Pub Date : 2024-10-29DOI: 10.1038/s42003-024-06952-6
Shourav Pednekar, Ankita Jain, Olav Rune Godø, Nicholas C. Makris
Sensing limitations have impeded knowledge about how individual predator-prey interactions build to organized multi-species group behaviour across an ecosystem. Population densities of overlapping interacting oceanic fish predator and prey species, however, can be instantaneously distinguished and quantified from roughly the elemental individual to spatial scales spanning thousands of square kilometres by wide-area multispectral underwater-acoustic sensing, as shown here. This enables fundamental mechanisms behind large-scale ordered predator-prey interactions to be investigated. Critical population densities that transition random individual behaviour to ordered group behaviour are found to rapidly propagate to form vast adversarial prey and predator shoals of capelin and surrounding cod in the Barents Sea Arctic ecosystem for these keystone species. This leads to a sudden major shift in predator-prey balance. Only a small change in local behaviour triggers the shift due to an unstable equilibrium. Such unstable equilibria and associated balance shifts at predation hotspots are often overlooked as blind spots in present ocean ecosystem monitoring and assessment due to use of highly undersampled spatio-temporal sampling methods. This study utilises OAWRS to demonstrate mass shoaling behaviour of predatory cod and their capelin prey in the Barents Sea. The result is a mass consumption event, skewing the predator-prey ratio with implications for ecosystem stability.
{"title":"Rapid predator-prey balance shift follows critical-population-density transmission between cod (Gadus morhua) and capelin (Mallotus villosus)","authors":"Shourav Pednekar, Ankita Jain, Olav Rune Godø, Nicholas C. Makris","doi":"10.1038/s42003-024-06952-6","DOIUrl":"10.1038/s42003-024-06952-6","url":null,"abstract":"Sensing limitations have impeded knowledge about how individual predator-prey interactions build to organized multi-species group behaviour across an ecosystem. Population densities of overlapping interacting oceanic fish predator and prey species, however, can be instantaneously distinguished and quantified from roughly the elemental individual to spatial scales spanning thousands of square kilometres by wide-area multispectral underwater-acoustic sensing, as shown here. This enables fundamental mechanisms behind large-scale ordered predator-prey interactions to be investigated. Critical population densities that transition random individual behaviour to ordered group behaviour are found to rapidly propagate to form vast adversarial prey and predator shoals of capelin and surrounding cod in the Barents Sea Arctic ecosystem for these keystone species. This leads to a sudden major shift in predator-prey balance. Only a small change in local behaviour triggers the shift due to an unstable equilibrium. Such unstable equilibria and associated balance shifts at predation hotspots are often overlooked as blind spots in present ocean ecosystem monitoring and assessment due to use of highly undersampled spatio-temporal sampling methods. This study utilises OAWRS to demonstrate mass shoaling behaviour of predatory cod and their capelin prey in the Barents Sea. The result is a mass consumption event, skewing the predator-prey ratio with implications for ecosystem stability.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-06952-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1038/s42003-024-07100-w
Samuel C. Carr, Fasih Rehman, Jillian M. Hagel, Xue Chen, Kenneth K. S. Ng, Peter J. Facchini
The evolution of morphinan alkaloid biosynthesis in plants of the genus Papaver includes permutation of several processes including gene duplication, fusion, neofunctionalization, and deletion resulting in the present chemotaxonomy. A critical gene fusion event resulting in the key bifunctional enzyme reticuline epimerase (REPI), which catalyzes the stereochemical inversion of (S)-reticuline, was suggested to precede neofunctionalization of downstream enzymes leading to morphine biosynthesis in opium poppy (Papaver somniferum). The ancestrally related aldo-keto reductases 1,2-dehydroreticuline reductase (DRR), which occurs in some species as a component of REPI, and codeinone reductase (COR) catalyze the second and penultimate steps, respectively, in the pathway converting (S)-reticuline to morphine. Orthologs for each enzyme isolated from the transcriptomes of 12 Papaver species were shown to catalyze their respective reactions in species that capture states of the metabolic pathway prior to key evolutionary events, including the gene fusion event leading to REPI, thus suggesting a patchwork model for pathway evolution. Analysis of the structure and substrate preferences of DRR orthologs in comparison with COR orthologs revealed structure-function relationships underpinning the functional latency of DRR and COR orthologs in the genus Papaver, thus providing insights into the molecular events leading to the evolution of the pathway. Conservation across the Papaver genus of two aldo-keto reductases catalyzing the second and penultimate steps in morphine biosynthesis reveals the latent activity of several enzymes and suggests a patchwork model of pathway evolution in opium poppy.
