PNAS nexus最新文献

{"title":"A versatile fluorescent reporter for Usutu virus drug screening and infection tracking.","authors":"Amy N Nelson, Aaron E Lin, Saloni Sinha, Sydney J Mullin, Jianche Liu, Alexandra G Bell, Sebastian S Carver, Jason Sethiadi, Jiayu Zhang, Brigitte L Heller, Cameron Myhrvold, Robert E Schwartz, Alexander Ploss","doi":"10.1093/pnasnexus/pgag328","DOIUrl":"10.1093/pnasnexus/pgag328","url":null,"abstract":"<p><p>Usutu virus (USUV) is an emerging mosquito-borne orthoflavivirus closely related to West Nile and Japanese encephalitis viruses. Despite its increasing prevalence in Europe and reports of neuroinvasive disease in humans, the molecular and immunological determinants of USUV infection remain poorly understood, largely due to the absence of tractable experimental tools. Here, we report the generation and characterization of the first full-length fluorescent reporter USUV. Using a previously established infectious clone of the Vienna 2001 strain, we inserted the <i>mScarlet-I</i> gene into a permissive region of the viral genome, generating a stable and replication-competent reporter virus. In human hepatoma cells, USUV-mScarlet exhibited replication kinetics comparable to wild-type virus and maintained fluorescence over at least 10 serial passages. Application of this system identified remdesivir and interferon-alpha 2a (IFN-α2a) as potent USUV inhibitors and revealed robust induction of the type I IFN response in infected mouse fibroblasts, despite overall attenuation in this cell type. In IFN signaling deficient mice, which are permissive for viral replication, USUV-mScarlet infection resulted in transient disease and reporter expression in multiple peripheral tissues. Among splenocytes, specific myeloid cell subsets were highly enriched in reporter expression, suggesting their role as targets of viral infection. Collectively, these findings demonstrate that USUV-mScarlet recapitulates wild-type infection dynamics in human hepatoma cells while enabling single-cell/quantitative visualization and sorting of infected cells to assess viral spread and host responses. This reporter platform provides a versatile tool for studying USUV biology and will facilitate the development of targeted antivirals and vaccines against this emerging orthoflavivirus.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 10","pages":"pgag328"},"PeriodicalIF":4.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear archaeology reassesses Heisenberg's last reactor experiment.","authors":"Patrick J Park, Brittany Robertson, Miriam E Hiebert, Jason Zhao, Ciara B Sivels, Timothy W Koeth","doi":"10.1093/pnasnexus/pgag282","DOIUrl":"10.1093/pnasnexus/pgag282","url":null,"abstract":"<p><p>The B8 pile, built in April 1945, was a natural uranium, heavy water reactor experiment and the culmination of Nazi Germany's nuclear program. Its designer, Werner Heisenberg, claimed in a 1947 <i>Nature</i> article that the B8 was \"just insufficient\" in achieving self-sustaining fission, lacking only a \"relatively small amount of uranium.\" In the following decades, historians have then suggested that the Germans should have pursued graphite reactors like the Americans. Here, we present forensics and document-based archaeology of the B8's uranium, heavy water, and graphites. We create a neutronics model that is validated by in situ 1945 measurements. Our calculations show that the B8, as built, had <math> <mrow><msub><mi>k</mi> <mrow><mi>e</mi> <mi>f</mi> <mi>f</mi></mrow> </msub> <mo>=</mo> <mn>0.94</mn></mrow> </math> . To achieve self-sustaining fission at <math> <mrow><msub><mi>k</mi> <mrow><mi>e</mi> <mi>f</mi> <mi>f</mi></mrow> </msub> <mo>=</mo> <mn>1.0</mn></mrow> </math> , the Germans would have needed about 2.0 times the uranium and about 2.2 times the heavy water than they used, far exceeding Heisenberg's predictions; these inventories were about 1.2 and 1.8 times, respectively, Germany's estimated available wartime inventories. Furthermore, we determine that their graphite, with 3.4 wppm boron impurities and re-used from the prior B7 experiment, would not allow criticality in a hypothetical graphite-natural uranium pile. German graphites were made of metallurgical coke, which naturally carry more boron than petroleum coke-based graphites, which were available in America and uniquely enabled Chicago Pile 1's criticality. Our findings indicate that Germany could not have built either a heavy water nor a graphite reactor in World War II.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 9","pages":"pgag282"},"PeriodicalIF":4.