Parker R. Stow, Kiefer O. Forsch, Emil Thomsen, Hiroaki Naka, Margo G. Haygood, Katherine A. Barbeau, Alison Butler
Bacteria compete for iron by producing small-molecule chelators known as siderophores. The triscatechol siderophores trivanchrobactin and ruckerbactin, produced by Vibrio campbellii DS40M4 and Yersinia ruckeri YRB, respectively, are naturally occurring diastereomers that form chiral ferric complexes in opposing enantiomeric configurations. Chiral recognition is a hallmark of specificity in biological systems, yet the biological consequences of chiral coordination compounds are relatively unexplored. We demonstrate stereoselective discrimination of microbial growth and iron uptake by chiral Fe(III)–siderophores. The siderophore utilization pathway in V. campbellii DS40M4 is stereoselective for Λ-Fe(III)–trivanchrobactin, but not the mismatched Δ-Fe(III)–ruckerbactin diastereomer. Chiral recognition is likely conferred by the stereospecificity of both the outer membrane receptor (OMR) protein FvtA and the periplasmic binding protein (PBP) FvtB, both of which must interact preferentially with the Λ-configured Fe(III)-coordination complexes.
{"title":"Stereospecific control of microbial growth by a combinatoric suite of chiral siderophores","authors":"Parker R. Stow, Kiefer O. Forsch, Emil Thomsen, Hiroaki Naka, Margo G. Haygood, Katherine A. Barbeau, Alison Butler","doi":"10.1073/pnas.2423730122","DOIUrl":"https://doi.org/10.1073/pnas.2423730122","url":null,"abstract":"Bacteria compete for iron by producing small-molecule chelators known as siderophores. The triscatechol siderophores trivanchrobactin and ruckerbactin, produced by <jats:italic>Vibrio campbellii</jats:italic> DS40M4 and <jats:italic>Yersinia ruckeri</jats:italic> YRB, respectively, are naturally occurring diastereomers that form chiral ferric complexes in opposing enantiomeric configurations. Chiral recognition is a hallmark of specificity in biological systems, yet the biological consequences of chiral coordination compounds are relatively unexplored. We demonstrate stereoselective discrimination of microbial growth and iron uptake by chiral Fe(III)–siderophores. The siderophore utilization pathway in <jats:italic>V. campbellii</jats:italic> DS40M4 is stereoselective for Λ-Fe(III)–trivanchrobactin, but not the mismatched Δ-Fe(III)–ruckerbactin diastereomer. Chiral recognition is likely conferred by the stereospecificity of both the outer membrane receptor (OMR) protein FvtA and the periplasmic binding protein (PBP) FvtB, both of which must interact preferentially with the Λ-configured Fe(III)-coordination complexes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"26 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538495","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}
Elizabeth A. Johnson, Raghad Nowar, Kirsten L. Viola, Weijian Huang, Sihang Zhou, Maíra A. Bicca, Wei Zhu, Daniel L. Kranz, William L. Klein, Richard B. Silverman
Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11 , e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer’s disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22 , 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.
{"title":"Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases","authors":"Elizabeth A. Johnson, Raghad Nowar, Kirsten L. Viola, Weijian Huang, Sihang Zhou, Maíra A. Bicca, Wei Zhu, Daniel L. Kranz, William L. Klein, Richard B. Silverman","doi":"10.1073/pnas.2402117122","DOIUrl":"https://doi.org/10.1073/pnas.2402117122","url":null,"abstract":"Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., <jats:italic>Clin. Transl. Med.</jats:italic> 11 , e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer’s disease neurodegeneration [M. Tolar et al., <jats:italic>Int. J. Mol. Sci.</jats:italic> 22 , 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"211 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538469","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}
Jonathan Wilson, Vanessa C. Bieker, Lotte van Boheemen, Tim Connallon, Michael D. Martin, Paul Battlay, Kathryn A. Hodgins
Adaptation is a critical determinant of the diversification, persistence, and geographic range limits of species. Yet the genetic basis of adaptation is often unknown and potentially underpinned by a wide range of mutational types—from single nucleotide changes to large-scale alterations of chromosome structure. Copy number variation (CNV) is thought to be an important source of adaptive genetic variation, as indicated by decades of candidate gene studies that point to CNVs underlying rapid adaptation to strong selective pressures. Nevertheless, population-genomic studies of CNVs face unique logistical challenges not encountered by other forms of genetic variation. Consequently, few studies have systematically investigated the contributions of CNVs to adaptation at a genome-wide scale. We present a genome-wide analysis of CNV contributing to the adaptation of an invasive weed, Ambrosia artemisiifolia . CNVs show clear signatures of parallel local adaptation between North American (native) and European (invaded) ranges, implying widespread reuse of CNVs during adaptation to shared heterogeneous patterns of selection. We used a local principal component analysis (PCA) to genotype CNV regions in whole-genome sequences of samples collected over the last two centuries. We identified 16 large CNV regions of up to 11.85 megabases in length, eight of which show signals of rapid evolutionary change, with pronounced frequency shifts between historic and modern populations. Our results provide compelling genome-wide evidence that CNV underlies rapid adaptation over contemporary timescales of natural populations.
