Proceedings of the National Academy of Sciences of the United States of America最新文献_第5页

Modulation of host gene expression by the zinc finger antiviral protein

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-27 DOI: 10.1073/pnas.2420819122

Daniel Gonçalves-Carneiro, Emily Mastrocola, Xiao Lei, Paul D. Bieniasz

引用次数: 0

Allosteric mechanism in the distinctive coupling of G q and G s to the parathyroid hormone type 1 receptor

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2426178122

Xuan Zhang, Ji Young Lee, Jonathan Pacheco, Ieva Sutkeviciute, Anju Krishnan Anitha, Heng Liu, Stephanie Singh, Carlos Ventura, Sofya Savransky, Ashok Khatri, Cheng Zhang, Ivet Bahar, Jean-Pierre Vilardaga

{"title":"Allosteric mechanism in the distinctive coupling of G q and G s to the parathyroid hormone type 1 receptor","authors":"Xuan Zhang, Ji Young Lee, Jonathan Pacheco, Ieva Sutkeviciute, Anju Krishnan Anitha, Heng Liu, Stephanie Singh, Carlos Ventura, Sofya Savransky, Ashok Khatri, Cheng Zhang, Ivet Bahar, Jean-Pierre Vilardaga","doi":"10.1073/pnas.2426178122","DOIUrl":"https://doi.org/10.1073/pnas.2426178122","url":null,"abstract":"The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G s , we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G s or G q . Single-cell-level experiments further validate the G protein–selective effects of the PTH binding pose by demonstrating the differential, G protein–dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to G s or G q and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"10 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712807","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}

引用次数: 0

The PVD neuron has male-specific structure and mating function in Caenorhabditis elegans

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2421376122

Yael Iosilevskii, David H. Hall, Menachem Katz, Benjamin Podbilewicz

{"title":"The PVD neuron has male-specific structure and mating function in Caenorhabditis elegans","authors":"Yael Iosilevskii, David H. Hall, Menachem Katz, Benjamin Podbilewicz","doi":"10.1073/pnas.2421376122","DOIUrl":"https://doi.org/10.1073/pnas.2421376122","url":null,"abstract":"Neurons display unique shapes and establish intricate networks, which may differ between sexes. In complex organisms, studying sex differences in structure and function of individual neurons is difficult. The nematode Caenorhabditis elegans hermaphrodites and males present an exceptional model for studying neuronal morphogenesis in a simple, sexually dimorphic system. We focus on the polymodal sensory bilateral neuron pair PVD, which forms a complex but stereotypic dendritic tree composed of multiple subunits that resemble candelabra. PVD is well studied in hermaphrodites, but not in males. We show here that during larval development, male PVD extends a similar architecture to the hermaphrodite utilizing the sexually shared Menorin patterning mechanism. In early adulthood, however, male PVD develops a unique extension into the copulatory tail structure. Alongside established tail ray neurons RnA and RnB, we show PVD is a third, previously unrecognized, neuron within the tail rays. Unlike RnA and RnB, PVD extends anterogradely, branches and turns within the ray hypodermis, and is nonciliated. This PVD sexually dimorphic arborization is absent in mutant backgrounds which perturb the Menorin guidance complex. SAX-7/L1CAM, a hypodermal component of this complex, shows a male-specific expression pattern which precedes PVD extension, and its presence allows PVD to enter the tail rays. Further, our results reveal that genetically altered arborization or ablation of the PVD results in male mating behavioral defects, particularly as males turn around the hermaphrodite. These results uncover an adult-stage sexual dimorphism of dendritic branching and a function for PVD in male sexual behavior.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"99 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712806","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}

引用次数: 0

In situ cavitation bubble manometry reveals a lack of light-activated guard cell turgor modulation in bryophytes

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2419887122

Craig R. Brodersen, Tim J. Brodribb, Uri Hochberg, N. Michele Holbrook, Scott A. M. McAdam, Joseph Zailaa, Brett A. Huggett, Philippe Marmottant

{"title":"In situ cavitation bubble manometry reveals a lack of light-activated guard cell turgor modulation in bryophytes","authors":"Craig R. Brodersen, Tim J. Brodribb, Uri Hochberg, N. Michele Holbrook, Scott A. M. McAdam, Joseph Zailaa, Brett A. Huggett, Philippe Marmottant","doi":"10.1073/pnas.2419887122","DOIUrl":"https://doi.org/10.1073/pnas.2419887122","url":null,"abstract":"Diversification of plant hydraulic architecture and stomatal function coincides with radical changes in the Earth’s atmosphere over the past 400 my. Due to shared stomatal anatomy with the earliest land plants, bryophyte stomatal behavior may provide insights into the evolution of stomatal function, but significant uncertainty remains due to technical limitations of measuring guard cell turgor pressure in situ. Here, we introduce a method for monitoring cell turgor pressure by nucleating microbubbles within the guard cells of intact plant tissue and then examining microbubble growth and dissolution dynamics. First, we show that maximum microbubble radius decreases with increasing pressure as the pressure of the surrounding fluid constrains its growth according to a modified version of the Epstein–Plesset equation. We then apply this method to monitor turgor pressure in dark- vs. light-acclimated guard cells across bryophyte taxa with stomata, where their role in gas-exchange remains ambiguous, and in vascular plants with well-documented light-dependent turgor modulation. Our findings show no light-activated change in turgor in bryophyte guard cells, with pressures not significantly different than neighboring epidermal cells. In contrast, vascular plants show distinct pressure modulation in response to light that drives reversible changes in stomatal aperture. Complete guard cell turgor loss had no effect on bryophyte stomatal aperture but resulted in partial or complete closure in vascular plants. These results suggest that despite conserved stomatal morphology, the sampled bryophytes lack dynamic control over guard cell turgor that is critical for sustaining photosynthesis and inhibiting desiccation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"33 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712802","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}