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Principal bundle geometry of qualia: Understanding the quality of consciousness from symmetry.","authors":"","doi":"10.1093/pnasnexus/pgag313","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgag313","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/pnasnexus/pgag261.].</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 9","pages":"pgag313"},"PeriodicalIF":4.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancient and animal-specific regulatory modes of EWS::FLI1 revealed by a minimal yeast model.","authors":"Diego Velázquez, Cristina Molnar, Jose Reina, Jaume Mora, Cayetano Gonzalez","doi":"10.1093/pnasnexus/pgag329","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgag329","url":null,"abstract":"<p><p>Ewing sarcoma (EwS) is an aggressive, human-exclusive tumor typically driven by the EWS::friend leukemia integration 1 (FLI1) fusion protein. To assess whether EWS::FLI1's neomorphic functions depend on evolutionarily recent cofactors, we expressed EWS::FLI1 in <i>Saccharomyces cerevisiae</i>, a minimal system in which the BAF complex is strongly diverged and ETS transcription factors (ETS-TFs), polycomb group (PcG) proteins, and CBP/p300 are absent. We used co-IP/mass spectrometry to map the yeast interactome, ChIP-seq to identify gDNA binding sequences, RNA-seq for gene expression, and engineered reporters to test conversion of GGAA tandem repeats (GGAAμSat) into neoenhancers. We found that the yeast EWS::FLI1 interactome was limited and distinct from its human counterpart, sharing core machinery (RNA polymerase II, FACT) but lacking BAF/SWI-SNF and spliceosome complexes, and showing enrichment for SAGA. EWS::FLI1 binds to hundreds of yeast genomic sites with preference for putative ETS-TF consensus sequences and CA dinucleotide repeats, and redirects RNA polymerase II to EWS::FLI1-bound loci. Yet, EWS::FLI1-expressing cells presented only minimal transcriptional dysregulation, in contrast to the extensive changes observed in human and Drosophila cells. Finally, EWS::FLI1 successfully converted silent GGAAμSat sequences into active enhancers in yeast. This remarkable result occurs despite the absence of homologs for key human activators, such as CBP/p300, suggesting that EWS::FLI1 can mobilize functionally related, nonhomologous pathways to establish neoenhancers at GGAAμSat sites. Altogether, our results indicate that EWS::FLI1's core ability to drive GGAAμSat-dependent gene expression is a conserved, ancient property, while GGAAμSat-independent extensive transcriptome reprogramming depends on animal-specific cofactors and pathways.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 10","pages":"pgag329"},"PeriodicalIF":4.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Building adaptive capacity of US Gulf Coast city practitioners to extreme weather events.","authors":"Gabrielle Wong-Parodi, Natalie Herbert, Sarah J Fendrich, Alexander B Basaraba, Simone J Domingue, Erica A Goto, Patty Hernandez, Teal Harrison, Kripa Jagannathan, Jenna L Jorns, Anima Scott Kalafatis, Lisa Maillard, Alexander Petersen, Mark Shafer, Joshua J Wimhurst, Derek Van Berkel, Maria Carmen Lemos","doi":"10.1093/pnasnexus/pgag330","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgag330","url":null,"abstract":"<p><p>Building city practitioners' capacity to prepare for and respond to climate change-driven events can increase coastal cities' resilience. We conducted a first-of-its-kind mixed methods research project from 2021 to 2023 with 46 US Gulf Coast small and midsize cities to measure the effectiveness of an adaptive capacity-building intervention: a stormwater planning tool called FloodWise Communities (FWC) deployed through the engagement between researchers and practitioners in each city. City practitioners were surveyed preintervention and postintervention between September 2021 and December 2022. Interviews were then conducted through July 2023. We found (i) FWC positively relates to perceptions of actionable knowledge and a change in adaptation intentions; (ii) city practitioners' adaptation-relevant roles and responsibilities positively related to their perceptions of actionable knowledge and adaptation intentions, with implications for their agency to build adaptive capacity; and (iii) anticipated and unanticipated uses of the FWC tool influenced city practitioners' perceptions of their adaptive capacity.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 10","pages":"pgag330"},"PeriodicalIF":4.