Moritz Machatschek, Martin Mark, Alexander Marsteller, Eric L. Martin, Christin Melzer, Susanne Mertens, Shailaja Mohanty, Jalal Mostafa, Klaus MĂŒller, Andrea Nava, Holger Neumann, Simon Niemes, Anthony Onillon, Diana S. Parno, Maura Pavan, Udomsilp Pinsook, Alan W. P. Poon, Jose Manuel Lopez Poyato, Stefano Pozzi, Florian Priester, Jan RĂĄliĆĄ, Shivani Ramachandran, R. G. Hamish Robertson, Caroline Rodenbeck, Marco Röllig, Carsten Röttele, Milos RyĆĄavĂœ, Rudolf Sack, Alejandro Saenz, Richard Salomon, Peter SchĂ€fer, Magnus Schlösser, Klaus Schlösser, Lisa SchlĂŒter, Sonja Schneidewind, Ulrich Schnurr, Michael Schrank, Jannis SchĂŒrmann, Ann-Kathrin SchĂŒtz, Alessandro Schwemmer, Adrian Schwenck, Michal Ć efčík, Daniel Siegmann, Frank Simon, Felix Spanier, Daniela Spreng, Warintorn Sreethawong, Markus Steidl, Jaroslav Ć torek, Xaver Stribl, Michael Sturm, Narumon Suwonjandee, Nicholas Tan Jerome, Helmut H. Telle, Larisa A. Thorne, Thomas ThĂŒmmler, Simon Tirolf, Nikita Titov, Igor Tkachev, Korbinian Urban, Kathrin Valerius, Drahoslav VĂ©nos, Christian Weinheimer, Stefan Welte, JĂŒrgen Wendel, Christoph Wiesinger, John F. Wilkerson, Joachim Wolf, Sascha WĂŒstling, Johanna Wydra, Weiran Xu, Sergey Zadorozhny, Genrich Zeller
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That neutrinos carry a nonvanishing rest mass is evidence of physics beyond the Standard Model of elementary particles. Their absolute mass holds relevance in fields from particle physics to cosmology. We report on the search for the effective electron antineutrino mass with the KATRIN experiment. KATRIN performs precision spectroscopy of the tritium ÎČ-decay close to the kinematic endpoint. On the basis of the first five measurement campaigns, we derived a best-fit value of m Îœ 2 = − 0.14 − 0.15 + 0.13 eV 2 , resulting in an upper limit of m Îœ < 0.45 eV at 90% confidence level. Stemming from 36 million electrons collected in 259 measurement days, a substantial reduction of the background level, and improved systematic uncertainties, this result tightens KATRIN’s previous bound by a factor of almost two.
GPT-4o mini: Non-social science research article
A neuroimmune circuit mediates cancer cachexia-associated apathy
Xiaoyue Aelita Zhu, Sarah Starosta, Miriam Ferrer, Junxiao Hou, Quentin Chevy, Federica Lucantonio, Rodrigo Muñoz-Castañeda, Fengrui Zhang, Kaikai Zang, Xiang Zhao, Francesca R. Fiocchi, Mason Bergstrom, Aubrey A. Siebels, Thomas Upin, Michael Wulf, Sarah Evans, Alexxai V. Kravitz, Pavel Osten, Tobias Janowitz, Marco Pignatelli, Adam Kepecs
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Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. We alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti–IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. Our findings uncovered a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.
GPT-4o mini: Non-social science research article
Vaccine-enhanced competition permits rational bacterial strain replacement in the gut
Verena Lentsch, Aurore Woller, Andrea Rocker, Selma Aslani, Claudia Moresi, Niina Ruoho, Louise Larsson, Stefan A. Fattinger, Nicolas Wenner, Elisa Cappio Barazzone, Wolf-Dietrich Hardt, Claude Loverdo, Médéric Diard, Emma Slack
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Colonization of the intestinal lumen precedes invasive infection for a wide range of enteropathogenic and opportunistic pathogenic bacteria. We show that combining oral vaccination with engineered or selected niche-competitor strains permits pathogen exclusion and strain replacement in the mouse gut lumen. This approach can be applied either prophylactically to prevent invasion of nontyphoidal Salmonella strains, or therapeutically to displace an established Escherichia coli. Both intact adaptive immunity and metabolic niche competition are necessary for efficient vaccine-enhanced competition. Our findings imply that mucosal antibodies have evolved to work in the context of gut microbial ecology by influencing the outcome of competition. This has broad implications for the elimination of pathogenic and antibiotic-resistant bacterial reservoirs and for rational microbiota engineering.
GPT-4o mini: Non-social science research article
Tissue-like multicellular development triggered by mechanical compression in archaea
Theopi Rados, Olivia S. Leland, Pedro Escudeiro, John Mallon, Katherine Andre, Ido Caspy, Andriko von KĂŒgelgen, Elad Stolovicki, Sinead Nguyen, InĂ©s LucĂ­a Patop, L. Thiberio Rangel, Sebastian Kadener, Lars D. Renner, Vera Thiel, Yoav Soen, Tanmay A. M. Bharat, Vikram Alva, Alex Bisson
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The advent of clonal multicellularity is a critical evolutionary milestone, seen often in eukaryotes, rarely in bacteria, and only once in archaea. We show that uniaxial compression induces clonal multicellularity in haloarchaea, forming tissue-like structures. These archaeal tissues are mechanically and molecularly distinct from their unicellular lifestyle, mimicking several eukaryotic features. Archaeal tissues undergo a multinucleate stage followed by tubulin-independent cellularization, orchestrated by active membrane tension at a critical cell size. After cellularization, tissue junction elasticity becomes akin to that of animal tissues, giving rise to two cell types—peripheral (Per) and central scutoid (Scu) cells—with distinct actin and protein glycosylation polarity patterns. Our findings highlight the potential convergent evolution of a biophysical mechanism in the emergence of multicellular systems across domains of life.
GPT-4o mini: Non-social science research article
Formation of hydrided Pt-Ce-H sites in efficient, selective oxidation catalysts
Ji Yang, Lorenz J. Falling, Siyang Yan, Biluan Zhang, Pragya Verma, Luke Daemen, Yongqiang Cheng, Xiao Zhao, Shuchen Zhang, Jeng-Lung Chen, Bingqing Yao, Shengdong Tan, Sudong Chae, Qian He, Slavomir Nemsak, Zili Wu, David Prendergast, Yanbing Guo, Jiaxu Liu, Miquel Salmeron, Ji Su
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Single-atom site catalysts can improve the rates and selectivity of many catalytic reactions. We have modified Pt 1 /CeO 2 single sites by combining them with molecular groups and with oxygen vacancies of the support. The new sites include hydrided (Pt 2+ -Ce 3+ H ÎŽ ) and hydroxylated (Pt 2+ -Ce 3+ OH) sites that exhibit higher reactivity and selectivity to previous single sites for several reactions, including a ninefold increase in the reaction rate for carbon monoxide (CO) oxidation, and a 2.3-fold improvement of propylene selectivity for oxidative dehydrogenation of propane. The atomic structure and reaction steps of these sites were determined with in situ and ex situ spectroscopy techniques and theoretical methods.
GPT-4o mini: Non-social science research article
Homogeneous-heterogeneous bifunctionality in Pd-catalyzed vinyl acetate synthesis
Deiaa M. Harraz, Kunal M. Lodaya, Bryan Y. Tang, Yogesh Surendranath
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Presently, mechanistic paradigms in catalysis generally posit that the active species remains either homogeneous or heterogeneous throughout the reaction. In this work, we show that a prominent industrial process, palladium (Pd)–catalyzed vinyl acetate synthesis, proceeds via interconversion of heterogeneous Pd(0) and homogeneous Pd(II) during catalysis, with each species playing a complementary role. Using electrochemical probes, we found that heterogeneous, nanoparticulate Pd(0) serves as an active oxygen reduction electrocatalyst to furnish the high potential required for corrosion to form homogeneous Pd(II), which then catalyzes selective ethylene acetoxylation with reformation of heterogeneous Pd(0). Inhibiting the corrosion of Pd(0) to Pd(II) by galvanic protection results in reversible poisoning of catalysis, evincing the essential role of phase conversion in this catalytic cycle. These results highlight how dynamic phase interconversion can harness and couple complementary reactivity across molecular and material active sites.
GPT-4o mini: Non-social science research article
Circular 3D printing of high-performance photopolymers through dissociative network design
Bo Yang, Tiantian Ni, Jingjun Wu, Zizheng Fang, Kexuan Yang, Ben He, Xingqun Pu, Guancong Chen, Chujun Ni, Di Chen, Qian Zhao, Wei Li, Sujing Li, Hao Li, Ning Zheng, Tao Xie
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One approach for closed-loop plastics recycling relies on reverting polymers back into monomers because one can then make new plastics without loss of properties. This depolymerization requirement restricts the molecular design to making polymers with high mechanical performance. We report a three-dimensional (3D) printing chemistry through stepwise photopolymerization by forming dithioacetal bonds. The polymerized network can be transformed back into a photoreactive oligomer by dissociation of the dithioacetal bonds. This network-oligomer transformation is reversible, therefore allowing circular 3D printing using the same material. Our approach offers the flexibility of making modular adjustments in the design of the network backbone of a polymer. This allows access to fully recyclable elastomers, crystalline polymers, and rigid glassy polymers with high mechanical toughness, making them potentially suitable for diverse applications.
GPT-4o mini: Non-social science research article
Rules of engagement for condensins and cohesins guide mitotic chromosome formation
Kumiko Samejima, Johan H. Gibcus, Sameer Abraham, Fernanda Cisneros-Soberanis, Itaru Samejima, Alison J. Beckett, Nina Puǎčeková, Maria Alba Abad, Christos Spanos, Bethan Medina-Pritchard, James R. Paulson, Linfeng Xie, A. Arockia Jeyaprakash, Ian A. Prior, Leonid A. Mirny, Job Dekker, Anton Goloborodko, William C. Earnshaw
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We used Hi-C, imaging, proteomics, and polymer modeling to define rules of engagement for SMC (structural maintenance of chromosomes) complexes as cells refold interphase chromatin into rod-shaped mitotic chromosomes. First, condensin disassembles interphase chromatin loop organization by evicting or displacing extrusive cohesin. Second, condensin bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion as sisters separate. Studies of mitotic chromosomes formed by cohesin, condensin II, and condensin I alone or in combination lead to refined models of mitotic chromosome conformation. In these models, loops are consecutive and not overlapping, implying that condensins stall upon encountering each other. The dynamics of Hi-C interactions and chromosome morphology reveal that during prophase, loops are extruded in vivo at ∌1 to 3 kilobases per second by condensins as they form a disordered discontinuous helical scaffold within individual chromatids.
GPT-4o mini: Non-social science research article
Pharmaceutical pollution influences river-to-sea migration in Atlantic salmon ( Salmo salar )
Jack A. Brand, Marcus Michelangeli, Samuel J. Shry, Eleanor R. Moore, Aneesh P. H. Bose, Daniel Cerveny, Jake M. Martin, Gustav Hellström, Erin S. McCallum, Annika Holmgren, Eli S. J. Thoré, Jerker Fick, Tomas Brodin, Michael G. Bertram
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Despite the growing threat of pharmaceutical pollution, we lack an understanding of whether and how such pollutants influence animal behavior in the wild. Using laboratory- and field-based experiments across multiple years in Atlantic salmon ( Salmo salar ; n = 730), we show that the globally detected anxiolytic pollutant clobazam accumulates in the brain of exposed fish and influences river-to-sea migration success. Clobazam exposure increased the speed with which fish passed through two hydropower dams along their migration route, resulting in more clobazam-exposed fish reaching the sea compared with controls. We argue that such effects may arise from altered shoaling behavior in fish exposed to clobazam. Drug-induced behavioral changes are expected to have wide-ranging consequences for the ecology and evolution of wild populations.
GPT-4o mini: Non-social science research article
Cat1 forms filament networks to degrade NAD + during the type III CRISPR-Cas antiviral response
Christian F. Baca, Puja Majumder, James H. Hickling, Dinshaw J. Patel, Luciano A. Marraffini
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Type III CRISPR-Cas systems defend against viral infection in prokaryotes using an RNA-guided complex that recognizes foreign transcripts and synthesizes cyclic oligo-adenylate (cOA) messengers to activate CARF immune effectors. Here we investigated a protein containing a CARF domain fused Toll/interleukin-1 receptor (TIR) domain, Cat1. We found that Cat1 provides immunity by cleaving and depleting NAD + molecules from the infected host, inducing a growth arrest that prevents viral propagation. Cat1 forms dimers that stack upon each other to generate long filaments that are maintained by bound cOA ligands, with stacked TIR domains forming the NAD + cleavage catalytic sites. Further, Cat1 filaments assemble into unique trigonal and pentagonal networks that enhance NAD + degradation. Cat1 presents an unprecedented chemistry and higher-order protein assembly for the CRISPR-Cas response.
GPT-4o mini: Non-social science research article
Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes
Jorge Diego Martin-Rufino, Alexis Caulier, Seayoung Lee, Nicole Castano, Emily King, Samantha Joubran, Marcus Jones, Seth R. Goldman, Uma P. Arora, Lara Wahlster, Eric S. Lander, Vijay G. Sankaran
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Most phenotype-associated genetic variants map to noncoding regulatory regions of the human genome, but their mechanisms remain elusive in most cases. We developed a highly efficient strategy, Perturb-multiome, to simultaneously profile chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of master transcription factors (TFs). We examined the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within TF-sensitive accessible chromatin regions in erythroid differentiation, although representing <0.3% of the genome, show a ~100-fold enrichment for blood cell phenotype heritability, which is substantially higher than that for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.
GPT-4o mini: Non-social science research article
Ectoderm barcoding reveals neural and cochlear compartmentalization
Sandra de Haan, Jingyan He, Agustin A. Corbat, Lenka Belicova, Michael Ratz, Elin Vinsland, Jonas Frisén, Matthew W. Kelley, Emma R. Andersson
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Placodes and the neural crest are defining features of vertebrates. In this study, we investigate their lineages in mice using in utero approaches. We demonstrated that nanoinjection at embryonic day 7.5 targeted the ectoderm, including the future nervous system, placodes, and neural crest, allowing highly efficient manipulation of the future nervous system and inner ear. By using heritable DNA barcodes and high-throughput next-generation single-cell lineage tracing, we elucidated convergent differentiation pathways and identified distinct nervous system–, neural crest–, and otic placode–derived lineages. Clonal analyses identified early neural and cochlear compartmentalization, linking differentiated cell types to their progenitors or cellular siblings. This provides foundational insights for neuroscience and developmental biology.
GPT-4o mini: Non-social science research article
Structural insights into chromatin remodeling by ISWI during active ATP hydrolysis
Youyang Sia, Han Pan, Kangjing Chen, Zhucheng Chen
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Chromatin remodelers utilize the energy of adenosine triphosphate (ATP) hydrolysis to slide nucleosomes, regulating chromatin structure and gene activity in cells. In this work, we report structures of imitation switch (ISWI) bound to the nucleosome during active ATP hydrolysis and remodeling, revealing conformational transitions of the remodeling motor across the adenosine triphosphatase (ATPase) cycle. The DNA strands are distorted accordingly, showing one full base-pair bulge and a loss of histone contact at the site of motor binding in the adenosine diphosphate* b and Apo* states. We also identify several important elements for regulation of the remodeling activity. Notably, an enzyme conformation exiting the remodeling cycle reveals a linker DNA–sensing brake mechanism. Together, our findings elucidate a multistate model of ISWI action, providing a comprehensive mechanism of DNA translocation and regulation underpinning chromatin remodeling.
GPT-4o mini: Non-social science research article
Targeted MYC2 stabilization confers citrus Huanglongbing resistance
Pingzhi Zhao, Huan Yang, Yanwei Sun, Jingyin Zhang, Kaixing Gao, Jinbao Wu, Chengrong Zhu, Cece Yin, Xiaoyue Chen, Qi Liu, Qiudong Xia, Qiong Li, Han Xiao, Hai-Xi Sun, Xiaoxiao Zhang, Long Yi, Changyong Zhou, Daniel J. Kliebenstein, Rongxiang Fang, Xuefeng Wang, Jian Ye
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Huanglongbing (HLB) is a devastating citrus disease. In this work, we report an HLB resistance regulatory circuit in Citrus composed of an E3 ubiquitin ligase, PUB21, and its substrate, the MYC2 transcription factor, which regulates jasmonate-mediated defense responses. A helitron insertion in the PUB21 promoter introduced multiple MYC2-binding cis-elements to create a regulatory circuit linking the PUB21 activity with MYC2 degradation. Ectopic expression of a natural dominant-negative PUB21 paralog discovered in distant Citrus relatives stabilized MYC2 and conferred resistance to HLB. Antiproteolysis peptides (APPs), identified by artificial intelligence, stabilized MYC2 by binding and inhibiting PUB21 activity. A 14–amino acid peptide, APP3-14, molecularly controlled HLB in greenhouse and field trials. This approach represents a strategy to combat uncultivable pathogens through targeted disease resistance protein stabilization.
GPT-4o mini: Non-social science research article
Don’t quit the long game
Stefan Raff-Heinen, Fiona E. Murray
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Living cells that produce biofuel; robots that assist factory workers; intelligent machines that guide drug discovery—these technologies are “deep” in that they achieve something extraordinary—often thought impossible—and push society forward. Indeed, so-called “deep tech” powers the future of medical breakthroughs, resilient energy grids, and clean industrial processes, among other frontiers. But deep tech requires more of everything to become a reality—research and development, specialized talent, time, risk-taking, and funding. The US government has been the world’s largest investor in this enterprise. Yet cuts to federal support for deep tech threaten this entrepreneurial engine at its source—university labs. Without sustained federal support, the country risks losing its technological edge, threatening economic competitiveness and national security.
GPT-4o mini: Non-social science research article
Nonlinear sound-sheet microscopy: Imaging opaque organs at the capillary and cellular scale
Baptiste Heiles, Flora Nelissen, Rick Waasdorp, Dion Terwiel, Byung Min Park, Eleonora Munoz Ibarra, Agisilaos Matalliotakis, Tarannum Ara, Pierina Barturen-Larrea, Mengtong Duan, Mikhail G. Shapiro, Valeria Gazzola, David Maresca
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Light-sheet fluorescence microscopy has revolutionized biology by visualizing dynamic cellular processes in three dimensions. However, light scattering in thick tissue and photobleaching of fluorescent reporters limit this method to studying thin or translucent specimens. In this study, we applied nondiffractive ultrasound beams in conjunction with a cross-amplitude modulation sequence and nonlinear acoustic reporters to enable fast and volumetric imaging of targeted biological functions. We reported volumetric imaging of tumor gene expression at the cubic centimeter scale using genetically encoded gas vesicles and localization microscopy of cerebral capillary networks using intravascular microbubble contrast agents. Nonlinear sound-sheet microscopy provides a ~64× acceleration in imaging speed, ~35× increase in imaged volume, and ~4× increase in classical imaging resolution compared with the state of the art in biomolecular ultrasound.
GPT-4o mini: Non-social science research article
A geological timescale for bacterial evolution and oxygen adaptation
AdriĂĄn A. DavĂ­n, Ben J. Woodcroft, Rochelle M. Soo, Benoit Morel, Ranjani Murali, Dominik Schrempf, James W. Clark, Sandra Álvarez-Carretero, Bastien Boussau, Edmund R. R. Moody, LĂ©nĂĄrd L. SzĂĄnthĂł, Etienne Richy, Davide Pisani, James Hemp, Woodward W. Fischer, Philip C. J. Donoghue, Anja Spang, Philip Hugenholtz, Tom A. Williams, Gergely J. SzöllƑsi
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Microbial life has dominated Earth’s history but left a sparse fossil record, greatly hindering our understanding of evolution in deep time. However, bacterial metabolism has left signatures in the geochemical record, most conspicuously the Great Oxidation Event (GOE). We combine machine learning and phylogenetic reconciliation to infer ancestral bacterial transitions to aerobic lifestyles, linking them to the GOE to calibrate the bacterial time tree. Extant bacterial phyla trace their diversity to the Archaean and Proterozoic, and bacterial families prior to the Phanerozoic. We infer that most bacterial phyla were ancestrally anaerobic and adopted aerobic lifestyles after the GOE. However, in the cyanobacterial ancestor, aerobic metabolism likely predated the GOE, which may have facilitated the evolution of oxygenic photosynthesis.