{"title":"Copy number variation contributes to parallel local adaptation in an invasive plant","authors":"Jonathan Wilson, Vanessa C. Bieker, Lotte van Boheemen, Tim Connallon, Michael D. Martin, Paul Battlay, Kathryn A. Hodgins","doi":"10.1073/pnas.2413587122","DOIUrl":"https://doi.org/10.1073/pnas.2413587122","url":null,"abstract":"Adaptation is a critical determinant of the diversification, persistence, and geographic range limits of species. Yet the genetic basis of adaptation is often unknown and potentially underpinned by a wide range of mutational types—from single nucleotide changes to large-scale alterations of chromosome structure. Copy number variation (CNV) is thought to be an important source of adaptive genetic variation, as indicated by decades of candidate gene studies that point to CNVs underlying rapid adaptation to strong selective pressures. Nevertheless, population-genomic studies of CNVs face unique logistical challenges not encountered by other forms of genetic variation. Consequently, few studies have systematically investigated the contributions of CNVs to adaptation at a genome-wide scale. We present a genome-wide analysis of CNV contributing to the adaptation of an invasive weed, <jats:italic>Ambrosia artemisiifolia</jats:italic> . CNVs show clear signatures of parallel local adaptation between North American (native) and European (invaded) ranges, implying widespread reuse of CNVs during adaptation to shared heterogeneous patterns of selection. We used a local principal component analysis (PCA) to genotype CNV regions in whole-genome sequences of samples collected over the last two centuries. We identified 16 large CNV regions of up to 11.85 megabases in length, eight of which show signals of rapid evolutionary change, with pronounced frequency shifts between historic and modern populations. Our results provide compelling genome-wide evidence that CNV underlies rapid adaptation over contemporary timescales of natural populations.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"34 11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538465","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}
Shaoqing Liu, Ovidiu Csillik, Elsa M. Ordway, Li-Ling Chang, Marcos Longo, Michael Keller, Paul R. Moorcroft
Forest canopy height is a fundamental ecosystem property—influencing patterns of forest carbon storage and forest ecosystem responses to climate variability and change. Previous studies have analyzed environmental drivers influencing spatial variation in canopy height at landscape-to-regional scales; however, far less is known about the environmental determinants underlying regional and global scale variation in forest canopy height. Using the canopy height metrics products from Global Ecosystem Dynamics Investigation (GEDI), a space-borne Light Detection and Ranging (LiDAR) instrument specifically designed to characterize forest structure, we analyze the environmental correlates of spatial variation of global tropical forest canopy height. Our study demonstrates that climate, topography, and soil properties account for 75% of the variation in tropical forest canopy height. Elevation, dry season length, and solar radiation are the most important drivers in determining canopy height both locally and regionally. These results emphasize the vulnerability of tropical forest structure to ongoing changes in the earth’s climate and provide a valuable empirical baseline for tropical forest management.
