Membrane-less organelles, formed by the condensation of biomolecules, play a pivotal role in eukaryotes. Artificial membrane-less organelles and condensates are effective tools for the creation of new cellular functions. However, it is poorly understood how to control the properties that affect condensate function, particularly in plants. Here, we report the construction of model artificial condensates using the condensation-prone proteins OsJAZ2 and AtFCA in a transient assay using rice (Oryza sativa) cells, and how condensate properties, such as subcellular localization, protein mobility, and size can be altered. We showed that proteins of interest can be recruited to condensates using nanobodies or chemically induced dimerization. Furthermore, by combining two types of condensation-prone proteins, we demonstrated that artificial hybrid condensates with heterogeneous material properties could be constructed. Finally, we showed that modified artificial condensates can be constructed in transgenic Arabidopsis thaliana plants. These results provide a framework for the basic design of synthetic membrane-less organelles in plants. Studies using condensation-prone proteins suggest that it is possible to construct and combine artificial condensates with various properties in plant cells, providing a framework for the basic design of synthetic membrane-less organelles in plants.
{"title":"Basic design of artificial membrane-less organelles using condensation-prone proteins in plant cells","authors":"Yoshito Koja, Takuya Arakawa, Yusuke Yoritaka, Yu Joshima, Hazuki Kobayashi, Kenta Toda, Shin Takeda","doi":"10.1038/s42003-024-07102-8","DOIUrl":"10.1038/s42003-024-07102-8","url":null,"abstract":"Membrane-less organelles, formed by the condensation of biomolecules, play a pivotal role in eukaryotes. Artificial membrane-less organelles and condensates are effective tools for the creation of new cellular functions. However, it is poorly understood how to control the properties that affect condensate function, particularly in plants. Here, we report the construction of model artificial condensates using the condensation-prone proteins OsJAZ2 and AtFCA in a transient assay using rice (Oryza sativa) cells, and how condensate properties, such as subcellular localization, protein mobility, and size can be altered. We showed that proteins of interest can be recruited to condensates using nanobodies or chemically induced dimerization. Furthermore, by combining two types of condensation-prone proteins, we demonstrated that artificial hybrid condensates with heterogeneous material properties could be constructed. Finally, we showed that modified artificial condensates can be constructed in transgenic Arabidopsis thaliana plants. These results provide a framework for the basic design of synthetic membrane-less organelles in plants. Studies using condensation-prone proteins suggest that it is possible to construct and combine artificial condensates with various properties in plant cells, providing a framework for the basic design of synthetic membrane-less organelles in plants.","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/s42003-024-07102-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496427","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/s42003-024-07084-7
Jinglu Chen, Vesa Putkinen, Kerttu Seppälä, Jussi Hirvonen, Kalliopi Ioumpa, Valeria Gazzola, Christian Keysers, Lauri Nummenmaa
Functional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behavior. However, the neuromolecular basis of individual differences in vicarious pain and helping is poorly understood. We investigated the role of the endogenous μ-opioid receptor (MOR) system in altruistic costly helping. MOR density was measured using [11C]carfentanil. In a separate fMRI experiment, participants could donate money to reduce a confederate’s pain from electric shocks. Participants were generally willing to help, and brain activity was observed in amygdala, anterior insula, anterior cingulate cortex (ACC), striatum, primary motor cortex, primary somatosensory cortex and thalamus when witnessing others’ pain. Haemodynamic responses were negatively associated with MOR availability in emotion circuits. However, MOR availability positively associated with the ACC and hippocampus during helping. These findings suggest that the endogenous MOR system modulates altruism in the human brain. This PET-fMRI fusion study reveals that endogenous u-opioid receptor system modulates altruistic brain activity and its individual differences.
