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

{"title":"LACE-UP: An ensemble machine-learning method for health subtype classification on multidimensional binary data","authors":"Rebecca Danning, Frank B. Hu, Xihong Lin","doi":"10.1073/pnas.2423341122","DOIUrl":"https://doi.org/10.1073/pnas.2423341122","url":null,"abstract":"Disease and behavior subtype identification is of significant interest in biomedical research. However, in many settings, subtype discovery is limited by a lack of robust statistical clustering methods appropriate for binary data. Here, we introduce LACE-UP [latent class analysis ensembled with UMAP (uniform manifold approximation and projection) and PCA (principal components analysis)], an ensemble machine-learning method for clustering multidimensional binary data that does not require prespecifying the number of clusters and is robust to realistic data settings, such as the correlation of variables observed from the same individual and the inclusion of variables unrelated to the underlying subtype. The method ensembles latent class analysis, a model-based clustering method; principal components analysis, a spectral signal processing method; and UMAP, a cutting-edge model-free dimensionality reduction algorithm. In simulations, LACE-UP outperforms gold-standard techniques across a variety of realistic scenarios, including in the presence of correlated and extraneous data. We apply LACE-UP to dietary behavior data from the UK Biobank to demonstrate its power to uncover interpretable dietary subtypes that are associated with lipids and cardiovascular risk.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"24 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866873","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 simple method for mapping the location of cross-β-forming regions within protein domains of low sequence complexity","authors":"Jinge Gu, Xiaoming Zhou, Lillian Sutherland, Glen Liszczak, Steven L. McKnight","doi":"10.1073/pnas.2503382122","DOIUrl":"https://doi.org/10.1073/pnas.2503382122","url":null,"abstract":"Protein domains of low sequence complexity are unable to fold into stable, three-dimensional structures. In test tube studies, these unusual polypeptide regions can self-associate in a manner causing phase separation from aqueous solution. This form of protein:protein interaction has been implicated in numerous examples of dynamic morphological organization within eukaryotic cells. In several cases, the basis for low complexity domain (LCD) self-association and phase separation has been traced to the formation of labile cross-β structures. The primary energetic force favoring formation of these transient and reversible structures is enabled by polypeptide backbone interactions. Short, contiguous networks of peptide backbone amino groups and carbonyl oxygens are zippered together intermolecularly by hydrogen bonding as described by Linus Pauling seven decades ago. Here, we describe a simple, molecular biological method useful for the identification of localized, self-associating regions within larger protein domains of low sequence complexity.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"71 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866876","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":"Mixing individual and collective behaviors to predict out-of-routine mobility","authors":"Sebastiano Bontorin, Simone Centellegher, Riccardo Gallotti, Luca Pappalardo, Bruno Lepri, Massimiliano Luca","doi":"10.1073/pnas.2414848122","DOIUrl":"https://doi.org/10.1073/pnas.2414848122","url":null,"abstract":"Predicting human displacements is crucial for addressing various societal challenges, including urban design, traffic congestion, epidemic management, and migration dynamics. While predictive models like deep learning and Markov models offer insights into individual mobility, they often struggle with out-of-routine behaviors. Our study introduces an approach that dynamically integrates individual and collective mobility behaviors, leveraging collective intelligence to enhance prediction accuracy. Evaluating the model on millions of privacy-preserving trajectories across five US cities, we demonstrate its superior performance in predicting out-of-routine mobility, surpassing even advanced deep learning methods. The spatial analysis highlights the model’s effectiveness near urban areas with a high density of points of interest, where collective behaviors strongly influence mobility. During disruptive events like the COVID-19 pandemic, our model retains predictive capabilities, unlike individual-based models. By bridging the gap between individual and collective behaviors, our approach offers transparent and accurate predictions, which are crucial for addressing contemporary mobility challenges.