综合性期刊最新文献

{"title":"An information-theoretic foreshadowing of mathematicians' sudden insights.","authors":"Shadab Tabatabaeian, Artemisia O'bi, David Landy, Tyler Marghetis","doi":"10.1073/pnas.2502791122","DOIUrl":"https://doi.org/10.1073/pnas.2502791122","url":null,"abstract":"<p><p>The \"eureka\" insights that drive progress in science and mathematics remain shrouded in mystery. Sudden, unexpected, appearing like \"flashes of lightning\", these insights have the hallmarks of critical transitions in complex systems. Here, zooming in on mathematicians working on proofs in their own departments, we show that sudden insights are anticipated by a system-agnostic, information-theoretic early warning signal. Using dense behavioral recordings of mathematicians' moment-to-moment activity, we find that their blackboard interactions (e.g., writing, gesturing; [Formula: see text]) became increasingly unpredictable before an insight, analogous to the critical fluctuations that anticipate transitions in physical and ecological systems. We explore analytically when this early warning signal applies to varied systems with discrete, symbolic dynamics. While bibliometric analyses offer a zoomed-out perspective on innovation, publications are a coarse-grained record of individuals' insights. Explaining the sudden insights of innovators, from scientists to sculptors, requires attending to the local, distributed systems of their intellectual activity.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 35","pages":"e2502791122"},"PeriodicalIF":9.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874890","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":"Programmable immunoprobiotics orchestrate antitumor immune response with Pin1 inhibition for pancreatic cancer treatment.","authors":"Sichen Yuan, Xicheng Yang, Alexa M Bremmer, Yixin Wang, Sherry Li, Yu Chen, Yawen You, Quanyin Hu","doi":"10.1073/pnas.2507711122","DOIUrl":"10.1073/pnas.2507711122","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options due to its desmoplastic and immunosuppressive tumor microenvironment (TME), which impedes drug delivery and limits T cell infiltration. Immune checkpoint blockade (ICB) has shown poor efficacy in PDAC, partly due to the desmoplastic stroma and low immunogenicity. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) promotes both fibrosis and immune evasion, making it a compelling target for TME remodeling. Here, we develop a dual-action, programmable immunoprobiotic delivery system (EcN@Nbs-NP@API-1) that combines Pin1 inhibition with PD-L1 blockade to enhance immunotherapy. This system uses <i>Escherichia coli</i> Nissle 1917 (EcN) to selectively deliver nanoparticles encapsulating the Pin1 inhibitor API-1 to PDAC, enabling sustained release to degrade the fibrotic stroma and upregulate PD-L1 on tumor cells, promoting immune infiltration. Engineered EcN also produces anti-PD-L1 nanobodies in situ, synergizing with API-1 to boost CD8⁺ T cell-mediated immunity. In orthotopic PDAC mouse models, this strategy remodels the TME, enhances immune cell infiltration, and improves antitumor response while minimizing systemic toxicity. Moreover, it shows efficacy in other ECM-rich tumors, such as triple-negative breast cancer, highlighting its broader potential. This work presents a promising platform to overcome immunotherapy resistance in solid tumors.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2507711122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874818","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":"Synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome.","authors":"McKenna Loop Yao, Nicholas A Zill, Colin Charles Barber, Yongle Du, Peijun Lin, Rui Zhai, Eunice Yoon, Dunya Al Marzooqi, Wenjun Zhang","doi":"10.1073/pnas.2504492122","DOIUrl":"10.1073/pnas.2504492122","url":null,"abstract":"<p><p>Despite extensive efforts, our understanding of the virulence factors contributing to oral biofilm formation-a hallmark of dental caries-remains incomplete. We present evidence that the specialized metabolism of the oral microbiome is a critical yet underexplored factor in oral biofilm formation. Through microbiome analysis, we identified a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding biosynthetic gene cluster that correlates with dental caries and is widely represented in oral pathogens, including <i>Streptococcus mutans</i>. This gene cluster produces two major mutanoclumpin metabolites, MC-584 and MC-586, which feature molecular scaffolds differing in a C-C macrocyclic linkage. Both metabolites synergistically promote robust biofilm formation of <i>S. mutans</i> through a rare dual-metabolite mode of action. Further, each metabolite binds uniquely to the <i>S. mutans</i> cell surface, resulting in distinct multicellular morphologies. The biosynthesis of mutanoclumpins employs a unique chemical logic that produces two major products, rare within PKS-NRPS assembly lines. This study underscores the importance of characterizing genes implicated in human diseases through microbiome analysis and lays the foundation for exploring strategies to inhibit streptococci-induced dental caries.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2504492122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874826","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":"A universal of speech timing: Intonation units form low-frequency rhythms.","authors":"Maya Inbar, Eitan Grossman, Ayelet N Landau","doi":"10.1073/pnas.2425166122","DOIUrl":"10.1073/pnas.2425166122","url":null,"abstract":"<p><p>Intonation units (IUs) are a hypothesized universal building block of human speech [W. Chafe, <i>Discourse, Consciousness and Time: The Flow and Displacement of Conscious Experience in Speaking and Writing</i> (1994); N. P. Himmelmann <i>et al.