Proceedings of the National Academy of Sciences of the United States of America最新文献

{"title":"Shapes of ideal stalagmites.","authors":"Piotr Szymczak, Anthony J C Ladd, Matej Lipar, Dean Pekarovič","doi":"10.1073/pnas.2513263122","DOIUrl":"https://doi.org/10.1073/pnas.2513263122","url":null,"abstract":"<p><p>Stalagmites are isolated columns of calcium carbonate growing on a cave floor; their growth is driven by the constant dripping of supersaturated solutions from the roof of the cave. In this paper, we derive a closed-form expression for the shape of a steadily growing stalagmite. Our analysis gives rise to three distinct shapes, all of them observable in nature, with the shape characterized by a single dimensionless parameter. Transitions between different shapes occur at a specific value of this parameter, with additional selection rules determining the shape and size of stalagmites evolving under specific cave conditions. Our theory shows that the stalagmite shape influences the [Formula: see text] isotope shifts, which are an important source of paleoclimatic information.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 42","pages":"e2513263122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In This Issue.","authors":"","doi":"10.1073/iti4225122","DOIUrl":"https://doi.org/10.1073/iti4225122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 42","pages":"eiti4225122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell receptor specificity landscape revealed through de novo peptide design.","authors":"Gian Marco Visani, Michael N Pun, Anastasia A Minervina, Philip Bradley, Paul G Thomas, Armita Nourmohammad","doi":"10.1073/pnas.2504783122","DOIUrl":"10.1073/pnas.2504783122","url":null,"abstract":"<p><p>T cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. Effective bindings between T cell receptors (TCRs) and pathogen derived peptides presented on major histocompatibility complexes (MHCs) mediate immune responses. However, predicting these interactions remains challenging due to limited functional data on T cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC-I alleles, and to design immunogenic peptides for specified TCR-MHC complexes. Our method leverages HERMES, a structure-based machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, HERMES's implicit physical reasoning enables us to make accurate predictions of both TCR-pMHC binding affinities and T cell activities across diverse viral and cancer epitopes, achieving up to 0.72 correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR-MHC systems, we demonstrate that our designs-with up to five substitutions from the native sequence-activate T cells at success rates of up to 50%. Last, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR-MHC's, offering key insights into T cell specificity. Our approach provides a platform for immunogenic peptide and neoantigen design, as well as for evaluating TCR specificity, offering a computational framework to inform design of engineered T cell therapies and vaccines.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 42","pages":"e2504783122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell sequencing uncovers sensory neuron-mediated CGRP signaling as a driver of sarcoma progression.","authors":"Sowmya Ramesh,Qizhi Qin,Zhao Li,Masnsen Cherief,Lingke Zhong,Mary Archer,Xin Xing,Neelima Thottappillil,Devadutta Balaji,Sam Bae,Mario Gomez-Salazar,Mingxin Xu,Manyu Zhu,Ankit Uniyal,Leslie Chang,Khadijah Mazhar,Monisha Mittal,Alexander Birbrair,Edward F McCarthy,Carol D Morris,Benjamin Levi,Yun Guan,Thomas L Clemens,Theodore J Price,Aaron W James","doi":"10.1073/pnas.2500161122","DOIUrl":"https://doi.org/10.1073/pnas.2500161122","url":null,"abstract":"Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, skewed tumor associated macrophage polarization, reduced tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multiomics analyses of human OS bone samples further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. Next and in two parallel approaches to inhibit nerve ingrowth, we repurposed FDA-approved bupivacaine liposomes and separately blocked CGRP signaling using FDA-approved Rimegepant. Both strategies led to significant reductions in sarcoma growth, vascularity, and sarcoma-induced hyperalgesia. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition disrupts CGRP signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of OS represent an adjunctive therapy to improve clinical outcomes and survival.