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"48 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866924","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":"Elevated UDP-glucuronic acid levels mend drug resistance and stress responses via a protease and a transporter in Cryptococcus gattii","authors":"Sujiraphong Pharkjaksu, Hongyi Cai, Peter J. Walter, Yun C. Chang, Kyung J. Kwon-Chung","doi":"10.1073/pnas.2503960122","DOIUrl":"https://doi.org/10.1073/pnas.2503960122","url":null,"abstract":"UDP-glucuronic acid (UDP-GlcUA) is a nucleotide sugar essential for various biological processes in many organisms, and its excess within the cell can disrupt cellular functions. In <jats:italic>Cryptococcus</jats:italic> , mutations in the <jats:italic>UXS1</jats:italic> gene which encodes an enzyme responsible for converting UDP-GlcUA into UDP-xylose, result in excessive accumulation of UDP-GlcUA and confer resistance to the antifungal drug 5-fluorocytosine. Here, we demonstrate that elevation of UDP-GlcUA affects several cellular processes in <jats:italic>Cryptococcus gattii</jats:italic> , including growth rate, ability to grow under various stress conditions and resistance to fluorinated pyrimidine analogs. RNA-seq analyses of the <jats:italic>uxs1Δ</jats:italic> mutant identify three acid protease genes, notably <jats:italic>PEP401</jats:italic> , that are differentially expressed. The absence of <jats:italic>PEP401</jats:italic> in the <jats:italic>uxs1Δ</jats:italic> background significantly reduces UDP-GlcUA levels and reverts all the phenotypes of the <jats:italic>uxs1Δ</jats:italic> mutant to the wild-type characteristics. High levels of UDP-GlcUA not only regulate expression of <jats:italic>PEP401</jats:italic> at RNA and protein levels but also enhance the proteolytic activity of total protein extracts in a <jats:italic>PEP401</jats:italic> -dependent manner, establishing a functional link between nucleotide sugar metabolism and proteolytic regulation. Moreover, the UDP-GlcUA transporter gene, <jats:italic>UUT1</jats:italic> , can further modulate the levels of UDP-GlcUA in the <jats:italic>uxs1Δ pep401Δ</jats:italic> double mutant and manifests drug resistance phenotypes observed in the <jats:italic>uxs1Δ</jats:italic> mutant. Collectively, these findings reveal a previously unrecognized regulatory network that links UDP-GlcUA metabolism to protease-mediated cellular processes and the transport of UDP-GlcUA. This interaction provides a foundation for targeting nucleotide sugar metabolism and protease regulation in the development of enhanced therapeutic strategies against cryptococcosis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"54 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866875","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":"Ligand-binding pockets in RNA and where to find them","authors":"Seth D. Veenbaas, Jordan T. Koehn, Patrick S. Irving, Nicole N. Lama, Kevin M. Weeks","doi":"10.1073/pnas.2422346122","DOIUrl":"https://doi.org/10.1073/pnas.2422346122","url":null,"abstract":"RNAs are critical regulators of gene expression, and their functions are often mediated by complex secondary and tertiary structures. Structured regions in RNA can selectively interact with small molecules—via well-defined ligand-binding pockets—to modulate the regulatory repertoire of an RNA. The broad potential to modulate biological function intentionally via RNA–ligand interactions remains unrealized, however, due to challenges in identifying compact RNA motifs with the ability to bind ligands with good physicochemical properties (often termed drug-like). Here, we devise <jats:italic>fpocketR</jats:italic> , a computational strategy that accurately detects pockets capable of binding drug-like ligands in RNA structures. Remarkably few, roughly 50, of such pockets have ever been visualized. We experimentally confirmed the ligandability of novel pockets detected with <jats:italic>fpocketR</jats:italic> using a fragment-based approach introduced here, Frag-MaP, that detects ligand-binding sites in cells. Analysis of pockets detected by <jats:italic>fpocketR</jats:italic> and validated by Frag-MaP reveals dozens of sites able to bind drug-like ligands, supports a model for RNA secondary structural motifs able to bind quality ligands, and creates a broad framework for understanding the RNA ligand-ome.