{"title":"Two ubiquitous aldo-keto reductases in the genus Papaver support a patchwork model for morphine pathway evolution","authors":"Samuel C. Carr, Fasih Rehman, Jillian M. Hagel, Xue Chen, Kenneth K. S. Ng, Peter J. Facchini","doi":"10.1038/s42003-024-07100-w","DOIUrl":"10.1038/s42003-024-07100-w","url":null,"abstract":"The evolution of morphinan alkaloid biosynthesis in plants of the genus Papaver includes permutation of several processes including gene duplication, fusion, neofunctionalization, and deletion resulting in the present chemotaxonomy. A critical gene fusion event resulting in the key bifunctional enzyme reticuline epimerase (REPI), which catalyzes the stereochemical inversion of (S)-reticuline, was suggested to precede neofunctionalization of downstream enzymes leading to morphine biosynthesis in opium poppy (Papaver somniferum). The ancestrally related aldo-keto reductases 1,2-dehydroreticuline reductase (DRR), which occurs in some species as a component of REPI, and codeinone reductase (COR) catalyze the second and penultimate steps, respectively, in the pathway converting (S)-reticuline to morphine. Orthologs for each enzyme isolated from the transcriptomes of 12 Papaver species were shown to catalyze their respective reactions in species that capture states of the metabolic pathway prior to key evolutionary events, including the gene fusion event leading to REPI, thus suggesting a patchwork model for pathway evolution. Analysis of the structure and substrate preferences of DRR orthologs in comparison with COR orthologs revealed structure-function relationships underpinning the functional latency of DRR and COR orthologs in the genus Papaver, thus providing insights into the molecular events leading to the evolution of the pathway. Conservation across the Papaver genus of two aldo-keto reductases catalyzing the second and penultimate steps in morphine biosynthesis reveals the latent activity of several enzymes and suggests a patchwork model of pathway evolution in opium poppy.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07100-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1038/s42003-024-07113-5
Luciano A. Abriata
The work by Hassabis and Jumper on protein structure prediction together with Baker’s supremacy in de novo protein design set the stage for a future where AI not only deciphers biology at the atomic level but also designs new molecules for biotechnology, medicine, and beyond. I provide an overview of the recent past, the present, and the future of AI in structural biology, from how it all started with the Critical Assessment of Structure Prediction (CASP) experiments and a protein engineering lab, to how the field could further evolve with AI models that eventually “understand” biology holistically. A Comment on the transformative progress of artificial intelligence for structural and protein biology, referencing the 2024 Nobel Prize in Chemistry.
{"title":"The Nobel Prize in Chemistry: past, present, and future of AI in biology","authors":"Luciano A. Abriata","doi":"10.1038/s42003-024-07113-5","DOIUrl":"10.1038/s42003-024-07113-5","url":null,"abstract":"The work by Hassabis and Jumper on protein structure prediction together with Baker’s supremacy in de novo protein design set the stage for a future where AI not only deciphers biology at the atomic level but also designs new molecules for biotechnology, medicine, and beyond. I provide an overview of the recent past, the present, and the future of AI in structural biology, from how it all started with the Critical Assessment of Structure Prediction (CASP) experiments and a protein engineering lab, to how the field could further evolve with AI models that eventually “understand” biology holistically. A Comment on the transformative progress of artificial intelligence for structural and protein biology, referencing the 2024 Nobel Prize in Chemistry.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07113-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Long-term single-molecule fluorescence measurements are widely used powerful tools to study the conformational dynamics of biomolecules in real time to further elucidate their conformational dynamics. Typically, thousands or even more single-molecule traces are analyzed to provide statistically meaningful information, which is labor-intensive and can introduce user bias. Recently, several deep-learning models have been developed to automatically classify single-molecule traces. In this study, we introduce DEBRIS (Deep lEarning Based fRagmentatIon approach for Single-molecule fluorescence event identification), a deep-learning model focusing on classifying local features and capable of automatically identifying steady fluorescence signals and dynamically emerging signals of different patterns. DEBRIS efficiently and accurately identifies both one-color and two-color single-molecule events, including their start and end points. By adjusting user-defined criteria, DEBRIS becomes the pioneer in using a deep learning model to accurately classify four different types of single-molecule fluorescence events using the same trained model, demonstrating its universality and ability to enrich the current toolbox. DEBRIS is a deep learning-based model that can classify local features and identify steady events and dynamically emerging events within two-color single-molecule traces of varying lengths based on user-defined criteria.