引用次数: 0

Bridging the human–AI knowledge gap through concept discovery and transfer in AlphaZero

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2406675122

Lisa Schut, Nenad Tomašev, Thomas McGrath, Demis Hassabis, Ulrich Paquet, Been Kim

{"title":"Bridging the human–AI knowledge gap through concept discovery and transfer in AlphaZero","authors":"Lisa Schut, Nenad Tomašev, Thomas McGrath, Demis Hassabis, Ulrich Paquet, Been Kim","doi":"10.1073/pnas.2406675122","DOIUrl":"https://doi.org/10.1073/pnas.2406675122","url":null,"abstract":"AI systems have attained superhuman performance across various domains. If the hidden knowledge encoded in these highly capable systems can be leveraged, human knowledge and performance can be advanced. Yet, this internal knowledge is difficult to extract. Due to the vast space of possible internal representations, searching for meaningful new conceptual knowledge can be like finding a needle in a haystack. Here, we introduce a method that extracts new chess concepts from AlphaZero, an AI system that mastered chess via self-play without human supervision. Our method excavates vectors that represent concepts from AlphaZero’s internal representations using convex optimization, and filters the concepts based on teachability (whether the concept is transferable to another AI agent) and novelty (whether the concept contains information not present in human chess games). These steps ensure that the discovered concepts are useful and meaningful. For the resulting set of concepts, prototypes (chess puzzle–solution pairs) are presented to experts for final validation. In a preliminary human study, four top chess grandmasters (all former or current world chess champions) were evaluated on their ability to solve concept prototype positions. All grandmasters showed improvement after the learning phase, suggesting that the concepts are at the frontier of human understanding. Despite the small scale, our result is a proof of concept demonstrating the possibility of leveraging knowledge from a highly capable AI system to advance the frontier of human knowledge; a development that could bear profound implications and shape how we interact with AI systems across many applications.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712801","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}

引用次数: 0

Actuating superparamagnetic nanoparticle monolayers

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2424073122

Edward P. Esposito, Hector Manuel Lopez Rios, Monica Olvera de la Cruz, Heinrich M. Jaeger

{"title":"Actuating superparamagnetic nanoparticle monolayers","authors":"Edward P. Esposito, Hector Manuel Lopez Rios, Monica Olvera de la Cruz, Heinrich M. Jaeger","doi":"10.1073/pnas.2424073122","DOIUrl":"https://doi.org/10.1073/pnas.2424073122","url":null,"abstract":"Magnetically responsive, mechanically flexible microstructures are desirable for applications ranging from smart sensors to remote-controlled actuation for surgery or robotics. Embedding magnetic nanoparticles into a thin matrix of elastic material enables high flexibility while exploiting the magnetic response of the individual particles. However, in the ultrathin limit of such nanocomposite materials, the particles become too small to sustain a permanent dipole moment. This implies that now large magnetic field gradients are required for actuation, which are difficult to achieve with externally applied fields. Here, we demonstrate through experiment and simulation that monolayer sheets of close-packed paramagnetic nanoparticles in a uniform applied field can generate large local field gradients through particle interactions. As a result, a strong collective magnetization is obtained that leads to large deflections of freestanding sheets already in moderate applied fields. Exploiting the vector nature of the applied field, we furthermore find that it is possible to induce more complex curvature and twist the sheets. Finally, we show that paramagnetic nanoparticle monolayers applied as coatings can generate sufficient force to deflect strips of nonmagnetic material that is several orders of magnitude thicker.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712805","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}

引用次数: 0

An atlas of protein phosphorylation dynamics during interferon signaling

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2412990122

Idoia Busnadiego, Marie Lork, Sonja Fernbach, Samira Schiefer, Nikos Tsolakos, Benjamin G. Hale