GPT-4o mini: Non-social science research article
Superior resistance to cyclic creep in a gradient structured steel
Qingsong Pan, Kunqing Ding, Song Guo, Ning Lu, Nairong Tao, Ting Zhu, Lei Lu
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Cyclic creep, or ratcheting, is a severe form of fatigue deformation caused by cumulative unidirectional plastic strain under asymmetrical stress cycling with a nonzero mean stress. It often causes premature failure of structural materials, and enhancing ratcheting resistance is a challenge in materials engineering. We demonstrate superior ratcheting resistance in high-strength austenitic stainless steel with a gradient hierarchy of dislocation cells. The ratcheting rate is two to four orders of magnitude lower than for coarse-grained counterparts. Its resistance results from sustained microstructural refinement through deformation-induced coherent martensitic transformations to hexagonal close-packed nanolayers within stable dislocation cells. The progressively refined microstructure mitigates cyclic softening and suppresses strain localization during stress cycling, thus reducing ratcheting strain. The gradient dislocation architecture represents a promising design for high-strength, ratcheting-resistant materials.
GPT-4o mini: Non-social science research article
Human high-order thalamic nuclei gate conscious perception through the thalamofrontal loop
Zepeng Fang, Yuanyuan Dang, An’an Ping, Chenyu Wang, Qianchuan Zhao, Hulin Zhao, Xiaoli Li, Mingsha Zhang
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Human high-order thalamic nuclei activity is known to closely correlate with conscious states. However, it is not clear how those thalamic nuclei and thalamocortical interactions directly contribute to the transient process of human conscious perception. We simultaneously recorded stereoelectroencephalography data from the thalamic nuclei and prefrontal cortex (PFC), while patients with implanted electrodes performed a visual consciousness task. Compared with the ventral nuclei and PFC, the intralaminar and medial nuclei presented earlier and stronger consciousness-related activity. Transient thalamofrontal neural synchrony and cross-frequency coupling were both driven by the Ξ phase of the intralaminar and medial nuclei during conscious perception. The intralaminar and medial thalamic nuclei thus play a gate role to drive the activity of the PFC during the emergence of conscious perception.
GPT-4o mini: Non-social science research article
Anyon braiding and telegraph noise in a graphene interferometer
Thomas Werkmeister, James R. Ehrets, Marie E. Wesson, Danial H. Najafabadi, Kenji Watanabe, Takashi Taniguchi, Bertrand I. Halperin, Amir Yacoby, Philip Kim
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The search for anyons, quasiparticles with fractional charge and exotic exchange statistics, has inspired decades of condensed matter research. Quantum Hall interferometers enable direct observation of the anyon braiding phase via discrete interference phase jumps when the number of encircled localized quasiparticles changes. Here, we observe this braiding phase in both the Îœ = 1/3 and 4/3 fractional quantum Hall states by probing three-state random telegraph noise (RTN) in real-time. We find that the observed RTN stems from anyon quasiparticle number n fluctuations and reconstruct three Aharonov-Bohm oscillation signals phase shifted by 2π/3, corresponding to the three possible interference branches from braiding around n (mod 3) anyons. Our methods can be readily extended to interference of non-abelian anyons.
GPT-4o mini: Non-social science research article
The genetic architecture of and evolutionary constraints on the human pelvic form
Liaoyi Xu, Eucharist Kun, Devansh Pandey, Joyce Y. Wang, Marianne F. Brasil, Tarjinder Singh, Vagheesh M. Narasimhan
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Human pelvic evolution following the human-chimpanzee divergence is thought to result in an obstetrical dilemma, a mismatch between large infant brains and narrowed female birth canals, but empirical evidence has been equivocal. By using deep learning on 31,115 dual-energy x-ray absorptiometry scans from UK Biobank, we identified 180 loci associated with seven highly heritable pelvic phenotypes. Birth canal phenotypes showed sex-specific genetic architecture, aligning with reproductive function. Larger birth canals were linked to slower walking pace and reduced back pain but increased hip osteoarthritis risk, whereas narrower birth canals were associated with reduced pelvic floor disorder risk but increased obstructed labor risk. Lastly, genetic correlation between birth canal and head widths provides evidence of coevolution between the human pelvis and brain, partially mitigating the dilemma.
GPT-4o mini: Non-social science research article
Strain-induced rubidium incorporation into wide-bandgap perovskites reduces photovoltage loss
Likai Zheng, Mingyang Wei, Felix T. Eickemeyer, Jing Gao, Bin Huang, Ummugulsum Gunes, Pascal Schouwink, David Wenhua Bi, Virginia Carnevali, Mounir Mensi, Francesco Biasoni, Yuxuan Zhang, Lorenzo Agosta, Vladislav Slama, Nikolaos Lempesis, Michael A. Hope, Shaik M. Zakeeruddin, Lyndon Emsley, Ursula Rothlisberger, Lukas Pfeifer, Yimin Xuan, Michael GrÀtzel
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A-site cation mixing can enhance the photovoltaic performance of a wide-bandgap (WBG) perovskite, but rubidium (Rb) cation mixing generally forms a nonperovskite phase. We report that lattice strain locks Rb ions into the α-phase of the lattice of a triple-halide WBG perovskite, preventing phase segregation into a nonperovskite Rb-cesium–rich phase. This process cooperates with chloride accommodation and promotes halide homogenization across the entire film volume. The resulting 1.67–electron volt WBG perovskite exhibits photoluminescence quantum yields exceeding 14% under 1-sun-equivalent irradiation, corresponding to a quasi–Fermi level splitting of ~1.34 electron volts. A WBG perovskite solar cell with an open-circuit voltage ( V OC ) of 1.30 volts was prepared, corresponding to 93.5% of the radiative V OC limit and representing the lowest photovoltage loss relative to the theoretical limit observed in WBG perovskites.
GPT-4o mini: Non-social science research article
Exogenous RNA surveillance by proton-sensing TRIM25
Myeonghwan Kim, Youngjoon Pyo, Seong-In Hyun, Minseok Jeong, Yeon Choi, V. Narry Kim
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Exogenous messenger RNAs (mRNAs) require cellular machinery for delivery and translation but also encounter inhibitory factors. To investigate their regulation, we performed genome-wide CRISPR screens with in vitro–transcribed mRNAs in lipid nanoparticles (LNPs). Heparan sulfate proteoglycans (HSPGs) and vacuolar adenosine triphosphatase (V-ATPase) were identified as mediators of LNP uptake and endosomal escape, respectively. TRIM25—an RNA binding E3 ubiquitin ligase—emerged as a key suppressor inducing turnover of both linear and circular mRNAs. The endoribonucleases N4BP1 and KHNYN, along with the antiviral protein ZAP, act redundantly in TRIM25-dependent surveillance. TRIM25 specifically targets mRNAs delivered by endosomes, and its RNA affinity increases at acidic pH, suggesting activation by protons released from ruptured endosomes. N 1 -methylpseudouridine modification reduces TRIM25’s RNA binding, helping RNAs evade its suppressive effect. This study comprehensively maps cellular pathways regulating LNP-mRNAs, offering insights into RNA immunity and therapeutics.
GPT-4o mini: Non-social science research article
Protein editing using a coordinated transposition reaction
Yi Hua, Nicholas E. S. Tay, Xuanjia Ye, Jeremy A. Owen, Hengyuan Liu, Robert E. Thompson, Tom W. Muir
Full text
Protein engineering through the ligation of polypeptide fragments has proven enormously powerful for studying biochemical processes. In general, this strategy necessitates a final protein-folding step, constraining the types of systems amenable to the approach. Here, we report a method that allows internal regions of target proteins to be replaced in a single operation. Conceptually, our system is analogous to a DNA transposition reaction but uses orthogonal pairs of engineered split inteins to mediate the editing process. This “protein transposition” reaction is applied to several systems, including folded protein complexes, allowing the efficient introduction of a variety of noncoded elements. By carrying out a molecular “cut and paste” under native protein-folding conditions, our approach substantially expands the scope of protein semisynthesis.
GPT-4o mini: Non-social science research article
Most bacterial gene families are biased toward specific chromosomal positions
Xiao-Pan Hu, Bayu Brahmantio, Krzysztof Bartoszek, Martin J. Lercher
Full text
The arrangement of genes along bacterial chromosomes influences their expression through growth rate–dependent gene copy number changes during DNA replication. Although translation- and transcription-related genes often cluster near the origin of replication, the extent of positional biases across gene families remains unclear. We hypothesized that natural selection broadly favors specific chromosomal positions to optimize growth rate–dependent expression. Analyzing 910 bacterial species and proteomics data from Escherichia coli and Bacillus subtilis , we found that about two-thirds of bacterial gene families are positionally biased. Natural selection drives genes mainly toward the origin or terminus of replication, with the strongest selection in fast-growing species. Our findings reveal chromosomal positioning as a fundamental mechanism for coordinating gene expression with growth rate, highlighting evolutionary constraints on bacterial genome architecture.
GPT-4o mini: Non-social science research article
Ultrahigh capacitive energy storage through dendritic nanopolar design
Yajing Liu, Yang Zhang, Jing Wang, Chao Yang, Hongguang Wang, Judith L. MacManus-Driscoll, Hao Yang, Peter A. van Aken, Weiwei Li, Ce-Wen Nan
Full text
Electrostatic dielectric capacitors with ultrahigh power densities are sought after for advanced electronic and electrical systems owing to their ultrafast charge-discharge capability. However, low energy density resulting from low breakdown strength and suppressed polarization still remains a daunting challenge for practical applications. We propose a microstructural strategy with dendritic nanopolar (DNP) regions self-assembled into an insulator, which simultaneously enhances breakdown strength and high-field polarizability and minimizes energy loss and thus markedly improves energy storage performance and stability. For illustration, in this study, we achieved a high energy density of 215.8 joules per cubic centimeter with an efficiency of 80.7% at a high electric field of 7.4 megavolts per centimeter in a DNP structure–designed PbZr 0.53 Ti 0.47 O 3 -MgO film. The proposed strategy is generally applicable for development of high-performance dielectric microcapacitors.
GPT-4o mini: Non-social science research article
Cryptic infection of a giant virus in a unicellular green alga
Maria P. Erazo-Garcia, Uri Sheyn, Zachary K. Barth, Rory J. Craig, Petronella Wessman, Abdeali M. Jivaji, W. Keith Ray, Maria Svensson-Coelho, Charlie K. Cornwallis, Karin Rengefors, Corina P. D. Brussaard, Mohammad Moniruzzaman, Frank O. Aylward
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Latency is a common strategy in a wide range of viral lineages, but its prevalence in giant viruses remains unknown. Here we describe a 617 kbp integrated giant viral element in the model green alga Chlamydomonas reinhardtii . We resolve the integrated viral genome using long-read sequencing, identify a putative polinton-like integrase, and show that viral particles accumulate primarily during the stationary growth phase. A diverse array of viral-encoded selfish genetic elements is expressed during viral activity, including several Fanzor nuclease-encoding transposable elements. In addition, we show that field isolates of Chlamydomonas sp. harbor signatures of endogenous giant viruses related to the C. reinhardtii virus that exhibit similar infection dynamics, suggesting that giant virus latency is prevalent in natural host communities. Our work describes an unusually large temperate virus of a unicellular eukaryote, substantially expanding the scope of cryptic viral infections in the virosphere.
GPT-4o mini: Non-social science research article
A male Denisovan mandible from Pleistocene Taiwan
Takumi Tsutaya, Rikai Sawafuji, Alberto J. Taurozzi, Zandra FagernÀs, Ioannis Patramanis, Gaudry Troché, Meaghan Mackie, Takashi Gakuhari, Hiroki Oota, Cheng-Hsiu Tsai, Jesper V. Olsen, Yousuke Kaifu, Chun-Hsiang Chang, Enrico Cappellini, Frido Welker
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Denisovans are an extinct hominin group defined by ancient genomes of Middle to Late Pleistocene fossils from southern Siberia. Although genomic evidence suggests their widespread distribution throughout eastern Asia and possibly Oceania, so far only a few fossils from the Altai and Tibet are confidently identified molecularly as Denisovan. We identified a hominin mandible (Penghu 1) from Taiwan (10,000 to 70,000 years ago or 130,000 to 190,000 years ago) as belonging to a male Denisovan by applying ancient protein analysis. We retrieved 4241 amino acid residues and identified two Denisovan-specific variants. The increased fossil sample of Denisovans demonstrates their wider distribution, including warm and humid regions, as well as their shared distinct robust dentognathic traits that markedly contrast with their sister group, Neanderthals.
Science abstract < 200 char.: Not a research article
Implementing equitable wildfire response plans
Junxiang Xu, Divya Jayakumar Nair, S. Travis Waller
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Science abstract < 200 char.: Not a research article
Diversity is a feature, not a bug The Sexual Evolution: How 500 Million Years of Sex, Gender, and Mating Shape Modern Relationships Nathan H. Lents Mariner Books, 2025. 352 pp.
Justin R. Garcia
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An interdisciplinary tour of sexual strategies in the animal kingdom offers lessons for humanity
Science abstract < 200 char.: Not a research article
How does cancer affect motivation?
Jeffrey W. Dalley, Mary-Ellen Lynall
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Inflammatory cytokines hijack a brain circuit to cause apathy in cancer
Science abstract < 200 char.: Not a research article
The AI revolution comes to protein sequencing
Robert F. Service
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By identifying unknown proteins, new systems could aid research in many areas
Science abstract < 200 char.: Not a research article
In Other Journals
Angela Hessler, Sumin Jin, Sarah H. Ross, Michael A. Funk, Stella M. Hurtley, Madeleine Seale, Di Jiang
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Editors’ selections from the current scientific literature
Science abstract < 200 char.: Not a research article
Squirrels in Ivory Coast may be an animal reservoir for mpox
Kai Kupferschmidt
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Outbreak in mangabeys gives researchers a unique opportunity to study the virus’ elusive origins
Science abstract < 200 char.: Not a research article
‘Uniquely human’ language capacity found in bonobos
Cathleen O’Grady
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Study is the first to show an animal combining different calls to make new meanings
Science abstract < 200 char.: Not a research article
In Science Journals
Sacha Vignieri, Mattia Maroso, Michael A. Funk, Marc S. Lavine, Phil Szuromi, Di Jiang, Wei Wong, Claire Olingy, Bianca Lopez, Stella M. Hurtley, Yevgeniya Nusinovich, Jake S. Yeston, Caroline Ash, Peter Stern, Madeleine Seale, Sarah H. Ross, Melissa L. Norton
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Highlights from the Science family of journals
Science abstract < 200 char.: Not a research article
NIH cancels research grants for COVID-19 and future pandemics
Jon Cohen
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Scientists reject claim that the work is no longer needed
Science abstract < 200 char.: Not a research article
Rubella and measles: The beginning of the endgame
Matthew J. Ferrari, William J. Moss
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Benchmarks must be established and progress tracked to set a global target and take action
Science abstract < 200 char.: Not a research article
Taking flight
Melanie Ortiz Alvarez De La Campa
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Science abstract < 200 char.: Not a research article
Convince me, control me The Instability of Truth: Brainwashing, Mind Control, and Hyper-Persuasion Rebecca Lemov Norton, 2025. 464 pp.
Katie Joice
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A historian probes the origins and evolution of psychological manipulation
Science abstract < 200 char.: Not a research article
Health agencies reeling as leaders, staff slashed
Jocelyn Kaiser
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NIH loses five heads of institutes; FDA and CDC offices also gutted
Science abstract < 200 char.: Not a research article
An awakening
Maria Martignoni
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Science abstract < 200 char.: Not a research article
Editor’s note
H. Holden Thorp
Full text
Science abstract < 200 char.: Not a research article
No one can replace the U.S. as it retreats from global health
Ida Jooste
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Other countries, foundations, international groups are unable to make up for billions in Trump administration cuts
Science abstract < 200 char.: Not a research article
Catalysis at the crossroads
Cathy L. Tway, Sorin V. Filip
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Homogeneous and heterogeneous catalysis work concurrently in a chemical process
Science abstract < 200 char.: Not a research article
Failure to communicate
Rebekah White
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Geoengineering could be crucial in the fight against climate change. But first scientists need to learn how to talk to the public about it
Science abstract < 200 char.: Not a research article
Beyond wear and tear at the joint
Chuan-ju Liu
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Bile acid metabolism meets glucagon-like peptide 1 signaling in osteoarthritis
Science abstract < 200 char.: Not a research article
Empower the age of smart mRNA medicine: Programmable RNA sensor and molecular tools refine therapeutic payload production
Xiaojing Gao
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Programmable RNA sensor and molecular tools refine therapeutic payload production
Science abstract < 200 char.: Not a research article
Stellarators, once fusion’s dark horse, hit their stride
Daniel Clery
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Multiple companies aim to build pilot plants using twisted magnets
Science abstract < 200 char.: Not a research article
Closing the gap in the neutrino mass
Loredana Gastaldo
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New measurements make an important step toward demystifying the fundamental particle
Science abstract < 200 char.: Not a research article
A natural defense against plant disease
Comzit Opachaloemphan, Sheng Yang He
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Wild citrus plants contain a natural defense against a devastating bacterial disease
Science abstract < 200 char.: Not a research article
Fixing the science of digital technology harms
Amy Orben, J. Nathan Matias
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Technology development outpaces scientific assessment of impacts
Science abstract < 200 char.: Not a research article
Ancient DNA illuminates ‘green Sahara’ dwellers
Andrew Curry
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Skeletons from an ancient, lush interlude offer genetic peek at a lost population
Science abstract < 200 char.: Not a research article
Archaea go multicellular under pressure
Eva K. Pillai, Thibaut Brunet
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A microbe from the Dead Sea switches to a tissue-like form when compressed
Science abstract < 200 char.: Not a research article
NSF has awarded almost 50% fewer grants
Jeffrey Mervis
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An analysis shows a drastic falloff since Trump took office. The finding conflicts with the director’s claims
Science abstract < 200 char.: Not a research article
Saving the cultural legacy of wild animals
Ammie K. Kalan, Lydia V. Luncz
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Loss of biodiversity threatens the study of tool use and other cultural behaviors in animals
Science abstract < 200 char.: Not a research article
When trainees seek other paths How to Mentor Anyone in Academia Maria LaMonaca Wisdom Princeton University Press, 2025. 280 pp.
Jonathan Wai
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A new book offers advice for mentoring those who do not aspire to follow in faculty’s footsteps
Science abstract < 200 char.: Not a research article
Reformation by light
Xabier Lopez de Pariza, Haritz Sardon
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Light-driven chemistry enables three-dimensional printing of recyclable polymer parts
Science abstract < 200 char.: Not a research article
Empires and their philosophies America, América: A New History of the New World Greg Grandin Penguin, 2025. 768 pp.
Jorge Cañizares-Esguerra
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Conflicting ideas about citizenship and sovereignty shaped the Americas, argues a historian
Science abstract < 200 char.: Not a research article
A passion for bats
Orji Sunday
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Biologists Benneth Obitte and Inoro Tanshi are exploring Nigeria’s bat diversity, and trying to save it
Science abstract < 200 char.: Not a research article
Is Indonesia’s rice farming megaproject doomed to fail?
