Proceedings of the National Academy of Sciences of the United States of America最新文献_第5页

Volumetric imaging of the 3D orientation of cellular structures with a polarized fluorescence light-sheet microscope.

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 : 2025-02-25 Epub Date: 2025-02-21 DOI: 10.1073/pnas.2406679122

Talon Chandler, Min Guo, Yijun Su, Jiji Chen, Yicong Wu, Junyu Liu, Atharva Agashe, Robert S Fischer, Shalin B Mehta, Abhishek Kumar, Tobias I Baskin, Valentin Jaumouillé, Huafeng Liu, Vinay Swaminathan, Amrinder S Nain, Rudolf Oldenbourg, Patrick J La Riviere, Hari Shroff

{"title":"Volumetric imaging of the 3D orientation of cellular structures with a polarized fluorescence light-sheet microscope.","authors":"Talon Chandler, Min Guo, Yijun Su, Jiji Chen, Yicong Wu, Junyu Liu, Atharva Agashe, Robert S Fischer, Shalin B Mehta, Abhishek Kumar, Tobias I Baskin, Valentin Jaumouillé, Huafeng Liu, Vinay Swaminathan, Amrinder S Nain, Rudolf Oldenbourg, Patrick J La Riviere, Hari Shroff","doi":"10.1073/pnas.2406679122","DOIUrl":"https://doi.org/10.1073/pnas.2406679122","url":null,"abstract":"Polarized fluorescence microscopy is a valuable tool for measuring molecular orientations in biological samples, but techniques for recovering three-dimensional orientations and positions of fluorescent ensembles are limited. We report a polarized dual-view light-sheet system for determining the diffraction-limited three-dimensional distribution of the orientations and positions of ensembles of fluorescent dipoles that label biological structures. We share a set of visualization, histogram, and profiling tools for interpreting these positions and orientations. We model the distributions based on the polarization-dependent efficiency of excitation and detection of emitted fluorescence, using coarse-grained representations we call orientation distribution functions (ODFs). We apply ODFs to create physics-informed models of image formation with spatio-angular point-spread and transfer functions. We use theory and experiment to conclude that light-sheet tilting is a necessary part of our design for recovering all three-dimensional orientations. We use our system to extend known two-dimensional results to three dimensions in FM1-43-labeled giant unilamellar vesicles, fast-scarlet-labeled cellulose in xylem cells, and phalloidin-labeled actin in U2OS cells. Additionally, we observe phalloidin-labeled actin in mouse fibroblasts grown on grids of labeled nanowires and identify correlations between local actin alignment and global cell-scale orientation, indicating cellular coordination across length scales.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2406679122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468542","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

Quantum tunneling and its absence in deep wells and strong magnetic fields.

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 : 2025-02-25 Epub Date: 2025-02-21 DOI: 10.1073/pnas.2420062122

Charles L Fefferman, Jacob Shapiro, Michael I Weinstein

引用次数: 0

STING-induced noncanonical autophagy regulates endolysosomal homeostasis.

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 : 2025-02-25 Epub Date: 2025-02-21 DOI: 10.1073/pnas.2415422122

Tuozhi Huang, Chenglong Sun, Fenghe Du, Zhijian J Chen

{"title":"STING-induced noncanonical autophagy regulates endolysosomal homeostasis.","authors":"Tuozhi Huang, Chenglong Sun, Fenghe Du, Zhijian J Chen","doi":"10.1073/pnas.2415422122","DOIUrl":"https://doi.org/10.1073/pnas.2415422122","url":null,"abstract":"The cGAS-STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well-established role in inducing inflammatory cytokines, activation of the cGAS-STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING-induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced formation of pH-elevated Golgi-derived vesicles that led to ATG16L1 and V-ATPase-dependent noncanonical autophagy. We showed that STING-induced noncanonical autophagy resulted in activation of the MiT/TFE family of transcription factors (TFEB, TFE3, and MITF), which regulate lysosome biogenesis. We found that lipidation of the ATG8 proteins, particularly GABARAPs, inhibited phosphorylation of MiT/TFE transcription factors by mTORC1. The lipidated GABARAPs bound to the Folliculin-interacting proteins (FNIPs), thereby sequestering the FNIP-folliculin protein complexes from activating mTORC1, resulting in dephosphorylation and nuclear translocation of MiT/TFE transcription factors. Furthermore, we found that STING-induced autophagy activated Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson's disease, through GABARAPs lipidation. We further showed that STING-induced autophagy induced ALIX-mediated ESCRT machinery recruitment to mitigate endolysosomal perturbation. These results reveal the multifaceted functions of STING-induced noncanonical autophagy in regulating endolysosomal homeostasis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2415422122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468539","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

