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

{"title":"Reactivation of memory-associated neurons induces downstream suppression of competing neuronal populations","authors":"Jacob F. Norman, Bahar Rahsepar, Anna Vena, Martin Thunemann, Anna Devor, Steve Ramirez, John A. White","doi":"10.1073/pnas.2410101122","DOIUrl":"https://doi.org/10.1073/pnas.2410101122","url":null,"abstract":"Inducing apparent memory recall by tagging and optogenetically reactivating cells in the hippocampus was demonstrated over a decade ago. However, the hippocampal dynamics resulting from this reactivation remain largely unknown. While calcium imaging is commonly used as a measure of neuronal activity, GCaMP, the most common calcium indicator, cannot be used with optogenetic neuronal reactivation because both require blue light excitation. To resolve this overlap, we demonstrate optogenetic reactivation with a red-shifted opsin, ChrimsonR. We then conduct dual-color calcium imaging in CA1 during memory reactivation in DG. In addition to measuring population dynamics in CA1, CA1 cells tagged during the original experience were identified. In the fear-conditioned animals (FC+), nontagged cells in CA1 decreased their firing rate during stimulation, while tagged cells maintained their activity level. In the FC+ animals, as the behavioral effect of stimulation decreased across days, so did the changes in neural activity during stimulation. Our results both demonstrate the technical feasibility of calcium imaging during optogenetic reactivation of memory-associated neurons and advance our understanding of the dynamics underlying this reactivation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"37 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757906","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":"Phenotypic changes of auditory nerve fibers after excitotoxicity","authors":"Artem Diuba, Paul Gratias, Penelope W. C. Jeffers, Régis Nouvian, Jean-Luc Puel, Sharon G. Kujawa, Jérôme Bourien","doi":"10.1073/pnas.2412332122","DOIUrl":"https://doi.org/10.1073/pnas.2412332122","url":null,"abstract":"There is a substantial body of evidence elucidating the pathophysiological aspects of excitotoxicity in the mammalian cochlea. However, the question of whether the resultant damage is reversible remains unresolved. To replicate an excitotoxic event, we investigated the long-term effects of kainate application in gerbil cochleae. Surprisingly, despite persistent synapse loss, the compound action potential of the auditory nerve fully recovered. This functional retrieval was associated with a phenotypic change in auditory nerve fibers. Thresholds were improved along the tonotopic axis. High-spontaneous rate (SR) fibers largely populated the apical region, while low-SR fibers from the basal region exhibited sound-driven activity indistinguishable from control high-SR fibers. This functional phenotype change may support the full recovery of neural response thresholds and amplitudes after excitotoxicity. Furthermore, hyperresponsiveness of the auditory nerve fibers could be a crucial factor in the development of hyperactivity in the central auditory pathways, a common occurrence following acoustic overstimulation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"74 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757899","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":"Intravital imaging of translocated bacteria via fluorogenic labeling of gut microbiota in situ","authors":"Xinqi Fan, Yingjun Zhou, Wenjuan Bai, Xue Li, Liyuan Lin, Huibin Lin, Ming Yang, Xiaofei Yu, Jing Wang, Liang Lin, Wei Wang","doi":"10.1073/pnas.2415845122","DOIUrl":"https://doi.org/10.1073/pnas.2415845122","url":null,"abstract":"The translocation of bacteria from intestinal tracts into blood vessels and distal organs plays pivotal roles in the pathogenesis of numerous severe diseases. Intravital monitoring of bacterial translocation, however, is not yet feasible, which greatly hinders us from comprehending this spatially and temporally dynamic process. Here we report an in vivo fluorogenic labeling method, which enables in situ imaging of mouse gut microbiota and real-time tracking of the translocated bacteria. By mimicking the peptidoglycan stem peptide in bacteria, a tetrapeptide probe composed of alternating D- and L-amino acids and separately equipped with a fluorophore and a quencher on the N- and C-terminal amino acid, is designed. Because of its resistance to host proteases, it can be directly used in gavage and achieves fluorogenic labeling of the microbiota in the gut via the functioning of the L,D-transpeptidases of the labeled bacteria. Using intravital two-photon microscopy, we then successfully visualize the translocation of gut bacteria into the bloodstream and liver in obesity mouse models. This technique can help further exploration into the spatiotemporal activities of gut microbiota in vivo, and be valuable in investigating the less understood pathogenicity of bacterial translocation in many severe diseases.