Juan Carlos Fernández del Castillo, Farhad Pashakhanloo, Venkatesh N. Murthy, Jacob A. Zavatone-Veth
The architecture of early olfactory processing is a striking example of convergent evolution. Typically, a panel of broadly tuned receptors is selectively expressed in sensory neurons (each neuron expressing only one receptor), and each glomerulus receives projections from just one neuron type. Taken together, these three motifs—broad receptors, selective expression, and glomerular convergence—constitute “canonical olfaction,” since a number of model organisms including mice and flies exhibit these features. The emergence of this distinctive architecture across evolutionary lineages suggests that it may be optimized for information processing, an idea known as efficient coding. In this work, we show that by maximizing mutual information one layer at a time, efficient coding recovers several features of canonical olfactory processing under realistic biophysical assumptions. We also explore the settings in which noncanonical olfaction may be advantageous. Along the way, we make several predictions relating olfactory circuits to features of receptor families and the olfactory environment.
{"title":"Convergent motifs of early olfactory processing are recapitulated by layer-wise efficient coding","authors":"Juan Carlos Fernández del Castillo, Farhad Pashakhanloo, Venkatesh N. Murthy, Jacob A. Zavatone-Veth","doi":"10.1073/pnas.2524661123","DOIUrl":"https://doi.org/10.1073/pnas.2524661123","url":null,"abstract":"The architecture of early olfactory processing is a striking example of convergent evolution. Typically, a panel of broadly tuned receptors is selectively expressed in sensory neurons (each neuron expressing only one receptor), and each glomerulus receives projections from just one neuron type. Taken together, these three motifs—broad receptors, selective expression, and glomerular convergence—constitute “canonical olfaction,” since a number of model organisms including mice and flies exhibit these features. The emergence of this distinctive architecture across evolutionary lineages suggests that it may be optimized for information processing, an idea known as efficient coding. In this work, we show that by maximizing mutual information one layer at a time, efficient coding recovers several features of canonical olfactory processing under realistic biophysical assumptions. We also explore the settings in which noncanonical olfaction may be advantageous. Along the way, we make several predictions relating olfactory circuits to features of receptor families and the olfactory environment.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"86 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507102","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}
Siwon Chung, Hannah Hudson, Kaitlin A. Stromberg, Andrew Sandstrom
Inflammasomes are cytosolic immune complexes that recognize pathogen-associated stimuli to initiate a potent inflammatory response. While some inflammasomes directly recognize pathogen-associated molecules, others, such as the NLRP1B inflammasome, respond to pathogen-associated activities. Specifically, the NLRP1B inflammasome senses the enzymatic activity of pathogen-secreted proteases and E3 ligases through a mechanism of “functional degradation”—effectors that promote the proteasomal degradation of NLRP1B induce activation of this inflammasome. However, why pathogens would target NLRP1B for degradation when doing so promotes a robust inflammatory response is unclear. We propose that NLRP1 acts as an integrated decoy receptor by mimicking other host proteins targeted for degradation by pathogens. Specifically, we hypothesize that NLRP1B encodes sequences and features such that these pathogen effectors are unable to distinguish between NLRP1B and their other targets. To test this hypothesis, we determine how the Shigella flexneri E3 ligase IpaH7.8 is recognized by NLRP1B and whether these interactions are equivalent to those between IpaH7.8 and its other substrates, the Gasdermin (GSDM) family of proteins. Here, we show that IpaH7.8 recognizes both the GSDMs and NLRP1B through a single shared interface and that NLRP1B presents a surface similar to that recognized by IpaH7.8 on the GSDMs. In this way, NLRP1B acts as a decoy for the GSDMs to subvert the activity of IpaH7.8 to promote inflammasome activation. These data demonstrate that NLRP1B acts as an integrated decoy receptor and establish the use of integrated decoy receptors by the vertebrate immune system.