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"200 1","pages":"e2500161122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Descattering and image restoration with a transformer-based neural network in deep tissue imaging.","authors":"Xiangcong Xu,Renlong Zhang,Chenggui Luo,Chi Zhang,Yanping Li,Danying Lin,Bin Yu,Liwei Liu,Xiaoyu Weng,Yiping Wang,Lingjie Kong,Jia Li,Junle Qu","doi":"10.1073/pnas.2503576122","DOIUrl":"https://doi.org/10.1073/pnas.2503576122","url":null,"abstract":"Imaging biological structures deep inside tissues is crucial but challenging due to common light scattering. This study proposes a multiattention network that directly maps degraded scattering two-photon excitation fluorescence (TPEF) images to high-quality scattering-free images, thereby computationally extending the imaging depth for TPEF without requiring complex optical additions. The model relies solely on simulated data rather than well-registered real data pairs, and is trained to descatter and restore hidden spatial information at greater depths. Quantitative evaluations on simulated fluorescent beads and vasculature show significant performance improvements in peak signal-to-noise ratio (23 to 29 dB) and structural similarity index (23×) compared to the raw data. We also apply the framework to various ex vivo and in vivo experiments, achieving clear visualization of lipid droplets up to a depth of 1,300 μm and of vascular structure and astrocytes up to 950 μm and 500 μm, respectively, in live mouse brains at lower excitation powers.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"129 1","pages":"e2503576122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From retinotopic to ordinal coding: Dissecting the cortical stages of visual word recognition.","authors":"Aakash Agrawal,Stanislas Dehaene","doi":"10.1073/pnas.2507291122","DOIUrl":"https://doi.org/10.1073/pnas.2507291122","url":null,"abstract":"Fluent reading requires the brain to precisely encode the positions of letters within words, distinguishing for instance FORM and FROM across variations in size, position, and font. Early visual areas, however, are known to encode retinotopic positions, and how these representations get transformed into a position-invariant neural code remains unclear. Building upon a computational model of reading, we used 7T functional MRI and magnetoencephalography (MEG) to reveal a cortical hierarchy in which early visual areas (V1-V4) predominantly encode retinotopic information, whereas higher-level regions, including the visual word form area, transition to an ordinal letter-position code. MEG analyses confirm that retinotopic encoding emerges early (60 to 200 ms), followed by a shift toward ordinal representations in later time windows (220 to 450 ms). Despite this transition, word position remained a dominant factor across all time points, suggesting a concurrent coding of both retinotopic and abstract positional information. These findings uncover the spatiotemporal dynamics by which the human brain transforms visual input into structured prelexical representations, shedding light on the cortical stages of reading and their developmental and clinical implications.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"19 1","pages":"e2507291122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19.","authors":"Rodrigo de Oliveira Formiga,Lucie Pesenti,François Chable de la Héronnière,Maha Zohra Ladjemi,Darko Stojkov,Shida Yousefi,Philippe Frachet,Lisa Krafft,Laura Tiberio,Daniela Bosisio,Muriel Andrieu,Souganya Many,Vaarany Karunanithy,Karine Bailly,Théo Dhôte,Giovanni Saraceni-Tasso,Manon Castel,Christophe Rousseau,Marick Rodrigues Starick,Edroaldo Lummertz da Rocha,Emilia Puig Lombardi,Cicero José Luíz Dos Ramos Almeida,Anderson Dos Santos Ramos,Fernando Queiroz Cunha,José Carlos Alves-Filho,Natália Ribeiro Cabacinha Nóbrega,Matheus Rodrigues Gonçalves,Celso Martins Queiroz-Junior,Viviane Lima Batista,Mauro Martins Teixeira,Vanessa Granger,Sylvie Chollet-Martin,Luc De Chaisemartin,Luc Mouthon,Anne Hosmalin,Margarita Hurtado-Nedelec,Clémence Martin,Fernando Spiller,Hans-Uwe Simon,Nicolas Tamassia,Marco Antonio Cassatella,Frédéric Pène,Thomas Vogl,Pierre-Regis Burgel,Vivian Vasconcelos Costa,Véronique Witko-Sarsat","doi":"10.1073/pnas.2503667122","DOIUrl":"https://doi.org/10.1073/pnas.2503667122","url":null,"abstract":"Neutrophils are central mediators of the hyperinflammatory response in severe SARS-CoV-2 infection. We report elevated cytosolic levels of proliferating cell nuclear antigen (PCNA) in neutrophils from patients with severe and critical COVID-19, correlating with enhanced NADPH oxidase-dependent reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. Using T2AA, a small-molecule inhibitor of the PCNA scaffold, we demonstrate potent suppression of NADPH oxidase activation and NET release, particularly in response to SARS-CoV-2 RNA. Mechanistically, we identify a previously unrecognized interaction between PCNA and the heterodimeric S100A8/S100A9 (calprotectin), predominantly enriched in CD16highCD62Llow neutrophils expanded during COVID-19. PCNA binds the dimeric S100A8/S100A9 complex mediated via S100A8 subunit with micromolar affinity, and this interaction is abrogated by tetramerization, suggesting regulation by intracellular calcium. Disruption of this complex by T2AA inhibited ROS production in an S100A8/S100A9-dependent manner, implicating calprotectin as a functional regulator of neutrophil activation. In a betacoronavirus mouse model, T2AA treatment attenuated lung inflammation, reduced NET and calprotectin levels, and shifted pulmonary neutrophils away from hyperactivated and immunosuppressive phenotypes, consistent with immune reprogramming toward resolution. These findings establish cytosolic PCNA as a central scaffold in neutrophil hyperactivation during COVID-19 and highlight its pharmacological disruption as a promising host-directed strategy to limit inflammation and prevent organ damage.