{"title":"Deep learning based local feature classification to automatically identify single molecule fluorescence events","authors":"Shuqi Zhou, Yu Miao, Haoren Qiu, Yuan Yao, Wenjuan Wang, Chunlai Chen","doi":"10.1038/s42003-024-07122-4","DOIUrl":"10.1038/s42003-024-07122-4","url":null,"abstract":"Long-term single-molecule fluorescence measurements are widely used powerful tools to study the conformational dynamics of biomolecules in real time to further elucidate their conformational dynamics. Typically, thousands or even more single-molecule traces are analyzed to provide statistically meaningful information, which is labor-intensive and can introduce user bias. Recently, several deep-learning models have been developed to automatically classify single-molecule traces. In this study, we introduce DEBRIS (Deep lEarning Based fRagmentatIon approach for Single-molecule fluorescence event identification), a deep-learning model focusing on classifying local features and capable of automatically identifying steady fluorescence signals and dynamically emerging signals of different patterns. DEBRIS efficiently and accurately identifies both one-color and two-color single-molecule events, including their start and end points. By adjusting user-defined criteria, DEBRIS becomes the pioneer in using a deep learning model to accurately classify four different types of single-molecule fluorescence events using the same trained model, demonstrating its universality and ability to enrich the current toolbox. DEBRIS is a deep learning-based model that can classify local features and identify steady events and dynamically emerging events within two-color single-molecule traces of varying lengths based on user-defined criteria.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07122-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1038/s42003-024-07088-3
Ruslan Masharipov, Irina Knyazeva, Alexander Korotkov, Denis Cherednichenko, Maxim Kireev
Higher brain functions require flexible integration of information across widely distributed brain regions depending on the task context. Resting-state functional magnetic resonance imaging (fMRI) has provided substantial insight into large-scale intrinsic brain network organisation, yet the principles of rapid context-dependent reconfiguration of that intrinsic network organisation are much less understood. A major challenge for task connectome mapping is the absence of a gold standard for deriving whole-brain task-modulated functional connectivity matrices. Here, we perform biophysically realistic simulations to control the ground-truth task-modulated functional connectivity over a wide range of experimental settings. We reveal the best-performing methods for different types of task designs and their fundamental limitations. Importantly, we demonstrate that rapid (100 ms) modulations of oscillatory neuronal synchronisation can be recovered from sluggish haemodynamic fluctuations even at typically low fMRI temporal resolution (2 s). Finally, we provide practical recommendations on task design and statistical analysis to foster task connectome mapping. Large-scale neural mass simulations revealed best task-modulated functional connectivity methods for different fMRI designs and fundamental limitations for detecting rapid modulations of neural synchronisation based on slow haemodynamic fluctuations.
