Proceedings of the National Academy of Sciences of the United States of America最新文献_第8页

Prolonged signaling of backbone-modified glucagon‐like peptide‐ 1 analogues with diverse receptor trafficking

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 : 2025-04-01 DOI: 10.1073/pnas.2407574122

Brian P. Cary, Marlies V. Hager, Zamara Mariam, Rylie K. Morris, Matthew J. Belousoff, Giuseppe Deganutti, Patrick M. Sexton, Denise Wootten, Samuel H. Gellman

{"title":"Prolonged signaling of backbone-modified glucagon‐like peptide‐ 1 analogues with diverse receptor trafficking","authors":"Brian P. Cary, Marlies V. Hager, Zamara Mariam, Rylie K. Morris, Matthew J. Belousoff, Giuseppe Deganutti, Patrick M. Sexton, Denise Wootten, Samuel H. Gellman","doi":"10.1073/pnas.2407574122","DOIUrl":"https://doi.org/10.1073/pnas.2407574122","url":null,"abstract":"Signal duration and subcellular location are emerging as important facets of G protein–coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cyclic adenosine monophosphate (cAMP) upon activation by the native hormone, GLP-1. cAMP production continues after the hormone–receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from ( S , S )- trans -2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryoelectron microscopy structures of two GLP-1 analogues bound to the GLP-1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R:Gs complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profiles. Our results advance understanding of the structural underpinnings of receptor activation and introduce tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"16 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757893","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

Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice

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 : 2025-04-01 DOI: 10.1073/pnas.2420497122

Chenglei Li, Ryan C. Burdick, Rokeya Siddiqui, Sanath Kumar Janaka, Ru-ching Hsia, Wei-Shau Hu, Vinay K. Pathak

{"title":"Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice","authors":"Chenglei Li, Ryan C. Burdick, Rokeya Siddiqui, Sanath Kumar Janaka, Ru-ching Hsia, Wei-Shau Hu, Vinay K. Pathak","doi":"10.1073/pnas.2420497122","DOIUrl":"https://doi.org/10.1073/pnas.2420497122","url":null,"abstract":"Lenacapavir (GS-6207; LEN) is a potent HIV-1 capsid inhibitor approved for treating multidrug-resistant infection. LEN binds to a hydrophobic pocket between neighboring capsid (CA) proteins in hexamers and stabilizes the capsid lattice, but its effect on HIV-1 capsids is not fully understood. Here, we labeled HIV-1 capsids with green fluorescent protein fused to CA (GFP-CA) or a fluid-phase GFP content marker (cmGFP) to assess LEN’s impact on HIV-1 capsids. HIV-1 cores labeled with GFP-CA, but not cmGFP, could be immunostained with an anti-GFP antibody and were less sensitive to the capsid-binding host restriction factor MX2, demonstrating that GFP-CA is incorporated into the capsid lattice and is a marker for capsid lattice stability, whereas cmGFP is an indicator of core integrity. LEN treatment of isolated HIV-1 cores resulted in a dose-dependent loss of cmGFP signal while preserving the GFP-CA signal, indicating that LEN disrupts core integrity but stabilizes the capsid lattice. In contrast, capsid inhibitor PF-3450074 (PF74) induced loss of core integrity and the capsid lattice. Electron microscopy of LEN- or PF74-treated viral cores revealed frequent breakage at the narrow end of the capsid and other morphological changes. Our results suggest that LEN treatment does not prevent nuclear envelope docking but inhibits nuclear import of cores with or without loss of core integrity. In contrast, PF74 treatment blocks nuclear import by inhibiting the nuclear envelope docking of viral cores, highlighting their different mechanisms of nuclear import inhibition.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757907","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 cingulate cortex facilitates auditory perception under challenging listening conditions 扣带回皮层在具有挑战性的听力条件下促进听觉感知

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 : 2025-04-01 DOI: 10.1073/pnas.2412453122

Kelsey L. Anbuhl, Marielisa Diez Castro, Nikki A. Lee, Vivian S. Lee, Dan H. Sanes

{"title":"The cingulate cortex facilitates auditory perception under challenging listening conditions","authors":"Kelsey L. Anbuhl, Marielisa Diez Castro, Nikki A. Lee, Vivian S. Lee, Dan H. Sanes","doi":"10.1073/pnas.2412453122","DOIUrl":"https://doi.org/10.1073/pnas.2412453122","url":null,"abstract":"We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggests that the cingulate cortex is engaged under difficult listening conditions and may exert top–down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either “Easy” or “Hard” blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of the primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1 and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"50 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757908","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

Signaling networks in cancer stromal senescent cells establish malignant microenvironment 癌症基质衰老细胞的信号网络建立了恶性微环境

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 : 2025-04-01 DOI: 10.1073/pnas.2412818122

Yue Zhang, Teh-Wei Wang, Maho Tamatani, Xinyi Zeng, Lindo Nakamura, Satotaka Omori, Kiyoshi Yamaguchi, Seira Hatakeyama, Eigo Shimizu, Satoshi Yamazaki, Yoichi Furukawa, Seiya Imoto, Yoshikazu Johmura, Makoto Nakanishi

