Pub Date : 2025-02-18Epub Date: 2025-02-14DOI: 10.1073/pnas.2417075122
Jonathan Bauermann, Roberto Benzi, David R Nelson, Suraj Shankar, Federico Toschi
Unlike coffee and cream that homogenize when stirred, growing micro-organisms (e.g., bacteria, baker's yeast) can actively kill each other and avoid mixing. How do such antagonistic interactions impact the growth and survival of competing strains, while being spatially advected by turbulent flows? By using numerical simulations of a continuum model, we study the dynamics of two antagonistic strains that are dispersed by incompressible turbulent flows in two spatial dimensions. A key parameter is the ratio of the fluid transport time to that of biological reproduction, which determines the winning organism that ultimately takes over the whole population from an initial heterogeneous state, a process known as fixation. By quantifying the probability and mean time for fixation along with the spatial structure of concentration fluctuations, we demonstrate how turbulence raises the threshold for biological nucleation and antagonism suppresses flow-induced mixing by depleting the population at interfaces. Our work highlights the unusual biological consequences of the interplay of turbulent fluid flows with antagonistic population dynamics, with potential implications for marine microbial ecology and origins of biological chirality.
{"title":"Turbulent mixing controls fixation of growing antagonistic populations.","authors":"Jonathan Bauermann, Roberto Benzi, David R Nelson, Suraj Shankar, Federico Toschi","doi":"10.1073/pnas.2417075122","DOIUrl":"https://doi.org/10.1073/pnas.2417075122","url":null,"abstract":"<p><p>Unlike coffee and cream that homogenize when stirred, growing micro-organisms (e.g., bacteria, baker's yeast) can actively kill each other and avoid mixing. How do such antagonistic interactions impact the growth and survival of competing strains, while being spatially advected by turbulent flows? By using numerical simulations of a continuum model, we study the dynamics of two antagonistic strains that are dispersed by incompressible turbulent flows in two spatial dimensions. A key parameter is the ratio of the fluid transport time to that of biological reproduction, which determines the winning organism that ultimately takes over the whole population from an initial heterogeneous state, a process known as fixation. By quantifying the probability and mean time for fixation along with the spatial structure of concentration fluctuations, we demonstrate how turbulence raises the threshold for biological nucleation and antagonism suppresses flow-induced mixing by depleting the population at interfaces. Our work highlights the unusual biological consequences of the interplay of turbulent fluid flows with antagonistic population dynamics, with potential implications for marine microbial ecology and origins of biological chirality.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2417075122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417053","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}
Tiantian Jiang, Jin Woo Lee, Jennifer E. Collins, Samuel Schaefer, Daisy Chen, Flore Nardella, Karen Wendt, Thilini G. Peramuna, Raphaella Paes, James L. McLellan, Jasveen Bhasin, Gregory L. Durst, Kirsten K. Hanson, Debopam Chakrabarti, Robert H. Cichewicz, Elizabeth A. Winzeler
Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus Trichocladium asperum that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in Plasmodium falciparum with the most potent member, NPDG-F (EC 50 of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure–activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the Plasmodium blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.
{"title":"Fungal-derived methyldeoxaphomins target Plasmodium falciparum segregation through the inhibition of PfActin1","authors":"Tiantian Jiang, Jin Woo Lee, Jennifer E. Collins, Samuel Schaefer, Daisy Chen, Flore Nardella, Karen Wendt, Thilini G. Peramuna, Raphaella Paes, James L. McLellan, Jasveen Bhasin, Gregory L. Durst, Kirsten K. Hanson, Debopam Chakrabarti, Robert H. Cichewicz, Elizabeth A. Winzeler","doi":"10.1073/pnas.2418871122","DOIUrl":"https://doi.org/10.1073/pnas.2418871122","url":null,"abstract":"Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus <jats:italic>Trichocladium asperum</jats:italic> that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in <jats:italic>Plasmodium falciparum</jats:italic> with the most potent member, NPDG-F (EC <jats:sub>50</jats:sub> of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure–activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the <jats:italic>Plasmodium</jats:italic> blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"24 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443285","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}
Han Fang, Mengling Shi, Cong Wang, Saiting Zhang, Na Kong, Mengyao Ji, Yan Wang, Yidan Zhou, Qiyun Zhu, Yu Zhang, Shishen Du, Shuai Xu, Caoqi Lei
Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. Pcsk9 −/− mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus–host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.