A long-distance inhibitory system regulates haustoria numbers in parasitic plants.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2424557122

Anna Kokla, Martina Leso, Jan Šimura, Cecilia Wärdig, Marina Hayashi, Naoshi Nishii, Yuichiro Tsuchiya, Karin Ljung, Charles W Melnyk

{"title":"A long-distance inhibitory system regulates haustoria numbers in parasitic plants.","authors":"Anna Kokla, Martina Leso, Jan Šimura, Cecilia Wärdig, Marina Hayashi, Naoshi Nishii, Yuichiro Tsuchiya, Karin Ljung, Charles W Melnyk","doi":"10.1073/pnas.2424557122","DOIUrl":"10.1073/pnas.2424557122","url":null,"abstract":"The ability of parasitic plants to withdraw nutrients from their hosts depends on the formation of an infective structure known as the haustorium. How parasites regulate their haustoria numbers is poorly understood, and here, we uncovered that existing haustoria in the facultative parasitic plants Phtheirospermum japonicum and Parentucellia viscosa suppressed the formation of new haustoria located on distant roots. Using Phtheirospermum, we found that this effect depended on the formation of mature haustoria and could be induced through the application of external nutrients. To understand the molecular basis of this root plasticity, we analyzed hormone response and found that existing infections upregulated cytokinin-responsive genes first at the haustoria and then more distantly in Phtheirospermum shoots. We observed that infections increased endogenous cytokinin levels in Phtheirospermum roots and shoots, and this increase appeared relevant since local treatments with exogenous cytokinins blocked the formation of both locally and distantly formed haustoria. In addition, local overexpression of a cytokinin-degrading enzyme in Phtheirospermum prevented this systemic interhaustoria repression and increased haustoria numbers locally. We propose that a long-distance signal produced by haustoria negatively regulates future haustoria, and in Phtheirospermum, such a signaling system is mediated by a local increase in cytokinin to regulate haustoria numbers and balance nutrient acquisition.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2424557122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441692","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

pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2422731122

Meiyu Zhang, Jinmei Li, Kepeng Yan, Haoyue Zhou, Song Mei, Benyu Wang, Dongyang Li, Xuexiang Du, Mingyue Liu, Peng Zhang, James K Fields, Lei Ye, Pan Zheng, Yang Liu, Michael J Lenardo, Yan Zhang

{"title":"pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies.","authors":"Meiyu Zhang, Jinmei Li, Kepeng Yan, Haoyue Zhou, Song Mei, Benyu Wang, Dongyang Li, Xuexiang Du, Mingyue Liu, Peng Zhang, James K Fields, Lei Ye, Pan Zheng, Yang Liu, Michael J Lenardo, Yan Zhang","doi":"10.1073/pnas.2422731122","DOIUrl":"10.1073/pnas.2422731122","url":null,"abstract":"Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2422731122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441718","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

Short-term exposure to filter-bubble recommendation systems has limited polarization effects: Naturalistic experiments on YouTube.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2318127122

Naijia Liu, Xinlan Emily Hu, Yasemin Savas, Matthew A Baum, Adam J Berinsky, Allison J B Chaney, Christopher Lucas, Rei Mariman, Justin de Benedictis-Kessner, Andrew M Guess, Dean Knox, Brandon M Stewart

{"title":"Short-term exposure to filter-bubble recommendation systems has limited polarization effects: Naturalistic experiments on YouTube.","authors":"Naijia Liu, Xinlan Emily Hu, Yasemin Savas, Matthew A Baum, Adam J Berinsky, Allison J B Chaney, Christopher Lucas, Rei Mariman, Justin de Benedictis-Kessner, Andrew M Guess, Dean Knox, Brandon M Stewart","doi":"10.1073/pnas.2318127122","DOIUrl":"10.1073/pnas.2318127122","url":null,"abstract":"An enormous body of literature argues that recommendation algorithms drive political polarization by creating \"filter bubbles\" and \"rabbit holes.\" Using four experiments with nearly 9,000 participants, we show that manipulating algorithmic recommendations to create these conditions has limited effects on opinions. Our experiments employ a custom-built video platform with a naturalistic, YouTube-like interface presenting real YouTube videos and recommendations. We experimentally manipulate YouTube's actual recommendation algorithm to simulate filter bubbles and rabbit holes by presenting ideologically balanced and slanted choices. Our design allows us to intervene in a feedback loop that has confounded the study of algorithmic polarization-the complex interplay between supply of recommendations and user demand for content-to examine downstream effects on policy attitudes. We use over 130,000 experimentally manipulated recommendations and 31,000 platform interactions to estimate how recommendation algorithms alter users' media consumption decisions and, indirectly, their political attitudes. Our results cast doubt on widely circulating theories of algorithmic polarization by showing that even heavy-handed (although short-term) perturbations of real-world recommendations have limited causal effects on policy attitudes. Given our inability to detect consistent evidence for algorithmic effects, we argue the burden of proof for claims about algorithm-induced polarization has shifted. Our methodology, which captures and modifies the output of real-world recommendation algorithms, offers a path forward for future investigations of black-box artificial intelligence systems. Our findings reveal practical limits to effect sizes that are feasibly detectable in academic experiments.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2318127122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441774","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

Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2424906122

Yinpin Huang, Jun Zhang, Wenbin Zhang, Jie Chen, Sijia Chen, Qincui Wu, Sanduo Zheng, Xiaodong Wang

{"title":"Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic.","authors":"Yinpin Huang, Jun Zhang, Wenbin Zhang, Jie Chen, Sijia Chen, Qincui Wu, Sanduo Zheng, Xiaodong Wang","doi":"10.1073/pnas.2424906122","DOIUrl":"10.1073/pnas.2424906122","url":null,"abstract":"Axon degeneration, driven by the NAD+ hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following nerve injury. However, the precise molecular mechanism underlying SARM1 activation remains to be fully elucidated. In this study, we report the identification of a potent proactivator of SARM1, G10, which is converted into a direct activator (M1) by the enzyme nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures of SARM1 bound to M1, as well as to M1 and a nonhydrolyzable NAD+ analog (1AD), captured two intermediate activation states and the fully active state, revealing a stepwise mechanism of SARM1 activation. Further, introducing a disulfide bond to prevent conformational transitions between the two intermediate states mediated by M1 stabilized SARM1 in its inactive form and blocked M1-induced cell death. Together, these findings propose a sequential, stepwise activation model for SARM1 and offer a framework for developing potential SARM1 inhibitors for the treatment of neurodegenerative diseases.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2424906122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441776","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

Fungal effector disables cathepsin-driven Toll immunity in insects.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2500911122

Rebecca J Tay, Yen-Ping Hsueh

引用次数: 0

Measuring population heterogeneity requires heterogeneous populations.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2425536122

Antonia Krefeld-Schwalb, Xuwen Hua, Eric J Johnson

引用次数: 0

Fluoride-based hydrogen bond chemistry in a layered double hydroxide cathode toward high-performance aqueous NH₄⁺ storage.

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 : 2025-02-25 Epub Date: 2025-02-18 DOI: 10.1073/pnas.2414112122

Fang-Fang Sun, Xinwei Guan, Zi-Hang Huang, Xu Han, Hui Li, Tianyi Ma

{"title":"Fluoride-based hydrogen bond chemistry in a layered double hydroxide cathode toward high-performance aqueous NH4+ storage.","authors":"Fang-Fang Sun, Xinwei Guan, Zi-Hang Huang, Xu Han, Hui Li, Tianyi Ma","doi":"10.1073/pnas.2414112122","DOIUrl":"10.1073/pnas.2414112122","url":null,"abstract":"In aqueous ammonium-ion storage, hydrogen bonds play a pivotal role in the reversible insertion/extraction of NH4+ within transition metal oxides/hydroxides. Although fluorine (F) is known for its strong electronegativity and potential to form robust hydrogen bonds with NH4+, its specific influence on NH4+ storage remains unexplored. Herein, we systematically investigate the effects of F-based hydrogen bond chemistry within a layered double hydroxide matrix, where F species are introduced and subsequently partially removed via an electrochemical method. Our findings demonstrate that while increasing F doping content accelerates NH4+ diffusion due to F's strong electronegativity, it also triggers crystal shrinkage and depresses storage capacity. To this end, controlled partial removal of F, employing a lye-assistant electrochemical strategy, induces expanded interlayer spacing and distinct edge lattice tearing, thereby facilitating improved NH4+ accommodation. The retained F sites couple with emerging exposed O sites maintain a high hydrogen bonding capability, which is further enhanced by the formation of highly active, curved hydroxyl groups centered around F sites. These manipulations significantly boost the NH4+ storage performance of the electrode, providing insights into leveraging the strongest F-based hydrogen bond chemistry in developing high-performance ammonium-ion energy storage devices.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 8","pages":"e2414112122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441670","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