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

{"title":"DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden.","authors":"Jeong-Ryeol Gong, Jungeun Lee, Younghyun Han, Kwang-Hyun Cho","doi":"10.1073/pnas.2412310122","DOIUrl":"https://doi.org/10.1073/pnas.2412310122","url":null,"abstract":"<p><p>High tumor mutational burden (TMB-H) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor (ICI) therapy that indicates whether immune cells can sufficiently recognize cancer cells as nonself. However, about 30% of all cancers from The Cancer Genome Atlas (TCGA) are classified as immune-desert tumors lacking T cell infiltration despite TMB-H. Since the underlying mechanism of these immune-desert tumors has yet to be unraveled, there is a pressing need to transform such immune-desert tumors into immune-inflamed tumors and thereby enhance their responsiveness to anti-PD1 therapy. Here, we present a systems framework for identifying immuno-oncotargets, based on analysis of gene regulatory networks, and validating the effect of these targets in transforming immune-desert into immune-inflamed tumors. In particular, we identify DEAD-box helicases 54 (DDX54) as a master regulator of immune escape in immune-desert lung cancer with TMB-H and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2412310122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764656","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":"Digital phenotyping using smartphones could help steer mental health treatment.","authors":"David Adam","doi":"10.1073/pnas.2505700122","DOIUrl":"https://doi.org/10.1073/pnas.2505700122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2505700122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764661","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":"microRNA-218-5p coordinates scaling of excitatory and inhibitory synapses during homeostatic synaptic plasticity.","authors":"David Colameo, Sara M Maley, Jochen Winterer, Waleed ElGrawani, Carlotta Gilardi, Simon Galkin, Roberto Fiore, Steven A Brown, Gerhard Schratt","doi":"10.1073/pnas.2500880122","DOIUrl":"https://doi.org/10.1073/pnas.2500880122","url":null,"abstract":"<p><p>Homeostatic synaptic plasticity (HSP) is a neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of microRNA-binding sites in genes changing upon PTX-induced HSD, we bioinformatically predict and experimentally validate increased miR-218-5p activity upon PTX treatment. By electrophysiological recordings and confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: It occludes the downscaling of excitatory synapses and dendritic spines, while at the same time attenuating inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a direct miR-218-5p target which potentially mediates the effect of miR-218-5p on homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic recordings, we further reveal that local inhibition of miR-218-5p in the somatosensory cortex reduces local slow-wave activity during non-rapid-eye-movement sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with implications for pathophysiology.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2500880122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764738","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":"Reply to Brown et al.: Significant sex differences in accelerated cortical thinning associated with the COVID-19 lockdowns.","authors":"Neva M Corrigan, Ariel Rokem, Patricia K Kuhl","doi":"10.1073/pnas.2426640122","DOIUrl":"https://doi.org/10.1073/pnas.2426640122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2426640122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764753","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":"Correction to Supporting Information for Ikeda et al., Seesaw protein: Design of a protein that adopts interconvertible alternative functional conformations and its dynamics.","authors":"","doi":"10.1073/pnas.2504749122","DOIUrl":"https://doi.org/10.1073/pnas.2504749122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2504749122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736129","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":"Correction for Kuan et al., Behavioral nudges prevent loan delinquencies at scale: A 13-million-person field experiment.","authors":"","doi":"10.1073/pnas.2504666122","DOIUrl":"https://doi.org/10.1073/pnas.2504666122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2504666122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736078","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":"Quirks of cognition explain why we dramatically overestimate the size of minority groups.","authors":"Brian Guay, Tyler Marghetis, Cara Wong, David Landy","doi":"10.1073/pnas.2413064122","DOIUrl":"https://doi.org/10.1073/pnas.2413064122","url":null,"abstract":"<p><p>Americans dramatically overestimate the size of African American, Latino, Muslim, Asian, Jewish, immigrant, and LGBTQ populations, leading to concerns about downstream racial attitudes and policy preferences. Such errors are common whenever the public is asked to estimate proportions relevant to political issues, from refugee crises and polarization to climate change and COVID-19. Researchers across the social sciences interpret these errors as evidence of widespread misinformation that is topic-specific and potentially harmful. Here, we show that researchers and journalists have misinterpreted the origins and meaning of these misestimates by overlooking systematic distortions introduced by the domain-general psychological processes involved in estimating proportions under uncertainty. In general, people systematically rescale estimates of proportions toward more central prior expectations, resulting in the consistent overestimation of smaller groups and underestimation of larger groups. We formalize this process and show that it explains much of the systematic error in estimates of demographic groups ([Formula: see text] estimates from 22 countries). This domain-general account far outperforms longstanding group-specific explanations (e.g., biases toward specific groups). We find, moreover, that people make the same errors when estimating the size of racial, nonracial, and entirely nonpolitical groups, such as the proportion of Americans who have a valid passport or own a washing machine. Our results call for researchers, journalists, and pundits alike to reconsider how to interpret misperceptions about the demographic structure of society.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 14","pages":"e2413064122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754226","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":"Correction to Supporting Information for Wang et al., Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia.","authors":"","doi":"10.1073/pnas.2504173122","DOIUrl":"https://doi.org/10.1073/pnas.2504173122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 13","pages":"e2504173122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670367","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":"Social control drove ant evolution.","authors":"Timothy A Linksvayer","doi":"10.1073/pnas.2502664122","DOIUrl":"https://doi.org/10.1073/pnas.2502664122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 13","pages":"e2502664122"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701374","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":"Lung B cells in ectopic germinal centers undergo affinity maturation","authors":"Stephane M. Guillaume, William S. Foster, Isabel San Martín Molina, Emily M. Watson, Silvia Innocentin, Grant M. Kennedy, Alice E. Denton, Michelle A. Linterman","doi":"10.1073/pnas.2416855122","DOIUrl":"https://doi.org/10.1073/pnas.2416855122","url":null,"abstract":"The lungs are constantly exposed to the external environment and a myriad of antigenic challenges within the air. Chronic exposure to allergens and other airborne antigens can result in the formation of lymphocyte aggregates in the lung, which can harbor ectopic germinal centers (GCs). After allergen exposure, GCs that form in the lung are much smaller and less densely packed with B cells than lymph node GCs. Despite this, ectopic lung GCs support somatic hypermutation and affinity-based maturation as in lymph node GCs, and export memory B cells (MBCs) directly into the lung tissue. This demonstrates that the lung can locally diversify B cell responses and supports the generation of tissue MBC populations in situ.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"22 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757960","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}