{"title":"Comparison of whole-brain task-modulated functional connectivity methods for fMRI task connectomics","authors":"Ruslan Masharipov, Irina Knyazeva, Alexander Korotkov, Denis Cherednichenko, Maxim Kireev","doi":"10.1038/s42003-024-07088-3","DOIUrl":"10.1038/s42003-024-07088-3","url":null,"abstract":"Higher brain functions require flexible integration of information across widely distributed brain regions depending on the task context. Resting-state functional magnetic resonance imaging (fMRI) has provided substantial insight into large-scale intrinsic brain network organisation, yet the principles of rapid context-dependent reconfiguration of that intrinsic network organisation are much less understood. A major challenge for task connectome mapping is the absence of a gold standard for deriving whole-brain task-modulated functional connectivity matrices. Here, we perform biophysically realistic simulations to control the ground-truth task-modulated functional connectivity over a wide range of experimental settings. We reveal the best-performing methods for different types of task designs and their fundamental limitations. Importantly, we demonstrate that rapid (100 ms) modulations of oscillatory neuronal synchronisation can be recovered from sluggish haemodynamic fluctuations even at typically low fMRI temporal resolution (2 s). Finally, we provide practical recommendations on task design and statistical analysis to foster task connectome mapping. Large-scale neural mass simulations revealed best task-modulated functional connectivity methods for different fMRI designs and fundamental limitations for detecting rapid modulations of neural synchronisation based on slow haemodynamic fluctuations.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Assessing mutation impact on the binding affinity change (ΔΔG) of protein–protein interactions (PPIs) plays a crucial role in unraveling structural-functional intricacies of proteins and developing innovative protein designs. In this study, we present a deep learning framework, PIANO, for improved prediction of ΔΔG in PPIs. The PIANO framework leverages a graph masked self-distillation scheme for protein structural geometric representation pre-training, which effectively captures the structural context representations surrounding mutation sites, and makes predictions using a multi-branch network consisting of multiple encoders for amino acids, atoms, and protein sequences. Extensive experiments demonstrated its superior prediction performance and the capability of pre-trained encoder in capturing meaningful representations. Compared to previous methods, PIANO can be widely applied on both holo complex structures and apo monomer structures. Moreover, we illustrated the practical applicability of PIANO in highlighting pathogenic mutations and crucial proteins, and distinguishing de novo mutations in disease cases and controls in PPI systems. Overall, PIANO offers a powerful deep learning tool, which may provide valuable insights into the study of drug design, therapeutic intervention, and protein engineering. PIANO: a deep learning framework providing a powerful tool and potentially unforeseen avenues for the prediction of mutation impact on the binding affinity changes of protein–protein interactions
评估突变对蛋白质-蛋白质相互作用（PPIs）的结合亲和力变化（ΔΔG）的影响在揭示蛋白质结构-功能的复杂性和开发创新蛋白质设计方面起着至关重要的作用。在本研究中，我们提出了一种深度学习框架 PIANO，用于改进 PPI 中 ΔΔG 的预测。PIANO框架利用图掩蔽自馏分方案进行蛋白质结构几何表征预训练，有效捕捉突变位点周围的结构上下文表征，并利用由氨基酸、原子和蛋白质序列的多个编码器组成的多分支网络进行预测。广泛的实验证明了其卓越的预测性能和预训练编码器捕捉有意义表征的能力。与之前的方法相比，PIANO 可广泛应用于全复合物结构和单体结构。此外，我们还展示了 PIANO 在突出致病突变和关键蛋白方面的实际应用能力，以及在 PPI 系统中区分疾病病例和对照组中的新发突变的能力。总之，PIANO 提供了一种强大的深度学习工具，可为药物设计、治疗干预和蛋白质工程研究提供有价值的见解。
{"title":"Graph masked self-distillation learning for prediction of mutation impact on protein–protein interactions","authors":"Yuan Zhang, Mingyuan Dong, Junsheng Deng, Jiafeng Wu, Qiuye Zhao, Xieping Gao, Dapeng Xiong","doi":"10.1038/s42003-024-07066-9","DOIUrl":"10.1038/s42003-024-07066-9","url":null,"abstract":"Assessing mutation impact on the binding affinity change (ΔΔG) of protein–protein interactions (PPIs) plays a crucial role in unraveling structural-functional intricacies of proteins and developing innovative protein designs. In this study, we present a deep learning framework, PIANO, for improved prediction of ΔΔG in PPIs. The PIANO framework leverages a graph masked self-distillation scheme for protein structural geometric representation pre-training, which effectively captures the structural context representations surrounding mutation sites, and makes predictions using a multi-branch network consisting of multiple encoders for amino acids, atoms, and protein sequences. Extensive experiments demonstrated its superior prediction performance and the capability of pre-trained encoder in capturing meaningful representations. Compared to previous methods, PIANO can be widely applied on both holo complex structures and apo monomer structures. Moreover, we illustrated the practical applicability of PIANO in highlighting pathogenic mutations and crucial proteins, and distinguishing de novo mutations in disease cases and controls in PPI systems. Overall, PIANO offers a powerful deep learning tool, which may provide valuable insights into the study of drug design, therapeutic intervention, and protein engineering. PIANO: a deep learning framework providing a powerful tool and potentially unforeseen avenues for the prediction of mutation impact on the binding affinity changes of protein–protein interactions","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1038/s42003-024-07094-5
Enikő Zakar-Polyák, Attila Csordas, Róbert Pálovics, Csaba Kerepesi
Although aging clocks predicting the age of individual organisms have been extensively studied, the age of individual cells remained largely unexplored. Most recently single-cell omics clocks were developed for the mouse, however, extensive profiling the age of human cells is still lacking. To fill this gap, here we use available scRNA-seq data of 1,058,909 blood cells of 508 healthy, human donors (between 19 and 75 years), for developing single-cell transcriptomic clocks and predicting the age of human blood cells. By the application of the proposed cell-type-specific single-cell clocks, our main observations are that (i) transcriptomic age is associated with cellular senescence; (ii) the transcriptomic age of classical monocytes as well as naive B and T cells is decreased in moderate COVID-19 followed by an increase for some cell types in severe COVID-19; and (iii) the human embryo cells transcriptomically rejuvenated at the morulae and blastocyst stages. In summary, here we demonstrate that single-cell transcriptomic clocks are useful tools to investigate aging and rejuvenation at the single-cell level. Single-cell transcriptomic clocks have been developed based on available data to predict the age of human blood cells. The proposed clocks are useful tools to investigate aging and rejuvenation at the single-cell level.