{"title":"NLRP1B is an integrated decoy that subverts Shigella flexneri E3 ligase activity to promote effector-triggered immunity","authors":"Siwon Chung, Hannah Hudson, Kaitlin A. Stromberg, Andrew Sandstrom","doi":"10.1073/pnas.2514645123","DOIUrl":"https://doi.org/10.1073/pnas.2514645123","url":null,"abstract":"Inflammasomes are cytosolic immune complexes that recognize pathogen-associated stimuli to initiate a potent inflammatory response. While some inflammasomes directly recognize pathogen-associated molecules, others, such as the NLRP1B inflammasome, respond to pathogen-associated activities. Specifically, the NLRP1B inflammasome senses the enzymatic activity of pathogen-secreted proteases and E3 ligases through a mechanism of “functional degradation”—effectors that promote the proteasomal degradation of NLRP1B induce activation of this inflammasome. However, why pathogens would target NLRP1B for degradation when doing so promotes a robust inflammatory response is unclear. We propose that NLRP1 acts as an integrated decoy receptor by mimicking other host proteins targeted for degradation by pathogens. Specifically, we hypothesize that NLRP1B encodes sequences and features such that these pathogen effectors are unable to distinguish between NLRP1B and their other targets. To test this hypothesis, we determine how the <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Shigella</jats:italic> flexneri </jats:italic> E3 ligase IpaH7.8 is recognized by NLRP1B and whether these interactions are equivalent to those between IpaH7.8 and its other substrates, the Gasdermin (GSDM) family of proteins. Here, we show that IpaH7.8 recognizes both the GSDMs and NLRP1B through a single shared interface and that NLRP1B presents a surface similar to that recognized by IpaH7.8 on the GSDMs. In this way, NLRP1B acts as a decoy for the GSDMs to subvert the activity of IpaH7.8 to promote inflammasome activation. These data demonstrate that NLRP1B acts as an integrated decoy receptor and establish the use of integrated decoy receptors by the vertebrate immune system.","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":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507103","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}
Rameshwar U. Kadam, Jarek Juraszek, Boerries Brandenburg, Divita Garg, Xueyong Zhu, Mandy Jongeneelen, Chan Tang, Wim B. G. Schepens, Christophe Buyck, Bart Stoops, Jan Vermond, Ronald Vogels, Robert H. E. Friesen, Maria J. P. van Dongen, Ian A. Wilson
Influenza continues to be a major threat to global health and a substantial economic burden. Innovative strategies are needed to tackle the growing resistance to established influenza therapeutics and to develop new therapeutics with novel mechanisms of action. Previous peptide and small molecule designs have been successful only against influenza group 1 hemagglutinin (HA). Here, we report on a CLIPS (Chemical Linkage of Peptides onto Scaffolds)-based approach to design potent peptidic inhibitors of influenza A viruses that now extend to both group 1 and group 2 HAs. This approach merges features of antibodies and small molecules to design constrained bicyclic peptides that engage the highly conserved HA stem. The heavy-chain complementarity-determining region 3 (HCDR3) of human broadly neutralizing antibody FI6v3 was grafted onto functionalized small molecule scaffolds. The designed peptides exhibited in vitro heterosubtypic cross-reactivity in binding to group 1 (H1 and H5) and group 2 (H3 and H7) HAs and in neutralization of H1N1, H5N1, and H7N3 viruses. A crystal structure of the bicyclic peptide with HA from H1N1 A/Puerto Rico/8/1934 (H1/PR8) at 2.35 Å resolution revealed that the designed peptide faithfully mimics the binding mode and functionality of the parent antibody FI6v3 to the highly conserved stem epitope. These structural and functional data illustrate how both group 1 and group 2 influenza A viruses can now be targeted by constrained peptidic ligands that should aid in development of pan-influenza therapeutics.