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying common G protein-coupled receptor interacting proteins independent of heterotrimeric G proteins and β-arrestins.","authors":"Chloe Hicks, Julia Gardner, Anand Chundi, Nicholas D Camarda, Chanpreet Jassal, Uyen Pham, Saisha Dhar, Hailey Rodriguez, J Fernando Bazan, Dylan Scott Eiger, Sudarshan Rajagopal","doi":"10.1093/pnasnexus/pgag327","DOIUrl":"10.1093/pnasnexus/pgag327","url":null,"abstract":"<p><p>The canonical paradigm of G protein-coupled receptor (GPCR) signaling recognizes G proteins, β-arrestins, and GPCR kinases as the primary transducers that shape GPCR signaling. However, multiple studies have demonstrated that other interacting proteins regulate GPCR function in addition to these pathways, termed GPCR-interacting proteins (GIPs). The atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and β-arrestins have been shown to be dispensable for many of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of β-arrestins. Among conserved proteins from our and several similar GPCR-based proximity labeling experiments, we discovered components of the endocytic machinery and other putative interacting proteins that can interact with GPCRs independent of G proteins and β-arrestins. Notably, we discovered that the bone morphogenetic protein 2-inducible kinase (BMP2K) interacts with ACKR3 in a phosphorylation-dependent manner that is distinct from its interaction with β-arrestin. We demonstrate BMP2K's ability to interact with many different GPCRs with varying dependency on β-arrestin. Using molecular dynamic simulations, we discovered an asparagine-proline-phenylephrine (NPF)-binding motif in BMP2K critical for its interaction with GPCRs and determined that this motif is conserved across many other GIPs. These findings reveal an expanded network of GIPs that interact with GPCRs independent of G proteins and β-arrestins, highlighting alternative mechanisms by which GPCR signaling may be transduced beyond canonical paradigms.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 10","pages":"pgag327"},"PeriodicalIF":4.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salient air pollution mobilizes bottom-up green engagement: Evidence from the world's largest green mobile program.","authors":"Jiafu An, Jiawen Huang, Chen Lin, Difang Huang","doi":"10.1093/pnasnexus/pgag326","DOIUrl":"10.1093/pnasnexus/pgag326","url":null,"abstract":"<p><p>Air pollution imposes large health and economic costs worldwide, yet most mitigation efforts still rely primarily on top-down regulation of major emitters. We examine whether salient deterioration in local air quality mobilizes bottom-up engagement with a green digital program. Using user-month panel data on 200,000 users of Ant Forest-the world's largest green mobile program-across 331 Chinese cities from 2019 to 2020, we show that the same individuals respond to severe local pollution by generating more green energy through eligible low-carbon activities, engaging more intensively and more frequently with the program to collect the resulting credits, and redeeming more credits for collaborative tree planting in the following month. The responses are dose-responsive-larger under \"Hazardous\" (AQI ≥ 300) than \"Very Unhealthy\" (AQI ≥ 200) conditions-and representative survey data show that pollution exposure raises stated environmental concern. Our findings indicate that digital green programs can help translate heightened environmental concern into measurable green engagement and downstream environmental contributions, complementing top-down regulation.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 10","pages":"pgag326"},"PeriodicalIF":4.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning without weight symmetry.","authors":"Li Ji-An, Marcus K Benna","doi":"10.1093/pnasnexus/pgag321","DOIUrl":"10.1093/pnasnexus/pgag321","url":null,"abstract":"<p><p>Backpropagation (BP), a foundational algorithm for training artificial neural networks, predominates in contemporary deep learning. Although highly successful, it is widely considered biologically implausible, because it relies on precise symmetry between feedforward and feedback weights to accurately propagate gradient signals that assign credit. The so-called weight transport problem concerns how biological brains learn to align feedforward and feedback paths while avoiding the nonbiological transport of feedforward weights into feedback weights. To address this, several credit assignment algorithms, such as feedback alignment and the Kolen-Pollack rule, have been proposed. While they can achieve the desired weight alignment, these algorithms imply that if a neuron sends a feedforward synapse to another neuron, it should also receive an identical or at least partially correlated feedback synapse from the latter neuron, thereby forming a bidirectional symmetric connection. However, experimental