{"title":"Environmental drivers of spatial variation in tropical forest canopy height: Insights from NASA’s GEDI spaceborne LiDAR","authors":"Shaoqing Liu, Ovidiu Csillik, Elsa M. Ordway, Li-Ling Chang, Marcos Longo, Michael Keller, Paul R. Moorcroft","doi":"10.1073/pnas.2401755122","DOIUrl":"https://doi.org/10.1073/pnas.2401755122","url":null,"abstract":"Forest canopy height is a fundamental ecosystem property—influencing patterns of forest carbon storage and forest ecosystem responses to climate variability and change. Previous studies have analyzed environmental drivers influencing spatial variation in canopy height at landscape-to-regional scales; however, far less is known about the environmental determinants underlying regional and global scale variation in forest canopy height. Using the canopy height metrics products from Global Ecosystem Dynamics Investigation (GEDI), a space-borne Light Detection and Ranging (LiDAR) instrument specifically designed to characterize forest structure, we analyze the environmental correlates of spatial variation of global tropical forest canopy height. Our study demonstrates that climate, topography, and soil properties account for 75% of the variation in tropical forest canopy height. Elevation, dry season length, and solar radiation are the most important drivers in determining canopy height both locally and regionally. These results emphasize the vulnerability of tropical forest structure to ongoing changes in the earth’s climate and provide a valuable empirical baseline for tropical forest management.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538470","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}
Tanvi Saxena, Anan Quan, Erica Chan, Nina Kozlova, Latika Matai, Jonathan D. Lee, Rajesha Rupaimoole, Francisco Beca, Taru Muranen, Frank J. Slack
Long noncoding RNAs (lncRNAs) play numerous roles in cellular biology and alterations in lncRNA expression profiles have been implicated in a variety of cancers. Here, we identify and characterize a lncRNA, TRIM28 Interacting DNA damage repair Enhancing Noncoding Transcript ( TRIDENT ), whose expression is induced upon epithelial growth factor receptor (EGFR) activation, and which exerts pro-oncogenic functions in EGFR-driven non–small cell lung cancer. Knocking down TRIDENT leads to decreased tumor-cell proliferation in both in vitro and in vivo model systems and induces sensitization to chemotherapeutic drugs. Using ChIRP-MS analysis we identified TRIM28 as a protein interactor of TRIDENT . TRIDENT promotes phosphorylation of TRIM28 and knocking down TRIDENT leads to accumulation of DNA damage in cancer cells via decreased TRIM28 phosphorylation. Altogether, our results reveal a molecular pathway in which TRIDENT regulates TRIM28 phosphorylation to promote tumor cell growth and drug resistance. Our findings suggest that TRIDENT can be developed as a biomarker or therapeutic target for EGFR mutant non–small cell lung cancer.
{"title":"EGFR-induced lncRNA TRIDENT promotes drug resistance in non–small cell lung cancer via phospho-TRIM28-mediated DNA damage repair","authors":"Tanvi Saxena, Anan Quan, Erica Chan, Nina Kozlova, Latika Matai, Jonathan D. Lee, Rajesha Rupaimoole, Francisco Beca, Taru Muranen, Frank J. Slack","doi":"10.1073/pnas.2415389122","DOIUrl":"https://doi.org/10.1073/pnas.2415389122","url":null,"abstract":"Long noncoding RNAs (lncRNAs) play numerous roles in cellular biology and alterations in lncRNA expression profiles have been implicated in a variety of cancers. Here, we identify and characterize a lncRNA, TRIM28 Interacting DNA damage repair Enhancing Noncoding Transcript ( <jats:italic>TRIDENT</jats:italic> ), whose expression is induced upon epithelial growth factor receptor (EGFR) activation, and which exerts pro-oncogenic functions in EGFR-driven non–small cell lung cancer. Knocking down <jats:italic>TRIDENT</jats:italic> leads to decreased tumor-cell proliferation in both in vitro and in vivo model systems and induces sensitization to chemotherapeutic drugs. Using ChIRP-MS analysis we identified TRIM28 as a protein interactor of <jats:italic>TRIDENT</jats:italic> . <jats:italic>TRIDENT</jats:italic> promotes phosphorylation of TRIM28 and knocking down <jats:italic>TRIDENT</jats:italic> leads to accumulation of DNA damage in cancer cells via decreased TRIM28 phosphorylation. Altogether, our results reveal a molecular pathway in which <jats:italic>TRIDENT</jats:italic> regulates TRIM28 phosphorylation to promote tumor cell growth and drug resistance. Our findings suggest that <jats:italic>TRIDENT</jats:italic> can be developed as a biomarker or therapeutic target for <jats:italic>EGFR</jats:italic> mutant non–small cell lung cancer.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538474","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}
Weilai Dong, Sheng Chih Jin, Michael C. Sierant, Ziyu Lu, Boyang Li, Qiongshi Lu, Sarah U. Morton, Junhui Zhang, Francesc López-Giráldez, Carol Nelson-Williams, James R. Knight, Hongyu Zhao, Junyue Cao, Shrikant Mane, Peter J. Gruber, Monkol Lek, Elizabeth Goldmuntz, John Deanfield, Alessandro Giardini, Seema Mital, Mark Russell, J. William Gaynor, James F. Cnota, Michael Wagner, Deepak Srivastava, Daniel Bernstein, George A. Porter, Jane Newburger, Amy E. Roberts, Mark Yandell, H. Joseph Yost, Martin Tristani-Firouzi, Richard Kim, Jonathan Seidman, Wendy K. Chung, Bruce D. Gelb, Christine E. Seidman, Richard P. Lifton, Martina Brueckner
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in GDF1 and PLD1 accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands. We identified genome-wide significant enrichment of RGs in C1orf127 , encoding a likely secreted protein expressed in embryonic mouse notochord and associated with laterality defects. Single-cell transcriptomes from gastrulation-stage mouse embryos revealed enrichment of RGs in genes highly expressed in the cardiomyocyte lineage, including contractility-related genes MYH6, UNC45B , MYO18B , and MYBPC3 in probands with left-sided CHD, consistent with abnormal contractile function contributing to these malformations. Genes with significant RG burden account for 1.3% of probands, more than half the inferred total. These results reveal the recessive contribution to CHD, and indicate that many genes remain to be discovered, with each likely accounting for a very small fraction of the total.