Dyna Rochmyaningsih
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Poor soils and dry climate could undermine effort to add 1 million hectares of paddies, scientists say
Science abstract < 200 char.: Not a research article
Dancing with the cells: How acoustically levitating a diamond enabled a redesign of biotech automation
Luke Cox
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How acoustically levitating a diamond enabled a redesign of biotech automation
Science abstract < 200 char.: Not a research article
Modernizing wildfire management in China
Junran Li
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Science abstract < 200 char.: Not a research article
Wildfires jeopardize drinking water safety
Xuan Li, Qizi Fu, Qilin Wang
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Science abstract < 200 char.: Not a research article
mRNA binding proteins join the longevity pipeline: Rebuilding muscle through the power of mRNA binding protein therapeutics
Dounia Abbadi
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Rebuilding muscle through the power of mRNA binding protein therapeutics
Science abstract < 200 char.: Not a research article
Science safeguards
Zhen Wang, Sara Shakir, Bram Servais, Safaa Osman, Yutong Hu, Yumna Gamal, Malk Elshrief, Karen Jacqueline Cloete, Alaa Mostafa, Julio Santos, Yuanxing Xia, Caitlyn X. Chen, Fengbo Li, Ibrahem Hamed Ibrahem Hilal, Ahmed Ezzat Elsayed, Yousef Abdallatif, Hao Zhang, Fotis Tsiroukis
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Science abstract < 200 char.: Not a research article
Killed NIH grants could waste billions of dollars
Sara Reardon
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More than $1.4 billion in sunk research costs may produce few results, analysis suggests
Science abstract < 200 char.: Not a research article
International scientists rethink U.S. conferences
Kate Langin
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Opposition to Trump administration and fears of customs run-ins are shifting travel plans
Science abstract < 200 char.: Not a research article
Landmark bioweapons pact needs upgrade, researchers say
Richard Stone
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Technological advances are challenging the effectiveness of the 50-year-old Biological Weapons Convention
Science abstract < 200 char.: Not a research article
A global warming ‘hole’ where you’d least expect it
Vaishnavi Chandrashekhar
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India has so far warmed at about half the global average. Scientists aren’t sure why
Beyond the Binary: Navigating AI’s Uncertain Future in Africa
Rose M. Mutiso
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The artificial intelligence (AI) debate is increasingly polarized in Africa, mirroring a trend across the globe. On one side, utopian headlines, such as “ 5 Ways To Harness AI And End Poverty Forever ,” claim that AI will revolutionize development. On the other, warnings that “ AI Is Bad News for the Global South ” paint the technology as an inevitable amplifier of inequality and exploitation.
Protecting pieces of us: The need for Indigenous perspectives in the fuzzy world of biometric data regulation
Tahu Kukutai
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The bankruptcy filing by commercial genetic testing company 23andMe has put the spotlight, once again, on the limits and effectiveness of data privacy laws. Since the company was founded in 2006, it has amassed a database of around 15 million customers who shared their genetic and health information in return for insights into their ancestry, traits, disease risks, and other aspects. About 80% also opted to have their deidentified data shared for medical research purposes, which included drug discovery research involving companies such as GlaxoSmithKline and Pfizer.

Science Advances

GPT-4o mini: Non-social science research article
Delivery of intraflagellar transport proteins to the ciliary base and assembly into trains
Aniruddha Mitra, Evangelos Gioukakis, Wouter Mul, Erwin J. G. Peterman
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Anterograde intraflagellar transport (IFT) trains, composed of IFT-B, IFT-A, and BBSome subcomplexes, are responsible for transporting ciliary proteins into the cilium. How IFT subcomplexes reach the ciliary base and assemble into IFT trains is poorly understood. Here, we perform quantitative single-molecule imaging in Caenorhabditis elegans chemosensory cilia to uncover how IFT subcomplexes arrive at the base, organize in IFT trains, and enter the cilium. We find that BBSomes reach the base via diffusion where they either associate with assembling IFT trains or with the membrane surrounding the base. In contrast, IFT-B and IFT-A reach the base via directed transport most likely on vesicles that stop at distinct locations near the base. Individual subcomplexes detach from the vesicles into a diffusive pool and associate to assembling trains. Our results show that IFT-B is first incorporated into IFT trains, followed by IFT-A, and finally BBSomes, indicating that the assembly of IFT trains is a highly regulated, step-wise process.
GPT-4o mini: Non-social science research article
Retromer promotes the lysosomal turnover of mtDNA
Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollå, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín
Full text
Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria’s association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.
GPT-4o mini: Non-social science research article
Tree-ring stable isotopes from the European Alps reveal long-term summer drying over the Holocene
Tito Arosio, Markus Leuenberger, Kurt Nicolussi, Jan Esper, Paul J. Krusic, Tatiana Bebchuk, Willy Tegel, Albert Hafner, Alexander Kirdyanov, Christian SchlĂŒchter, Frederick Reinig, Francesco Muschitiello, Ulf BĂŒntgen
Full text
Here, we use 7437 stable oxygen (Ύ 18 O) isotope ratios extracted from 192 living and relict Alpine trees to reconstruct trends and extremes in European summer hydroclimate from 8980 before the present to 2014 Common Era. Our continuous tree-ring Ύ 18 O record reveals a significant long-term drying trend over much of the Holocene ( P  < 0.001), which is in line with orbital forcing and independent evidence from proxy reconstructions and model simulations. Wetter conditions in the early-to-mid Holocene coincide with the African Humid Period, whereas the most severe summer droughts of the past 9000 years are found during the Little Ice Age in the 18th and 19th centuries Common Era. We suggest that much of Europe was not only warmer but also wetter during most of the preindustrial Holocene, which implies a close relationship between insolation changes and long-term hydroclimate trends that likely affected natural and societal systems across a wide range of spatiotemporal scales.
GPT-4o mini: Non-social science research article
Experimental quantification of nuclear quantum effects on the hydrogen bond of liquid water
Kuo-Yang Chiang, Johannes Hunger, Mischa Bonn, Yuki Nagata
Full text
Nuclear quantum effects (NQEs) significantly influence material properties upon isotopic substitution, particularly with light atoms such as hydrogen. While water is rich in hydrogen, its hydrogen-bonded structure exhibits only moderate NQEs. Simulations ascribe this to competing zero-point energies (ZPEs): Intermolecular ZPEs stabilize hydrogen-bonds, while intramolecular ZPEs destabilize them. However, experimental validation has been lacking due to the difficulty in quantifying NQEs. The air/water interface provides an ideal platform to quantify NQEs in liquid water using surface-specific vibrational spectroscopy. By analyzing the excess/depletion of interfacial HOD, H 2 O, and D 2 O molecules with one free OH/OD group and the other H-bonded OH/OD group, we found that the intermolecular ZPE destabilizes the hydrogen-bonds by 0.74 ± 0.20 kilojoule per mole upon isotope substitution from H to D, while the intramolecular ZPE stabilizes them by 0.78 ± 0.33 kilojoule per mole. This near-complete cancellation explains the overall moderate NQE in liquid water. The interface thus allows for quantifying NQEs in water.
GPT-4o mini: Non-social science research article
Exploring the Berezinskii-Kosterlitz-Thouless transition in a two-dimensional dipolar bose gas
Yifei He, Ziting Chen, Haoting Zhen, Mingchen Huang, Mithilesh K. Parit, Gyu-Boong Jo
Full text
Long-range and anisotropic dipolar interactions induce complex order in quantum systems, particularly interesting in 2D where superfluidity emerges via the Berezinskii-Kosterlitz-Thouless (BKT) mechanism. We observe a superfluid phase with algebraically decaying correlation in a quasi-2D dipolar Bose gas of erbium atoms and further identify the superfluid phase transition by monitoring extended coherence. We also measure equations of state with tunable dipolar interactions. Our findings show a transition point shift due to dipole orientation, aligning with BKT transition with effective short-range interaction. However, we observe that in-plane tilted dipoles show nonlocal effects in the superfluid regime, preventing the effective short-range interaction from revealing universal behavior near the BKT critical point. We also measure anisotropic atom number fluctuations in the superfluid regime, highlighting its dipolar nature. Our results provide a foundation for understanding dipolar bosons in 2D and pave the way for investigating complex orders in dipolar superfluids.
GPT-4o mini: Non-social science research article
Armored polymer-fluid gels with integrated damping and impact protection across broad temperatures
Guoqing Chen, Jiabin Wu, Zhenwu Wang, He Zhu, Shiping Zhu, Qi Zhang
Full text
Unpreferable vibrations and impacts pose substantial risks to sensitive devices, structures, and the human body, demanding materials capable of providing both high energy dissipation and impact protection across a broad temperature range. Traditional damping materials often fail to meet these demands because of a trade-off between damping and mechanical strength. We introduce an innovative strategy to fabricate armored polymer-fluid gels (APFGs) that combine high damping and high modulus for effective damping and impact protection under extreme conditions. By using a controlled surface cross-linking process through diffusion, we greatly enhance the mechanical strength of polymer-fluid gels without sacrificing their damping capabilities. This asymmetric design results in an unprecedented loss factor (tanή > 0.5 from −45 degrees to 135 degrees Celsius, peaking at tanή = 2.2) while achieving a tensile modulus of 20 megapascals. This method resolves the long-standing damping-modulus trade-off, positioning APFGs as promising candidates for robust damping and impact protection in electronics and human motion applications.
GPT-4o mini: Non-social science research article
Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma
Weiming Mou, Zhixing Deng, Lingxuan Zhu, Aimin Jiang, Anqi Lin, Liling Xu, Gengwen Deng, Hongsen Huang, Zeji Guo, Bang Zhu, Shuqi Wu, Tao Yang, Lu Wang, Zaoqu Liu, Ting Wei, Jian Zhang, Liang Cheng, Haojie Huang, Rui Chen, Yi Shao, Quan Cheng, Linhui Wang, Shuofeng Yuan, Peng Luo
Full text
The intratumoral mycobiome plays a crucial role in the tumor microenvironment, but its impact on renal cell carcinoma (RCC) remains unclear. We collected and quantitatively profiled the intratumoral mycobiome data from 1044 patients with RCC across four international cohorts, of which 466 patients received immunotherapy. Patients were stratified into mycobiota ecology-depauperate and mycobiota ecology-flourishing (MEF) groups based on fungal abundance. The MEF group had worse prognosis, higher fungal diversity, down-regulated lipid catabolism, and exhausted CD8 + T cells. We developed the intratumoral mycobiota signature and intratumoral mycobiota-related genes expression signature, which robustly predicted prognosis and immunotherapy outcomes in RCC and other cancers. Aspergillus tanneri was identified as a potential key fungal species influencing RCC prognosis. Our findings suggest that the intratumoral mycobiome suppresses lipid catabolism and induces T cell exhaustion in RCC.
GPT-4o mini: Non-social science research article
CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses
Kilyna A. Nguyen, Zhihui Liu, John S. Davies, Crystal P. McIntosh, Lindsey M. Draper, Scott M. Norberg, Zachary Rae, Sooraj R. Achar, Gregoire Altan-Bonnet, Ling Zhang, Xiaolin Wu, Thomas J. Meyer, Michael C. Kelly, Naomi Taylor, Christian S. Hinrichs, Kazusa Ishii
Full text
Chimeric antigen receptor (CAR) T cells effectively treat B cell malignancies. However, CAR-T cells cause inflammatory toxicities such as cytokine release syndrome (CRS), which is in contrast to T cell receptor (TCR)–engineered T cells against various antigens that historically have rarely been associated with CRS. To study whether and how differences in receptor types affect the propensity for eliciting inflammatory responses in a model system wherein TCR and CAR target equalized sources of clinically relevant antigen, we discovered a CD22-specific TCR and compared it to CD22 CAR. Both CD22 TCR-T and CD22 CAR-T cells eradicated leukemia in xenografts, but only CD22 CAR-T cells induced dose-dependent systemic inflammation. Compared to TCR-T cells, CAR-T cells disproportionately upregulated inflammatory pathways without concordant augmentation in pathways involved in direct cytotoxicity upon antigen engagement. These differences in antileukemia responses comparing TCR-T and CAR-T cells highlight the potential opportunity to improve therapeutic safety by using TCRs.
GPT-4o mini: Non-social science research article
FairDiffusion: Enhancing equity in latent diffusion models via fair Bayesian perturbation
Yan Luo, Muhammad Osama Khan, Congcong Wen, Muhammad Muneeb Afzal, Titus Fidelis Wuermeling, Min Shi, Yu Tian, Yi Fang, Mengyu Wang
Full text
Recent advancements in generative AI, particularly diffusion models, have proven valuable for text-to-image synthesis. In health care, these models offer immense potential in generating synthetic datasets and aiding medical training. Despite these strong performances, it remains uncertain whether the image generation quality is consistent across different demographic subgroups. To address this, we conduct a comprehensive analysis of fairness in medical text-to-image diffusion models. Evaluations of the Stable Diffusion model reveal substantial disparities across gender, race, and ethnicity. To reduce these biases, we propose FairDiffusion, an equity-aware latent diffusion model that improves both image quality and the semantic alignment of clinical features. In addition, we design and curate FairGenMed, a dataset tailored for fairness studies in medical generative models. FairDiffusion is further assessed on HAM10000 (dermatoscopic images) and CheXpert (chest x-rays), demonstrating its effectiveness in diverse medical imaging modalities. Together, FairDiffusion and FairGenMed advance research in fair generative learning, promoting equitable benefits of generative AI in health care.
GPT-4o mini: Non-social science research article
Topological elastic liquid diode
Yurong Zhang, Lijun Li, Gang Li, Zhen Lin, Ruteng Wang, Daobing Chen, Yifeng Lei, Di Tan, Zuankai Wang, Yan Zhao, Longjian Xue
Full text
On-demand liquid transportation is fundamentally important and holds great potential in various fields, such as water collection and biological engineering. However, it remains highly challenging to in situ manipulate the direction of liquid flow on a lyophilic surface. Here, a topological elastic liquid diode (TELD) that could manipulate the flow direction is developed by combining the Araucaria leaf inspired ratchet array and the elasticity of silicon rubber. The flow pathway on the lyophilic TELD can be conveniently managed by regulating the competition forces along orthogonal directions at the liquid front, which is instantly realized by adjusting the mechanical strain in TELD (mode 1 regulation) or inserting extra forces at the liquid front (mode 2 regulation). Furthermore, TELD can serve as a logic gate, stress valve, microfluidic reactor, and fog collector. Thus, the work here establishes strategies for in situ and instant manipulation of liquid flow on a lyophilic surface.
GPT-4o mini: Non-social science research article
Galvanostatic cycling of a micron-sized solid-state battery: Visually linking void evolution to electrochemistry
Haowen Gao, Chen Lin, Yuanpeng Liu, Jiashun Shi, Bowen Zhang, Zhefei Sun, Zhao Li, Yu Wang, Menghao Yang, Yong Cheng, Ming-Sheng Wang
Full text
The formation of interface voids, peculiar to the solid-solid contact between metal anodes and solid electrolytes (SEs), has become a fundamental obstacle for developing practical lithium metal solid-state batteries (SSBs). Addressing this issue requires the operando observation of void evolution with high spatio-temporal resolution and the direct linkage of voids to solid-state electrochemistry. Here, we present such an attempt by visualizing both the stripping and plating interfaces of a micron-sized SSB cycled in galvanostatic mode in a transmission electron microscope. Various voltage responses in the charge/discharge curves are well correlated to the nucleation, growth, and refilling of single voids. Notably, two distinct modes of Li stripping, namely, void-growth stripping and void-free stripping, are experimentally identified. We unveil the roles of stack pressure and current density on void evolutions, which suggests a mechanism of void suppression without involving plastic deformation of Li metal. Furthermore, Li|SE|Li symmetric SSBs enabling repeated void-free cycling without stack pressure are in situ demonstrated.
GPT-4o mini: Non-social science research article
Global inland-water oxygen cycle has changed in the Anthropocene
Junjie Wang, Xiaochen Liu, Alexander F. Bouwman, Lauriane Vilmin, Arthur H.W. Beusen, José M. Mogollón, Wim J. van Hoek, Jack J. Middelburg
Full text
Inland waters are an important resource, a highly diverse habitat, and a key component of global biogeochemical cycles. Oxygen plays a major role in inland-water ecosystem functioning, but long-term changes in its cycling remain unknown. Here, we quantify global inland-water oxygen production, consumption, and exchange with the atmosphere during 1900–2010 using a spatially explicit, mass-balanced, mechanistic model that takes into account changes in climate, hydrology, human activities, and the coupled biogeochemical (oxygen-nutrient-organic matter) dynamics. The model results show that global inland-water oxygen turnover increased during 1900–2010: production from 0.16 to 0.94 Pg year −1 and consumption from 0.44 to 1.47 Pg year −1 . Inland waters overall remained heterotrophic and a sink of atmospheric oxygen. Direct human perturbations (changes in hydrology and nutrient supply) were more important in increasing oxygen turnover than indirect effects via warming.
GPT-4o mini: Non-social science research article
Vibrio MARTX toxin binding of biantennary N-glycans at host cell surfaces
Jiexi Chen, Felix Goerdeler, Thapakorn Jaroentomeechai, Francisco X. S. Hernandez, Xiaozhong Wang, Henrik Clausen, Yoshiki Narimatsu, Karla J. F. Satchell
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Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are a diverse effector delivery platform of many Gram-negative bacteria that infect mammals, insects, and aquatic animal hosts. The mechanisms by which these toxins recognize host cell surfaces have remained elusive. Here, we map a surface interaction domain of a MARTX toxin from the highly lethal foodborne pathogen Vibrio vulnificus . This domain corresponds to a 273–amino acid sequence with predicted symmetrical immunoglobulin-like folds. We demonstrate that this domain binds internal N -acetylglucosamine on complex biantennary N-glycans with select preference for L1CAM and other N-glycoproteins with multiple N-glycans on host cell surfaces. This domain is also essential for V. vulnificus pathogenesis during intestinal infection. The identification of a highly conserved motif universally present as part of all N-glycans correlates with the V. vulnificus MARTX toxin having broad specificity and targeting nearly all cell types.
GPT-4o mini: Non-social science research article
Neural mechanisms of resource allocation in working memory
Hsin-Hung Li, Thomas C. Sprague, Aspen H. Yoo, Wei Ji Ma, Clayton E. Curtis
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To mitigate capacity limits of working memory, people allocate resources according to an item’s relevance. However, the neural mechanisms supporting such a critical operation remain unknown. Here, we developed computational neuroimaging methods to decode and demix neural responses associated with multiple items in working memory with different priorities. In striate and extrastriate cortex, the gain of neural responses tracked the priority of memoranda. We decoded higher-priority memoranda with smaller error and lower uncertainty. Moreover, these neural differences predicted behavioral differences in memory prioritization between and within participants. Trial-wise variability in the magnitude of delay activity in the frontal cortex predicted differences in decoded precision between low- and high-priority items in visual cortex. These results support a model in which feedback signals broadcast from frontal cortex sculpt the gain of memory representations in the visual cortex according to behavioral relevance, thus identifying a neural mechanism for resource allocation.