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"98 1","pages":"e2503667122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond adoption: The persistence of conservation and climate-smart agricultural practices in the United States.","authors":"Paul J Ferraro,Maria Bowman,Hannah E Correia,Jing Gao,Kelsey R Larson,Kent D Messer,Laura A Paul,Bryan Pratt,Linda S Prokopy","doi":"10.1073/pnas.2518373122","DOIUrl":"https://doi.org/10.1073/pnas.2518373122","url":null,"abstract":"Achieving sustainability goals requires that humans change their behavior not just once but persistently. Yet despite decades of research on the adoption of conservation and climate-smart agricultural practices, little is known about the extent to which these practices persist over time. One key reason is the lack of longitudinal, field-level data. Using ground-verified, longitudinal data on cover cropping across thousands of farm parcels in Indiana (USA), we find that persistence is low and contrasts sharply with the predictions made by Indiana conservation experts. We also find low persistence in a new national dataset of self-reported cover cropping by farm operators. The potential for low behavioral persistence in sustainable agricultural practices raises essential questions about the design of conservation programs and the modeling and valuation of ecosystem services.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"11 1","pages":"e2518373122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-site cooperation for synergistic optimization of the band structure and spin state to facilitate C-N coupling reaction.","authors":"Qizhu Qian,Qilong Liu,Mengxiang Wang,Jingjing Yang,Huiyi Li,Wei Bai,Wentao Wang,Changzheng Wu,Chong Xiao,Yi Xie","doi":"10.1073/pnas.2508077122","DOIUrl":"https://doi.org/10.1073/pnas.2508077122","url":null,"abstract":"The emerging electrocatalytic C-N coupling reaction provides an attractive route toward green urea synthesis, but a lack of in-depth insight into the catalytic mechanism and the geometric/electronic configurations that determine the key C- and N-coupling intermediates formation hampers the exploration of efficient catalysts. Herein, we design a bimetallic oxide (Fe-Mo-O) with dual active sites of Fe and Mo for the adsorption and activation of NO2- and CO2, respectively. Constructing dual-metal catalyst leads to an upshift of the d-band center and the generation of an intermediate-spin Fe center, which not only favors the selective conversion of *CO2 into the key intermediate *CO on Mo sites, but also facilitates the adsorption and reduction of NO2- on Fe sites. Operando characterizations and theoretical calculations together elucidate that urea generation is associated with the formation of *CONH2 intermediate by coupling *CO and *NH2 on the alternating Mo and intermediate-spin Fe active sites, ultimately synergistically lowering the C-N coupling energy barrier. Specifically, the Fe-Mo-O catalyst delivers a high urea yield rate of 681.8 μg h-1 mg-1cat. and an excellent Faradaic efficiency of 60% at -0.5 V (vs. RHE). Furthermore, a C-N coupling paired with a glycerol oxidation system allows for energy-saving electrochemical coproduction of urea and formic acid. Our findings offer a feasible strategy to develop cutting-edge electrocatalysts for urea synthesis by active site design and electronic structure regulation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"26 1","pages":"e2508077122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capillary self-thinning of threads of polyelectrolyte solutions with axial electric fields.","authors":"Patrick Martin,Gleb Vasilyev,Eyal Zussman,Alexander L Yarin","doi":"10.1073/pnas.2422879122","DOIUrl":"https://doi.org/10.1073/pnas.2422879122","url":null,"abstract":"A theory of solutions of charged polyelectrolyte (PE) macromolecules, treating them as electric dipoles, is proposed. In a thin thread of PE solution sustained between two disks-whether wettable or nonwettable-these dipoles are reoriented by an axial electric field, aligning themselves with the field direction. This alignment causes significant axial elastic stresses and affects capillary self-thinning dynamics of the thread, slowing the process and potentially arresting it entirely, and even leading to oscillatory regimes. Accordingly, the evolution of the thread radius deviates significantly from the exponential decay characteristic of solutions of flexible polymer macromolecules and the linear decay characteristic of Newtonian fluids. At relatively high electric field strengths, in a thread where elastic stresses become dominant, an oscillatory regime emerges. Here, the cross-sectional radius not only decreases but also increases and oscillates in time-a behavior rooted in an ill-posedness of the problem reducing to the Laplace equation in case of strong electric fields. This indicates a manifestation of Hadamard instability. The theory is supported by experimental data acquired in this work.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"39 1","pages":"e2422879122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}