流感仍然是对全球健康的重大威胁和沉重的经济负担。需要创新战略来解决对现有流感疗法日益增长的耐药性问题，并开发具有新的作用机制的新疗法。先前的肽和小分子设计仅成功地对抗流感1组血凝素（HA）。在这里，我们报道了一种基于CLIPS （Chemical Linkage of Peptides to Scaffolds）的方法来设计甲型流感病毒的有效肽抑制剂，这种抑制剂现在可以扩展到1组和2组ha。这种方法结合了抗体和小分子的特征，设计出与高度保守的血凝素干细胞结合的受限双环肽。将人宽中和抗体FI6v3的重链互补决定区3 （HCDR3）移植到功能化的小分子支架上。所设计的肽在与1组（H1和H5）和2组（H3和H7） ha结合以及中和H1N1、H5N1和H7N3病毒方面表现出体外异亚型交叉反应性。从H1N1 A/Puerto Rico/8/1934 （H1/PR8）中提取的HA双环肽在2.35 Å分辨率下的晶体结构显示，所设计的肽忠实地模仿了亲本抗体FI6v3与高度保守的干细胞表位的结合模式和功能。这些结构和功能数据说明了1组和2组甲型流感病毒现在如何可以被限制性肽配体靶向，这应该有助于开发泛流感治疗方法。
{"title":"Small molecule–constrained paratope mimetic bicyclic peptides as potent inhibitors of group 1 and 2 influenza A virus hemagglutinins","authors":"Rameshwar U. Kadam, Jarek Juraszek, Boerries Brandenburg, Divita Garg, Xueyong Zhu, Mandy Jongeneelen, Chan Tang, Wim B. G. Schepens, Christophe Buyck, Bart Stoops, Jan Vermond, Ronald Vogels, Robert H. E. Friesen, Maria J. P. van Dongen, Ian A. Wilson","doi":"10.1073/pnas.2537533123","DOIUrl":"https://doi.org/10.1073/pnas.2537533123","url":null,"abstract":"Influenza continues to be a major threat to global health and a substantial economic burden. Innovative strategies are needed to tackle the growing resistance to established influenza therapeutics and to develop new therapeutics with novel mechanisms of action. Previous peptide and small molecule designs have been successful only against influenza group 1 hemagglutinin (HA). Here, we report on a CLIPS (Chemical Linkage of Peptides onto Scaffolds)-based approach to design potent peptidic inhibitors of influenza A viruses that now extend to both group 1 and group 2 HAs. This approach merges features of antibodies and small molecules to design constrained bicyclic peptides that engage the highly conserved HA stem. The heavy-chain complementarity-determining region 3 (HCDR3) of human broadly neutralizing antibody FI6v3 was grafted onto functionalized small molecule scaffolds. The designed peptides exhibited in vitro heterosubtypic cross-reactivity in binding to group 1 (H1 and H5) and group 2 (H3 and H7) HAs and in neutralization of H1N1, H5N1, and H7N3 viruses. A crystal structure of the bicyclic peptide with HA from H1N1 A/Puerto Rico/8/1934 (H1/PR8) at 2.35 Å resolution revealed that the designed peptide faithfully mimics the binding mode and functionality of the parent antibody FI6v3 to the highly conserved stem epitope. These structural and functional data illustrate how both group 1 and group 2 influenza A viruses can now be targeted by constrained peptidic ligands that should aid in development of pan-influenza therapeutics.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"219 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507106","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}
Maxime Poinsot, Marine Dos Santos, Baptiste Marthy, Ana Borges-Correia, Eduardo Gascon, Benoit Charlot, Maxime Cazorla
The mammalian cerebral cortex projects to the striatum in a precise, hierarchical topography, forming parallel loops that underlie sensorimotor, associative, and limbic processing. Despite the striatum’s lack of clear anatomical boundaries, these projections remain functionally segregated, suggesting the existence of intrinsic organizing principles. Disruptions in corticostriatal connectivity and excitability are common in neurodevelopmental disorders, but it remains unclear whether such abnormalities are a cause or a consequence of circuit dysfunction. Here, we hypothesized that the excitability state of cortical neurons plays a direct role in shaping the topographic organization of their striatal projections. To test this, we engineered a biologically faithful in vitro platform inspired by the Tesla valve, enabling adjacent corticostriatal territories to be modeled under controlled excitability regimes. We found that cortical hyperexcitability disrupted the normal developmental transition from axonal growth to stabilization, leading to premature invasion of neighboring territories and the formation of ectopic convergence zones. As a result, the segregation between parallel pathways was lost, while local connectivity patterns remained unaffected. These findings reveal that intrinsic, activity-sensitive mechanisms constrain long-range axonal growth to shape the wiring diagram of the corticostriatal projectome. They also highlight the power of biologically grounded on-chip models to uncover how early circuit vulnerabilities can lead to connectivity defects characteristic of disorders such as autism spectrum disorder, schizophrenia, epilepsy, and obsessive-compulsive disorder.