{"title":"An atlas of protein phosphorylation dynamics during interferon signaling","authors":"Idoia Busnadiego, Marie Lork, Sonja Fernbach, Samira Schiefer, Nikos Tsolakos, Benjamin G. Hale","doi":"10.1073/pnas.2412990122","DOIUrl":"https://doi.org/10.1073/pnas.2412990122","url":null,"abstract":"Interferons (IFNs, types I-III) have pleiotropic functions in promoting antiviral and antitumor responses, as well as in modulating inflammation. Dissecting the signaling mechanisms elicited by different IFNs is therefore critical to understand their phenotypes. Here, we use mass spectrometry to investigate the early temporal dynamics of cellular protein phosphorylation in a human lung epithelial cell-line as it responds to stimulation with IFNα2, IFNβ, IFNω, IFNγ, or IFNλ1, representing all IFN types. We report an atlas of over 700 common or unique phosphorylation events reprogrammed by these different IFNs, revealing both previously known and uncharacterized modifications. While the proteins differentially phosphorylated following IFN stimulation have diverse roles, there is an enrichment of factors involved in chromatin remodeling, transcription, and RNA splicing. Functional screening and mechanistic studies identify that several proteins modified in response to IFNs contribute to host antiviral responses, either directly or by supporting IFN-stimulated gene or protein production. Among these, phosphorylation of PLEKHG3 at serine-1081 creates a phospho-regulated binding motif for the docking of 14-3-3 proteins, and together these factors contribute to coordinating efficient IFN-stimulated gene expression independent of early Janus kinase/signal transducer and activator of transcription signaling. Our findings map the global phosphorylation landscapes regulated by IFN types I, II, and III, and provide a key resource to explore their functional consequences.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"212 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712803","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}

引用次数: 0

Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier K + current: Implications for Andersen–Tawil syndrome

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2418021122

Nathaniel Elia, Marbella Quiñonez, Fenfen Wu, Ekaterina Mokhonova, Marino DiFranco, Melissa J. Spencer, Stephen C. Cannon

{"title":"Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier K + current: Implications for Andersen–Tawil syndrome","authors":"Nathaniel Elia, Marbella Quiñonez, Fenfen Wu, Ekaterina Mokhonova, Marino DiFranco, Melissa J. Spencer, Stephen C. Cannon","doi":"10.1073/pnas.2418021122","DOIUrl":"https://doi.org/10.1073/pnas.2418021122","url":null,"abstract":"Andersen–Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations of KCNJ2 encoding the Kir2.1 potassium channel subunit are found in 60% of ATS families. As with most channelopathies, episodic attacks in ATS are frequently triggered by environmental stresses: exercise for periodic paralysis or stress with adrenergic stimulation for arrhythmia. Fluctuations in K + , either low or high, are potent triggers for attacks of weakness in other variants of periodic paralysis (hypokalemic periodic paralysis or hyperkalemic periodic paralysis). For ATS, the [K + ] dependence is less clear; with reports describing weakness in high-K + or low-K + . Patient trials with controlled K + challenges are not possible, due to arrhythmias. We have developed two mouse models (genetic and pharmacologic) with reduced Kir currents, to address the question of K + -sensitive loss of force. These animal models and computational simulations both show K + -dependent weakness occurs only when Kir current is <30% of wildtype. As the Kir deficit becomes more severe, the phenotype shifts from high-K + -induced weakness to a combination where either high-K + or low-K + triggers weakness. A K + channel agonist, retigabine, protects muscle from K + -sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"72 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712804","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}

引用次数: 0

Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-26 DOI: 10.1073/pnas.2423776122

Andrey Damianov, Chia-Ho Lin, Jian Zhang, James L. Manley, Douglas L. Black

{"title":"Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing","authors":"Andrey Damianov, Chia-Ho Lin, Jian Zhang, James L. Manley, Douglas L. Black","doi":"10.1073/pnas.2423776122","DOIUrl":"https://doi.org/10.1073/pnas.2423776122","url":null,"abstract":"Myelodysplastic syndromes and other cancers are often associated with mutations in the U2 snRNP protein SF3B1. Common SF3B1 mutations, including K700E, disrupt SF3B1 interaction with the protein SUGP1 and induce aberrant activation of alternative 3′ splice sites (ss), presumably resulting from aberrant U2/branch site (BS) recognition by the mutant spliceosome. Here, we apply a method of U2 IP-seq to profile BS binding across the transcriptome of K562 leukemia cells carrying the SF3B1 K700E mutation. For alternative 3′ ss activated by K700E, we identify their associated BSs and show that they are indeed shifted from the WT sites. Unexpectedly, we also identify thousands of additional changes in BS binding in the mutant cells that do not alter splicing. These new BSs are usually very close to the natural sites, occur upstream or downstream, and either exhibit stronger base-pairing potential with U2 snRNA or are adjacent to stronger polypyrimidine tracts than the WT sites. The widespread imprecision in BS recognition induced by K700E with limited changes in 3′ ss selection expands the physiological consequences of this oncogenic mutation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"183 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712799","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}

引用次数: 0

Reply to Fiscella: Why study erosion now? And why these risk factors?

IF 9.4 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-03-25 Epub Date: 2025-03-13 DOI: 10.1073/pnas.2501249122

Eli G Rau, Susan C Stokes

引用次数: 0