{"title":"Profiling the transcriptomic age of single-cells in humans","authors":"Enikő Zakar-Polyák, Attila Csordas, Róbert Pálovics, Csaba Kerepesi","doi":"10.1038/s42003-024-07094-5","DOIUrl":"10.1038/s42003-024-07094-5","url":null,"abstract":"Although aging clocks predicting the age of individual organisms have been extensively studied, the age of individual cells remained largely unexplored. Most recently single-cell omics clocks were developed for the mouse, however, extensive profiling the age of human cells is still lacking. To fill this gap, here we use available scRNA-seq data of 1,058,909 blood cells of 508 healthy, human donors (between 19 and 75 years), for developing single-cell transcriptomic clocks and predicting the age of human blood cells. By the application of the proposed cell-type-specific single-cell clocks, our main observations are that (i) transcriptomic age is associated with cellular senescence; (ii) the transcriptomic age of classical monocytes as well as naive B and T cells is decreased in moderate COVID-19 followed by an increase for some cell types in severe COVID-19; and (iii) the human embryo cells transcriptomically rejuvenated at the morulae and blastocyst stages. In summary, here we demonstrate that single-cell transcriptomic clocks are useful tools to investigate aging and rejuvenation at the single-cell level. Single-cell transcriptomic clocks have been developed based on available data to predict the age of human blood cells. The proposed clocks are useful tools to investigate aging and rejuvenation at the single-cell level.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07094-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To achieve high efficiency in microbial cell factories, it is crucial to redesign central carbon fluxes to ensure an adequate supply of precursors for producing high-value compounds. In this study, we employed a multi-omics approach to rearrange the central carbon flux of the pyruvate dehydrogenase (PDH) bypass, thereby enhancing the supply of intermediate precursors, specifically acetyl-CoA. This enhancement aimed to improve the biosynthesis of acetyl-CoA-derived compounds, such as terpenoids and fatty acid-derived molecules, in Saccharomyces cerevisiae. Through transcriptomic and lipidomic analyses, we identified ALD4 as a key regulatory gene influencing lipid metabolism. Genetic validation demonstrated that overexpression of the mitochondrial acetaldehyde dehydrogenase (ALDH) gene ALD4 resulted in a 20.1% increase in lipid production. This study provides theoretical support for optimising the performance of S. cerevisiae as a “cell factory” for the production of commercial compounds. The carbon flux rearrangement based on PDH bypass enhances the accumulation of acetyl-CoA and promotes the synthesis of lipid compounds downstream in Saccharomyces cerevisiae.