{"title":"Endogenous opioid receptor system mediates costly altruism in the human brain","authors":"Jinglu Chen, Vesa Putkinen, Kerttu Seppälä, Jussi Hirvonen, Kalliopi Ioumpa, Valeria Gazzola, Christian Keysers, Lauri Nummenmaa","doi":"10.1038/s42003-024-07084-7","DOIUrl":"10.1038/s42003-024-07084-7","url":null,"abstract":"Functional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behavior. However, the neuromolecular basis of individual differences in vicarious pain and helping is poorly understood. We investigated the role of the endogenous μ-opioid receptor (MOR) system in altruistic costly helping. MOR density was measured using [11C]carfentanil. In a separate fMRI experiment, participants could donate money to reduce a confederate’s pain from electric shocks. Participants were generally willing to help, and brain activity was observed in amygdala, anterior insula, anterior cingulate cortex (ACC), striatum, primary motor cortex, primary somatosensory cortex and thalamus when witnessing others’ pain. Haemodynamic responses were negatively associated with MOR availability in emotion circuits. However, MOR availability positively associated with the ACC and hippocampus during helping. These findings suggest that the endogenous MOR system modulates altruism in the human brain. This PET-fMRI fusion study reveals that endogenous u-opioid receptor system modulates altruistic brain activity and its individual differences.","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/PMC11513155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496434","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/s42003-024-07093-6
Shinya Takamuku, Beata Struckova, Matthew J. Bancroft, Hiroaki Gomi, Patrick Haggard, Diego Kaski
Self vs. external attribution of motions based on vestibular cues is suggested to underlie our coherent perception of object motion and self-motion. However, it remains unclear whether such attribution also underlies sensorimotor responses. Here, we examined this issue in the context of touch. We asked participants to lightly touch a moving object with their thumb while standing still on an unstable surface. We measured both the accuracy of judging the object motion direction and the postural response. If the attribution underlies both object-motion perception and posture control, sensitivity of posture to object motion should decrease with motion speed since high speed motion is unlikely to reflect self-motion. Furthermore, when motion perception is erroneous, there should be a corresponding increase in postural responses. Our results are consistent with these predictions and suggest that self-external attribution of somatosensory motion underlies both object motion perception and postural responses. Simultaneous measurements of postural response and motion perception triggered by touched surface motion reveal a process of self-external attribution of somatosensory motion signals that underlies motor and perceptual processes
{"title":"Inverse relation between motion perception and postural responses induced by motion of a touched object","authors":"Shinya Takamuku, Beata Struckova, Matthew J. Bancroft, Hiroaki Gomi, Patrick Haggard, Diego Kaski","doi":"10.1038/s42003-024-07093-6","DOIUrl":"10.1038/s42003-024-07093-6","url":null,"abstract":"Self vs. external attribution of motions based on vestibular cues is suggested to underlie our coherent perception of object motion and self-motion. However, it remains unclear whether such attribution also underlies sensorimotor responses. Here, we examined this issue in the context of touch. We asked participants to lightly touch a moving object with their thumb while standing still on an unstable surface. We measured both the accuracy of judging the object motion direction and the postural response. If the attribution underlies both object-motion perception and posture control, sensitivity of posture to object motion should decrease with motion speed since high speed motion is unlikely to reflect self-motion. Furthermore, when motion perception is erroneous, there should be a corresponding increase in postural responses. Our results are consistent with these predictions and suggest that self-external attribution of somatosensory motion underlies both object motion perception and postural responses. Simultaneous measurements of postural response and motion perception triggered by touched surface motion reveal a process of self-external attribution of somatosensory motion signals that underlies motor and perceptual processes","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/PMC11513030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496452","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 : 2024-10-25DOI: 10.1038/s42003-024-07082-9
Anja Pavlin, Nadine Fornelos, Maja Popović, Neža Praček, Gregor Bajc, Margarita Salas, Matej Butala
Betatectiviruses are prophages consisting of linear extrachromosomal genomes without obvious plasmid modules. It remains unclear how betatectiviruses are maintained in low-copy numbers in host cells and how they are vertically transmitted. Phage GIL01 is a model betatectivirus that infects the mosquito pathogen Bacillus thuringiensis serovar israelensis. Previous studies identified two closely spaced promoters, P1 and P2, responsible for the expression of GIL01 genes required for prophage replication and the switch from the lysogenic to lytic cycle. Here, we report that the GIL01-encoded 58-amino acid long gp1 protein forms a large nucleoprotein complex that represses its transcription from the strong promoter P2. Notably, ectopic expression of gp1 resulted in the loss of GIL01 in exponential cultures and immunized cells against infection with GIL01, indicating that gp1 plays a repressive role in the phage cycle. This finding is consistent with mutations in gp1 committing GIL01 to the lytic cycle and we show that maintenance of this phage variant in the bacterial population is contingent on the accumulation of deletions in the P1-P2 region. The fact that gp1 is conserved across most sequenced betatectiviruses suggests that the regulatory mechanism of gp1 that controls prophage maintenance is widespread among these bacteriophages. Gp1, a 58-amino acid DNA-binding protein encoded by betatectivirus GIL01, is responsible for maintenance of the GIL01 linear prophage genome in host Bacillus thuringiensis serovar israelensis.