{"title":"Biologically grounded on-chip model identifies selective topographic reorganization within hyperexcitable corticostriatal networks","authors":"Maxime Poinsot, Marine Dos Santos, Baptiste Marthy, Ana Borges-Correia, Eduardo Gascon, Benoit Charlot, Maxime Cazorla","doi":"10.1073/pnas.2513459123","DOIUrl":"https://doi.org/10.1073/pnas.2513459123","url":null,"abstract":"The mammalian cerebral cortex projects to the striatum in a precise, hierarchical topography, forming parallel loops that underlie sensorimotor, associative, and limbic processing. Despite the striatum’s lack of clear anatomical boundaries, these projections remain functionally segregated, suggesting the existence of intrinsic organizing principles. Disruptions in corticostriatal connectivity and excitability are common in neurodevelopmental disorders, but it remains unclear whether such abnormalities are a cause or a consequence of circuit dysfunction. Here, we hypothesized that the excitability state of cortical neurons plays a direct role in shaping the topographic organization of their striatal projections. To test this, we engineered a biologically faithful in vitro platform inspired by the Tesla valve, enabling adjacent corticostriatal territories to be modeled under controlled excitability regimes. We found that cortical hyperexcitability disrupted the normal developmental transition from axonal growth to stabilization, leading to premature invasion of neighboring territories and the formation of ectopic convergence zones. As a result, the segregation between parallel pathways was lost, while local connectivity patterns remained unaffected. These findings reveal that intrinsic, activity-sensitive mechanisms constrain long-range axonal growth to shape the wiring diagram of the corticostriatal projectome. They also highlight the power of biologically grounded on-chip models to uncover how early circuit vulnerabilities can lead to connectivity defects characteristic of disorders such as autism spectrum disorder, schizophrenia, epilepsy, and obsessive-compulsive disorder.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"93 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507099","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}
Mohamed I. Barmada, Erin N. McGinity, Suparno Nandi, Debayan Dey, Natalia Zelinskaya, George M. Harris, Lindsay R. Comstock, Christine M. Dunham, Graeme L. Conn
Ribosomal RNA (rRNA) modifications are important for ribosome function and can influence bacterial susceptibility to ribosome-targeting antibiotics. The universally conserved 16S rRNA nucleotide C1402, for example, is the only 2’- O -methylated nucleotide in the bacterial small (30S) ribosomal subunit and this modification fine-tunes the shape and structure of the peptidyl tRNA binding site. The Cm1402 modification is incorporated by the conserved bacterial 16S rRNA methyltransferase RsmI, but it is unclear how RsmI recognizes its 30S substrate and specifically modify its buried target nucleotide. We determined a 2.42 Å resolution cryo-EM structure of the RsmI–30S complex and, with accompanying functional analyses, show that RsmI anchors itself to the 30S subunit through multiple contacts with a conserved 16S rRNA surface previously only seen in the assembled subunit. This positions RsmI to bind a h44 conformation that is substantially reorganized compared to its structure in the mature 30S subunit allowing access to C1402. These analyses also reveal an essential contribution to 30S subunit interaction made by the previously structurally uncharacterized RsmI C-terminal domain, RsmI-induced RNA–RNA interactions with C1402, and an unappreciated dependence on a divalent metal ion for activity that suggests RsmI may be a member of a distinct class of metal- and SAM-dependent RNA O -methyltransferases. This study significantly expands our mechanistic understanding of how intrinsic bacterial methyltransferases like RsmI modify their rRNA targets. Further, recognition of distant ribosome features and reorganization of a critical rRNA functional center point to a potential role in accurate 30S subunit biogenesis.
{"title":"Mechanism of 30S subunit recognition and modification by the conserved bacterial ribosomal RNA methyltransferase RsmI","authors":"Mohamed I. Barmada, Erin N. McGinity, Suparno Nandi, Debayan Dey, Natalia Zelinskaya, George M. Harris, Lindsay R. Comstock, Christine M. Dunham, Graeme L. Conn","doi":"10.1073/pnas.2523453123","DOIUrl":"https://doi.org/10.1073/pnas.2523453123","url":null,"abstract":"Ribosomal RNA (rRNA) modifications are important for ribosome function and can influence bacterial susceptibility to ribosome-targeting antibiotics. The universally conserved 16S rRNA nucleotide C1402, for example, is the only 2’- <jats:italic toggle=\"yes\">O</jats:italic> -methylated nucleotide in the bacterial small (30S) ribosomal subunit and this modification fine-tunes the shape and structure of the peptidyl tRNA binding site. The Cm1402 modification is incorporated by the conserved bacterial 16S rRNA methyltransferase RsmI, but it is unclear how RsmI recognizes its 30S substrate and specifically modify its buried target nucleotide. We determined a 2.42 Å resolution cryo-EM structure of the RsmI–30S complex and, with accompanying functional analyses, show that RsmI anchors itself to the 30S subunit through multiple contacts with a conserved 16S rRNA surface previously only seen in the assembled subunit. This positions RsmI to bind a h44 conformation that is substantially reorganized compared to its structure in the mature 30S subunit allowing access to C1402. These analyses also reveal an essential contribution to 30S subunit interaction made by the previously structurally uncharacterized RsmI C-terminal domain, RsmI-induced RNA–RNA interactions with C1402, and an unappreciated dependence on a divalent metal ion for activity that suggests RsmI may be a member of a distinct class of metal- and SAM-dependent RNA <jats:italic toggle=\"yes\">O</jats:italic> -methyltransferases. This study significantly expands our mechanistic understanding of how intrinsic bacterial methyltransferases like RsmI modify their rRNA targets. Further, recognition of distant ribosome features and reorganization of a critical rRNA functional center point to a potential role in accurate 30S subunit biogenesis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"17 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507100","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}