{"title":"Regulating the metabolic flux of pyruvate dehydrogenase bypass to enhance lipid production in Saccharomyces cerevisiae","authors":"Cairong Lei, Xiaopeng Guo, Miaomiao Zhang, Xiang Zhou, Nan Ding, Junle Ren, Meihan Liu, Chenglin Jia, Yajuan Wang, Jingru Zhao, Ziyi Dong, Dong Lu","doi":"10.1038/s42003-024-07103-7","DOIUrl":"10.1038/s42003-024-07103-7","url":null,"abstract":"To achieve high efficiency in microbial cell factories, it is crucial to redesign central carbon fluxes to ensure an adequate supply of precursors for producing high-value compounds. In this study, we employed a multi-omics approach to rearrange the central carbon flux of the pyruvate dehydrogenase (PDH) bypass, thereby enhancing the supply of intermediate precursors, specifically acetyl-CoA. This enhancement aimed to improve the biosynthesis of acetyl-CoA-derived compounds, such as terpenoids and fatty acid-derived molecules, in Saccharomyces cerevisiae. Through transcriptomic and lipidomic analyses, we identified ALD4 as a key regulatory gene influencing lipid metabolism. Genetic validation demonstrated that overexpression of the mitochondrial acetaldehyde dehydrogenase (ALDH) gene ALD4 resulted in a 20.1% increase in lipid production. This study provides theoretical support for optimising the performance of S. cerevisiae as a “cell factory” for the production of commercial compounds. The carbon flux rearrangement based on PDH bypass enhances the accumulation of acetyl-CoA and promotes the synthesis of lipid compounds downstream in Saccharomyces cerevisiae.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed slightly delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomic analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments. A combination of Atomic Force Microscopy, transcriptomics, and comprehensive phenotype analysis, presents compelling supporting evidence for the validation of mtx-2 K.O. C. elegans as a disease model for MADaM, a progeroid (accelerate aging) syndrome.
{"title":"Validation of metaxin-2 deficient C. elegans as a model for MandibuloAcral Dysplasia associated to mtx-2 (MADaM) syndrome","authors":"Chloé Talarmin-Gas, Georges Smolyakov, Cleo Parisi, Cyril Scandola, Valérie Andrianasolonirina, Cloé Lecoq, Valentine Houtart, Song-Hua Lee, Homa Adle-Biassette, Bénédicte Thiébot, Timothy Ganderton, Philippe Manivet","doi":"10.1038/s42003-024-06967-z","DOIUrl":"10.1038/s42003-024-06967-z","url":null,"abstract":"MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed slightly delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomic analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments. A combination of Atomic Force Microscopy, transcriptomics, and comprehensive phenotype analysis, presents compelling supporting evidence for the validation of mtx-2 K.O. C. elegans as a disease model for MADaM, a progeroid (accelerate aging) syndrome.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1038/s42003-024-07118-0
Hao Zhang, Zebin Deng, Yilong Wang, Xiaoping Zheng, Lizhi Zhou, Shu Yan, Yinhuai Wang, Yingbo Dai, Yashpal. S. Kanwar, Fangzhi Chen, Fei Deng
Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrated that CHIP was abundantly expressed in the renal proximal tubular epithelia, and its expression was downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated NUR77 to promote its degradation, which consequently shielded BCL2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrated that CHIP interacted with NUR77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicated that CHIP ubiquitinated and degraded its substrate NUR77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI. CHIP interacts with NUR77 via its coiled-coil domain in renal proximal tubular cells, and their interaction leads to the K48 ubiquitination of NUR77 and its subsequent proteasomal degradation, resulting in the alleviation of cisplatin-induced AKI.
{"title":"CHIP drives proteasomal degradation of NUR77 to alleviate oxidative stress and intrinsic apoptosis in cisplatin-induced nephropathy","authors":"Hao Zhang, Zebin Deng, Yilong Wang, Xiaoping Zheng, Lizhi Zhou, Shu Yan, Yinhuai Wang, Yingbo Dai, Yashpal. S. Kanwar, Fangzhi Chen, Fei Deng","doi":"10.1038/s42003-024-07118-0","DOIUrl":"10.1038/s42003-024-07118-0","url":null,"abstract":"Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrated that CHIP was abundantly expressed in the renal proximal tubular epithelia, and its expression was downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated NUR77 to promote its degradation, which consequently shielded BCL2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrated that CHIP interacted with NUR77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicated that CHIP ubiquitinated and degraded its substrate NUR77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI. CHIP interacts with NUR77 via its coiled-coil domain in renal proximal tubular cells, and their interaction leads to the K48 ubiquitination of NUR77 and its subsequent proteasomal degradation, resulting in the alleviation of cisplatin-induced AKI.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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