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"5 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863073","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":"40 Hz sensory stimulation enhances CA3–CA1 coordination and prospective coding during navigation in a mouse model of Alzheimer’s disease","authors":"Abigail L. Paulson, Lu Zhang, Ashley M. Prichard, Annabelle C. Singer","doi":"10.1073/pnas.2419364122","DOIUrl":"https://doi.org/10.1073/pnas.2419364122","url":null,"abstract":"40 Hz sensory stimulation (“flicker”) has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimer’s disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1,000s of neurons during a goal-directed spatial navigation task. We find that an hour of daily exposure to 40 Hz audio-visual stimulation over 8 d leads to higher coordination between hippocampal subregions CA3 and CA1 during navigation. Consistent with CA3’s role in generating sequential activity that represents future positions, 40 Hz flicker exposure increased prospective coding of future positions. In turn, prospective coding was more prominent during efficient navigation behavior. Our findings show how 40 Hz flicker enhances key hippocampal activity during behavior that is important for memory.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863060","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":"Reducing the effects of radiation damage in cryo-EM using liquid helium temperatures","authors":"Joshua L. Dickerson, Katerina Naydenova, Mathew J. Peet, Hugh Wilson, Biplob Nandy, Greg McMullan, Robert Morrison, Christopher J. Russo","doi":"10.1073/pnas.2421538122","DOIUrl":"https://doi.org/10.1073/pnas.2421538122","url":null,"abstract":"The physical limit in determining the atomic structure of biological molecules is radiation damage. In electron cryomicroscopy, there have been numerous attempts to reduce the effects of radiation damage by cooling the specimen beyond liquid-nitrogen temperatures, yet all failed to realize the potential improvement for single-particle structure determination. We have identified the physical causes of information loss at liquid-helium temperatures, and overcome them using a combination of nanoscale electron beam illumination and a gold specimen support with 100 nm diameter holes. This combination allowed structure determination where every frame in the exposure contained more information than was available with cryomicroscopy at liquid-nitrogen temperatures, matching expectations from crystal diffraction. Since a 100 nm hole is smaller than the field of view of a typical micrograph, the edges of the foil are directly visible in each micrograph. Protein molecules that are degraded tend to aggregate at the edges of foil holes and can constitute a significant fraction of the micrograph. This and the need for minimal water-foil irradiation will both be important to consider as new cryomicroscopes and specimen supports are developed for imaging molecules at extremely low temperatures where the effects of radiation damage are reduced.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863059","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":"Extreme weather variability on hot rocky exoplanet 55 Cancri e explained by magma temperature–cloud feedback","authors":"Kaitlyn Loftus, Yangcheng Luo, Bowen Fan, Edwin S. Kite","doi":"10.1073/pnas.2423473122","DOIUrl":"https://doi.org/10.1073/pnas.2423473122","url":null,"abstract":"Observations of the hot rocky exoplanet 55 Cancri e report significant but unexplained variability in brightness across visible and infrared bands, e.g., on subweekly timescales, its mid-infrared brightness temperature fluctuates by approximately 1,400 K (with hundreds of Kelvin uncertainty). We propose a magma temperature–cloud feedback as a potential explanation that relies on the planet’s atmosphere and surface. In this feedback, under cloud-free conditions, stellar radiation heats surface magma, releasing silicate vapor that condenses into clouds. Once formed, these clouds attenuate stellar insolation, thereby cooling the surface, reducing vapor supply, and decreasing cloudiness. A time lag between surface temperature increase and cloud formation, likely due to lagged atmospheric transport of cloud-forming vapor, enables self-sustained oscillations in surface temperature and cloudiness. These oscillations manifest as variations in both the planet’s thermal emission and reflected starlight, causing variability in secondary eclipse depths across wavelengths without significantly affecting the transit depth. Using a simple model, we find that