Luo-Qin Shen, Lu Wang, Zhiyuan Yao, Da Lin, Yu-Qiu Ye, Wan-rong Zhang, Mao Ye, Ming-Ming Sun, Shuai Du, Di Wu, Patrick O’Connor, Dong Zhu
Heavy metals are increasingly recognized as major drivers of antibiotic resistance gene (ARG) dissemination in soil ecosystems. However, the role of phages in heavy metal–driven ARG dissemination and the underlying mechanisms remain poorly understood. Here, through integrative metagenomic, viromics, and metabolomic analyses of paddy soils across China, we reveal that soil phages promote ARG dissemination under heavy metal stress, likely through two potential mechanisms. First, phage-encoded auxiliary metabolic genes (AMGs) reprogram host metabolism to enhance bacterial survival and adaptation, thereby facilitating the cotransfer of adjacent ARGs and indirectly promoting horizontal dissemination. Second, phage-encoded heavy metal detoxification genes (HDGs) directly mediate metal detoxification, driving the cotransfer of neighboring ARG fragments and inducing lipid peroxidation–associated increases in membrane permeability, which collectively enhance ARG mobilization. We further identify a significant enrichment of lysogenic phages coharboring ARGs with AMGs or HDGs (AMG–ARG and HDG–ARG fragments), underscoring their contribution to ARG dissemination. Phage transplantation experiments confirm that elevated heavy metal stress triggers lysogenic phage-mediated ARG transduction to bacterial hosts. Cumulatively, our experiments highlight the pivotal role of phages in mediating ARG transfer under heavy metal pressure and underscore the necessity of incorporating phage dynamics into ARG risk assessments.
{"title":"Phages drive the dissemination of antibiotic resistance genes by facilitating host adaptation to heavy metal stress","authors":"Luo-Qin Shen, Lu Wang, Zhiyuan Yao, Da Lin, Yu-Qiu Ye, Wan-rong Zhang, Mao Ye, Ming-Ming Sun, Shuai Du, Di Wu, Patrick O’Connor, Dong Zhu","doi":"10.1073/pnas.2535653123","DOIUrl":"https://doi.org/10.1073/pnas.2535653123","url":null,"abstract":"Heavy metals are increasingly recognized as major drivers of antibiotic resistance gene (ARG) dissemination in soil ecosystems. However, the role of phages in heavy metal–driven ARG dissemination and the underlying mechanisms remain poorly understood. Here, through integrative metagenomic, viromics, and metabolomic analyses of paddy soils across China, we reveal that soil phages promote ARG dissemination under heavy metal stress, likely through two potential mechanisms. First, phage-encoded auxiliary metabolic genes (AMGs) reprogram host metabolism to enhance bacterial survival and adaptation, thereby facilitating the cotransfer of adjacent ARGs and indirectly promoting horizontal dissemination. Second, phage-encoded heavy metal detoxification genes (HDGs) directly mediate metal detoxification, driving the cotransfer of neighboring ARG fragments and inducing lipid peroxidation–associated increases in membrane permeability, which collectively enhance ARG mobilization. We further identify a significant enrichment of lysogenic phages coharboring ARGs with AMGs or HDGs (AMG–ARG and HDG–ARG fragments), underscoring their contribution to ARG dissemination. Phage transplantation experiments confirm that elevated heavy metal stress triggers lysogenic phage-mediated ARG transduction to bacterial hosts. Cumulatively, our experiments highlight the pivotal role of phages in mediating ARG transfer under heavy metal pressure and underscore the necessity of incorporating phage dynamics into ARG risk assessments.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"43 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507123","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 : 2026-03-24Epub Date: 2026-03-19DOI: 10.1073/pnas.2516664123
Yinan Huang, David F Gleich, Pan Li
Magnetic graphs, originally developed to model quantum systems under magnetic fields, have recently emerged as a powerful framework for analyzing complex directed networks. Existing research has primarily used the spectral properties of the magnetic graph matrix to study global and stationary network features. However, their capacity to model local, nonequilibrium behaviors, often described by matrix powers, remains largely unexplored. We present a combinatorial interpretation of the magnetic graph matrix powers through directed walk profiles-counts of graph walks indexed by the number of edge reversals. Crucially, we establish that walk profiles correspond to a Fourier transform of magnetic matrix powers. The connection allows exact reconstruction of walk profiles from magnetic matrix powers at multiple discrete potentials, and more importantly, an even smaller number of potentials often suffices for accurate approximate reconstruction in real networks. This shows the empirical compressibility of the information captured by the magnetic matrix. This fresh perspective suggests further applications; for example, we illustrate how powers of the magnetic matrix can identify frustrated directed cycles (e.g., feedforward loops) and can be effectively employed for link prediction by encoding local structural details in directed graphs.