GPT-4o mini: Non-social science research article
Synthesis of Campylobacter jejuni capsular oligosaccharides and identification of a potential O -antigen against campylobacteriosis
Jianjun Wang, Xuemei Yang, Zirong Huang, Yong Su, Xinxin Zhang, Ni Song, Peng Wang, Chen Yang, Hongzhi Cao, Xue-Wei Liu, Xuechen Li, Sheng Chen, Ming Li
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The vaccines against campylobacteriosis are urgently needed because of the rising multidrug resistance of pathogenic Campylobacter jejuni . The capsular polysaccharides of these bacteria, containing unique 6-deoxy-ÎČ- d - ido -heptopyranosyl or l - glycero -ÎČ- d - ido -heptopyranosyl residues, have emerged as attractive antigens. Expeditious assembly of the oligosaccharides derived from these glycans is challenging because ÎČ- d -idopyranosidic linkages are formidable to directly construct. Furthermore, whether the synthetic C. jejuni oligosaccharides could induce sufficient immunogenicity as the potential antigens remains unexplored. Here, we report a protocol for directly forming ÎČ- d -idopyranosidic bonds using α- d -6-deoxy- ido -heptopyranosyl, α- d -idopyranosyl, and d -/ l - glycero -α- d - ido -heptopyranosyl ortho -hexynylbenzoates as glycosylating agents under gold(I) catalysis. To demonstrate the versatility of these methods, concise synthesis of conjugatable C. jejuni capsular di-/tetra-/hexa-/octasaccharides, having a backbone of [→3)-6-deoxy-ÎČ- d - ido -heptopyranosyl-(1→4)-2-acetamido-2-deoxy-ÎČ- d -glucopyranosyl-(1→], has been achieved. The immunogenicity assessment of the glycoconjugates, prepared by conjugating the synthesized oligosaccharides to cross-reactive material 197, reveals the disaccharide as a potential O -antigen for developing vaccines against campylobacteriosis. This work should facilitate development of synthetic vaccines against Campylobacter infections.
GPT-4o mini: Non-social science research article
Preference-based assistance optimization for lifting and lowering with a soft back exosuit
Philipp Arens, D. Adam Quirk, Weiwei Pan, Yaniv Yacoby, Finale Doshi-Velez, Conor J. Walsh
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Wearable robotic devices have become increasingly prevalent in both occupational and rehabilitative settings, yet their widespread adoption remains inhibited by usability barriers related to comfort, restriction, and noticeable functional benefits. Acknowledging the importance of user perception in this context, this study explores preference-based controller optimization for a back exosuit that assists lifting. Considering the high mental and metabolic effort discrete motor tasks impose, we used a forced-choice Bayesian Optimization approach that promotes sampling efficiency by leveraging domain knowledge about just noticeable differences between assistance settings. Optimizing over two control parameters, preferred settings were consistent within and uniquely different between participants. We discovered that overall, participants preferred asymmetric parameter configurations with more lifting than lowering assistance, and that preferences were sensitive to user anthropometrics. These findings highlight the potential of perceptually guided assistance optimization for wearable robotic devices, marking a step toward more pervasive adoption of these systems in the real world.
GPT-4o mini: Non-social science research article
MprF from Pseudomonas aeruginosa is a promiscuous lipid scramblase with broad substrate specificity
Matthew T. K. Hankins, Matyas Parrag, Alisa A. Garaeva, Jennifer C. Earp, Markus A. Seeger, Phillip J. Stansfeld, Maike Bublitz
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The multiple peptide resistance factor (MprF) is a bifunctional membrane protein found in many bacteria, including Pseudomonas aeruginosa and Staphylococcus aureus . MprF modifies inner leaflet lipid headgroups through aminoacylation and translocates modified lipid to the outer leaflet. This activity provides increased resistance to antimicrobial agents. MprF presents a promising target in multiresistant pathogens, but structural information is limited and both substrate specificity and energization of MprF-mediated lipid transport are poorly understood. Here, we present the cryo-EM structure of MprF from P. aeruginosa ( Pa MprF) bound to a synthetic nanobody. Pa MprF adopts an “open” conformation with a wide, lipid-exposed groove on the periplasmic side that induces a local membrane deformation in molecular dynamics simulations. Using an in vitro liposome transport assay, we demonstrate that Pa MprF translocates a wide range of different lipids without an external energy source. This suggests that Pa MprF is the first dedicated lipid scramblase to be characterized in bacteria.
GPT-4o mini: Non-social science research article
Asparagine transporter supports macrophage inflammation via histone phosphorylation
Chuanlong Wang, Yuyi Ye, Muyang Zhao, Qingyi Chen, Bingnan Liu, Wenkai Ren
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Solute carrier (SLC) family is essential for immune responses; nevertheless, whether and how SLCs regulate macrophage inflammation remains unclear. Here, we demonstrate that K636 acetylation mediates high abundance of SLC6A14 in inflammatory macrophages. Notably, the pharmacological inhibition or genetic modulation of SLC6A14 reduces macrophage interleukin-1ÎČ (IL-1ÎČ) secretion dependently of lower asparagine uptake and subsequently enhanced nuclear LKB1. Mechanistically, nuclear LKB1 lessens MAPK pathway–mediated NLRP3 inflammasome activation by increased histone 3 S10/28 phosphorylation-dependent cyclin O transcription. Moreover, myeloid Slc6a14 deficiency alleviates pulmonary inflammation via suppressing inflammatory macrophage responses. Overall, these results uncover a network by which SLC6A14-mediated asparagine uptake orchestrates macrophage inflammation through histone phosphorylation, providing a crucial target for modulation of inflammatory diseases.
GPT-4o mini: Non-social science research article
Remove the innermost atom of a magnetic multi-shell gold nanoparticle for near-unity conversion of CO 2 to CO
Guoqing Bian, Dong Chen, Yuping Chen, Wei Zhang, Liang Fang, Qing You, Runguo Wang, Wanmiao Gu, Yue Zhou, Nan Yan, Shengli Zhuang, Shiyu Ji, Meng Zhou, Chengming Wang, Lingwen Liao, Qing Tang, Jun Yang, Zhikun Wu
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Few reports on paramagnetic metal nanoparticles with atomic precision and their difficult tailoring retard the insightful investigation of metal nanoparticle paramagnetism. Herein, we introduced a thiol-iodine mixture ligand–protecting strategy to successfully synthesize multi-shell paramagnetic [Au 127 I 4 (TBBT) 48 (I: iodine, TBBT: 4-tert-butylphenylthiolate)]. The innermost Au atom was successfully removed via thiol induction without altering the structure framework to produce diamagnetic Au 126 I 4 (TBBT) 48 with local ligand arrangement changed (butterfly effect), which could be further transformed into paramagnetic [Au 126 I 4 (TBBT) 48 ] + via hydrogen peroxide oxidation. The spin populations of both paramagnetic nanoparticles are more densely distributed on surface iodine than sulfur. Diamagnetic Au 126 I 4 (TBBT) 48 exhibited a Faradaic efficiency of ~100% at −0.57 volt during the electrocatalytic reduction of carbon dioxide to carbon monoxide, while paramagnetic Au 127 I 4 (TBBT) 48 and [Au 126 I 4 (TBBT) 48 ] + exhibited the maximum Faradaic efficiency of 87% at −0.67 volt and 90% at −0.57 volt, respectively, indicating the spin-catalytic activity correlation.
GPT-4o mini: Non-social science research article
Invention of an oral medication for cardiac Fabry disease caused by RNA mis-splicing
Tomonari Awaya, Masahiko Ajiro, Hiroko Kobayashi, Teruo Sawada, Kentoku Gotanda, Toshiharu Noji, Naohiro Takemoto, Kei Iida, Megumu K. Saito, Dau-Ming Niu, Masatoshi Hagiwara
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Pathogenic RNA splicing variants have emerged as promising therapeutic targets due to their role in disease while preserving coding sequences. In this study, we developed RECTAS-2.0, a small molecule designed to correct RNA mis-splicing caused by the GLA c.639+919G>A mutation, which leads to the inclusion of a 57-nucleotide poison exon, resulting in later-onset Fabry disease, particularly prevalent in East Asia. RECTAS-2.0 restored normal GLA mRNA splicing and α-galactosidase activity in patient-derived B-lymphoblastoid cell lines and induced pluripotent stem cell–derived cardiomyocytes. Furthermore, oral administration of RECTAS-2.0 effectively corrected splicing in a transgenic mouse model, demonstrating its substantial splice-switching activity and safety for clinical application. RECTAS-2.0 demonstrated potential applicability to other genetic disorders that involve similar exon competition. These findings underscore the therapeutic potential of RECTAS-2.0 for Fabry disease and highlight its broader implications for RNA splicing–targeted therapies in genetic disorders.
GPT-4o mini: Non-social science research article
Assessing depletion attractions between colloidal nanocrystals
Charles K. Ofosu, Tanner A. Wilcoxson, Tsung-Lun Lee, William D. Brackett, Jinny Choi, Thomas M. Truskett, Delia J. Milliron
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Adding nonadsorbing polymers to hard microsphere dispersions generates osmotic depletion attractions that can be quantitatively predicted and designed to manipulate colloidal phase behavior. Whether depletion described by classical theories is the mechanism for polymer-mediated nanosphere attractions is less evident. Colloidal hard nanospheres and nonadsorbing polymers are challenging to realize given the diverse interactions typically present in nanoparticle dispersions. Here, we use small-angle x-ray scattering to assess whether the depletion mechanism holds at the nanoscale, leveraging a recent finding that uncharged, oleate-capped indium oxide nanocrystals exhibit near–hard-sphere interactions in toluene. Classical modeling of polystyrene depletant as penetrable spheres predicts depletion-induced phase boundaries, nanocrystal second osmotic virial coefficients, and colloidal structuring in agreement with experiments for polymer radii of gyration up to 80% of the nanocrystal radius. Experimentally observed weakening of depletion interactions for larger polymer-to-nanocrystal size ratios qualitatively follows theoretical predictions that account for how polymer physics influences depletant interactions.
GPT-4o mini: Non-social science research article
Hot Schrödinger cat states
Ian Yang, Thomas Agrenius, Vasilisa Usova, Oriol Romero-Isart, Gerhard Kirchmair
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The observation of quantum phenomena often necessitates sufficiently pure states, a requirement that can be challenging to achieve. In this study, our goal is to prepare a nonclassical state originating from a mixed state, using dynamics that preserve the initial low purity of the state. We generate a quantum superposition of displaced thermal states within a microwave cavity using only unitary interactions with a transmon qubit. We measure the Wigner functions of these “hot” Schrödinger cat states for an initial purity as low as 0.06. This corresponds to a cavity mode temperature of up to 1.8 kelvin, 60 times hotter than the cavity’s physical environment. Our realization of highly mixed quantum superposition states could be implemented with other continuous-variable systems, e.g., nanomechanical oscillators, for which ground-state cooling remains challenging.
GPT-4o mini: Non-social science research article
A gain route to reversed Cherenkov radiation
Ruoxi Chen, Zheng Gong, Zun Wang, Xiangfeng Xi, Bowen Zhang, Yi Yang, Baile Zhang, Ido Kaminer, Hongsheng Chen, Xiao Lin
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In his landmark paper from 1968, Veselago showed that Cherenkov radiation can be reversed in materials with a negative index of refraction, inspiring substantial research into such materials in what became one of the cornerstone concepts of the field of metamaterials. Following and ongoing investigations of reversed Cherenkov radiation considered it impossible to occur from a homogeneous isotropic slab with a positive refractive index. Here, we break this long-held belief by finding the emergence of reversed Cherenkov radiation from a positive-index isotropic slab by exploiting optical gain. We find precise conditions under which the backward-propagating Cherenkov radiation is maintained while the forward-propagating one is suppressed. Counterintuitively, the intensity and the angular spread of reversed Cherenkov radiation can be made robust to the slab thickness. Under this scenario, increasing the optical gain could decrease the intensity and increase the radiation angular spread.
GPT-4o mini: Non-social science research article
Robust semi-automatic vessel tracing in the human retinal image by an instance segmentation neural network
Siyi Chen, Linh Hoang, Amir H. Kashani, Ji Yi
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Vasculature morphology and hierarchy are essential for blood perfusion. Human retinal circulation is an intricate vascular system emerging and remerging at the optic nerve head (ONH). Tracing retinal vascular branching from ONH can allow detailed morphological quantification, and yet remains a challenging task. We presented a robust semi-automatic vessel tracing algorithm on human fundus images by an instance segmentation neural network (InSegNN). InSegNN separates and labels individual vascular trees and enables tracing each tree throughout its branching. We have three strategies to improve robustness and accuracy: pseudotemporal learning, spatial multisampling, and dynamic probability map. We achieved 83% specificity, 50% improvement in symmetric best dice (SBD) compared to literature, and outperformed baseline U-net, and achieved 91% precision with 71% sensitivity. We have demonstrated tracing individual vessel trees from fundus images, and simultaneously retain vessel hierarchy information. InSegNN paves a way for subsequent analysis of vascular morphology in relation to retinal diseases.
GPT-4o mini: Non-social science research article
Leveraging data mining, active learning, and domain adaptation for efficient discovery of advanced oxygen evolution electrocatalysts
Rui Ding, Jianguo Liu, Kang Hua, Xuebin Wang, Xiaoben Zhang, Minhua Shao, Yuxin Chen, Junhong Chen
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Developing advanced catalysts for acidic oxygen evolution reaction (OER) is crucial for sustainable hydrogen production. This study presents a multistage machine learning (ML) approach to streamline the discovery and optimization of complex multimetallic catalysts. Our method integrates data mining, active learning, and domain adaptation throughout the materials discovery process. Unlike traditional trial-and-error methods, this approach systematically narrows the exploration space using domain knowledge with minimized reliance on subjective intuition. Then, the active learning module efficiently refines element composition and synthesis conditions through iterative experimental feedback. The process culminated in the discovery of a promising Ru-Mn-Ca-Pr oxide catalyst. Our workflow also enhances theoretical simulations with domain adaptation strategy, providing deeper mechanistic insights aligned with experimental findings. By leveraging diverse data sources and multiple ML strategies, we demonstrate an efficient pathway for electrocatalyst discovery and optimization. This comprehensive, data-driven approach represents a paradigm shift and potentially benchmark in electrocatalysts research.
GPT-4o mini: Non-social science research article
Chiral lasing enabled by strong coupling
Huachun Deng, Xiong Jiang, Yao Zhang, Yixuan Zeng, Hamdi Barkaoui, Shumin Xiao, Shaohua Yu, Yuri Kivshar, Qinghai Song
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Chiral quasi-bound states in the continuum are spin-dependent high- Q resonances in meta-photonic structures that are realized by perturbing symmetry-protected optical states by engineering in-plane and out-of-plane asymmetries, and they support chiral lasing in the vertical direction. Here, we explore the coupling between two resonances in a chiral metasurface and introduce a mechanism for high-purity chiral laser emission. We reveal that two resonances with nearly orthogonal polarizations become strongly coupled in an engineered chiral metasurface. The inherent phase difference of the resonances, associated with the coherent destruction on the decay channel, can endow high- Q factor and maximize chirality to one of the hybrid modes. We verify this approach experimentally by measuring transmission spectra, angle-resolved photoluminescence, and laser emission. We believe that this mechanism allows breaking restrictions on conventional chiral quasi-BIC lasing, enabling the realization of chiral emission at any designed direction.
GPT-4o mini: Non-social science research article
Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
Moriah R. Arnold, Gabriel M. Cohn, Kezia Catharina Oxe, Somarr N. Elliott, Cynthia Moore, Allison May Zhou, Peter V. Laraia, Sahar Shekoohi, Dillon Brownell, Rosalie C. Sears, Randall L. Woltjer, Charles K. Meshul, Stephan N. Witt, Dorthe H. Larsen, Vivek K. Unni
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Although an increased risk of the skin cancer melanoma in people with Parkinson’s disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (αSyn) in melanoma cells may be important. Our previous work suggests that αSyn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that αSyn is preferentially enriched within the nucleolus in melanoma, where it colocalizes with DNA damage markers and DSBs. Inducing DSBs specifically within nucleolar ribosomal DNA (rDNA) increases αSyn levels near sites of damage. αSyn knockout increases DNA damage within the nucleolus at baseline, after specific rDNA DSB induction, and prolongs the rate of recovery from this induced damage. αSyn is important downstream of ataxia-telangiectasia–mutated signaling to facilitate MDC1-mediated 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion.
GPT-4o mini: Non-social science research article
Fully circular shapable transparent paperboard with closed-loop recyclability and marine biodegradability across shallow to deep sea
Noriyuki Isobe, Keiko Tanaka, Shun’ichi Ishii, Yasuhiro Shimane, Satoshi Okada, Kazuho Daicho, Wataru Sakuma, Kojiro Uetani, Toshihiro Yoshimura, Katsunori Kimoto, Satoshi Kimura, Tsuguyuki Saito, Ryota Nakajima, Masashi Tsuchiya, Tetsuro Ikuta, Shinsuke Kawagucci, Tadahisa Iwata, Hidetaka Nomaki
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To mitigate marine pollution from single-use plastics, it is crucial to transition to next-generation commodity materials that are derived from biomass and are recyclable and marine biodegradable even at abyssal depths in case of the accidental release to the ocean. Here, we develop an optically transparent millimeter-thick paperboard called transparent paperboard (tPB) through dissolution and coagulation of cellulose. The tPB is made entirely of pristine cellulose and compositionally identical to paper. A cup-shaped tPB can hold just-boiled water without an internal film coating because of its high wet tensile properties and anisotropic thermal properties. In addition, the spent tPB is material recyclable in a closed system, where all chemicals and water are also recyclable. Furthermore, the marine biodegradability of tPB across shallow to abyssal depths is confirmed by on-site degradation tests and metagenomic analyses. Hence, tPB is expected to serve as a key fully circular commodity material in sustainable societies of the future.
GPT-4o mini: Non-social science research article
Revealing the charge transport physics in metallic coordination nanosheets by thermoelectric and magnetotransport measurements
Tian Wu, Xinglong Ren, David Cornil, Claudio Quarti, Ian E. Jacobs, Lu Zhang, Naoya Fukui, David Beljonne, Hiroshi Nishihara, Henning Sirringhaus
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We have studied the charge transport physics of high-quality conducting coordination nanosheets films based on the benchmark material copper benzenehexathiol (CuBHT) by measuring multiple thermoelectric and magnetotransport coefficients on the same film. The films exhibit a metallic temperature dependence of the conductivity over a wide temperature range, but below 15 kelvin charge transport becomes dominated by weak localization and electron-electron interactions. Temperature-dependent Hall, Seebeck, and Nernst measurements consistently indicate the existence of ambipolar transport characteristics in CuBHT. A two-band analysis has been used to extract transport parameters for electron and hole carriers as a function of temperature. The results show that contributions from electron and hole conduction in CuBHT are of comparable magnitude, revealing the complexity of charge transport and allowing one to identify strategies for enhancing the thermoelectric transport coefficients of such conducting coordination nanosheets.
GPT-4o mini: Non-social science research article
Computer vision–guided rapid and precise automated cranial microsurgeries in mice
Zahra S. Navabi, Ryan Peters, Beatrice Gulner, Arun Cherkkil, Eunsong Ko, Farnoosh Dadashi, Jacob O. Brien, Michael Feldkamp, Suhasa B. Kodandaramaiah
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A common procedure that allows interfacing with the brain is cranial microsurgery, wherein small to large craniotomies are performed on the overlying skull for insertion of neural interfaces or implantation of optically clear windows for long-term cranial observation. Performing craniotomies requires skill, time, and precision to avoid damaging the brain and dura. Here, we present a computer vision–guided craniotomy robot (CV-Craniobot) that uses machine learning to accurately estimate the dorsal skull anatomy from optical coherence tomography images. Instantaneous information of skull morphology is used by a robotic mill to rapidly and precisely remove the skull from a desired craniotomy location. We show that the CV-Craniobot can perform small (2- to 4-millimeter diameter) craniotomies with near 100% success rates within 2 minutes and large craniotomies encompassing most of the dorsal cortex in less than 10 minutes. Thus, the CV-Craniobot enables rapid and precise craniotomies, reducing surgery time compared to human practitioners and eliminating the need for long training.