{"title":"Recessive genetic contribution to congenital heart disease in 5,424 probands","authors":"Weilai Dong, Sheng Chih Jin, Michael C. Sierant, Ziyu Lu, Boyang Li, Qiongshi Lu, Sarah U. Morton, Junhui Zhang, Francesc López-Giráldez, Carol Nelson-Williams, James R. Knight, Hongyu Zhao, Junyue Cao, Shrikant Mane, Peter J. Gruber, Monkol Lek, Elizabeth Goldmuntz, John Deanfield, Alessandro Giardini, Seema Mital, Mark Russell, J. William Gaynor, James F. Cnota, Michael Wagner, Deepak Srivastava, Daniel Bernstein, George A. Porter, Jane Newburger, Amy E. Roberts, Mark Yandell, H. Joseph Yost, Martin Tristani-Firouzi, Richard Kim, Jonathan Seidman, Wendy K. Chung, Bruce D. Gelb, Christine E. Seidman, Richard P. Lifton, Martina Brueckner","doi":"10.1073/pnas.2419992122","DOIUrl":"https://doi.org/10.1073/pnas.2419992122","url":null,"abstract":"Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in <jats:italic>GDF1</jats:italic> and <jats:italic>PLD1</jats:italic> accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands. We identified genome-wide significant enrichment of RGs in <jats:italic>C1orf127</jats:italic> , encoding a likely secreted protein expressed in embryonic mouse notochord and associated with laterality defects. Single-cell transcriptomes from gastrulation-stage mouse embryos revealed enrichment of RGs in genes highly expressed in the cardiomyocyte lineage, including contractility-related genes <jats:italic>MYH6, UNC45B</jats:italic> , <jats:italic>MYO18B</jats:italic> , and <jats:italic>MYBPC3</jats:italic> in probands with left-sided CHD, consistent with abnormal contractile function contributing to these malformations. Genes with significant RG burden account for 1.3% of probands, more than half the inferred total. These results reveal the recessive contribution to CHD, and indicate that many genes remain to be discovered, with each likely accounting for a very small fraction of the total.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538464","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}
Jordan J. Winetrout, Zilu Li, Qi Zhao, Landon Gaber, Vinu Unnikrishnan, Vikas Varshney, Yanxun Xu, Yusu Wang, Hendrik Heinz
Graphene-based nanostructures hold immense potential as strong and lightweight materials, however, their mechanical properties such as modulus and strength are difficult to fully exploit due to challenges in atomic-scale engineering. This study presents a database of over 2,000 pristine and defective nanoscale CNT bundles and other graphitic assemblies, inspired by microscopy, with associated stress–strain curves from reactive molecular dynamics (MD) simulations using the reactive INTERFACE force field (IFF-R). These 3D structures, containing up to 80,000 atoms, enable detailed analyses of structure-stiffness-failure relationships. By leveraging the database and physics- and chemistry-informed machine learning (ML), accurate predictions of elastic moduli and tensile strength are demonstrated at speeds 1,000 to 10,000 times faster than efficient MD simulations. Hierarchical Graph Neural Networks with Spatial Information (HS-GNNs) are introduced, which integrate chemistry knowledge. HS-GNNs as well as extreme gradient boosted trees (XGBoost) achieve forecasts of mechanical properties of arbitrary carbon nanostructures with only 3 to 6% mean relative error. The reliability equals experimental accuracy and is up to 20 times higher than other ML methods. Predictions maintain 8 to 18% accuracy for large CNT bundles, CNT junctions, and carbon fiber cross-sections outside the training distribution. The physics- and chemistry-informed HS-GNN works remarkably well for data outside the training range while XGBoost works well with limited training data inside the training range. The carbon nanostructure database is designed for integration with multimodal experimental and simulation data, scalable beyond 100 nm size, and extendable to chemically similar compounds and broader property ranges. The ML approaches have potential for applications in structural materials, nanoelectronics, and carbon-based catalysts.