{"title":"Powers of magnetic graph matrix: Fourier spectrum, walk compression, and applications.","authors":"Yinan Huang, David F Gleich, Pan Li","doi":"10.1073/pnas.2516664123","DOIUrl":"https://doi.org/10.1073/pnas.2516664123","url":null,"abstract":"<p><p>Magnetic graphs, originally developed to model quantum systems under magnetic fields, have recently emerged as a powerful framework for analyzing complex directed networks. Existing research has primarily used the spectral properties of the magnetic graph matrix to study global and stationary network features. However, their capacity to model local, nonequilibrium behaviors, often described by matrix powers, remains largely unexplored. We present a combinatorial interpretation of the magnetic graph matrix powers through directed walk profiles-counts of graph walks indexed by the number of edge reversals. Crucially, we establish that walk profiles correspond to a Fourier transform of magnetic matrix powers. The connection allows exact reconstruction of walk profiles from magnetic matrix powers at multiple discrete potentials, and more importantly, an even smaller number of potentials often suffices for accurate approximate reconstruction in real networks. This shows the empirical compressibility of the information captured by the magnetic matrix. This fresh perspective suggests further applications; for example, we illustrate how powers of the magnetic matrix can identify frustrated directed cycles (e.g., feedforward loops) and can be effectively employed for link prediction by encoding local structural details in directed graphs.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 12","pages":"e2516664123"},"PeriodicalIF":9.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487131","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}
Gariné Magarditchian, Ivan Berest, Aikaterini Ziogou, Mai Matsushita, Michelle Reid, Alaa Othman, Manfred Kopf
Iron-dependent phospholipid (PL) peroxidation, which is reduced by glutathione peroxidase 4, is recognized as the hallmark of cells undergoing ferroptosis. Although studies have attempted to elucidate the molecular mechanisms underlying ferroptosis in cancer cells, the regulation of ferroptosis in effector and memory T cells remains largely unknown. Here, using genome-wide CRISPR-Cas9 knockout screens, we demonstrate that acyl-CoA synthetase long-chain family member 4 (ACSL4) is the predominant ferroptosis inducer in primary T cells cultured in vitro, while other identified iron- and lipid metabolism–related genes only slightly modulate their sensitivity to ferroptosis. However, ACSL4 dependency relies on the PL composition of the cells. In vitro cultured T cells treated with polyunsaturated fatty acids (PUFAs), as well as effector CD8 + T cells that are enriched in PUFA-containing PLs (PUFA-PLs), undergo ferroptosis in the absence of ACSL4. In contrast to effector T cells, naive and memory T cells share a similar PL profile, characterized by a scarcity of PUFA-PLs, and are resistant to ferroptosis. Overall, the PL composition is a central feature and determines the differential susceptibility of effector and memory T cells to ferroptosis and its molecular mechanism.