GPT-4o mini: Non-social science research article
Silicate-based therapy for inflammatory dilated cardiomyopathy by inhibiting the vicious cycle of immune inflammation via FOXO signaling
Ping Sun, Zhaowenbin Zhang, Fei Gao, Chen Yang, Ge Mang, Shuai Fu, Jiawei Tian, Jiang Chang
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Inflammatory dilated cardiomyopathy (iDCM) represents a severe immune-related condition provoked by the progression of myocarditis. In patients suffering from myocarditis, a vicious cycle of inflammation orchestrated by CD4 + T cells, neutrophils, and fibroblasts is the culprit that drives the deterioration of myocarditis into iDCM. This study designed composite microneedles and ion solutions using calcium silicate bioceramics, which deliver SiO 3 2− directly into myocardial tissue or indirectly via systemic circulation. These interventions modulate the cell microenvironment by regulating CD4 + T/T helper 17 (T H 17) cells and their interactions with neutrophils and fibroblasts through the forkhead box O (FOXO) signaling pathway. Specifically, SiO 3 2− inhibits the hyperdifferentiation of CD4 + T cells to T H 17 cells by regulating FOXO1 and neutrophils to neutrophil extracellular traps as well as fibroblasts to myofibroblasts by regulating FOXO3, thereby ultimately disrupting the vicious cycle of myocardial inflammation and subsequent fibrotic lesions in iDCM. This discovery indicates that the biomaterial-based strategy may have great potential for the treatment of iDCM.
GPT-4o mini: Non-social science research article
Unveiling high ductility in boron carbide crystal at room temperature
Penghui Li, Jun Li, Qilong Feng, Tianye Jin, Yeqiang Bu, Chong Wang, Kun Luo, Shoucong Ning, Bo Xu, Yihan Zhu, Qi An, Hongtao Wang, Anmin Nie, Yongjun Tian
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Ductility is critical for preventing materials catastrophic fracture. However, achieving tensile ductility in covalent materials remains challenging and unexplored because of the strong, directional covalent bonds. Here, we unveiled the remarkable tensile ductility driven by vacancies in boron carbide (B 4 C). Using advanced electron ptychography techniques, we identified the presence of carbon-vacancy-carbon chains with boron vacancies in B 4 C lattice. The fabricated B 4 C beams exhibit a high ductility (~26.8%) at room temperature, a characteristic previously unattained in covalent materials and comparable to metals. In situ high-resolution transmission electron microscopy revealed that the formation of local amorphous regions after B 4 C lattice exceeded its elastic strain limit, causing plastic deformation. Atomistic simulations, using experimentally observed B 4 C models, reveal that the creation of carbon-carbon bonds in chains containing boron vacancies causes localized amorphization and contributes to the plastic deformation. This research highlights the significance of vacancies in facilitating plastic deformation in B 4 C and suggests a potential strategy to improve the ductility of strong covalent materials.
GPT-4o mini: Non-social science research article
Discovery of diverse and high-quality mRNA capping enzymes through a language model–enabled platform
Tianze Wang, Bowen R. Qin, Sihong Li, Zimo Wang, Xuejian Li, Yuanxu Jiang, Chenrui Qin, Qi Ouyang, Chunbo Lou, Long Qian
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Mining and expanding high-quality genetic parts for synthetic biology and bioengineering are urgent needs in the research and development of next-generation biotechnology. However, gene mining has relied on sequence homology or ample expert knowledge, which fundamentally limits the establishment of a comprehensive genetic part catalog. In this work, we propose SYMPLEX (synthetic biological part mining platform by large language model–enabled knowledge extraction), a universal gene-mining platform based on large language models. We applied SYMPLEX to mine enzymes responsible for messenger RNA (mRNA) capping, a key process in eukaryotic posttranscriptional modification, and obtained thousands of diverse candidates with traceable evidence from biomedical literature and databases. Of the 46 experimentally tested integral capping enzyme candidates, 14 demonstrated in vivo cross-species capping activity, and 2 displayed superior in vitro activity over the commercial vaccinia capping enzymes currently used in mRNA vaccine production. SYMPLEX provides a distinct paradigm for functional gene mining and offers powerful tools to facilitate knowledge discovery in fundamental research.
GPT-4o mini: Non-social science research article
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy
James T. Hagen, McLane M. Montgomery, Raphael T. Aruleba, Brett R. Chrest, Polina Krassovskaia, Thomas D. Green, Emely A. Pacheco, Miki Kassai, Tonya N. Zeczycki, Cameron A. Schmidt, Debajit Bhowmick, Su-Fern Tan, David J. Feith, Charles E. Chalfant, Thomas P. Loughran, Darla Liles, Mark D. Minden, Aaron D. Schimmer, Md Salman Shakil, Matthew J. McBride, Myles C. Cabot, Joseph M. McClung, Kelsey H. Fisher-Wellman
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OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F 1 -ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F 1 -ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell–intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.
GPT-4o mini: Non-social science research article
Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer
Yongyong Yang, Ting-You Wang, Qianru Li, Jiawen Lu, Yanan Ren, Adam B. Weiner, Joshua Fry, Qi Liu, Chaehyun Yum, Rui Wang, Qingxiang Guo, Yu Wan, Zhe Ji, Xuesen Dong, Tamara L. Lotan, Edward M. Schaeffer, Rendong Yang, Qi Cao
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Mounting evidence indicates that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in prostate cancer (PCa) are still largely unknown. In this study, we found an lncRNA, PCa-associated transcript 71 (PRCAT71), highly expressed in metastatic and primary PCa compared to benign prostate tissues. Silencing PRCAT71 inhibited cancerous properties of PCa cells and androgen receptor (AR) signaling. Mechanistically, PRCAT71 acts as a scaffold to recruit K homology (KH)–type splicing regulatory protein (KHSRP) to AR messenger RNA (mRNA) and stabilize AR mRNA, leading to activated AR signaling. KHSRP plays a critical role in PCa progression. PRCAT71 is transcriptionally regulated by AR-driven enhancers, forming a positive regulatory loop between AR and PRCAT71 in PCa. Our study demonstrates a coordinated regulation of AR mRNA by lncRNA PRCAT71 and RNA binding protein KHSRP and provides insight that the PRCAT71-KHSRP-AR axis is a promising therapeutic target for treating PCa.
GPT-4o mini: Non-social science research article
Melt-mixed superlayer cocrystal formation using symmetric and unsymmetric organic semiconductors
Kiyoshi Nikaido, Seita Kuroda, Satoru Inoue, Tatsuo Hasegawa
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Organic molecules with a rigid, π-conjugated core (π-core) and flexible alkyl chains (C n ) naturally exhibit liquid crystal (LC) phases, promoting self-assembly of quasi–two-dimensional semiconducting layered crystals. However, particular roles of rigid and flexible parts in layer formations remain elusive. Here, we demonstrate formation of an unprecedented superlayer cocrystal phase via a unique smectic LC phase in the equimolar melt mixture of symmetrically distinct molecules. The molecules used are a monoalkylated [(π-core)-C n ] using 2-octyl[1]benzothieno[3,2- b ][1]benzothiophene (mono-C 8 -BTBT) and a dialkylated [C n -(π-core)-C n ] using 2,7-dioctyl[1]benzothieno[3,2- b ][1]benzothiophene (di-C 8 -BTBT). Thermal analyses show that the superlayer cocrystal is exclusively induced at the equimolar mixture via melt crystallization from the LC phase. X-ray structure analysis reveals a reversible C n -(π-core)-C n ···(π-core)-C n stacking arrangement in the superlayer cocrystal, where π-cores and alkyl chains form nearly independent layers. Notably, this melt crystallization allows solvent-free fabrication of semiconductive polycrystalline films for excellent thin-film transistors. These findings pave the way for tailoring a quasi–two-dimensional structure in LC materials toward molecular electronics.
GPT-4o mini: Non-social science research article
Cholinergic signaling to CA1 astrocytes controls fear extinction
Yulan Li, Lixuan Li, Yibei Wang, Xinyi Li, Xiaopeng Ding, Lingjie Li, Fan Fei, Yanrong Zheng, Li Cheng, Shumin Duan, Vladimir Parpura, Yi Wang, Zhong Chen
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Fear extinction is an evolutionarily conserved biological process that allows an organism to better re-adapt; its deficits can lead to psychiatric disorders. Fear extinction is considered to rely mostly on neuronal function. However, whether and how astrocytes contribute to fear extinction is largely unknown. Here, we show that hippocampal CA1 astrocytes exhibit de novo Ca 2+ dynamics during fear extinction. Inhibition of these astrocytic Ca 2+ dynamics impairs, while their activation facilitates, fear extinction. In this regulation of fear extinction, the posterior basal forebrain (pBF) cholinergic input to hippocampus drives CA1 astrocytic Ca 2+ dynamics through the activation of α4 and α7 subunits of nicotinic acetylcholine receptors. Clinically used acetylcholinesterase inhibitor donepezil increases CA1 astrocytic Ca 2+ dynamics and facilitates fear extinction. Thus, our findings demonstrate a previously unrecognized and crucial pathway from pBF cholinergic neurons to CA1 astrocytes that governs natural fear extinction. This neuron-glia signaling pathway may constitute a promising target for treatment of fear- and anxiety-related disorders.
GPT-4o mini: Non-social science research article
A high-throughput experimentation platform for data-driven discovery in electrochemistry
Dian-Zhao Lin, Kai-Jui Pan, Yuyin Li, Charles B. Musgrave III, Lingyu Zhang, Krish N. Jayarapu, Tianchen Li, Jasmine Vy Tran, William A. Goddard, Zhengtang Luo, Yayuan Liu
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Automating electrochemical analyses combined with artificial intelligence is poised to accelerate discoveries in renewable energy sciences and technologies. This study presents an automated high-throughput electrochemical characterization (AHTech) platform as a cost-effective and versatile tool for rapidly assessing liquid analytes. The Python-controlled platform combines a liquid handling robot, potentiostat, and customizable microelectrode bundles for diverse, reproducible electrochemical measurements in microtiter plates, minimizing chemical consumption and manual effort. To showcase the capability of AHTech, we screened a library of 180 small molecules as electrolyte additives for aqueous zinc metal batteries, generating data for training machine learning models to predict Coulombic efficiencies. Key molecular features governing additive performance were elucidated using Shapley Additive exPlanations and Spearman’s correlation, pinpointing high-performance candidates like cis -4-hydroxy- d -proline, which achieved an average Coulombic efficiency of 99.52% over 200 cycles. The workflow established herein is highly adaptable, offering a powerful framework for accelerating the exploration and optimization of extensive chemical spaces across diverse energy storage and conversion fields.
GPT-4o mini: Non-social science research article
Spin-chirality-driven second-harmonic generation in two-dimensional magnet CrSBr
Dezhao Wu, Yong Xu, Meng Ye, Wenhui Duan
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The interplay between magnetism and light can create abundant optical phenomena. Here, we demonstrate the emergence of an unconventional magnetization-induced second-harmonic generation (MSHG) stemming from vector spin chirality, denoted as chiral second-harmonic generation (SHG). Taking the antiferromagnetic (AFM) CrSBr bilayer as a prototype, we theoretically show that, via spin canting, the chiral SHG can be continuously tuned from zero to a value one order of magnitude larger than its intrinsic MSHG. Chiral SHG is found to be proportional to spin chirality and spin-canting-induced electric polarization, while intrinsic MSHG is proportional to the NĂ©el vector, demonstrating their different physical mechanisms. Additionally, we reveal a unique interference effect between these two types of MSHG under the reversal of spin-canting direction, generating a giant modulation of SHG signals. Our work not only uncovers a unique SHG with exceptional tunability but also promotes the applications of AFM optical devices and magnetoelectric detection techniques.
GPT-4o mini: Non-social science research article
Structural architecture of TolQ-TolR inner membrane protein complex from opportunistic pathogen Acinetobacter baumannii
Elina Karimullina, Yirui Guo, Hanif M. Khan, Tabitha Emde, Bradley Quade, Rosa Di Leo, Zbyszek Otwinowski, D. Peter Tieleman, Dominika Borek, Alexei Savchenko
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Gram-negative bacteria harness the proton motive force (PMF) within their inner membrane (IM) to uphold cell envelope integrity, an indispensable aspect for both division and survival. The IM TolQ-TolR complex is the essential part of the Tol-Pal system, serving as a conduit for PMF energy transfer to the outer membrane. Here we present cryo–electron microscopy reconstructions of Acinetobacter baumannii TolQ in apo and TolR-bound forms at atomic resolution. The apo TolQ configuration manifests as a symmetric pentameric pore, featuring a transmembrane funnel leading toward a cytoplasmic chamber. In contrast, the TolQ-TolR complex assumes a proton nonpermeable stance, characterized by the TolQ pentamer’s flexure to accommodate the TolR dimer, where two protomers undergo a translation-based relationship. Our structure-guided analysis and simulations support the rotor-stator mechanism of action, wherein the rotation of the TolQ pentamer harmonizes with the TolR protomers’ interplay. These findings broaden our mechanistic comprehension of molecular stator units empowering critical functions within the Gram-negative bacterial cell envelope.
GPT-4o mini: Non-social science research article
Modular synthesis of bis-α-chiral amines using Ellman sulfinamide for consecutive S -to- C chirality induction/transfer
Guangwu Sun, Herui Liu, Baobiao Dong, Yuchao Zhang, Zilong Zhao, Bing Gao
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Amines are ubiquitous components in pharmaceuticals. Increasing saturated substitutions ( sp 3 -hybridized carbon) at the amino center and the number of chiral centers can enrich the molecular diversity and chemical space, ultimately enhancing the success of drug development. However, the synthesis of such advanced amines is challenging due to a higher level of structural complexity and stereo-control. Here, we report a modular protocol for short de novo synthesis of bis-α-chiral amines. This protocol uses commercially available Ellman sulfinamide, tert -butanesulfinamide ( t BS), as the exclusive chiral source to selectively produce all possible stereoisomers. Sequential formation of contiguous α-amino chiral carbons is achieved by chirality induction and transfer mechanisms that are both enabled by t BS, the stereoselective imine functionalization and alkyne-participated rearrangement reaction. The second step we developed is crucial for high diastereoselectivity, which is problematic in previous methods. The other coupling partners used in this protocol are abundant feedstocks, providing desirable chemical diversity in the products.
GPT-4o mini: Non-social science research article
PIP 2 promotes the incorporation of CD43, PSGL-1, and CD44 into nascent HIV-1 particles
Ricardo de Souza Cardoso, Tomoyuki Murakami, Binyamin Jacobovitz, Sarah L. Veatch, Akira Ono
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Determinants regulating sorting of host transmembrane proteins at sites of enveloped virus assembly on the plasma membrane (PM) remain poorly understood. Here, we demonstrate that the PM acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) regulates this sorting into an enveloped virus, HIV-1. Incorporation of CD43, PSGL-1, and CD44 into HIV-1 particles has profound effects on viral spread; however, the mechanisms promoting their incorporation were unknown. We found that depletion of cellular PIP 2 blocks incorporation of CD43, PSGL-1, and CD44 into HIV-1 particles. Expansion microscopy revealed that PIP 2 depletion diminishes nanoscale coclustering between viral structural protein Gag and the three transmembrane proteins at the PM and that Gag induces PIP 2 enrichment at its vicinity. CD43, PSGL-1, and CD44 also increased local PIP 2 density, revealing their PIP 2 affinity. Together, these results support a previously unknown mechanism where local enrichment of an acidic phospholipid drives coclustering between viral structural and cellular transmembrane proteins, thereby modulating the content, and hence the fate, of progeny virus particles.
GPT-4o mini: Non-social science research article
Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics
Tasneem Qaqorh, Yusuke Takahashi, Kohei Sameshima, Kentaro Otani, Issei Yazawa, Yuya Nishida, Kohei Tonai, Yoshitaka Fujihara, Mizuki Honda, Shinya Oki, Yasuyuki Ohkawa, David R. Thorburn, Ann E. Frazier, Atsuhito Takeda, Yoshihiko Ikeda, Heima Sakaguchi, Takuya Watanabe, Norihide Fukushima, Yasumasa Tsukamoto, Naomasa Makita, Osamu Yamaguchi, Kei Murayama, Akira Ohtake, Yasushi Okazaki, Takanari Kimura, Hisakazu Kato, Hijiri Inoue, Ken Matsuoka, Seiji Takashima, Yasunori Shintani
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Oxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, ATF3 . Genetic ablation of Atf3 in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of ATF3 in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.
GPT-4o mini: Non-social science research article
Complex-valued matrix-vector multiplication using a scalable coherent photonic processor
Yiwei Xie, Xiyuan Ke, Shihan Hong, Yuxin Sun, Lijia Song, Huan Li, Pan Wang, Daoxin Dai
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Matrix-vector multiplication is a fundamental operation in modern signal processing and artificial intelligence. Developing a chip-scale photonic matrix-vector multiplication processor (MVMP) offers the potential for notably enhanced computing speed and energy efficiency beyond microelectronics. Here, we propose and demonstrate a 16-channel programmable on-chip coherent photonic processor capable of performing complex-valued matrix-vector multiplication at a computing speed of 1.28 tera-operations per second (TOPS). Low phase error Mach-Zehnder interferometers mesh and ultralow-loss broadened photonic waveguide delay lines are firstly combined for optical computing, enabling the encoding of amplitude and phase information, along with high-speed coherent detection. The proposed MVMP demonstrates high flexibility in implementing various functions, including arbitrary matrix transformation, parallel image processing, and handwritten digital recognition. Our work demonstrates the MVMP’s advantages in scalability and function flexibility, enabled by the low-loss and low phase error designs, making a substantial advancement in high-speed and large-scale photonic computing technologies.
GPT-4o mini: Non-social science research article
Simultaneous acclimation to nitrogen and iron scarcity in open ocean cyanobacteria revealed by sparse tensor decomposition of metatranscriptomes
Stephen Blaskowski, Marie Roald, Paul M. Berube, Rogier Braakman, E. Virginia Armbrust
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Microbes respond to changes in their environment by adapting their physiology through coordinated adjustments to the expression levels of functionally related genes. To detect these shifts in situ, we developed a sparse tensor decomposition method that derives gene co-expression patterns from inherently complex whole community RNA sequencing data. Application of the method to metatranscriptomes of the abundant marine cyanobacteria Prochlorococcus and Synechococcus identified responses to scarcity of two essential nutrients, nitrogen and iron, including increased transporter expression, restructured photosynthesis and carbon metabolism, and mitigation of oxidative stress. Further, expression profiles of the identified gene clusters suggest that both cyanobacteria populations experience simultaneous nitrogen and iron stresses in a transition zone between North Pacific oceanic gyres. The results demonstrate the power of our approach to infer organism responses to environmental pressures, hypothesize functions of uncharacterized genes, and extrapolate ramifications for biogeochemical cycles in a changing ecosystem.
GPT-4o mini: Non-social science research article
Mg 2+ influx mediated by TRPM7 triggers the initiation of muscle stem cell activation
Kotaro Hirano, Chika Nakabayashi, Mao Sasaki, Miki Suzuki, Yuta Aoyagi, Kaori Tanaka, Akira Murakami, Masaki Tsuchiya, Eiji Umemoto, Shuji Takabayashi, Yasuo Kitajima, Yusuke Ono, Takehisa Matsukawa, Masayuki Matsushita, Yasuyuki Ohkawa, Yasuo Mori, Yuji Hara
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Muscle satellite cells (MuSCs) respond immediately to environmental cues upon skeletal muscle injuries. Despite decades of research into muscle regeneration, the specific molecular factors that trigger the transition of MuSCs from a quiescent to an active state remain largely unidentified. Here, we identify transient receptor potential melastatin 7 (TRPM7), an Mg 2+ -permeable ion channel, as a critical regulator of MuSC activation. Trpm7 deletion in MuSCs reduced Mg 2+ influx, impairing myofiber regeneration and leading to decreased MuSC numbers and cell cycle arrest during regeneration. These changes were linked to disrupted mTOR signaling, which drives the transition of MuSCs from G 0 to G Alert phase. In addition, Trpm7 -deficient MuSCs exhibited impaired early responses, including quiescent projection retraction and AP-1 induction. Mg 2+ supplementation rescued these defects, restoring normal MuSC activation. Our findings reveal a previously unrecognized mechanism where Mg 2+ permeation through TRPM7 is essential for MuSC activation and efficient skeletal muscle regeneration, highlighting TRPM7 as a critical regulator of muscle repair.