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"58 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734308","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":"Meltdown of trust in weakly governed economies","authors":"Stephen Polasky, Marten Scheffer, John M. Anderies","doi":"10.1073/pnas.2320528122","DOIUrl":"https://doi.org/10.1073/pnas.2320528122","url":null,"abstract":"A well-functioning society requires well-functioning institutions that ensure prosperity, fair distribution of wealth, social participation, security, and informative media. Such institutions are built on a foundation of trust. However, while trust is essential for economic success and good governance, interconnected mechanisms inherent in weakly governed market economies tend to undermine the very trust on which such success depends. These mechanisms include the intrinsic tendency for inequality to grow, media to boost perceived unfairness, and self-interest to gain rewards at the expense of others. These mechanisms, if left unchecked, allow wealth concentration to result in state capture where institutions facilitate further wealth concentration instead of the promoting the common good. As a result, people may become alienated and untrusting of fellow citizens and of institutions. Several democracies now experience such dynamics, the United States being a prime example. We discuss ways in which well-functioning democracies can design institutions to help avoid this social trap, and the much harder challenge of escaping the trap once in it. Successful cases such as the ability of Scandinavian democracies to maintain high-trust, and the US progressive era in the early 20th century provide instructive examples.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"30 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734309","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":"Linear Recursive Feature Machines provably recover low-rank matrices","authors":"Adityanarayanan Radhakrishnan, Mikhail Belkin, Dmitriy Drusvyatskiy","doi":"10.1073/pnas.2411325122","DOIUrl":"https://doi.org/10.1073/pnas.2411325122","url":null,"abstract":"A fundamental problem in machine learning is to understand how neural networks make accurate predictions, while seemingly bypassing the curse of dimensionality. A possible explanation is that common training algorithms for neural networks implicitly perform dimensionality reduction—a process called feature learning. Recent work [A. Radhakrishnan, D. Beaglehole, P. Pandit, M. Belkin, <jats:italic>Science</jats:italic> 383 , 1461–1467 (2024).] posited that the effects of feature learning can be elicited from a classical statistical estimator called the average gradient outer product (AGOP). The authors proposed Recursive Feature Machines (RFMs) as an algorithm that explicitly performs feature learning by alternating between 1) reweighting the feature vectors by the AGOP and 2) learning the prediction function in the transformed space. In this work, we develop theoretical guarantees for how RFM performs dimensionality reduction by focusing on the class of overparameterized problems arising in sparse linear regression and low-rank matrix recovery. Specifically, we show that RFM restricted to linear models (lin-RFM) reduces to a variant of the well-studied Iteratively Reweighted Least Squares (IRLS) algorithm. Furthermore, our results connect feature learning in neural networks and classical sparse recovery algorithms and shed light on how neural networks recover low rank structure from data. In addition, we provide an implementation of lin-RFM that scales to matrices with millions of missing entries. Our implementation is faster than the standard IRLS algorithms since it avoids forming singular value decompositions. It also outperforms deep linear networks for sparse linear regression and low-rank matrix completion.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"100 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734304","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":"Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688","authors":"Yan Wang, Long Sun, Luciana Fernandes, Yu-Hsiu Wang, Jing Zou, Samuel J. Franklin, Yanping Hu, Lee K. Palmer, Jason Yeung, Daniela Barriga, William K. Russell, Stephanie A. Moquin, Pei-Yong Shi, Colin Skepper, Xuping Xie","doi":"10.1073/pnas.2426922122","DOIUrl":"https://doi.org/10.1073/pnas.2426922122","url":null,"abstract":"Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent panserotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts preexisting complexes in vitro and DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.","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":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734306","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":"Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase","authors":"Winda Ariyani, Chiharu Yoshikawa, Haruka Tsuneoka, Izuki Amano, Itaru Imayoshi, Hiroshi Ichinose, Chiho Sumi-Ichinose, Noriyuki Koibuchi, Tadahiro Kitamura, Daisuke Kohno","doi":"10.1073/pnas.2411069122","DOIUrl":"https://doi.org/10.1073/pnas.2411069122","url":null,"abstract":"Feeding behavior is controlled by various neural networks in the brain that are involved in different feeding phases: Food procurement, consumption, and termination. However, the specific neural circuits controlling the food consumption phase remain poorly understood. Here, we investigated the roles of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PVH) in the feeding behavior in mice. Our results indicated that the PVH dopaminergic neurons were critical for extending the food consumption phase and involved in the development of obesity through epigenetic mechanisms. These neurons synchronized with proopiomelanocortin neurons during consumption, were stimulated by proopiomelanocortin activation, and projected to the lateral habenula (LHb), where dopamine receptor D2 was involved in the increase in food consumption. In addition, upregulated tyrosine hydroxylase (TH) expression in PVH was associated with obesity and indispensable for obesity induction in mice lacking <jats:italic>Dnmt3a</jats:italic> . Taken together, our results highlight the roles of PVH dopaminergic neurons in promoting food consumption and obesity induction.","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":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734307","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":"Discovery and functional characterization of a bombesin-type neuropeptide signaling system in an invertebrate","authors":"Weiling Huang, Xingxing Zhong, Cleidiane G. Zampronio, Andrew R. Bottrill, Kite G. E. Jones, Ana B. Tinoco, Lijin Guo, Michaela Egertová, Olivier