Proceedings of the National Academy of Sciences of the United States of America最新文献_第2页

Specialized molecular pathways drive the formation of light-scattering assemblies in leucophores. 特殊的分子途径驱动光散射组件在白垩质的形成。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2424979122

Yuval Barzilay, Zohar Eyal, Yael Noy, Neta Varsano, Tsviya Olender, Sourabh Bera, Tali Lerer-Goldshtein, Merav Kedmi, Ziv Porat, Iddo Pinkas, Smadar Levin-Zaidman, Nili Dezorella, Dvir Gur

{"title":"Specialized molecular pathways drive the formation of light-scattering assemblies in leucophores.","authors":"Yuval Barzilay, Zohar Eyal, Yael Noy, Neta Varsano, Tsviya Olender, Sourabh Bera, Tali Lerer-Goldshtein, Merav Kedmi, Ziv Porat, Iddo Pinkas, Smadar Levin-Zaidman, Nili Dezorella, Dvir Gur","doi":"10.1073/pnas.2424979122","DOIUrl":"https://doi.org/10.1073/pnas.2424979122","url":null,"abstract":"Pigmentation plays a vital role in the survival of organisms, supporting functions such as camouflage, communication, and mate attraction. In vertebrates, these functions are mediated by specialized pigment cells known as chromatophores of which, uric acid crystal-forming leucophores remain the least understood, with little known about their molecular mechanisms. A key question in pigment cell biology is whether different crystal chemistries require distinct molecular pathways, or whether similar cellular processes drive the formation of diverse crystals. This study was designed to unravel the uncharacterized process of uric acid crystallization in leucophores and compare them to guanine crystal formation in iridophores and pterin formation in xanthophores. The results of our transcriptomic, ultrastructural, and metabolomic analyses, demonstrate that leucophores share molecular pathways with iridophores, particularly those connected to organelle organization and purine metabolism, but express discrete genes involved in uric acid biosynthesis and storage. Additionally, leucophores share intracellular trafficking and pterin biosynthesis genes with xanthophores, suggesting universally conserved processes. Ultrastructural studies reveal star-like fibrous structures in leucosomes, which likely serve as scaffolds for unique one-dimensional uric acid assemblies that radiate from the core and act as efficient light scatterers. These findings provide insights into leucophore cell biology and the specialized mechanisms driving molecular crystalline assembly, and reveal that while some cellular processes are conserved, the specific chemistry of each crystal type drives the evolution of distinct molecular pathways.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 22","pages":"e2424979122"},"PeriodicalIF":9.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161706","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

Host complement C3 promotes malaria transmission by killing symbiotic bacteria in the mosquito midgut. 宿主补体C3通过杀死蚊子中肠中的共生细菌促进疟疾传播。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2424570122

Biao He, Meilin Li, Shuai Guo, Feng Zhu, Zhiwei Jiao, Jianyong Li, Nie Tan, Shiming Jiao, Taiping Liu, Jian Zhang, Yongling Fan, Yuanli Gao, Taoli Zhou, Jian Li, Wei Huang, Lubin Jiang, Zurui Lin, Sibao Wang, Wenyue Xu

{"title":"Host complement C3 promotes malaria transmission by killing symbiotic bacteria in the mosquito midgut.","authors":"Biao He, Meilin Li, Shuai Guo, Feng Zhu, Zhiwei Jiao, Jianyong Li, Nie Tan, Shiming Jiao, Taiping Liu, Jian Zhang, Yongling Fan, Yuanli Gao, Taoli Zhou, Jian Li, Wei Huang, Lubin Jiang, Zurui Lin, Sibao Wang, Wenyue Xu","doi":"10.1073/pnas.2424570122","DOIUrl":"https://doi.org/10.1073/pnas.2424570122","url":null,"abstract":"Host-derived factors ingested during mosquito blood feeding are poorly understood modulators of malaria transmission. Here, we demonstrated that host complement C3, acquired by mosquitoes during Plasmodium infection, significantly enhanced rodent malaria infection in laboratory-reared mosquitoes. This effect was recapitulated in field-caught Anopheles sinensis mosquitoes, confirming its relevance to malaria transmission in a more natural setting. Moreover, host-derived C3 significantly reduced the efficacy of anti-Pfs25 antibodies in blocking malaria transmission. Mechanistically, host-derived C3 lyses the mosquito midgut symbiont Elizabethkingia anophelis (E. anophelis)-a bacterium that intrinsically suppresses parasite development by blocking the zygote-to-ookinete transition. Strikingly, host-derived C3 in mosquitoes appears to be activated by the alternative pathway, and inhibiting Factor B with Iptacopan (LNP023) reduced Plasmodium falciparum (P. falciparum) infection, while increased the efficacy of anti-Pfs25 antibodies to blocking P. falciparum transmission in the standard membrane-feeding assay. Therefore, this study describes a strategy of the malaria parasite to utilize host complement C3 to promote its transmission and provides us with an avenue to block malaria transmission and improve the blocking efficacy of anti-Pfs25 antibodies by the inhibition of C3 activation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 22","pages":"e2424570122"},"PeriodicalIF":9.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161747","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

Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments. 微管抽吸显示核仁亚室不同的rna依赖粘弹性。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2407423122

Holly H Cheng, James V Roggeveen, Huan Wang, Howard A Stone, Zheng Shi, Clifford P Brangwynne

{"title":"Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments.","authors":"Holly H Cheng, James V Roggeveen, Huan Wang, Howard A Stone, Zheng Shi, Clifford P Brangwynne","doi":"10.1073/pnas.2407423122","DOIUrl":"https://doi.org/10.1073/pnas.2407423122","url":null,"abstract":"The nucleolus is a multiphasic biomolecular condensate that facilitates ribosome biogenesis, a complex process involving hundreds of proteins and RNAs. The proper execution of ribosome biogenesis likely depends on the material properties of the nucleolus. However, these material properties remain poorly understood due to the challenges of in vivo measurements. Here, we use micropipette aspiration (MPA) to directly characterize the viscoelasticity and interfacial tensions of nucleoli within transcriptionally active Xenopus laevis oocytes. We examine the major nucleolar subphases, the outer granular component (GC) and the inner dense fibrillar component (DFC), which itself contains a third small phase known as the fibrillar center (FC). We show that the behavior of the GC is more liquid-like, while the behavior of the DFC/FC is consistent with that of a partially viscoelastic solid. To determine the role of ribosomal RNA in nucleolar material properties, we degrade RNA using RNase A, which causes the DFC/FC to become more fluid-like and alters interfacial tension. Together, our findings suggest that RNA underlies the partially solid-like properties of the DFC/FC and provide insights into how material properties of nucleoli in a near-native environment are related to their RNA-dependent function.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 22","pages":"e2407423122"},"PeriodicalIF":9.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161768","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 Siqueira-Batista and Gómez: Underscoring the importance of biosafety for the return of Martian samples. 回复Siqueira-Batista和Gómez：强调生物安全对火星样本返回的重要性。

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 : 2025-06-03 Epub Date: 2025-05-27 DOI: 10.1073/pnas.2508447122

Charles W Whetsel, Joel S Levine, Stephen J Hoffman, Erik L Antonsen

引用次数: 0

An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of Syk-receptor association. 具有强连通性的静电网络是一种调节syk受体关联亲和力的磷酸化传感器。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2421663122

Duy P Hua, Jacob J Kinnun, Carol Beth Post

{"title":"An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of Syk-receptor association.","authors":"Duy P Hua, Jacob J Kinnun, Carol Beth Post","doi":"10.1073/pnas.2421663122","DOIUrl":"https://doi.org/10.1073/pnas.2421663122","url":null,"abstract":"Spleen tyrosine kinase (Syk) mediates early signaling events in immunity by coupling membrane receptors to immune responses. Syk comprises a tandem SH2 (tSH2) regulatory module-two SH2 domains connected by a structured linker-and a kinase domain. The association of tSH2 with a doubly tyrosine-phosphorylated motif (dpITAM) on membrane immunoreceptors is central to controlling Syk's signaling activity. tSH2-dpITAM association is regulated by Y131-phosphorylation on linker A, distant from the Syk-immunoreceptor binding sites. A unique thermodynamic signature was reported to control this protein-protein interaction by phosphorylation, yet the molecular mechanism for the phosphorylation effect is unknown. Molecular dynamics (MD) simulation affords the detail needed to fill this knowledge deficiency. Long MD simulations revealed a highly correlated interdomain electrostatic network (distance correlation coefficients > 0.75) that is lost upon Y131-phosphorylation. Some of the strongly correlated interdomain pairs carry the same charge or are separated by distances greater than a salt-bridge pair. The strong interdomain connectivity accounts for the single, narrow free energy basin in the domain-structure conformational landscape for unphosphorylated tSH2. Linker phosphorylation disrupts this network and yields a broader free energy landscape with multiple networks formed by the same group of residues adopting alternative interdomain conformations. A salt dependence of NMR rotational tumbling times substantiates the electrostatic nature of tSH2 domain-domain coupling. Syk tandem SH2 is thus a sensor whose conformational plasticity is sensitive to Y131 phosphorylation. This phospho-sensing response provides the basis for an entropically driven regulatory mechanism that is so-far unique to Syk-immunoreceptor protein-protein association.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 22","pages":"e2421663122"},"PeriodicalIF":9.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161728","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

Martian samples, hazards, and biosecurity: Between science and bioethics. 火星样本、危险和生物安全：在科学和生物伦理之间。