{"title":"The phospholipid profile of T cells shapes ACSL4 dependency and ferroptosis sensitivity of naive, effector, and memory T cells","authors":"Gariné Magarditchian, Ivan Berest, Aikaterini Ziogou, Mai Matsushita, Michelle Reid, Alaa Othman, Manfred Kopf","doi":"10.1073/pnas.2528153123","DOIUrl":"https://doi.org/10.1073/pnas.2528153123","url":null,"abstract":"Iron-dependent phospholipid (PL) peroxidation, which is reduced by glutathione peroxidase 4, is recognized as the hallmark of cells undergoing ferroptosis. Although studies have attempted to elucidate the molecular mechanisms underlying ferroptosis in cancer cells, the regulation of ferroptosis in effector and memory T cells remains largely unknown. Here, using genome-wide CRISPR-Cas9 knockout screens, we demonstrate that acyl-CoA synthetase long-chain family member 4 (ACSL4) is the predominant ferroptosis inducer in primary T cells cultured in vitro, while other identified iron- and lipid metabolism–related genes only slightly modulate their sensitivity to ferroptosis. However, ACSL4 dependency relies on the PL composition of the cells. In vitro cultured T cells treated with polyunsaturated fatty acids (PUFAs), as well as effector CD8 <jats:sup>+</jats:sup> T cells that are enriched in PUFA-containing PLs (PUFA-PLs), undergo ferroptosis in the absence of ACSL4. In contrast to effector T cells, naive and memory T cells share a similar PL profile, characterized by a scarcity of PUFA-PLs, and are resistant to ferroptosis. Overall, the PL composition is a central feature and determines the differential susceptibility of effector and memory T cells to ferroptosis and its molecular mechanism.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"13 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507096","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}
Tomasz Slezak, Kelly M. O’Leary, Tanya Guevara Avella, Natalia Musial, Jinyang Li, Anna Andrzejczak, Elizabeth F. Scott, Duc Anh Le, Anthony A. Kossiakoff
Inside-Out (I-O) protein display, the noncanonical surface localization of intracellular proteins, represents an underexplored feature of tumor cell biology. Here, we map the molecular landscape and trafficking mechanisms that control the presentation of I-O proteins on cancer cell membranes. Employing APEX2-mediated proximity biotinylation and a custom antibody generation and validation platform, we identified approximately 140 high-confidence I-O proteins, primarily ribosomal, proteasomal, chaperone, and translation factors, notably enriched in protein families associated with stress-response pathways. Validation of 500 antibodies encompassing 40 I-O targets across seven tumor cell lines confirmed selective and robust surface localization, while in vivo imaging in mouse xenografts demonstrated pronounced and tumor-specific antibody accumulation. I-O proteins were absent on peripheral blood mononuclear cells (PBMCs) and in normal tissues, indicating cancer cell selectivity. Functional analyses revealed that I-O protein tethering to the membrane is dependent on heparan sulfate interactions; enzymatic removal of these glycans led to the clearance of I-O proteins from the cell surface. Notably, the removed proteins returned to baseline levels within 6 h, indicating a dynamic balance related to Endoplasmic Reticulum (ER)-Golgi trafficking and cellular stress. Nearly half of these I-O proteins overlapped with known stress granule (SG) components; however, stress elements that promote SG formation do not similarly affect surface display of I-O proteins. Furthermore, I-O proteins are present on standard cancer cell lines under lower stress levels needed to induce SG formation, suggesting parallel yet mechanistically distinct aspects of the stress response. These findings position I-O display as a paradigm in protein trafficking, different from traditional secretion pathways and closely linked to stress response.
{"title":"Dynamic translocation of Inside-Out proteins to the cell surface underlies cellular adaptation to cancer-induced stress","authors":"Tomasz Slezak, Kelly M. O’Leary, Tanya Guevara Avella, Natalia Musial, Jinyang Li, Anna Andrzejczak, Elizabeth F. Scott, Duc Anh Le, Anthony A. Kossiakoff","doi":"10.1073/pnas.2529493123","DOIUrl":"https://doi.org/10.1073/pnas.2529493123","url":null,"abstract":"Inside-Out (I-O) protein display, the noncanonical surface localization of intracellular proteins, represents an underexplored feature of tumor cell biology. Here, we map the molecular landscape and trafficking mechanisms that control the presentation of I-O proteins on cancer cell membranes. Employing APEX2-mediated proximity biotinylation and a custom antibody generation and validation platform, we identified approximately 140 high-confidence I-O proteins, primarily ribosomal, proteasomal, chaperone, and translation factors, notably enriched in protein families associated with stress-response pathways. Validation of 500 antibodies encompassing 40 I-O targets across seven tumor cell lines confirmed selective and robust surface localization, while in vivo imaging in mouse xenografts demonstrated pronounced and tumor-specific antibody accumulation. I-O proteins were absent on peripheral blood mononuclear cells (PBMCs) and in normal tissues, indicating cancer cell selectivity. Functional analyses revealed that I-O protein tethering to the membrane is dependent on heparan sulfate