GPT-4o mini: Non-social science research article
Observation of the magnonic Dicke superradiant phase transition
Dasom Kim, Sohail Dasgupta, Xiaoxuan Ma, Joong-Mok Park, Hao-Tian Wei, Xinwei Li, Liang Luo, Jacques Doumani, Wanting Yang, Di Cheng, Richard H. J. Kim, Henry O. Everitt, Shojiro Kimura, Hiroyuki Nojiri, Jigang Wang, Shixun Cao, Motoaki Bamba, Kaden R. A. Hazzard, Junichiro Kono
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Two-level atoms ultrastrongly coupled with single-mode cavity photons are predicted to exhibit a quantum phase transition, entering a phase in which both the atomic polarization and the photonic field are finite even without external driving. However, this phenomenon, the superradiant phase transition (SRPT), is forbidden by a no-go theorem due to the existence of the diamagnetic term. Here, we present spectroscopic evidence for a magnonic SRPT in ErFeO 3 , where the role of the photonic mode (two-level atoms) in the photonic SRPT is played by an Fe 3+ magnon mode (Er 3+ spins). The absence of the diamagnetic term in the Fe 3+ -Er 3+ exchange coupling ensures that the no-go theorem does not apply. Ultrabroadband terahertz and gigahertz magnetospectroscopy experiments revealed the signatures of the SRPT in thermal equilibrium, a kink and a softening, respectively, of two spin-magnon hybridized modes at the critical point. Systems near this phase are expected to harbor large-scale squeezing, which will potentially provide a route to next-generation quantum technologies.
GPT-4o mini: Non-social science research article
Hybrid locomotion at the insect scale: Combined flying and jumping for enhanced efficiency and versatility
Yi-Hsuan Hsiao, Songnan Bai, Zhongtao Guan, Suhan Kim, Zhijian Ren, Pakpong Chirarattananon, Yufeng Chen
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Insect-scale robots face two major locomotive challenges: constrained energetics and large obstacles that far exceed their size. Terrestrial locomotion is efficient yet mostly limited to flat surfaces. In contrast, flight is versatile for overcoming obstacles but requires high power to stay aloft. Here, we present a hopping design that combines a subgram flapping-wing robot with a telescopic leg. Our robot can hop continuously while controlling jump height and frequency in the range of 1.5 to 20 centimeters and 2 to 8.4 hertz. The robot can follow positional set points, overcome tall obstacles, and traverse challenging surfaces. It can also hop on a dynamically rotating plane, recover from strong collisions, and perform somersaults. Compared to flight, this design reduces power consumption by 64 percent and increases payload by 10 times. Although the robot relies on offboard power and control, the substantial payload and efficiency improvement open opportunities for future study on autonomous locomotion.
GPT-4o mini: Non-social science research article
Effective recognition of double-stranded RNA does not require activation of cellular inflammation
Karolina Drazkowska, Julia Cieslicka, Michal Kitowicz, Anna Pastucha, Lukasz Markiewicz, Wiktoria Szymanek, Krzysztof Goryca, Tomasz Kowalczyk, Dominik Cysewski, Andreas R. Bausch, Pawel J. Sikorski
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Excess double-stranded RNA (dsRNA) is present in the cytoplasm of human cells, usually following viral infections. Recognition of dsRNAs activates innate immune pathways, leading to cellular inflammation and inhibition of cell growth. Here, we show that an effective dsRNA response may occur without the onset of inflammation. Pro-inflammatory [RLR (retinoic acid–inducible gene I–like receptor)–dependent pathway] and cell growth inhibitory mechanisms [oligoadenylate synthetase (OAS)/ribonuclease L (RNase L)– and dsRNA-activated protein kinase (PKR)–dependent pathways] can act independently. We found that the 5â€Č ends of dsRNA direct the onset of cellular inflammation, whereas the RNA duplex activates the OAS/RNase L and PKR pathways. Unexpectedly, three of the most common human RNA epitranscriptomic marks—i.e., N 6-methyladenosine, 5-methylcytosine, and pseudouridine—had almost no influence on the immunogenicity of dsRNA; however, the presence of N 6-methyladenosine inhibited the OAS/RNase L pathway. Our observations demonstrate how precisely innate immunity is fine tuned in cells to take appropriate countermeasures when a specific threat arises.
GPT-4o mini: Non-social science research article
EIF3D safeguards the homeostasis of key signaling pathways in human primed pluripotency
Chikako Okubo, Michiko Nakamura, Masae Sato, Yuichi Shichino, Mari Mito, Yasuhiro Takashima, Shintaro Iwasaki, Kazutoshi Takahashi
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Although pluripotent stem cell (PSC) properties, such as differentiation and infinite proliferation, have been well documented within the frameworks of transcription factor networks, epigenomes, and signal transduction, they remain unclear and fragmented. Directing attention toward translational regulation as a bridge between these events can yield additional insights into previously unexplained mechanisms. Our functional CRISPR interference screen–based approach revealed that EIF3D, a translation initiation factor, is crucial for maintaining primed pluripotency. Loss of EIF3D disrupted the balance of pluripotency-associated signaling pathways, thereby compromising primed pluripotency. Moreover, EIF3D ensured robust proliferation by controlling the translation of various p53 regulators, which maintain low p53 activity in the undifferentiated state. In this way, EIF3D-mediated translation contributes to tuning the homeostasis of the primed pluripotency networks, ensuring the maintenance of an undifferentiated state with high proliferative potential. This study provides further insights into the translation network in maintaining pluripotency.
GPT-4o mini: Non-social science research article
MyoGestic: EMG interfacing framework for decoding multiple spared motor dimensions in individuals with neural lesions
Raul C. Sßmpetru, Dominik I. Braun, Arndt U. Simon, Michael MÀrz, Vlad Cnejevici, Daniela Souza de Oliveira, Nico Weber, Jonas Walter, Jörg Franke, Daniel Höglinger, Cosima Prahm, Matthias Ponfick, Alessandro Del Vecchio
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Restoring motor function in individuals with spinal cord injuries (SCIs), strokes, or amputations is a crucial challenge. Recent studies show that spared motor neurons can still be voluntarily controlled using surface electromyography (EMG), even without visible movement. To harness these signals, we developed a wireless, high-density EMG bracelet and a software framework, MyoGestic. Our system enables rapid adaptation of machine learning models to users’ needs, allowing real-time decoding of spared motor dimensions. In our study, we successfully decoded motor intent from two participants with traumatic SCI, two with spinal stroke, and three with amputations in real time, achieving multiple controllable motor dimensions within minutes. The decoded neural signals could control a digitally rendered hand, an orthosis, a prosthesis, or a two-dimensional cursor. MyoGestic’s participant-centered approach allows a collaborative and iterative development of myocontrol algorithms, bridging the gap between researcher and participant, to advance intuitive EMG interfaces for neural lesions.
GPT-4o mini: Non-social science research article
Preclinical evaluation of AGT mRNA replacement therapy for primary hyperoxaluria type I disease
Taihua Yang, Jiahao Ge, Lei Huang, Xinye Zhu, Dexin Zhang, Siyuan Tang, Jie Zhao, Yinhe Ma, Mei Long, Xiaochen Bo, Jie Li, Yiqing Zhang, Qinggong Yuan, Amar Deep Sharma, Michael Ott, Hongquan Geng, Yicheng Zhao, Liang Zhang, Haifa Shen, Hangwen Li, Dali Li, Ping Wan, Qiang Xia
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Primary hyperoxaluria type 1 (PH1) is a rare inherited liver disorder caused by alanine glyoxylate aminotransferase (AGT) dysfunction, leading to accumulation of glyoxylate which is then converted into oxalate. Excessive oxalate results in kidney damage due to deposition of oxalate crystals. We have developed an mRNA-based protein replacement therapy for PH1 to restore normal glyoxylate to glycine metabolism. Sequence optimized human AGT mRNA ( hAGT mRNA) was encapsulated in lipopolyplex (LPP) and produced functional AGT enzyme in peroxisomes. Pharmacokinetics and pharmacodynamics (PK/PD) were evaluated in vitro and in vivo. PK demonstrated that AGT mRNA and AGT protein maintained high expression levels for up to 48 hours. A single 2 mg/kg dose in Agxt Q84 −/− rats achieved a 70% reduction in urinary oxalate. Toxicological assessment identified the highest nonserious toxic dose (HNSTD) as 2 mg/kg. These findings affirm the efficacy and safety of hAGT mRNA/LPP and support its clinical application in PH1 treatment.
GPT-4o mini: Non-social science research article
Identifying and controlling inactive and active conformations of a serine protease
Eunjeong Lee, Norman Tran, Jasmina S. Redzic, Harmanpreet Singh, Lorena Alamillo, Todd Holyoak, Donald Hamelberg, Elan Zohar Eisenmesser
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Serine proteases have been proposed to dynamically sample inactive and active conformations, but direct evidence at atomic resolution has remained elusive. Using nuclear magnetic resonance (NMR), we identified a single residue, D164, in exfoliative toxin A (ETA) that acts as a molecular “switch” to regulate global dynamic sampling. Mutations at this site shift the balance between inactive and active states, correlating directly with catalytic activity. Beyond identifying this dynamic switch, we demonstrate how it works in concert with other allosterically coupled sites to rationally control enzyme movements and catalytic function. This study provides a framework for linking conformational dynamics to function and paves the way for engineering enzymes, in particular, proteases, with tailored activities for applications in medicine and biotechnology.
GPT-4o mini: Non-social science research article
MIST: An interpretable and flexible deep learning framework for single–T cell transcriptome and receptor analysis
Wenpu Lai, Yangqiu Li, Oscar Junhong Luo
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Joint analysis of transcriptomic and T cell receptor (TCR) features at single-cell resolution provides a powerful approach for in-depth T cell immune function research. Here, we introduce a deep learning framework for single–T cell transcriptome and receptor analysis, MIST (Multi-insight for T cell). MIST features three latent spaces: gene expression, TCR, and a joint latent space. Through analyses of antigen-specific T cells, and T cell datasets related to lung cancer immunotherapy and COVID19, we demonstrate MIST’s interpretability and flexibility. MIST easily and accurately resolves cell function and antigen specificity by vectorizing and integrating transcriptome and TCR data of T cells. In addition, using MIST, we identified the heterogeneity of CXCL13 + subsets in lung cancer infiltrating CD8 + T cells and their association with immunotherapy, providing additional insights into the functional transition of CXCL13 + T cells related to anti–PD-1 therapy that were not reported in the original study.
GPT-4o mini: Non-social science research article
Architecture and conformational dynamics of the BAM-SurA holo insertase complex
Philippe A. Lehner, Morris Degen, Roman P. Jakob, Seyed Majed Modaresi, Morgane Callon, Björn M. Burmann, Timm Maier, Sebastian Hiller
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The proper folding of outer membrane proteins in Gram-negative bacteria relies on their delivery to the ÎČ-barrel assembly machinery (BAM) complex. The mechanism by which survival protein A (SurA), the major periplasmic chaperone, facilitates this process is not well understood. We determine the structure of the holo insertase complex, where SurA binds BAM for substrate delivery. High-resolution cryo–electron microscopy structures of four different states and a three-dimensional variability analysis show that the holo insertase complex has a large motional spectrum. SurA bound to BAM can undergo a large swinging motion between two states. This motion is uncoupled from the conformational flexibility of the BamA barrel, which can open and close without affecting SurA binding. Notably, we observed conformational coupling of the SurA swing state and the carboxyl-terminal helix grip domain of BamC. Substrate delivery by SurA to BAM appears to follow a concerted motion that encodes a gated delivery pathway through the BAM accessory proteins to the membrane entry site.
GPT-4o mini: Non-social science research article
Diagnosing Parkinson’s disease via behavioral biometrics of keystroke dynamics
Trinny Tat, Guorui Chen, Jing Xu, Xun Zhao, Yunsheng Fang, Jun Chen
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Parkinson’s disease (PD) is one of the rapidly growing neurodegenerative diseases, affecting more than 10 million people worldwide. Early and accurate diagnosis of PD is highly desirable for therapeutic interventions but remains a substantial challenge. We developed a soft, portable intelligent keyboard leveraging magnetoelasticity to detect subtle pressure variations in keystroke dynamics by converting continuous keystrokes into high-fidelity electrical signals, thus enabling the quantitative analysis of PD motor symptoms using machine learning. Relying on a fundamental working mechanism, the intelligent keyboard demonstrates highly sensitive, intrinsically waterproof, and biocompatible properties, with the successful demonstration in a pilot study on patients with PD. To facilitate the potential continuous monitoring of PD, a customized cellphone application was developed to integrate the intelligent keyboard into a wireless platform. Together, the intelligent keyboard system’s compelling properties position it as a promising tool for advancing early diagnosis and facilitating personalized, predictive, preventative, and participatory approaches to PD healthcare.
GPT-4o mini: Non-social science research article
An autonomous snapper featuring adaptive actuation and embodied intelligence
Duygu S. Polat, Zihua Chen, SamĂŒel A. M. Weima, Satoshi Aya, Danqing Liu
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Developing artificial systems with autonomous motion is essential for creating devices that emulate nature’s adaptive mechanisms. Here, we introduce a light-driven liquid crystalline network snapper that integrates both sensing and actuation capabilities, enabling adaptive responses to environmental conditions. Under constant light illumination, the snapper undergoes spontaneous snap-through transformation driven by the elastic instability embedded within the material. The snapper achieves out-of-equilibrium motion through continuous energy transfer with the environment, enabling it to sustain dynamic, reversible cycles of snapping without external control. We demonstrate the ability of the liquid crystalline network snapper to detect environmental changes—such as shifts in temperature, surface roughness, and color—demonstrating a form of embodied intelligence. This work offers a distinctive strategy for designing biomimetic devices that merge embodied intelligence with autonomous motion, opening pathways for advanced, adaptive systems for soft robotics.
GPT-4o mini: Non-social science research article
ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution
Michael J. McKenna, Felix Kraus, JoĂŁo P.L. Coelho, Muskaan Vasandani, Jiuchun Zhang, Benjamin M. Adams, Joao A. Paulo, J. Wade Harper, Sichen Shao
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Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incompletely understood. Here, we show that ARMC1 partitioning between distinct mitochondrial protein complexes is a key determinant of mitochondrial distribution. In one complex, the mitochondrial trafficking adaptor MIRO recruits ARMC1, which mediates the assembly of a mitochondrial fission regulator (MTFR). MTFR stability depends on ARMC1, and MIRO-MTFR complexes specifically antagonize retrograde mitochondrial movement. In another complex, DNAJC11 facilitates ARMC1 release from mitochondria. Disrupting MIRO-MTFR assembly fails to rescue aberrant mitochondrial distributions clustered in the perinuclear area observed with ARMC1 deletion, while disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, the abundance and trafficking impact of MIRO-MTFR complexes require ARMC1, whose mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.
GPT-4o mini: Non-social science research article
Climate mitigation potential for targeted forestation after considering climate change, fires, and albedo
Shijing Liang, Alan D. Ziegler, Peter B. Reich, Kai Zhu, Dashan Wang, Xin Jiang, Deliang Chen, Philippe Ciais, Zhenzhong Zeng
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Afforestation and reforestation, both of which refer to forestation strategies, are widely promoted as key tools to mitigate anthropogenic warming. However, the carbon sequestration potential of these efforts remains uncertain in satellite-based assessments, particularly when accounting for dynamic climate conditions, vegetation-climate feedback, fire-dominated disturbance, and the trade-offs associated with surface albedo changes. Leveraging a coupled Earth system model, we estimated that global forestation mitigates 31.3 to 69.2 Pg C eq (carbon equivalent) during 2021–2100 under a sustainable shared socioeconomic pathway. Regionally, the highest carbon mitigation potential of forestation concentrates in tropical areas, while mid-high-latitude regions demonstrate higher heterogeneity, highlighting the need for region-specific strategies and further refinement of nature-based mitigation plans. Our findings underscore the importance of considering disturbances and minimizing adverse albedo changes when estimating the carbon mitigation potential of forestation initiatives. We also advocate for the development of consistent, high-resolution maps of suitable areas for targeted forestation, avoiding environmentally sensitive lands and potential conflicts with other human activities.
GPT-4o mini: Non-social science research article
Grasping and rolling in-plane manipulation using deployable tape spring appendages
Gengzhi He, Curtis Sparks, Nick Gravish
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Rigid robot arms face a tradeoff between their overall reach distance and how compactly they can be collapsed. However, the tradeoff between long reach and small storage volume can be resolved using deployable structures such as tape springs. We developed bidirectional tape spring “fingers” that have large buckling strength compared to single tape springs and that can be spooled into a compact state or unspooled to manipulate objects. We integrate fingers into a robot manipulator that allows for object Grasping and Rolling In Planar configurations (called GRIP-tape). The continuum kinematics of the fingers enables a multitude of manipulation capabilities such as translation, rotation, twisting, and multi-object conveyance. Furthermore, the dual mechanical properties of stiffness and softness in the fingers endow the gripper with inherent safety from collisions and enables soft-contact with objects. Deployable structures such as tape springs offer opportunities for manipulation in cluttered or remote environments.
GPT-4o mini: Non-social science research article
High-voltage water-scarce hydrogel electrolytes enable mechanically safe stretchable Li-ion batteries
Peisheng He, Jong Ha Park, Yingkai Jiao, Rushil Ganguli, Yigen Huang, Ashley Lee, Christine Heera Ahn, Monong Wang, Yande Peng, Yu Long, Chun-Ming Chen, Zihan Wang, Ziting Tian, Baoxia Mi, Ana Claudia Arias, Chao Fang, Anju Toor, Liwei Lin
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Soft Li-ion batteries, based on conventional organic electrolytes, face performance degradation challenges due to moisture penetration and safety concerns due to possible leakage of toxic fluorine compounds and flammable solvents under mechanical damage. We design a water-scarce hydrogel electrolyte with fluorine-free lithium salt to achieve wide electrochemical stability window (up to 3.11 volts) in ambient air without hermetic packaging while balancing high stretchability (1348%), ion conductivity (41 millisiemens per centimeter), and self-healing capabilities for mechanically and chemically safe stretchable Li-ion batteries. Molecular synergy between hydrophilicity and lithiophilicity of zwitterionic polymer backbone is revealed by molecular dynamics simulations. The battery exhibits capacity retention under harsh mechanical stresses—enduring stretching, twisting, folding, and multiple through-punctures by a needle—while self-healing from repeated through cuts by a razor blade. Stable ambient operation for 1 month over 500 charge-discharge cycles (average coulomb efficiency, 95%) is achieved. A prototype self-healing electronic system with embedded soft batteries demonstrates practical application as a durable embodied energy source.
GPT-4o mini: Non-social science research article
Autocatalytic assembly of a chimeric aminoacyl-RNA synthetase ribozyme
Aleksandar Radakovic, Marco Todisco, Anmol Mishra, Jack W. Szostak
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Autocatalytic reactions driving the self-assembly of biological polymers are important for the origin of life, yet few experimental examples of such reactions exist. Here we report an autocatalytic assembly pathway that generates a chimeric, amino acid–bridged aminoacyl-RNA synthetase ribozyme. The noncovalent complex of ribozyme fragments initiates low-level aminoacylation of one of the fragments, which, after loop-closing ligation, generates a highly active covalently linked chimeric ribozyme. The generation of this ribozyme is increasingly efficient over time due to the autocatalytic assembly cycle that sustains the ribozyme over indefinite cycles of serial dilution. Because of its trans activity, this ribozyme also assembles ribozymes distinct from itself, such as the hammerhead, suggesting that RNA aminoacylation, coupled with nonenzymatic ligation, could have facilitated the emergence and propagation of ribozymes.