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 : 2025-06-03 Epub Date: 2025-05-27 DOI: 10.1073/pnas.2507961122

Rodrigo Siqueira-Batista, Felipe Gómez

引用次数: 0

Reversible molecular simulation for training classical and machine-learning force fields. 训练经典力场和机器学习力场的可逆分子模拟。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2426058122

Joe G Greener

引用次数: 0

Synthesizing decades of research into one tree for birds. 将几十年的研究成果综合到一棵鸟类树上。

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 : 2025-06-03 Epub Date: 2025-05-27 DOI: 10.1073/pnas.2507805122

Josefin Stiller

引用次数: 0

Nanoimmunomodulation of the Aβ-STING feedback machinery in microglia for Alzheimer's disease treatment. 小胶质细胞中Aβ-STING反馈机制的纳米免疫调节治疗阿尔茨海默病。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2427257122

Limin Tian, Guangyu Long, Siqi Zhu, Yuelong Wang, Pengcheng Xu, Lifeng Liu, Hong Yao, Shentong Fang, Shuqing Chen, Suxin Li

{"title":"Nanoimmunomodulation of the Aβ-STING feedback machinery in microglia for Alzheimer's disease treatment.","authors":"Limin Tian, Guangyu Long, Siqi Zhu, Yuelong Wang, Pengcheng Xu, Lifeng Liu, Hong Yao, Shentong Fang, Shuqing Chen, Suxin Li","doi":"10.1073/pnas.2427257122","DOIUrl":"https://doi.org/10.1073/pnas.2427257122","url":null,"abstract":"Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their combined influence on AD progression, is poorly understood. Here, we show that while microglia play a protective role in clearing extracellular Aβ, excessive Aβ engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS-STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further Aβ clearance. To address this, we present a nanomedicine approach termed \"Aβ-STING Synergistic ImmunoSilencing Therapy (ASSIST)\". ASSIST comprises STING inhibitors encapsulated within a blood-brain barrier (BBB)-permeable polymeric micelle that also serves as an Aβ scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes Aβ plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aβ by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aβ uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aβ clearance. Intravenous administration of ASSIST significantly reduces Aβ burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 22","pages":"e2427257122"},"PeriodicalIF":9.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161721","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

Allelic variations and gene cluster modularity act as nonlinear bottlenecks for cholera emergence. 等位基因变异和基因簇模块化是霍乱发生的非线性瓶颈。

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 : 2025-06-03 Epub Date: 2025-05-28 DOI: 10.1073/pnas.2417915122

Mario López-Pérez, Deepak Balasubramanian, Alicia Campos-Lopez, Cole Crist, Trudy-Ann Grant, Jose M Haro-Moreno, Asier Zaragoza-Solas, Salvador Almagro-Moreno

{"title":"Allelic variations and gene cluster modularity act as nonlinear bottlenecks for cholera emergence.","authors":"Mario López-Pérez, Deepak Balasubramanian, Alicia Campos-Lopez, Cole Crist, Trudy-Ann Grant, Jose M Haro-Moreno, Asier Zaragoza-Solas, Salvador Almagro-Moreno","doi":"10.1073/pnas.2417915122","DOIUrl":"https://doi.org/10.1073/pnas.2417915122","url":null,"abstract":"The underlying factors that lead to specific strains within a species to emerge as human pathogens remain mostly enigmatic. The diarrheal disease cholera is caused by strains from a phylogenetically confined group within the Vibrio cholerae species, the pandemic cholera group (PCG), making it an ideal model system to tackle this puzzling phenomenon. Comprehensive analyses of over 1,840 V. cholerae genomes, including environmental isolates from this study, reveal that the species consists of eleven groups, with the PCG belonging to the largest and located within a lineage shared with environmental strains. This hierarchical classification provided us with a framework to unravel the ecoevolutionary dynamics of the genetic determinants associated with the emergence of toxigenic V. cholerae. Our analyses indicate that this phenomenon is largely dependent on the acquisition of unique modular gene clusters and allelic variations that confer a competitive advantage during intestinal colonization. We determined that certain PCG-associated alleles are essential for successful colonization whereas others provide a nonlinear competitive advantage, acting as a critical bottleneck that clarifies the isolated emergence of PCG. For instance, toxigenic strains encoding non-PCG alleles of a) tcpF or b) a sextuple allelic exchange mutant for genes tcpA, toxT, VC0176, VC1791, rfbT, and ompU, lose their ability to colonize the intestine. Interestingly, these alleles do not play a role in the colonization of newly established model environmental reservoirs. Our study uncovers the evolutionary roots of toxigenic V. cholerae offering a tractable approach for investigating the emergence of pathogenic clones within an environmental population.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 22","pages":"e2417915122"},"PeriodicalIF":9.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161724","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