interactions; enzymatic removal of these glycans led to the clearance of I-O proteins from the cell surface. Notably, the removed proteins returned to baseline levels within 6 h, indicating a dynamic balance related to Endoplasmic Reticulum (ER)-Golgi trafficking and cellular stress. Nearly half of these I-O proteins overlapped with known stress granule (SG) components; however, stress elements that promote SG formation do not similarly affect surface display of I-O proteins. Furthermore, I-O proteins are present on standard cancer cell lines under lower stress levels needed to induce SG formation, suggesting parallel yet mechanistically distinct aspects of the stress response. These findings position I-O display as a paradigm in protein trafficking, different from traditional secretion pathways and closely linked to stress response.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"14 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507122","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}
Delai Huang, Tiffany Liu, August A. Carr, Pietro H. de Mello, Yipeng Liang, Leah P. Shriver, François Chauvigné, Stephen L. Johnson, Joan Cerdà, Gary J. Patti, David M. Parichy
Neural crest–derived cells offer valuable opportunities to dissect mechanisms of cell fate specification and differentiation and the underpinnings of cell type diversification over evolutionary time. Particularly useful for such analyses are pigment cells of ectothermic vertebrates that arise from neural crest cells or via latent neural crest–derived stem cells. Among these are white cells, leucophores, present in a variety of species that contribute to patterns on the body or ornamentation on the fins. To better understand developmental and evolutionary origins of these cells, we examined leucophores harboring deposits of yellow/orange carotenoids—xantholeucophores—of zebrafish and leucophores of white cloud minnow. We show that white phenotypes of both cell types require sepiapterin reductase and an accumulation of pale and colorless pteridines. We further demonstrate that xantholeucophores of zebrafish develop from yellow, sepiapterin-rich xanthophore-like cells and that this transition requires both gap junctional communication and the aquaglyceroporin/peroxiporin channel Aquaporin 3, revealing similarities and differences in differentiation and patterning compared to pigment cells on the body. These findings identify xantholeucophores of zebrafish and leucophores of white cloud minnow as distinct developmentally, genetically, and biochemically from other white cells of zebrafish—melanoleucophores—that develop directly from melanophores and depend on guanine crystals, as well as white cells of medaka fish and anemonefish. Our results highlight remarkable convergences and parallelisms in the acquisition of white cell phenotypes within and between phylogenetic lineages and identify this as a rich system for enquiries into the evolutionary individuation of novel cell types.
{"title":"Cell type diversification and phenotype convergence underlying white fin-ornamentation of cyprinid fishes","authors":"Delai Huang, Tiffany Liu, August A. Carr, Pietro H. de Mello, Yipeng Liang, Leah P. Shriver, François Chauvigné, Stephen L. Johnson, Joan Cerdà, Gary J. Patti, David M. Parichy","doi":"10.1073/pnas.2537571123","DOIUrl":"https://doi.org/10.1073/pnas.2537571123","url":null,"abstract":"Neural crest–derived cells offer valuable opportunities to dissect mechanisms of cell fate specification and differentiation and the underpinnings of cell type diversification over evolutionary time. Particularly useful for such analyses are pigment cells of ectothermic vertebrates that arise from neural crest cells or via latent neural crest–derived stem cells. Among these are white cells, leucophores, present in a variety of species that contribute to patterns on the body or ornamentation on the fins. To better understand developmental and evolutionary origins of these cells, we examined leucophores harboring deposits of yellow/orange carotenoids—xantholeucophores—of zebrafish and leucophores of white cloud minnow. We show that white phenotypes of both cell types require sepiapterin reductase and an accumulation of pale and colorless pteridines. We further demonstrate that xantholeucophores of zebrafish develop from yellow, sepiapterin-rich xanthophore-like cells and that this transition requires both gap junctional communication and the aquaglyceroporin/peroxiporin channel Aquaporin 3, revealing similarities and differences in differentiation and patterning compared to pigment cells on the body. These findings identify xantholeucophores of zebrafish and leucophores of white cloud minnow as distinct developmentally, genetically, and biochemically from other white cells of zebrafish—melanoleucophores—that develop directly from melanophores and depend on guanine crystals, as well as white cells of medaka fish and anemonefish. Our results highlight remarkable convergences and parallelisms in the acquisition of white cell phenotypes within and between phylogenetic lineages and identify this as a rich system for enquiries into the evolutionary individuation of novel cell types.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"60 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507101","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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