</i>, <i>Phonology</i> <b>35</b>, 207-245 (2018)). Linguistic research suggests they are found across languages and that they fulfill important communicative functions such as the pacing of ideas in discourse and swift turn-taking. We study the rate of IUs in 48 languages from every continent and from 27 distinct language families. Using an analytic method to annotate natural speech recordings, we identify a low-frequency rate of IUs across the sample, with a peak at 0.6 Hz, and little variation between sexes or across the life span. We find that IU rate is only weakly related to speech rate quantified at the syllable level, and crucially, that cross-linguistic variation in IU rate does not stem from cross-linguistic variation in syllable rate.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2425166122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874854","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":"Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B.","authors":"Romain Forey, Charlène Raclot, Cyril Pulver, Olga Rosspopoff, Sandra Offner, Julien Duc, Evarist Planet, Filipe Martins, Priscilla Turelli, Didier Trono","doi":"10.1073/pnas.2505021122","DOIUrl":"10.1073/pnas.2505021122","url":null,"abstract":"<p><p>ZNF93 is a primate-restricted Krüppel-associated box zinc finger protein responsible for repressing 20- to 12-My-old L1 transposable elements. Here, we reveal that ZNF93 also regulates the key cancer driver APOBEC3B-a mutagenic enzyme linked to tumorigenesis and cancer progression. ZNF93 depletion impairs DNA synthesis, activates replication and DNA damage checkpoints, and triggers proinflammatory phenotypes. Conversely, its overexpression enhances resistance to exogenous genotoxic stress, mirroring the effects observed with APOBEC3B depletion. ZNF93 expression correlates with cell proliferation rates and is overexpressed in many cancer types. These findings suggest that ZNF93 serves as a critical guardian of genome integrity, co-opted by cancer cells to counterbalance APOBEC3B-induced and L1-derived genomic instability and inflammation.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2505021122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874862","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":"Warming climate and water withdrawals threaten river flow connectivity in China.","authors":"Jiaojiao Gou, Chiyuan Miao, Jinren Ni, Soroosh Sorooshian, Qingyun Duan, Denghua Yan, Louise Slater, Zongxue Xu, Alistair G L Borthwick, Lu Su, Qi Zhang, Yoshihide Wada","doi":"10.1073/pnas.2421046122","DOIUrl":"https://doi.org/10.1073/pnas.2421046122","url":null,"abstract":"<p><p>River flow connectivity, the continuity of fluvial discharge in space and time, provides a crucial lifeline for most biotic communities on Earth. Yet there is still limited understanding of the impacts of climate change and human water withdrawal on river connectivity. Here, we assess the river flow connectivity of 217,001 river reaches in mainland China from 1961 to 2020 and the impact of different climate warming trends and water withdrawals for different sectors. We estimate that naturally intermittent rivers represent about 13% of all river reaches, with a large contrast between northern and southern China (12% vs. 1%, respectively). Although river intermittency decreased slightly during this period (i.e., river connectivity lengthened due to increasing precipitation), warming temperatures offset this decrease by reducing surface water persistence, causing the decrease (-476 vs. -233 km/y) to double when removing the long-term temperature trend. Critically, the length of intermittent rivers increased remarkably from 13 to 50% when considering human water withdrawal by agricultural, domestic, and industrial sectors, in addition to environmental flow requirements. Our findings highlight the urgent need to maintain sustainable water resources in a warming climate in which unregulated water abstractions increasingly threaten river flow connectivity, particularly in drying regions.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2421046122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874889","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":"Soil eDNA reflects regionally dominant species rather than local composition of tropical tree communities.","authors":"Francesc Borràs Sayas, Ottavia Iacovino, María Uriarte, Jess K Zimmerman, Christopher J Nytch, Glenn Dunshea, Robert Muscarella","doi":"10.1073/pnas.2505772122","DOIUrl":"10.1073/pnas.2505772122","url":null,"abstract":"<p><p>Environmental DNA (eDNA) is increasingly used for biodiversity monitoring, but validation of the spatial scale(s) at which eDNA reflects extant communities is scarce, particularly in tropical forests: the terrestrial biome with the most concentrated diversity on earth. We leveraged spatially explicit tree inventory data from the 16-ha Luquillo Forest Dynamics Plot (LFDP) in Puerto Rico to validate soil eDNA as a spatially explicit indicator of tree diversity/composition. Using a comprehensive local chloroplast <i>trnL</i>-P6 reference library, we analyzed soil samples at multiple scales through eDNA <i>trnL</i>-P6 metabarcoding. We compared eDNA taxonomic diversity/composition, considering several bioinformatic thresholds, with inventory data across a range of spatial scales, as well as random points to compare observed correlations with random expectations. Despite considerable fine-scale heterogeneity in soil plant eDNA composition, we detected 53 tree Operational Taxonomic Units (OTUs) across the LFDP, corresponding to 68% of tree OTUs from the census data. Encouragingly, this equated to 98% of the total basal area (and 98% of the total stems). An initial confusion matrix evaluation suggested a highly localized eDNA signal (within 5 m of the sampled locations). However, comparison with random expectations revealed a lack of support for a fine-scale spatial signal due to misclassification (i.e., eDNA false presence or/and false absence) of relatively common taxa. Our study shows that \"universal\" PCR primer metabarcoding of tree eDNA in tropical soils may be useful for assessing dominant taxa at landscape scales, but not for spatially explicit characterization of rare species and community composition at local scales.