GPT-4o mini: Non-social science research article
Real-time antiproton annihilation vertexing with submicrometer resolution
Michael Berghold, Davide Orsucci, Francesco Guatieri, Sara Alfaro, Marcis Auzins, Benedikt Bergmann, Petr Burian, Roberto Sennen Brusa, Antoine Camper, Ruggero Caravita, Fabrizio Castelli, Giovanni Cerchiari, Roman Jerzy CiuryƂo, Ahmad Chehaimi, Giovanni Consolati, Michael Doser, Kamil Eliaszuk, Riley Craig Ferguson, Matthias Germann, Anna Giszczak, Lisa Glöggler, Ɓukasz Graczykowski, Malgorzata Grosbart, Natali Gusakova, Fredrik Gustafsson, Stefan Haider, Saiva Huck, Christoph Hugenschmidt, Malgorzata Anna Janik, Tymoteusz Henryk Januszek, Grzegorz Kasprowicz, Kamila Kempny, Ghanshyambhai Khatri, Ɓukasz KƂosowski, Georgy Kornakov, Valts Krumins, Lidia Lappo, Adam Linek, Sebastiano Mariazzi, Pawel Moskal, Dorota Nowicka, Piyush Pandey, Daniel PĘcak, Luca Penasa, Vojtech Petracek, Mariusz PiwiƄski, Stanislav Pospisil, Luca Povolo, Francesco Prelz, Sadiqali Rangwala, Tassilo Rauschendorfer, Bharat Rawat, Benjamin RienĂ€cker, Volodymyr Rodin, Ole RĂžhne, Heidi Sandaker, Sushil Sharma, Petr Smolyanskiy, Tomasz SowiƄski, Dariusz Tefelski, Theodoros Vafeiadis, Marco Volponi, Carsten Peter Welsch, Michal Zawada, Jakub Zielinski, Nicola Zurlo, character(0)
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Primary goal of the AEឥIS experiment is to precisely measure the free fall of antihydrogen within Earth’s gravitational field. To this end, cold (≈50 K) antihydrogen will traverse a two-grid moirĂ© deflectometer before annihilating onto a position-sensitive detector, which shall determine the vertical position of the annihilation vertex relative to the grids with micrometric accuracy. Here, we introduce a vertexing detector based on a modified mobile camera sensor and experimentally demonstrate that it can measure the position of antiproton annihilations within 0.62 − 0.22 + 0.40 ÎŒm, a 35-fold improvement over the previous state of the art for real-time antiproton vertexing. These methods are directly applicable to antihydrogen. Moreover, the sensitivity to light of the sensor enables in situ calibration of the moirĂ© deflectometer, substantially reducing systematic errors. This sensor emerges as a breakthrough technology toward the AEឥIS scientific goals and will constitute the basis for the development of a large-area detector for conducting antihydrogen gravity measurements.
GPT-4o mini: Non-social science research article
Sustainable regeneration of 20 aminoacyl-tRNA synthetases in a reconstituted system toward self-synthesizing artificial systems
Katsumi Hagino, Keiko Masuda, Yoshihiro Shimizu, Norikazu Ichihashi
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In vitro construction of self-reproducible artificial systems is a major challenge in bottom-up synthetic biology. Here, we developed a reconstituted system capable of sustainably regenerating all 20 aminoacyl-transfer RNA synthetases (AARS), which are major components of the translation system. To achieve this, we needed five types of improvements: (i) optimization of AARS sequences for efficient translation, (ii) optimization of the composition of the translation system to enhance translation, (iii) employment of another bacterial AlaRS and SerRS to improve each aminoacylation activity, (iv) diminishing the translational inhibition caused by certain AARS sequences by codon optimization and EF-P addition, and (v) balancing the DNA concentrations of 20 AARS to match each requirement. After these improvements, we succeeded in the sustainable regeneration of all 20 AARS for up to 20 cycles of 2.5-fold serial dilutions. These methodologies and results provide a substantial advancement toward the realization of self-reproducible artificial systems.
GPT-4o mini: Non-social science research article
Genomic insights and the conservation potential of captive breeding: The case of Chinese alligator
Tao Pan, Jiashun Miao, Ke Sun, Haitao Nie, Nicholas M. Luscombe, Wengang Li, Song Zhang, Liuyang Yang, Huan Wang, Yongkang Zhou, Genjun Tu, Yilin Shu, Baowei Zhang, Xiaobing Wu
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Despite 40 years of conservation of the critically endangered Chinese alligator ( Alligator sinensis ), the genomic underpinnings of its status remained uncharted. Genome sequencing data of 244 individuals uncovered relatively low overall genomic diversity/heterozygosity and long runs of homozygosity, with captive populations exhibiting higher heterozygosity and smaller inbreeding coefficients compared to wild individuals. The decreased level of inbreeding in the captive population demonstrates the contribution of the large captive breeding population. The estimated recent effective population size was around a few dozen. To combat challenges of inbreeding depression and reduced adaptability, we used genome-wide SNP-based kinship analysis on captive populations to enable a genome-informed breeding program that minimizes inbreeding. Long-term field monitoring revealed that the Chinese government greatly advanced the conservation of A. sinensis through conservation measures and reintroduction programs. Our research enriches the understanding of the Chinese alligator’s genetic landscape, offering invaluable genomic resources for breeding and conservation strategies.
GPT-4o mini: Non-social science research article
Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle
Ana G. Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus KrĂŒger, Bert Blaauw
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Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5â€Č-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.
GPT-4o mini: Non-social science research article
Reconstructing historical climate fields with deep learning
Nils Bochow, Anna Poltronieri, Martin Rypdal, Niklas Boers
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Historical records of climate fields are often sparse because of missing measurements, especially before the introduction of large-scale satellite missions. Several statistical and model-based methods have been introduced to fill gaps and reconstruct historical records. Here, we use a recently introduced deep learning approach based on Fourier convolutions, trained on numerical climate model output, to reconstruct historical climate fields. Using this approach, we are able to realistically reconstruct large and irregular areas of missing data and to reproduce known historical events, such as strong El Niño or La Niña events, with very little given information. Our method outperforms the widely used statistical kriging method, as well as other recent machine learning approaches. The model generalizes to higher resolutions than the ones it was trained on and can be used on a variety of climate fields. Moreover, it allows inpainting of masks never seen before during the model training.
GPT-4o mini: Non-social science research article
Direct observation and force modulation of single-bond reactions at the ion/metal interface
Cong Zhao, Kun Li, Jie Hao, Yanlei Wang, Hongyan He, Chuancheng Jia, Xuefeng Guo
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Elucidating the mechanisms of ion-involved interfacial reactions at the single-bond level is important for understanding interface science. Here, the reaction between pyridine ions and protons at the solid-liquid interface is studied in situ using a single-molecule conductance measurement technique. By manipulating the interfacial electrostatic potential, an ion/metal interfacial state relying on electrostatic interactions has been discovered, comprising terminal group-hydrogen-gold in specific. The reversible interfacial protonation reaction mechanism is revealed in situ at the single-bond level based on this interfacial state. Experiment results also indicate that external forces can effectively regulate this ion-involved interfacial reaction. This work provides a single-bond approach for in situ investigations of ion-involved interfacial reactions with an ion/metal interfacial state, thus promoting the development of interface science.
GPT-4o mini: Non-social science research article
Quantification of low-temperature gas emissions reveals CO 2 flux underestimates at SoufriĂšre Hills volcano, Montserrat
Alexander Riddell, Mike Burton, Ben Esse, Brendan McCormick Kilbride, Antonio Chiarugi, Thomas Christopher, Francesco D’Amato, Graham A. Ryan, Adam Stinton, Silvia Viciani
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We performed helicopter-borne optical MultiGAS measurements of volcanic gas emissions from SoufriÚre Hills Volcano, Montserrat, revealing distinct spikes in SO 2 and HCl concentrations within a larger CO 2 -rich plume. Acid-rich concentration spikes matched the distribution of high-temperature fumaroles, whereas CO 2 is emitted broadly from high- and low-temperature fumaroles. The CO 2 flux was 15 to 41 kilograms per second from hot fumaroles and 61 to 131 kilograms per second for the overall plume. The typical CO 2 flux calculation of multiplying CO 2 /SO 2 ratio with SO 2 flux underestimates total CO 2 flux by at least threefold. We quantified substantial magmatic gas scrubbing by the hydrothermal system, with 56 to 79% of initial HCl and 33 to 68% of initial SO 2 lost. This study highlights the importance of precise acid-gas measurements for detecting heterogeneous degassing and suggests that traditional CO 2 flux measurements may substantially underestimate contributions from cold CO 2 degassing, leading to underestimated global volcanic fluxes.
GPT-4o mini: Non-social science research article
Contorted acene ribbons for stable and ultrasensitive neural probes
Shayan Louie, Qifeng Jiang, Duncan J. Wisniewski, Si Tong Bao, Honghu Zhang, Kaushik Chivukula, Qiyi Fang, Ashutosh Garudapalli, Scott R. Docherty, Fay Ng, Michael Steigerwald, Yu Zhong, Dion Khodagholy, Colin Nuckolls
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Organic materials that conduct both electrons and ions are integral to implantable bioelectronics because of their conformable nature. There is a dearth of these materials that are highly sensitive to cations, which are the majority ions on the surface of neurons. This manuscript offers a solution using an extended ribbon structure that is defect-free, providing high electronic mobility along its fused backbone, while the edge structure of these ribbons promotes high ionic conductivity. We incorporated these mixed ion/electron conductors into neural probes and implanted them in a rodent brain where they offer a suite of useful properties: high cation sensitivity, stability over several weeks after implantation, and biocompatibility. These materials represent an innovative class of implantable biosensors.
GPT-4o mini: Non-social science research article
Autism-like atypical face processing in Shank3 mutant dogs
Siqi Yuan, Chenyu Pang, Liang Wu, Li Yi, Kun Guo, Yong-hui Jiang, Yong Q. Zhang, Shihui Han
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Atypical face processing is a neurocognitive basis of social deficits in autism spectrum disorder (ASD) and a candidate cognitive marker for the disease. Although hundreds of risk genes have been identified in ASD, it remains unclear whether mutations in a specific gene may cause ASD-like atypical face processing. Dogs have acquired exquisite face processing abilities during domestication and may serve as an effective animal model for studying genetic associations of ASD-like atypical face processing. Here, we showed that dogs with Shank3 mutations exhibited behavioral and attentional avoidance of faces, contrasting with wild-type controls. Moreover, neural responses specific to faces (versus objects) recorded from the electrodes over the temporal cortex were significantly decreased and delayed in Shank3 mutants compared to wild-type controls. Cortical responses in the frontal/parietal region underlying categorization of faces by species/breeds were reduced in Shank3 mutants. Our findings of atypical face processing in dogs with Shank3 mutations provide a useful animal model for studying ASD mechanisms and treatments.
GPT-4o mini: Non-social science research article
Curriculum is more influential than haptic feedback when learning object manipulation
Pegah Ojaghi, Romina Mir, Ali Marjaninejad, Andrew Erwin, Michael Wehner, Francisco J. Valero-Cuevas
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Dexterous manipulation remains an aspirational goal for autonomous robotic systems, particularly when learning to lift and rotate objects against gravity with intermittent finger contacts. We use model-free reinforcement learning to compare the effect of curriculum (i.e., combinations of lift and rotation tasks) and haptic information (i.e., no-tactile versus 3D-force) on learning with a simulated three-finger robotic hand. In addition, a novel curriculum-based learning rate scheduler accelerates convergence. We demonstrate that the choice of curriculum biases the progression of learning for dexterous manipulation across objects with different weights, sizes, and shapes—underscoring the robustness of our learning approach. Unexpectedly, learning is achieved even in the absence of haptic information. This challenges conventional thinking about task “complexity” and the necessity of haptic information for dexterous manipulation for this task. This work invites the analogy of curriculum learning as a malleable developmental process from a pluripotent state driven by the nature of the learning experience.
GPT-4o mini: Non-social science research article
A predatory gene drive for targeted control of self-transmissible plasmids
Ryan Tsoi, Hye-In Son, Grayson S. Hamrick, Katherine Tang, Jonathan H. Bethke, Jia Lu, Rohan Maddamsetti, Lingchong You
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Suppressing plasmid transfer in microbial communities has profound implications due to the role of horizontal gene transfer (HGT) in spreading and maintaining diverse functional traits such as metabolic functions, virulence factors, and antibiotic resistance. However, existing tools for inhibiting HGT are limited in their modes of delivery, efficacy, and scalability. Here, we present a versatile denial-of-spread (DoS) strategy to target and eliminate specific conjugative plasmids. Our strategy exploits retrotransfer, whereby an engineered DoS plasmid is introduced into host cells containing a target plasmid. Acting as a predatory gene drive, DoS propagates itself at the expense of the target plasmid, through competition or active elimination. Once the target plasmid is eradicated, DoS is removed via induced plasmid suicide, resulting in a community containing neither plasmid. The strategy is tunable and scalable for various conjugative plasmids, different mechanisms of plasmid inheritance interruption, and diverse environmental contexts. DoS represents a new tool for precise control of gene persistence in microbial communities.
GPT-4o mini: Non-social science research article
Ultrafast momentum-resolved visualization of the interplay between phonon-mediated scattering and plasmons in graphite
Francesco Barantani, RĂ©mi Claude, Fadil Iyikanat, Ivan Madan, Alexey A. Sapozhnik, Michele Puppin, Bruce Weaver, Thomas LaGrange, F. Javier GarcĂ­a de Abajo, Fabrizio Carbone
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Scattering between charges and collective modes in materials governs phenomena such as electrical resistance, energy dissipation, and phase switching. Studying such scattering requires simultaneous access to ultrafast and momentum-resolved dynamics of single-particle and collective excitations, which remains an experimental challenge. Here, we present time- and momentum-resolved electron energy loss spectroscopy, and we apply it to graphite, demonstrating that large (Δ q ≃1.2 Å −1 ) photoexcited electron-hole pockets induce a renormalization of in-plane and bulk plasmons. This effect is explained by intra- and intervalley scattering processes mediated by E 2g and A â€Č 1 phonon modes, which we directly observe via ultrafast electron diffraction and identify via ab initio calculations. Conversely, smaller electron-hole pockets (Δ q ≃0.7 Å −1 ) result in the renormalization of in-plane plasmons, which can only be partially explained by phonon-mediated scattering and thermal expansion. Our results highlight the importance of combining momentum- and time-resolved information to elucidate electronic scattering processes.
GPT-4o mini: Non-social science research article
Structural dynamics-guided engineering of a riboswitch RNA for evolving c-di-AMP synthases
Dian Chen, Jun Li, You Wu, Liang Hong, Yu Liu
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Cyclic diadenosine monophosphate (C-di-AMP) synthases are key enzymes for synthesizing c-di-AMP, a potent activator of the stimulator of interferon genes (STING) immune pathway. However, characterizing these enzymes has been hampered by the lack of effective sensors. While c-di-AMP riboswitches, as natural aptamers, hold the potential as RNA biosensors, their poorly comprehended structural dynamics and inherent "OFF" genetic output pose substantial challenges. To address these limitations, we synthesized over 10 fluorophore-labeled samples to probe the conformational changes of the riboswitch at the single-molecule level. By integrating these dynamic findings with steady-state fluorescence titration, mutagenesis, in vivo assays, and strand displacement strategy, we transformed the natural aptamer into a c-di-AMP biosensor. This engineered biosensor reversed its genetic output from "OFF" to "ON" upon c-di-AMP binding, exhibiting a 50-fold improvement in the c-di-AMP detection limit. Leveraging this refined biosensor, we developed a robust strategy for high-throughput in vivo evolution of c-di-AMP synthases.
GPT-4o mini: Non-social science research article
Starfish-inspired wearable bioelectronic systems for physiological signal monitoring during motion and real-time heart disease diagnosis
Sicheng Chen, Qunle Ouyang, Xianglin Meng, Yibo Yang, Can Li, Xuanbo Miao, Zehua Chen, Ganggang Zhao, Yaguo Lei, Bernard Ghanem, Sandeep Gautam, Jianlin Cheng, Zheng Yan
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Soft bioelectronics enable noninvasive, continuous monitoring of physiological signals, essential for precision health care. However, capturing biosignals during physical activity, particularly biomechanical signals like cardiac mechanics, remains challenging due to motion-induced interference. Inspired by starfish’s pentaradial symmetry, we introduce a starfish-like wearable bioelectronic system designed for high-fidelity signal monitoring during movement. The device, featuring five flexible, free-standing sensing arms connected to a central electronic hub, substantially reduces mechanical interference and enables high-fidelity acquisition of cardiac electrical (electrocardiogram) and mechanical (seismocardiogram and gyrocardiogram) signals during motion when coupled with signal compensation and machine learning. Using these three cardiac signal types as inputs, machine learning models deployed on smart devices achieve real-time, high-accuracy (more than 91%) diagnoses of heart conditions such as atrial fibrillation, myocardial infarction, and heart failure. These findings open previously undiscovered avenues by leveraging bioinspired device concepts combined with cutting-edge data science to boost bioelectronic performance and diagnostic precision.
GPT-4o mini: Non-social science research article
Structural basis for hygromycin B inhibition of yeast pseudouridine-deficient ribosomes
Yu Zhao, Chong Xu, Xin Chen, Hong Jin, Hong Li
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Eukaryotic ribosomes are enriched with pseudouridine, particularly at the functional centers targeted by antibiotics. Here, we investigated the roles of pseudouridine in aminoglycoside-mediated translation inhibition by comparing the structural and functional properties of the yeast wild-type and the pseudouridine-free ribosomes. We showed that the pseudouridine-free ribosomes have decreased thermostability and high sensitivity to aminoglycosides. When presented with a model internal ribosomal entry site RNA, elongation factor eEF2, GTP (guanosine triphosphate), and sordarin, hygromycin B preferentially binds to the pseudouridine-free ribosomes during initiation by blocking eEF2 binding, stalling ribosomes in a nonrotated conformation. The structures captured hygromycin B bound at the intersubunit bridge B2a enriched with pseudouridine and a deformed codon-anticodon duplex, revealing a functional link between pseudouridine and aminoglycoside inhibition. Our results suggest that pseudouridine enhances both thermostability and conformational fitness of the ribosomes, thereby influencing their susceptibility to aminoglycosides.
GPT-4o mini: Non-social science research article
Alpha-synuclein seed amplification assays: Data sharing, standardization needed for clinical use
Hilal A. Lashuel, D. James Surmeier, Tanya Simuni, Kalpana Merchant, Byron Caughey, Claudio Soto, Mohamed-Bilal Fares, Roland G. Heym, Ronald Melki
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Alpha-synuclein seed amplification assays can improve neurodegenerative disease diagnosis and care, but widespread use depends on a framework that standardizes protocols and encourages data sharing.
GPT-4o mini: Non-social science research article
Fibroblast atlas: Shared and specific cell types across tissues
Kaidong Liu, Yanrui Cui, Huiming Han, Erliang Guo, Xingyang Shi, Kai Xiong, Nan Zhang, Songmei Zhai, Shaocong Sang, Mingyue Liu, Bo Chen, Yunyan Gu
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Understanding the heterogeneity of fibroblasts depends on decoding the complexity of cell subtypes, their origin, distribution, and interactions with other cells. Here, we integrated 249,156 fibroblasts from 73 studies across 10 tissues to present a single-cell atlas of fibroblasts. We provided a high-resolution classification of 18 fibroblast subtypes. In particular, we revealed a previously undescribed cell population, TSPAN8 + chromatin remodeling fibroblasts, characterized by high expression of genes with functions related to histone modification and chromatin remodeling. Moreover, TSPAN8 + chromatin remodeling fibroblasts were detectable in spatial transcriptome data and multiplexed immunofluorescence assays. Compared with other fibroblast subtypes, TSPAN8 + chromatin remodeling fibroblasts exhibited higher scores in cell differentiation and resident fibroblast, mainly interacting with endothelial cells and T cells through ligand VEGFA and receptor F2R , and their presence was associated with poor prognosis. Our analyses comprehensively defined the shared and specific characteristics of fibroblast subtypes across tissues and provided a user-friendly data portal, Fibroblast Atlas.