{"title":"Signaling networks in cancer stromal senescent cells establish malignant microenvironment","authors":"Yue Zhang, Teh-Wei Wang, Maho Tamatani, Xinyi Zeng, Lindo Nakamura, Satotaka Omori, Kiyoshi Yamaguchi, Seira Hatakeyama, Eigo Shimizu, Satoshi Yamazaki, Yoichi Furukawa, Seiya Imoto, Yoshikazu Johmura, Makoto Nakanishi","doi":"10.1073/pnas.2412818122","DOIUrl":"https://doi.org/10.1073/pnas.2412818122","url":null,"abstract":"The tumor microenvironment (TME) encompasses various cell types, blood and lymphatic vessels, and noncellular constituents like extracellular matrix (ECM) and cytokines. These intricate interactions between cellular and noncellular components contribute to the development of a malignant TME, such as immunosuppressive, desmoplastic, angiogenic conditions, and the formation of a niche for cancer stem cells, but there is limited understanding of the specific subtypes of stromal cells involved in this process. Here, we utilized p16-Cre ERT2 -tdTomato mouse models to investigate the signaling networks established by senescent cancer stromal cells, contributing to the development of a malignant TME. In pancreatic ductal adenocarcinoma (PDAC) allograft models, these senescent cells were found to promote cancer fibrosis, enhance angiogenesis, and suppress cancer immune surveillance. Notably, the selective elimination of senescent cancer stromal cells improves the malignant TME, subsequently reducing tumor progression in PDAC. This highlights the antitumor efficacy of senolytic treatment alone and its synergistic effect when combined with conventional chemotherapy. Taken together, our findings suggest that the signaling crosstalk among senescent cancer stromal cells plays a key role in the progression of PDAC and may be a promising therapeutic target.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"62 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757903","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

LMX1B missense-perturbation of regulatory element footprints disrupts serotonergic forebrain axon arborization LMX1B调控元件足迹的错义扰乱了5-羟色胺能前脑轴突的轴向化

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 : 2025-04-01 DOI: 10.1073/pnas.2411716122

Brent Eastman, Nobuko Tabuchi, Xinrui L. Zhang, William C. Spencer, Evan S. Deneris

{"title":"LMX1B missense-perturbation of regulatory element footprints disrupts serotonergic forebrain axon arborization","authors":"Brent Eastman, Nobuko Tabuchi, Xinrui L. Zhang, William C. Spencer, Evan S. Deneris","doi":"10.1073/pnas.2411716122","DOIUrl":"https://doi.org/10.1073/pnas.2411716122","url":null,"abstract":"Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitotic Pet1 neurons that give rise to mature serotonin (5-HT) neurons; over two hundred pathogenic heterozygous mutations have been discovered in human LMX1B, yet their impact on brain development has not been investigated. Here, we developed mouse models with different LMX1B DNA-binding missense mutations. Missense heterozygosity broadly altered Pet1 neuron transcriptomes, but expression changes converged on axon and synapse genes. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital genomic footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains, or no change in motif binding and accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Further, Lmx1b missense heterozygosity caused wide disruption of Lmx1b-dependent GRNs comprising diverse TFs expressed in Pet1 neurons. These findings reveal an unanticipated continuum of Lmx1b missense-forced perturbations on Pet1 neuron regulatory element TF binding and accessibility. Our work illustrates DGF’s utility for gaining unique insight into how expressed TF missense mutations interfere with developing neuronal GRNs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"38 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757905","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

Large language models for identifying social determinants of health.

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 : 2025-04-01 Epub Date: 2025-03-20 DOI: 10.1073/pnas.2501506122

Yu Wang

引用次数: 0

Reply to Wang: Improving large language model approaches for identifying social determinants of health from clinical notes.

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 : 2025-04-01 Epub Date: 2025-03-20 DOI: 10.1073/pnas.2503187122

Rodney A Gabriel

引用次数: 0

Reactivation of memory-associated neurons induces downstream suppression of competing neuronal populations 记忆相关神经元的重新激活会诱导竞争神经元群受到下游抑制

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 : 2025-04-01 DOI: 10.1073/pnas.2410101122

Jacob F. Norman, Bahar Rahsepar, Anna Vena, Martin Thunemann, Anna Devor, Steve Ramirez, John A. White

{"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}

引用次数: 0

Phenotypic changes of auditory nerve fibers after excitotoxicity 兴奋性中毒后听觉神经纤维的表型变化

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 : 2025-04-01 DOI: 10.1073/pnas.2412332122

Artem Diuba, Paul Gratias, Penelope W. C. Jeffers, Régis Nouvian, Jean-Luc Puel, Sharon G. Kujawa, Jérôme Bourien

{"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}

引用次数: 0

Intravital imaging of translocated bacteria via fluorogenic labeling of gut microbiota in situ

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 : 2025-03-28 DOI: 10.1073/pnas.2415845122

Xinqi Fan, Yingjun Zhou, Wenjuan Bai, Xue Li, Liyuan Lin, Huibin Lin, Ming Yang, Xiaofei Yu, Jing Wang, Liang Lin, Wei Wang

{"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}

引用次数: 0