diverse planetary parameters can reproduce the observed infrared brightness variability. We also demonstrate that brightness at different wavelengths can oscillate out of phase, consistent with recent observations by the James Webb Space Telescope. Additionally, we propose that time-varying and spatially nonuniform cloud cover can result in changing amplitude and phase offset of the planet’s phase curve, potentially explaining observations. Finally, we discuss observational strategies to test this proposed mechanism on 55 Cancri e. If confirmed, these observable ocean–atmosphere dynamics on exoplanets would provide valuable insights into the composition, evolution, and long-term fate of rocky planet volatiles.","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":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863072","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":"Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation","authors":"Nicole M. Fisher, Mark von Zastrow","doi":"10.1073/pnas.2420623122","DOIUrl":"https://doi.org/10.1073/pnas.2420623122","url":null,"abstract":"Many GPCRs initiate a second phase of G protein-mediated signaling from endosomes. This inherently requires the GPCR to increase cognate G protein activity on the endosome surface. G <jats:sub>s</jats:sub> -coupled GPCRs are thought to achieve this by internalizing and mediating a second round of allosteric coupling to G proteins on the endosome membrane. Here, we provide evidence that the μ-opioid receptor (MOR), a G <jats:sub>i</jats:sub> -coupled GPCR, is able to increase endosomal G protein activity in a different way. Leveraging conformational biosensors, we show that MOR activation triggers a transient increase of active-state G <jats:sub>i/o</jats:sub> on the plasma membrane that is followed by a prolonged increase on endosomes. Contrary to the G <jats:sub>s</jats:sub> -coupled GPCR paradigm, however, we show that the MOR-induced increase of active-state G <jats:sub>i/o</jats:sub> on endosomes requires neither internalization of MOR nor the presence of activated MOR in the endosome membrane. We propose a distinct and additional cellular mechanism of endosomal signaling by G <jats:sub>i/o</jats:sub> that is communicated through trafficking of the activated G protein rather than its activating GPCR.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"13 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863055","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":"Phospholipid flippase ATP11A brokers uterine epithelial integrity and function","authors":"Alexa Krala, Aleksandra O. Tsolova, Bethany N. Radford, Anshul S. Jadli, Xiang Zhao, Danielle Blackwell, Ankita Narang, Wendy Dean, Myriam Hemberger","doi":"10.1073/pnas.2420617122","DOIUrl":"https://doi.org/10.1073/pnas.2420617122","url":null,"abstract":"Uterine adaptations driven by the steroid hormones estrogen and progesterone are pivotal for embryo implantation and, ultimately, for a successful pregnancy. Here, we show in mice that genetic ablation of the membrane lipid flippase <jats:italic>Atp11a</jats:italic> causes severe deficits in this hormonal response and profound defects in the morphological organization and transcriptional profile of the uterine epithelial compartment where <jats:italic>Atp11a</jats:italic> is expressed. <jats:italic>Atp11a</jats:italic> -null uterine epithelial cells lack tight junctions, and the luminal epithelium exhibits profound disruptions to cellular morphology. Interestingly, the specification of luminal epithelial cells remains incomplete as they maintain expression of the normally gland-restricted marker FOXA2. The uterine glands of <jats:italic>Atp11a</jats:italic> -null females are depleted for progenitor cells marked by SOX9, PAX8, LGR5, and PROM1. Collectively, these findings point to a uterine receptivity deficit that underpins the frequent failure of <jats:italic>Atp11a</jats:italic> -depleted females to establish a successful pregnancy. Most intriguingly, however, loss of only a single functional <jats:italic>Atp11a</jats:italic> allele causes a higher frequency of abnormal placental trophoblast differentiation as well as a higher incidence of developmental heart defects in wild-type embryos. These data emphasize the far-reaching impact of uterine dysfunction on reproductive outcome and highlight the importance of the maternal genotype in the etiology of developmental disorders.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"108 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863076","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}