{"title":"Prediction of carbon nanostructure mechanical properties and the role of defects using machine learning","authors":"Jordan J. Winetrout, Zilu Li, Qi Zhao, Landon Gaber, Vinu Unnikrishnan, Vikas Varshney, Yanxun Xu, Yusu Wang, Hendrik Heinz","doi":"10.1073/pnas.2415068122","DOIUrl":"https://doi.org/10.1073/pnas.2415068122","url":null,"abstract":"Graphene-based nanostructures hold immense potential as strong and lightweight materials, however, their mechanical properties such as modulus and strength are difficult to fully exploit due to challenges in atomic-scale engineering. This study presents a database of over 2,000 pristine and defective nanoscale CNT bundles and other graphitic assemblies, inspired by microscopy, with associated stress–strain curves from reactive molecular dynamics (MD) simulations using the reactive INTERFACE force field (IFF-R). These 3D structures, containing up to 80,000 atoms, enable detailed analyses of structure-stiffness-failure relationships. By leveraging the database and physics- and chemistry-informed machine learning (ML), accurate predictions of elastic moduli and tensile strength are demonstrated at speeds 1,000 to 10,000 times faster than efficient MD simulations. Hierarchical Graph Neural Networks with Spatial Information (HS-GNNs) are introduced, which integrate chemistry knowledge. HS-GNNs as well as extreme gradient boosted trees (XGBoost) achieve forecasts of mechanical properties of arbitrary carbon nanostructures with only 3 to 6% mean relative error. The reliability equals experimental accuracy and is up to 20 times higher than other ML methods. Predictions maintain 8 to 18% accuracy for large CNT bundles, CNT junctions, and carbon fiber cross-sections outside the training distribution. The physics- and chemistry-informed HS-GNN works remarkably well for data outside the training range while XGBoost works well with limited training data inside the training range. The carbon nanostructure database is designed for integration with multimodal experimental and simulation data, scalable beyond 100 nm size, and extendable to chemically similar compounds and broader property ranges. The ML approaches have potential for applications in structural materials, nanoelectronics, and carbon-based catalysts.","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":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538475","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}
Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that Tex38 knockout (KO) male mice are infertile. Tex38 KO spermatids exhibit excess retention of residual cytoplasm around the head, resulting in abnormal sperm morphology with backward head bending. TEX38 interacts and colocalizes with ZDHHC19, a testis-enriched acyltransferase catalyzing protein S-palmitoylation, at the plasma membrane of spermatids. ZDHHC19 and TEX38 are each downregulated in mouse testes lacking the other protein. TEX38 stabilizes and localizes ZDHHC19 to the plasma membrane of cultured cells and vice versa, consolidating their interdependence. Mice deficient in ZDHHC19 or harboring a C142S mutation that disables the palmitoyltransferase activity of ZDHHC19 display phenotypes resembling those of Tex38 KO mice. Strikingly, ZDHHC19 palmitoylates ARRDC5, an arrestin family protein regulating sperm differentiation. Overall, our findings indicate that TEX38 forms a stable complex with ZDHHC19 at the plasma membrane of spermatids, which governs downstream S-palmitoylation of proteins essential for morphological transformation of spermatids.