{"title":"Autoregulation ensures vertical transmission of the linear prophage GIL01","authors":"Anja Pavlin, Nadine Fornelos, Maja Popović, Neža Praček, Gregor Bajc, Margarita Salas, Matej Butala","doi":"10.1038/s42003-024-07082-9","DOIUrl":"10.1038/s42003-024-07082-9","url":null,"abstract":"Betatectiviruses are prophages consisting of linear extrachromosomal genomes without obvious plasmid modules. It remains unclear how betatectiviruses are maintained in low-copy numbers in host cells and how they are vertically transmitted. Phage GIL01 is a model betatectivirus that infects the mosquito pathogen Bacillus thuringiensis serovar israelensis. Previous studies identified two closely spaced promoters, P1 and P2, responsible for the expression of GIL01 genes required for prophage replication and the switch from the lysogenic to lytic cycle. Here, we report that the GIL01-encoded 58-amino acid long gp1 protein forms a large nucleoprotein complex that represses its transcription from the strong promoter P2. Notably, ectopic expression of gp1 resulted in the loss of GIL01 in exponential cultures and immunized cells against infection with GIL01, indicating that gp1 plays a repressive role in the phage cycle. This finding is consistent with mutations in gp1 committing GIL01 to the lytic cycle and we show that maintenance of this phage variant in the bacterial population is contingent on the accumulation of deletions in the P1-P2 region. The fact that gp1 is conserved across most sequenced betatectiviruses suggests that the regulatory mechanism of gp1 that controls prophage maintenance is widespread among these bacteriophages. Gp1, a 58-amino acid DNA-binding protein encoded by betatectivirus GIL01, is responsible for maintenance of the GIL01 linear prophage genome in host Bacillus thuringiensis serovar israelensis.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496426","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 : 2024-10-25DOI: 10.1038/s42003-024-07096-3
Neha Joshi, Wing Yiu Ng, Karan Thakkar, Daniel Duque, Pingbo Yin, Jonathan Fritz, Mounya Elhilali, Shihab Shamma
Perceptual segregation of complex sounds such as speech and music simultaneously emanating from multiple sources is a remarkable ability that is common in humans and other animals alike. Unlike animal physiological experiments with simplified sounds or human investigations with spatially broad imaging techniques, this study combines insights from animal single-unit recordings with segregation of speech-like sound mixtures. Ferrets are trained to attend to a female voice and detect a target word, both in presence and absence of a concurrent equally salient male voice. Recordings are made in primary and secondary auditory cortical fields, and in frontal cortex. During task performance, representation of the female words becomes enhanced relative to the male in all, but especially in higher cortical regions. Analysis of the temporal and spectral response characteristics during task performance reveals how speech segregation gradually emerges in the auditory cortex. A computational model evaluated on the same voice mixtures replicates and extends these results to different attentional targets (attention to female or male voices). These findings underscore the role of the principle of temporal coherence whereby attention to a target voice binds together all neural responses coherently modulated with the target, thus ultimately forming and extracting a common auditory stream. Ferrets learned to attend and react to words of a female voice embedded in a speech mixture with a male. Recordings in auditory cortex reveal rapidly enhanced responses to the attended female voice and a simultaneous suppression of the male distractor.