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2505772122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874822","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":"Sparse autoencoders uncover biologically interpretable features in protein language model representations.","authors":"Onkar Gujral, Mihir Bafna, Eric Alm, Bonnie Berger","doi":"10.1073/pnas.2506316122","DOIUrl":"10.1073/pnas.2506316122","url":null,"abstract":"<p><p>Foundation models in biology-particularly protein language models (PLMs)-have enabled ground-breaking predictions in protein structure, function, and beyond. However, the \"black-box\" nature of these representations limits transparency and explainability, posing challenges for human-AI collaboration and leaving open questions about their human-interpretable features. Here, we leverage sparse autoencoders (SAEs) and a variant, transcoders, from natural language processing to extract, in a completely unsupervised fashion, interpretable sparse features present in both protein-level and amino acid (AA)-level representations from ESM2, a popular PLM. Unlike other approaches such as training probes for features, the extraction of features by the SAE is performed without any supervision. We find that many sparse features extracted from SAEs trained on protein-level representations are tightly associated with Gene Ontology (GO) terms across all levels of the GO hierarchy. We also use Anthropic's Claude to automate the interpretation of sparse features for both protein-level and AA-level representations and find that many of these features correspond to specific protein families and functions such as the NAD Kinase, IUNH, and the PTH family, as well as proteins involved in methyltransferase activity and in olfactory and gustatory sensory perception. We show that sparse features are more interpretable than ESM2 neurons across all our trained SAEs and transcoders. These findings demonstrate that SAEs offer a promising unsupervised approach for disentangling biologically relevant information present in PLM representations, thus aiding interpretability. This work opens the door to safety, trust, and explainability of PLMs and their applications, and paves the way to extracting meaningful biological insights across increasingly powerful models in the life sciences.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2506316122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874824","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":"Evolution of developmental bias explains divergent patterns of phenotypic evolution in two nematode clades.","authors":"Joao Picao-Osorio, Charlotte Bouleau, Pablo M Gonzalez de la Rosa, Lewis Stevens, Nina Fekonja, Mark Blaxter, Christian Braendle, Marie-Anne Félix","doi":"10.1073/pnas.2507529122","DOIUrl":"10.1073/pnas.2507529122","url":null,"abstract":"<p><p>Rates of phenotypic evolution vary across traits, and these evolutionary patterns themselves evolve. Understanding how development contributes to such patterns remains a challenge because it requires large-scale measurement of phenotypic variation resulting from random mutations across multiple species. Using the experimentally tractable system of nematode vulval development, we quantified the evolution and mutational sensitivity of six cell fates across two clades. First, we find that the cell whose fate evolves fastest is distinct for each clade: P3.p in <i>Caenorhabditis</i> and P4.p in <i>Oscheius</i>. Second, we show that this evolutionary pattern matches the pattern of variation within species of each clade. Third, we find that within each clade, the differential effect on each cell of random mutation, quantified as their mutational phenotypic variance, is sufficient to explain the observed phenotypic evolution. Finally, we propose that the difference between clades is explained by a simple spatial shift across cells of the sensitive region in a Wnt dose-response curve. These findings underscore the importance of integrating the evolving structure of the genotype-phenotype map and measures of developmental sensitivity into the understanding of phenotypic change at both micro- and macroevolutionary scales.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2507529122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874869","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":"The rise of diversity terminology in biomedical research.","authors":"Brandon L Kramer, Catherine Lee","doi":"10.1073/pnas.2401805122","DOIUrl":"10.1073/pnas.2401805122","url":null,"abstract":"<p><p>Recent scholarship has highlighted the rise of \"diversity projects\" across various educational and business contexts, but few studies have explored the meaning of diversity in biomedical research. In this paper, we employ a computationally driven matching technique to examine quantitative trends in the use of various forms of diversity and population terminology in a sample of nearly two million biomedical abstracts spanning a 30-y period. The curated dictionaries we leverage to detect these trends were formalized into open-source software that are publicly available for other researchers to use. Our analyses demonstrate marked growth in diversity, sex, gender, life course, and socioeconomic terms while terms relating to race and ethnicity largely plateaued or declined in usage, beginning in the mid-2000s. In addition, the use of national, continental, and subcontinental population labels increased dramatically over the same period. We also present logistic regression analyses to investigate what may be fueling the rise in use of diversity terminology. We argue that the use of diversity has grown to encompass concepts beyond its historical origins in race-based programs as it has in fields like higher education and employment. Despite some critics' claims regarding the role of diversity in research, we do not find evidence that its use signals retreat from or commitment to equity and inclusion efforts.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 34","pages":"e2401805122"},"PeriodicalIF":9.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874886","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}