{"title":"TEX38 localizes ZDHHC19 to the plasma membrane and regulates sperm head morphogenesis in mice","authors":"Yuki Kaneda, Yonggang Lu, Jiang Sun, Keisuke Shimada, Chihiro Emori, Taichi Noda, Takayuki Koyano, Makoto Matsuyama, Haruhiko Miyata, Masahito Ikawa","doi":"10.1073/pnas.2417943122","DOIUrl":"https://doi.org/10.1073/pnas.2417943122","url":null,"abstract":"Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that <jats:italic>Tex38</jats:italic> knockout (KO) male mice are infertile. <jats:italic>Tex38</jats:italic> KO spermatids exhibit excess retention of residual cytoplasm around the head, resulting in abnormal sperm morphology with backward head bending. TEX38 interacts and colocalizes with ZDHHC19, a testis-enriched acyltransferase catalyzing protein S-palmitoylation, at the plasma membrane of spermatids. ZDHHC19 and TEX38 are each downregulated in mouse testes lacking the other protein. TEX38 stabilizes and localizes ZDHHC19 to the plasma membrane of cultured cells and vice versa, consolidating their interdependence. Mice deficient in ZDHHC19 or harboring a C142S mutation that disables the palmitoyltransferase activity of ZDHHC19 display phenotypes resembling those of <jats:italic>Tex38</jats:italic> KO mice. Strikingly, ZDHHC19 palmitoylates ARRDC5, an arrestin family protein regulating sperm differentiation. Overall, our findings indicate that TEX38 forms a stable complex with ZDHHC19 at the plasma membrane of spermatids, which governs downstream S-palmitoylation of proteins essential for morphological transformation of spermatids.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538496","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}
Botond B. Antal, Helena van Nieuwenhuizen, Anthony G. Chesebro, Helmut H. Strey, David T. Jones, Kieran Clarke, Corey Weistuch, Eva-Maria Ratai, Ken A. Dill, Lilianne R. Mujica-Parodi
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal “landmarks” of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain’s regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons’ energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife “critical window” for early metabolic intervention.
{"title":"Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention","authors":"Botond B. Antal, Helena van Nieuwenhuizen, Anthony G. Chesebro, Helmut H. Strey, David T. Jones, Kieran Clarke, Corey Weistuch, Eva-Maria Ratai, Ken A. Dill, Lilianne R. Mujica-Parodi","doi":"10.1073/pnas.2416433122","DOIUrl":"https://doi.org/10.1073/pnas.2416433122","url":null,"abstract":"Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal “landmarks” of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain’s regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons’ energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife “critical window” for early metabolic intervention.","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":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538471","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}
Jinjun Gao, Ruilong Liu, Kevin Huang, Ziyuan Li, Xinlei Sheng, Kasturi Chakraborty, Chang Han, Di Zhang, Lev Becker, Yingming Zhao
The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (K L-la ), two isomeric modifications, lysine D-lactylation (K D-la ) and N-ε-(carboxyethyl) lysine (K ce ), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular K L-la , but not K D-la or K ce , is up-regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on K D-la , K ce , or hypoxia-induced K L-la . Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of K L-la but increased K D-la and K ce . We further observed a correlation between the level of K L-la and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and K L-la in lung cancer tissues and that patient samples with higher grade tend to have higher K L-la levels. Using a proteomics approach, we quantified 66 K L-la sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced K L-la . Collectively, our study demonstrates that K L-la , rather than K D-la or K ce , is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between K L-la and the hypoxia-induced adaptation of tumor cells.
{"title":"Dynamic investigation of hypoxia-induced L-lactylation","authors":"Jinjun Gao, Ruilong Liu, Kevin Huang, Ziyuan Li, Xinlei Sheng, Kasturi Chakraborty, Chang Han, Di Zhang, Lev Becker, Yingming Zhao","doi":"10.1073/pnas.2404899122","DOIUrl":"https://doi.org/10.1073/pnas.2404899122","url":null,"abstract":"The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (K <jats:sub>L-la</jats:sub> ), two isomeric modifications, lysine D-lactylation (K <jats:sub>D-la</jats:sub> ) and N-ε-(carboxyethyl) lysine (K <jats:sub>ce</jats:sub> ), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular K <jats:sub>L-la</jats:sub> , but not K <jats:sub>D-la</jats:sub> or K <jats:sub>ce</jats:sub> , is up-regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on K <jats:sub>D-la</jats:sub> , K <jats:sub>ce</jats:sub> , or hypoxia-induced K <jats:sub>L-la</jats:sub> . Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of K <jats:sub>L-la</jats:sub> but increased K <jats:sub>D-la</jats:sub> and K <jats:sub>ce</jats:sub> . We further observed a correlation between the level of K <jats:sub>L-la</jats:sub> and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and K <jats:sub>L-la</jats:sub> in lung cancer tissues and that patient samples with higher grade tend to have higher K <jats:sub>L-la</jats:sub> levels. Using a proteomics approach, we quantified 66 K <jats:sub>L-la</jats:sub> sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced K <jats:sub>L-la</jats:sub> . Collectively, our study demonstrates that K <jats:sub>L-la</jats:sub> , rather than K <jats:sub>D-la</jats:sub> or K <jats:sub>ce</jats:sub> , is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between K <jats:sub>L-la</jats:sub> and the hypoxia-induced adaptation of tumor cells.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"36 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538463","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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