studies of cortical connectivity do not support the widespread prevalence of such symmetric connections, and in fact report many unidirectional connections, thus imposing a biological constraint on credit assignment. We refer to the failure of existing algorithms to satisfy this constraint as the weight symmetry problem. To address this challenge of biological constraints on connectivity, we introduce the product feedback alignment (PFA) algorithm. We demonstrate that PFA can eliminate explicit weight symmetry entirely while closely approximating BP and achieving comparable performance in deep convolutional networks. Our results offer an approach to solve the longstanding problem of credit assignment in the brain, leading to more biologically plausible learning in deep networks compared to previous methods.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 10","pages":"pgag321"},"PeriodicalIF":4.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why the mortality penalty of smoking is rising over time.","authors":"Ralph Lawton, Jennifer Beam Dowd, Jonathan Skinner, Ellen Meara","doi":"10.1093/pnasnexus/pgag280","DOIUrl":"10.1093/pnasnexus/pgag280","url":null,"abstract":"<p><p>The adverse association between smoking and mortality is well known, yet estimated risks for smokers have risen markedly in recent decades. Explanations range from physiological impacts of changes in smoking intensity to shifts in the social characteristics of smokers. However, these hypotheses have rarely been tested. Using National Health Interview Survey data linked to the National Death Index through 2018, we confirm the mortality penalty associated with smoking increased by nearly 50% from 1987-1990 to 2012-2013, controlling for age. We show that this growing gradient between smokers and nonsmokers is driven largely by changes in the age distribution of smokers. This occurs even as more recent cohorts of smokers exhibit lower education, worse health, and greater psychological distress. These findings illustrate how evolving population composition can shape estimated mortality risks for exposures such as smoking and hold implications for understanding temporal changes in other risk factors like obesity.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 9","pages":"pgag280"},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Forecasting the future of American mass shootings with Bayesian agent-based model calibration.","authors":"Andrew M Dickson, Mira Bhatt, Tiffany Yu, Mohammad R K Mofrad","doi":"10.1093/pnasnexus/pgag294","DOIUrl":"10.1093/pnasnexus/pgag294","url":null,"abstract":"<p><p>Mass shootings represent a persistent and devastating public health crisis in the United States, yet their rarity makes them difficult to model using standard statistical approaches. This is especially true for agent-based models (ABMs), which offer a mechanistic framework for understanding human behavior, but have historically struggled to capture low-probability, high-impact events in a way that is both interpretable and statistically well-calibrated. Here, we develop a high-throughput ABM that models mass shootings as arising from the intersection of three factors: the emergence of a motivated potential perpetrator, access to firearms, and the presence of a suitable target population. Through density estimation of the predicted severity of events from our ABM model, we evaluate the log-likelihood of historical US mass shooting data, enabling Bayesian posterior inference over the ABM parameters. We then apply variational Bayesian Monte Carlo (VBMC) methods to fit ABMs to historical data, while also producing predictive distributions with principled uncertainty quantification. Calibrated models are directly compared through Bayesian metrics and yield estimates of latent societal parameters, such as the baseline rate at which potential perpetrators emerge, that are grounded in a plausible generative process. We find that Federal Firearms License density is the dominant predictor of risk while population density has a positive but quickly saturating, impact. Through Widely Applicable Information Criterion evaluation of models, we find that an ABM accounting for high-lethality weapons, but assuming randomized mass-shooting targets, outperforms both naive Poisson-Weibull baselines and plausible behavioral variants. Our results demonstrate that mechanistic ABMs calibrated by VBMC can match or exceed standard statistical baselines while supporting counterfactual policy simulation.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":"5 9","pages":"pgag294"},"PeriodicalIF":4.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}