{"title":"PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS","authors":"Han Fang, Mengling Shi, Cong Wang, Saiting Zhang, Na Kong, Mengyao Ji, Yan Wang, Yidan Zhou, Qiyun Zhu, Yu Zhang, Shishen Du, Shuai Xu, Caoqi Lei","doi":"10.1073/pnas.2412206122","DOIUrl":"https://doi.org/10.1073/pnas.2412206122","url":null,"abstract":"Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. <jats:italic> Pcsk9 <jats:sup>−/−</jats:sup> </jats:italic> mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus–host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"361 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443287","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}
Pub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1073/pnas.2500424122
{"title":"Correction for Li et al., Recurrent DNA nicks drive massive expansions of (GAA)<sub>n</sub> repeats.","authors":"","doi":"10.1073/pnas.2500424122","DOIUrl":"https://doi.org/10.1073/pnas.2500424122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2500424122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067485","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}
Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.
{"title":"Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia.","authors":"Jun-Yu Wang, Tuan-Tuan Gui, Bo Jiao, Xuan Liu, Xiao-Lin Ma, Cheng Wang, Jing Qiao, Wei-Yang Liu, Li-Jun Peng, Jia-Yi Ren, Yong-Mei Zhu, Xiang-Qin Weng, Chao Wang, Qian-Qian Zhang, Gao-Xian Song, Yu-Ting Dai, Zhen-Yi Wang, Gang Lv, Chen-Xu Gao, Niu Qiao, Ming Zhang, Yun Tan, Yuan-Fang Liu, Sheng-Yue Wang, Jian Hou, Duo-Hui Jing, An-Kang Lyu, Jian-Qing Mi, Zhu Chen, Wen-Lian Chen, Tong Yin, Hai Fang, Jin Wang, Sai-Juan Chen","doi":"10.1073/pnas.2423169122","DOIUrl":"https://doi.org/10.1073/pnas.2423169122","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2423169122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415078","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}
Pub Date : 2025-02-18Epub Date: 2025-02-12DOI: 10.1073/pnas.2410246122
Philippe Rufin, Patrick Meyfroidt, Felicia O Akinyemi, Lyndon Estes, Esther Shupel Ibrahim, Meha Jain, Hannah Kerner, Sá Nogueira Lisboa, David Lobell, Catherine Nakalembe, Claudio Persello, Michelle C A Picoli, Natasha Ribeiro, Almeida Alberto Sitoe, Katharina Waha, Sherrie Wang
{"title":"To enhance sustainable development goal research, open up commercial satellite image archives.","authors":"Philippe Rufin, Patrick Meyfroidt, Felicia O Akinyemi, Lyndon Estes, Esther Shupel Ibrahim, Meha Jain, Hannah Kerner, Sá Nogueira Lisboa, David Lobell, Catherine Nakalembe, Claudio Persello, Michelle C A Picoli, Natasha Ribeiro, Almeida Alberto Sitoe, Katharina Waha, Sherrie Wang","doi":"10.1073/pnas.2410246122","DOIUrl":"https://doi.org/10.1073/pnas.2410246122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2410246122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409889","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}
Pub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1073/pnas.2427297122
{"title":"Correction for Hasson et al., Automated determination of transport and depositional environments in sand and sandstones.","authors":"","doi":"10.1073/pnas.2427297122","DOIUrl":"https://doi.org/10.1073/pnas.2427297122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2427297122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067478","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}
Pub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1073/pnas.2500334122
{"title":"Correction for Joshy et al., Accelerated cell-type-specific regulatory evolution of the human brain.","authors":"","doi":"10.1073/pnas.2500334122","DOIUrl":"https://doi.org/10.1073/pnas.2500334122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2500334122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067480","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}
Pub Date : 2025-02-18Epub Date: 2025-02-06DOI: 10.1073/pnas.2426753122
{"title":"Correction for Sun et al., JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation.","authors":"","doi":"10.1073/pnas.2426753122","DOIUrl":"https://doi.org/10.1073/pnas.2426753122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2426753122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365394","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}
Pub Date : 2025-02-18Epub Date: 2025-02-10DOI: 10.1073/pnas.2426773122
Aviram Rasouly, Evgeny Nudler
{"title":"In the shadow of antibiotics.","authors":"Aviram Rasouly, Evgeny Nudler","doi":"10.1073/pnas.2426773122","DOIUrl":"https://doi.org/10.1073/pnas.2426773122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2426773122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391545","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}
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