Mirabeau, Maurice R. Elphick","doi":"10.1073/pnas.2420966122","DOIUrl":"https://doi.org/10.1073/pnas.2420966122","url":null,"abstract":"Neuropeptide signaling systems are key regulators of physiological and behavioral processes in animals. However, the evolutionary history of some neuropeptides originally discovered in vertebrates is unknown. The peptide bombesin (BN) was first isolated from the skin of the toad <jats:italic>Bombina bombina</jats:italic> and subsequently BN-related neuropeptides have been identified in other chordates, including gastrin-releasing peptide (GRP) and neuromedin B (NMB) in mammals, and a GRP-like peptide in the cephalochordate <jats:italic>Branchiostoma japonicum</jats:italic> . However, BN-type neuropeptides have hitherto not been identified in any nonchordate animals. Here, we report the discovery and functional characterization of a BN-type neuropeptide signaling system in an echinoderm—the starfish <jats:italic>Asterias rubens</jats:italic> . BN-type precursor proteins were identified in several echinoderm species based on their amino acid sequences and gene structures, and the mature structure of the <jats:italic>A. rubens</jats:italic> BN-type neuropeptide ArBN was determined using mass spectrometry. A protein related to vertebrate GRP/NMB-type G protein–coupled receptors was identified experimentally as the receptor for ArBN in <jats:italic>A. rubens</jats:italic> . Analysis of the distribution of the ArBN precursor in <jats:italic>A. rubens</jats:italic> using mRNA in situ hybridization and immunohistochemistry revealed a widespread pattern of expression in the central nervous system, digestive system, and locomotory organs. Moreover, effects of ArBN in <jats:italic>A. rubens</jats:italic> included contraction and retraction of the evertible stomach and inhibition of feeding behavior. Our findings show that the evolutionary history of BN-type neuropeptide signaling can be traced back to the deuterostome common ancestor of echinoderms and chordates. Furthermore, an ancient role of BN-type neuropeptides as regulators of feeding behavior has been revealed.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"36 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734305","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 emergence of eukaryotes as an evolutionary algorithmic phase transition","authors":"Enrique M. Muro, Fernando J. Ballesteros, Bartolo Luque, Jordi Bascompte","doi":"10.1073/pnas.2422968122","DOIUrl":"https://doi.org/10.1073/pnas.2422968122","url":null,"abstract":"The origin of eukaryotes represents one of the most significant events in evolution since it allowed the posterior emergence of multicellular organisms. Yet, it remains unclear how existing regulatory mechanisms of gene activity were transformed to allow this increase in complexity. Here, we address this question by analyzing the length distribution of proteins and their corresponding genes for 6,519 species across the tree of life. We find a scale-invariant relationship between gene mean length and variance maintained across the entire evolutionary history. Using a simple model, we show that this scale-invariant relationship naturally originates through a simple multiplicative process of gene growth. During the first phase of this process, corresponding to prokaryotes, protein length follows gene growth. At the onset of the eukaryotic cell, however, mean protein length stabilizes around 500 amino acids. While genes continued growing at the same rate as before, this growth primarily involved noncoding sequences that complemented proteins in regulating gene activity. Our analysis indicates that this shift at the origin of the eukaryotic cell was due to an algorithmic phase transition equivalent to that of certain search algorithms triggered by the constraints in finding increasingly larger proteins.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723305","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":"Belief in belief: Even atheists in secular countries show intuitive preferences favoring religious belief","authors":"Will M. Gervais, Ryan T. McKay, Jazmin L. Brown-Iannuzzi, Robert M. Ross, Gordon Pennycook, Jonathan Jong, Jonathan A. Lanman","doi":"10.1073/pnas.2404720122","DOIUrl":"https://doi.org/10.1073/pnas.2404720122","url":null,"abstract":"We find evidence of <jats:italic>belief in belief</jats:italic> —intuitive preferences for religious belief over atheism, even among atheist participants—across eight comparatively secular countries. Religion is a cross-cultural human universal, yet explicit markers of religiosity have rapidly waned in large parts of the world in recent decades. We explored whether intuitive religious influence lingers, even among nonbelievers in largely secular societies. We adapted a classic experimental philosophy task to test for this intuitive belief in belief among people in eight comparatively nonreligious countries: Canada, China, Czechia, Japan, the Netherlands, Sweden, the United Kingdom, and Vietnam (total <jats:italic>N</jats:italic> = 3,804). Our analyses revealed strong evidence that 1) people intuitively favor religious belief over atheism and that 2) this pattern was not moderated by participants’ own self-reported atheism. Indeed, 3) even atheists in relatively secular societies intuitively prefer belief to atheism. These inferences were robust across different analytic strategies and across other measures of individual differences in religiosity and religious instruction. Although explicit religious belief has rapidly declined in these countries, it is possible that belief in belief may still persist. These results speak to the complex psychological and cultural dynamics of secularization.","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":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723307","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}