GPT-4o mini: Non-social science research article
Tuning catalyst-support interactions enable steering of electrochemical CO 2 reduction pathways
Meng Wang, Yuke Li, Jinfeng Jia, Tanmay Ghosh, Ping Luo, Yu-Jhih Shen, Sibo Wang, Jiguang Zhang, Shibo Xi, Ziyu Mi, Mingsheng Zhang, Wan Ru Leow, Bernt Johannessen, Zainul Aabdin, Sung-Fu Hung, Jia Zhang, Yanwei Lum
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Tuning of catalyst-support interactions potentially offers a powerful means to control activity. However, rational design of the catalyst support is challenged by a lack of clear property-activity relationships. Here, we uncover how the electronegativity of a support influences reaction pathways in electrochemical CO 2 reduction. This was achieved by creating a model system consisting of Cu nanoparticles hosted on a series of carbon supports, each with a different heteroatom dopant of varying electronegativity. Notably, we discovered that dopants with high electronegativity reduce the electron density on Cu and induce a selectivity shift toward multicarbon (C 2+ ) products. With this design principle, we built a composite Cu and F-doped carbon catalyst that achieves a C 2+ Faradaic efficiency of 82.5% at 400 mA cm −2 , with stable performance for 44 hours. Using simulated flue gas, the catalyst attains a C 2+ FE of 27.3%, which is a factor of 5.3 times higher than a reference Cu catalyst.
GPT-4o mini: Non-social science research article
Neuroecology of alcohol risk and reward: Methanol boosts pheromones and courtship success in Drosophila melanogaster
Ian W. Keesey, Georg Doll, Sudeshna Das Chakraborty, Amelie Baschwitz, Marion Lemoine, Martin Kaltenpoth, AleĆĄ SvatoĆĄ, Silke Sachse, Markus Knaden, Bill S. Hansson
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Attraction of Drosophila melanogaster toward by-products of alcoholic fermentation, especially ethanol, has been extensively studied. Previous research has provided several interpretations of this attraction, including potential drug abuse, or a self-medicating coping strategy after mate rejection. We posit that the ecologically adaptive value of alcohol attraction has not been fully explored. Here, we assert a simple yet vital biological rationale for this alcohol preference. Flies display attraction to fruits rich in alcohol, specifically ethanol and methanol, where contact results in a rapid amplification of fatty acid–derived pheromones that enhance courtship success. We also identify olfactory sensory neurons that detect these alcohols, where we reveal roles in both attraction and aversion, and show that valence is balanced around alcohol concentration. Moreover, we demonstrate that methanol can be deadly, and adult flies must therefore accurately weigh the trade-off between benefits and costs for exposure within their naturally fermented and alcohol-rich environments.
GPT-4o mini: Non-social science research article
Microbial dipeptidyl peptidases of the S9B family as host-microbe isozymes
Mashael R. Aljumaah, Jeffery Roach, Yunan Hu, John Gunstad, M. Andrea Azcarate-Peril
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Human dipeptidyl peptidase 4 (hDPP-4) has been a pharmacological target for metabolic diseases, particularly diabetes, since the early 2000s. As a ubiquitous enzyme found in both prokaryotic and eukaryotic organisms, hDPP-4 plays crucial roles in host homeostasis and disease progression. While many studies have explored hDPP-4’s properties, research on gut microbially derived DPP-4 (mDPP-4) remains limited. This review discusses the significance of mDPP-4 and its health implications, analyzing crystal structures of mDPP-4 in comparison to human counterparts. We examine how hDPP-4 inhibitors could influence gut microbiome composition and mDPP-4 activity. Additionally, this review connects ongoing discussions regarding DPP-4 substrate specificity and potential access routes for mDPP-4, emphasizing the urgent need for further research on mDPP-4’s role in health and improve the precision of DPP-4 inhibitor therapies.
GPT-4o mini: Non-social science research article
Understanding DNA-encoded carbon nanotube sorting and sensing via sub-nm-resolution structural determination
Yinong Li, Yawei Wen, Leticia C. BeltrĂĄn, Li Zhu, Shishan Tian, Jialong Liu, Xuan Zhou, Piaoyi Chen, Edward H. Egelman, Ming Zheng, Zhiwei Lin
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DNA has demonstrated the abilities to differentiate single-wall carbon nanotubes (SWCNTs) with various chiralities and manipulate their analyte sensing properties. However, the fundamental mechanisms underlying these remarkable abilities remain unclear due to the lack of high-resolution determination of DNA structures on SWCNTs. Here, we combine atomic force microscopy and single-particle cryo–electron microscopy to determine DNA structures on five different types of single-chirality SWCNTs, achieving unprecedented subnanometer resolution. This resolution enables the direct observation of left-handed helical DNA structures with pitches ranging from 1.59 to 2.20 nm, depending on the DNA sequence and nanotube chirality. These findings provide structural insights into the mechanisms by which DNA differentiates the chirality of SWCNTs, and governs the sensitivity, dynamic response range, and analyte differentiability of SWCNT sensors. We propose a non–Watson-Crick hydrogen-bonding network model, which not only accounts for the observed ordered DNA structures but also facilitates the design of DNA sequences for targeted SWCNT purification and desired SWCNT sensor performance.
GPT-4o mini: Non-social science research article
Self-supervised machine learning framework for high-throughput electron microscopy
Joodeok Kim, Jinho Rhee, Sungsu Kang, Mingyu Jung, Jihoon Kim, Miji Jeon, Junsun Park, Jimin Ham, Byung Hyo Kim, Won Chul Lee, Soung-Hun Roh, Jungwon Park
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Transmission electron microscopy (TEM) is a crucial analysis method in materials science and structural biology, as it offers a high spatiotemporal resolution for structural characterization and reveals structure-property relationships and structural dynamics at atomic and molecular levels. Despite technical advancements in EM, the nature of the electron beam makes the EM imaging inherently detrimental to materials even in low-dose applications. We introduce SHINE, the Self-supervised High-throughput Image denoising Neural network for Electron microscopy, accelerating minimally invasive low-dose EM of diverse material systems. SHINE uses only a single raw image dataset with intrinsic noise, which makes it suitable for limited-size datasets and eliminates the need for expensive ground-truth training datasets. We quantitatively demonstrate that SHINE overcomes the information limit in the current high-resolution TEM, in situ liquid phase TEM, time-series scanning TEM, and cryo-TEM, facilitating unambiguous high-throughput structure analysis across a broad spectrum of materials.
GPT-4o mini: Non-social science research article
Chronic ethanol exposure produces sex-dependent impairments in value computations in the striatum
Yifeng Cheng, Robin Magnard, Angela J. Langdon, Daeyeol Lee, Patricia H. Janak
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Value-based decision-making relies on the striatum, where neural plasticity can be altered by chronic ethanol (EtOH) exposure, but the effects of such plasticity on striatal neural dynamics during decision-making remain unclear. This study investigated the long-term impacts of EtOH on reward-driven decision-making and striatal neurocomputations in male and female rats using a dynamic probabilistic reversal learning task. Following a prolonged withdrawal period, EtOH-exposed male rats exhibited deficits in adaptability and exploratory behavior, with aberrant outcome-driven value updating that heightened preference for chosen action. These behavioral changes were linked to altered neural activity in the dorsomedial striatum (DMS), where EtOH increased outcome-related encoding and decreased choice-related encoding. In contrast, female rats showed minimal behavioral changes with distinct EtOH-evoked alterations of neural activity, revealing significant sex differences in the impact of chronic EtOH. Our findings underscore the impact of chronic EtOH exposure on adaptive decision-making, revealing enduring changes in neurocomputational processes in the striatum underlying cognitive deficits that differ by sex.
GPT-4o mini: Non-social science research article
Neural heterogeneity enhances reliable neural information processing: Local sensitivity and globally input-slaved transient dynamics
Shengdun Wu, Haiping Huang, Shengjun Wang, Guozhang Chen, Changsong Zhou, Dongping Yang
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Cortical neuronal activity varies over time and across repeated trials, yet consistently represents stimulus features. The dynamical mechanism underlying this reliable representation and computation remains elusive. This study uncovers a mechanism for reliable neural information processing, leveraging a biologically plausible network model incorporating neural heterogeneity. First, we investigate neuronal timescale diversity, revealing that it disrupts intrinsic coherent spatiotemporal patterns, induces firing rate heterogeneity, enhances local responsive sensitivity, and aligns network activity closely with input. The system exhibits globally input-slaved transient dynamics, essential for reliable neural information processing. Other neural heterogeneities, such as nonuniform input connections, spike threshold heterogeneity, and network in-degree heterogeneity, play similar roles, highlighting the importance of neural heterogeneity in shaping consistent stimulus representation. This mechanism offers a potentially general framework for understanding neural heterogeneity in reliable computation and informs the design of reservoir computing models endowed with liquid wave reservoirs for neuromorphic computing.
GPT-4o mini: Non-social science research article
Coassembly of hybrid microscale biomatter for robust, water-processable, and sustainable bioplastics
Yijin Qiu, Dachuan Zhang, Min Long, Zhixuan Zhou, Changdan Gao, Shuai Ma, Jinfa Qin, Kaijuan Chen, Chaoji Chen, Ze Zhao, Hongbing Deng
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Unlike conventional methods that typically involve extracting biopolymers/monomers from biomass using lots of hazardous chemicals and high energy, the direct utilization of biological matter (biomatter) without extraction offers a more sustainable alternative for bioplastic production. However, it often suffers from insufficient mechanical performances or limited processabilities. Herein, we proposed a hybrid microscale biomatter coassembly strategy that leverages the interactions between the inherent microarchitectures of waste cotton fiber and pollen particles. With minimal preprocessing, they form a castable slurry that can spontaneously organize into a dense fiber-laminate bioplastic network, exhibiting high mechanical properties (52.22 megapascals and 2.24 gigapascals) without using toxic organic chemicals or heavy machinery. The resulting bioplastic features controlled hydration-induced microstructural disassembly/reassembly, enabling water-based processability into complex, dynamic architectural systems. In addition, it demonstrates good biodegradability, closed-loop recyclability, and satisfactory environmental benefits, outperforming most common plastics. This study provides an instant nature-derived paradigm for bioplastics’ sustainable production, processing, and recycling, offering a promising solution for facilitating eco-friendly advanced applications.
GPT-4o mini: Non-social science research article
Rapid sorting and auxiliary evaluation of malignant breast tumors by accurate imaging analysis of metastasis-related biomarker
Shan Zuo, Yanhua Li, Yushi Chen, Gangwei Jiang, Zhixuan Zhou, Tian-Bing Ren, Lanlan Chen, Sulai Liu, Shulin Huang, Xiao-Bing Zhang, Lin Yuan
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Accurate differentiation of benign and malignant breast tumors is paramount for establishing schemes of breast cancer treatment and prognosis. Here we report a near-infrared (NIR) fluorescence probe (YF-1) with the overexpressed cathepsin C (CTSC) in metastatic breast tumors as the detecting substrate. This probe allows accurate identification of malignant tumor tissue specimens among tumor tissue specimens with unknown properties in a blind study. Importantly, a series of visible to NIR CTSC-activated fluorescence probes based on the same strategy realize effective identification of malignant tumor tissues, suggesting that CTSC could be the specific identification substrate of malignant breast tumors. Furthermore, a hydrophilic PEG moiety is coupled into YF-1, producing another CTSC-activated NIR probe (YF-2). YF-2 has excellent tumor-targeting capability, enabling the visualization of lung-metastatic breast tumors. The excellent detection accuracy and construction versatility of CTSC probes pave the way for preoperative diagnosis of malignant breast tumors.
GPT-4o mini: Non-social science research article
Ligand spin immobilization in metal-organic frameworks enables high-performance chemispintronic detection of radical gas molecules
Cheng Liu, Xiao-Cheng Zhou, Guoao Li, Jian Su, Lingyu Tang, Qinglong Liu, Xiao Han, Sen Lv, Zhangyan Mu, Yamei Sun, Shuai Yuan, Fei Gao, Jing-Lin Zuo, Shuhua Li, Mengning Ding
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The precise quantification of gaseous radicals in exhaled breath, such as fractional exhaled nitric oxide, serves as an invaluable noninvasive clinical diagnosis particularly in discerning various respiratory disorders. To date, the development of high-performance nitric oxide sensors compatible to modern electronic devices remains fundamentally challenging. We report that metal-organic frameworks (MOFs) with ligand spin immobilization demonstrate superior chemispintronic sensitivity and selectivity toward nitric oxide. Tetrathiafulvalene radical cations (TTF· + ) within the MOF lattice considerably enhance the nitric oxide recognition via spin exchange interactions, leading to a five–order of magnitude reduction in the limit of detection (LOD), as compared to volatile organic compounds (VOCs) via carrier-doping mechanism. Record-low LOD of 0.12 parts per billion was achieved in M-TTF-spin (M = cobalt, zinc, and cadmium) MOFs, which also demonstrates exceptional selectivity over typical nitrogen oxides (NO x ) and VOCs. This work opens up a distinct sensing platform for radical-like analytes through strategic design of spin-immobilized molecular functional motifs toward the spintronic device configurations.
GPT-4o mini: Non-social science research article
Predicting Atlantic and Benguela Niño events with deep learning
Marie-Lou BachĂšlery, Julien Brajard, Massimiliano Patacchiola, Serena Illig, Noel Keenlyside
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Atlantic and Benguela Niño events substantially affect the tropical Atlantic region, with far-reaching consequences on local marine ecosystems, African climates, and El Niño Southern Oscillation. While accurate forecasts of these events are invaluable, state-of-the-art dynamic forecasting systems have shown limited predictive capabilities. Thus, the extent to which the tropical Atlantic variability is predictable remains an open question. This study explores the potential of deep learning in this context. Using a simple convolutional neural network architecture, we show that Atlantic/Benguela Niños can be predicted up to 3 to 4 months ahead. Our model excels in forecasting peak-season events with remarkable accuracy extending lead time to 5 months. Detailed analysis reveals our model’s ability to exploit known physical precursors, such as long-wave ocean dynamics, for accurate predictions of these events. This study challenges the perception that the tropical Atlantic is unpredictable and highlights deep learning’s potential to advance our understanding and forecasting of critical climate events.
GPT-4o mini: Non-social science research article
An engineering-reinforced extracellular vesicle–integrated hydrogel with an ROS-responsive release pattern mitigates spinal cord injury
Jian Cao, Xunqi Zhang, Jing Guo, Jiahe Wu, Lingmin Lin, Xurong Lin, Jiafu Mu, Tianchen Huang, Manning Zhu, Lan Ma, Weihang Zhou, Xinchi Jiang, Xuhua Wang, Shiqing Feng, Zhen Gu, Jian-Qing Gao
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The local delivery of mesenchymal stem cell–derived extracellular vesicles (EVs) via hydrogel has emerged as an effective approach for spinal cord injury (SCI) treatment. However, achieving on-demand release of EVs from hydrogel to address dynamically changing pathology remains challenging. Here, we used a series of engineering methods to further enhance EVs’ efficacy and optimize their release pattern from hydrogel. Specifically, the pro-angiogenic, neurotrophic, and anti-inflammatory effects of EVs were reinforced through three-dimensional culture and dexamethasone (Dxm) encapsulation. Then, the prepared Dxm-loaded 3EVs (3EVs-Dxm) were membrane modified with ortho-dihydroxy groups (-2OH) and formed an EV-integrated hydrogel (3EVs-Dxm-Gel) via the cross-link with phenylboronic acid–modified hyaluronic acid and tannic acid. The phenylboronic acid ester in 3EVs-Dxm-Gel enabled effective immobilization and reactive oxygen species–responsive release of EVs. Topical injection of 3EVs-Dxm-Gel in SCI rats notably mitigated injury severity and promoted functional recovery, which may offer opportunities for EV-based therapeutics in central nervous system injury.
GPT-4o mini: Non-social science research article
Viscosity-dependent hydrothermal synthesis of multinary titanate perovskites
Hong-Bo Cui, Guijian Guan, Ming-Yong Han
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An innovative viscosity-dependent hydrothermal strategy is developed for the controlled synthesis of multinary titanate perovskites, specifically Na 0.5 Y 0.39 Yb 0.1 Er 0.01 TiO 3 . By manipulating the viscosity of the reaction solution using various stable additives in both type and quantity, we identify a critical viscosity threshold of ~100 centipoise, which is essential for producing uniform faceted particles. With sodium hydroxide as an additive, a clear morphological evolution occurs as hydroxide concentration increases, shifting from regular cubes to edge-truncated, half-corner-truncated, and fully corner-truncated cube particles. Furthermore, the inclusion of additional sodium chloride and acetate substantially increases the viscosity, facilitating the formation of uniform faceted particles with reduced sizes ranging from ~2.0 micrometers to 200 nanometers. This method is successfully applied to synthesize other uniform perovskites, including Na 0.5 Y 0.395 Yb 0.1 Tm 0.005 TiO 3 , Na 0.5 Y 0.4 Eu 0.1 TiO 3 , Na 0.5 Y 0.39 Yb 0.1 Ho 0.01 TiO 3 , and Na 0.5 Bi 0.5 TiO 3 . Our findings provide valuable insights into viscosity-controlled synthesis for creating multinary perovskites and enhance their potential for designing optical functional materials and advancing various applications in optical temperature sensing, anti-counterfeiting security, and fingerprint recognition.
GPT-4o mini: Non-social science research article
Genomic insights into evolution of parthenogenesis and triploidy in the flowerpot snake
Yunyun Lv, Wei Wu, Jin-Long Ren, Matthew K. Fujita, Menghuan Song, Zeng Wang, Ke Jiang, Dechun Jiang, Chaochao Yan, Changjun Peng, Zhongliang Peng, Jia-Tang Li
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The flowerpot snake ( Indotyphlops braminus ) is the only known parthenogenetic and triploid species within Serpentes. However, the genetic basis underlying this phenomenon remains unresolved. We investigated the genomic complexities of this rare all-female triploid reptile. On the basis of the newly assembled genome, we revealed 40 chromosomes grouped into three subgenomes (A, B, and C). Comparative genomic analysis with related diploid species revealed a chromosome fusion event in ancestral genomes. This event shaped the unique genetic landscape of the flowerpot snake. We examined gene expression specificity in ovarian tissues and identified pathways essential for DNA replication and repair. Our findings suggest a potential mechanism of homologous chromosome pairing during meiosis in allopolyploid parthenogenesis. This research provides insights into the evolutionary adaptations and genetic mechanisms underlying parthenogenesis in reptilian species, challenging traditional views on reproductive strategies and genomic evolution in asexual organisms.
The inflammatory and genetic mechanisms underlying the cumulative effect of co-occurring pain conditions on depression
Rongtao Jiang, Paul Geha, Matthew Rosenblatt, Yunhe Wang, Zening Fu, Maya Foster, Wei Dai, Vince D. Calhoun, Jing Sui, Marisa N. Spann, Dustin Scheinost
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Chronic pain conditions frequently coexist and share common genetic vulnerabilities. Despite evidence showing associations between pain and depression, the additive effect of co-occurring pain conditions on depression risk and the underlying mechanisms remain unclear. Leveraging data from 431,038 UK Biobank participants with 14-year follow-up, we found a significantly increased risk of depression incidence in individuals reporting pain, irrespective of body site or duration (acute or chronic), compared with pain-free individuals. The depression risk increased with the number of co-occurring pain sites. Mendelian randomization supported potential causal inference. We constructed a composite pain score by combining individual effects of acute or chronic pain conditions across eight body sites in a weighted manner. We found that depression risks increased monotonically in parallel with composite pain scores. Moreover, some inflammatory markers, including C-reactive protein, partially mediated the association between composite pain scores and depression risk. Considering the high prevalence of comorbid depression and pain, pain screening may help identify high-risk individuals for depression.