{"title":"Temporal coherence shapes cortical responses to speech mixtures in a ferret cocktail party","authors":"Neha Joshi, Wing Yiu Ng, Karan Thakkar, Daniel Duque, Pingbo Yin, Jonathan Fritz, Mounya Elhilali, Shihab Shamma","doi":"10.1038/s42003-024-07096-3","DOIUrl":"10.1038/s42003-024-07096-3","url":null,"abstract":"Perceptual segregation of complex sounds such as speech and music simultaneously emanating from multiple sources is a remarkable ability that is common in humans and other animals alike. Unlike animal physiological experiments with simplified sounds or human investigations with spatially broad imaging techniques, this study combines insights from animal single-unit recordings with segregation of speech-like sound mixtures. Ferrets are trained to attend to a female voice and detect a target word, both in presence and absence of a concurrent equally salient male voice. Recordings are made in primary and secondary auditory cortical fields, and in frontal cortex. During task performance, representation of the female words becomes enhanced relative to the male in all, but especially in higher cortical regions. Analysis of the temporal and spectral response characteristics during task performance reveals how speech segregation gradually emerges in the auditory cortex. A computational model evaluated on the same voice mixtures replicates and extends these results to different attentional targets (attention to female or male voices). These findings underscore the role of the principle of temporal coherence whereby attention to a target voice binds together all neural responses coherently modulated with the target, thus ultimately forming and extracting a common auditory stream. Ferrets learned to attend and react to words of a female voice embedded in a speech mixture with a male. Recordings in auditory cortex reveal rapidly enhanced responses to the attended female voice and a simultaneous suppression of the male distractor.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496475","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 : 2024-10-25DOI: 10.1038/s42003-024-07071-y
Paula O. Cooper, Jiang Yang, Hsing-Hui Wang, Meaghan M. Broman, Shyaman Madhawa Jayasundara, Subhransu Sekhar Sahoo, Bingyu Yan, Gada D. Awdalkreem, Gregory M. Cresswell, Liang Wang, Emery Goossens, Nadia A. Lanman, Rebecca W. Doerge, Faye Zheng, Liang Cheng, Saeed Alqahtani, Scott A. Crist, Robert E. Braun, Majid Kazemian, Travis J. Jerde, Timothy L. Ratliff
Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilize a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigate the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We find that inflammation significantly enhances AR levels and activity in bPSC. More importantly, we identify interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA is one of the top molecules upregulated by inflammation, and inhibiting IL-1RA reverses the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appears to activate AR by counteracting IL-1α''s inhibitory effect. Furthermore, using a lineage tracing model, we observe that inflammation induces bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovers mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia. Inflammation enhances androgen receptor levels and activity in basal prostate stem cells via IL-1RA, promoting their proliferation and differentiation, potentially contributing to benign prostate hyperplasia in mice.
{"title":"Inflammation impacts androgen receptor signaling in basal prostate stem cells through interleukin 1 receptor antagonist","authors":"Paula O. Cooper, Jiang Yang, Hsing-Hui Wang, Meaghan M. Broman, Shyaman Madhawa Jayasundara, Subhransu Sekhar Sahoo, Bingyu Yan, Gada D. Awdalkreem, Gregory M. Cresswell, Liang Wang, Emery Goossens, Nadia A. Lanman, Rebecca W. Doerge, Faye Zheng, Liang Cheng, Saeed Alqahtani, Scott A. Crist, Robert E. Braun, Majid Kazemian, Travis J. Jerde, Timothy L. Ratliff","doi":"10.1038/s42003-024-07071-y","DOIUrl":"10.1038/s42003-024-07071-y","url":null,"abstract":"Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilize a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigate the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We find that inflammation significantly enhances AR levels and activity in bPSC. More importantly, we identify interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA is one of the top molecules upregulated by inflammation, and inhibiting IL-1RA reverses the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appears to activate AR by counteracting IL-1α''s inhibitory effect. Furthermore, using a lineage tracing model, we observe that inflammation induces bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovers mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia. Inflammation enhances androgen receptor levels and activity in basal prostate stem cells via IL-1RA, promoting their proliferation and differentiation, potentially contributing to benign prostate hyperplasia in mice.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496451","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 : 2024-10-25DOI: 10.1038/s42003-024-07089-2
Geurim Son, Yongwoo Na, Yongsung Kim, Ji-Hoon Son, Gregory D. Clemenson, Simon T. Schafer, Jong-Yeon Yoo, Sarah L. Parylak, Apua Paquola, Hyunsu Do, Dayeon Kim, Insook Ahn, Mingyu Ju, Chanhee S. Kang, Younghee Ju, Eunji Jung, Aidan H. McDonald, Youngjin Park, Gilhyun Kim, Se-Bum Paik, Junho Hur, Joon Kim, Yong-Mahn Han, Seung-Hee Lee, Fred H. Gage, Jong-Seo Kim, Jinju Han
Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions. miR-124 as a driver of metabolic change initiating neurogenesis by governing the mitochondrial oxidative phosphorylation pathway.
{"title":"miR-124 coordinates metabolic regulators acting at early stages of human neurogenesis","authors":"Geurim Son, Yongwoo Na, Yongsung Kim, Ji-Hoon Son, Gregory D. Clemenson, Simon T. Schafer, Jong-Yeon Yoo, Sarah L. Parylak, Apua Paquola, Hyunsu Do, Dayeon Kim, Insook Ahn, Mingyu Ju, Chanhee S. Kang, Younghee Ju, Eunji Jung, Aidan H. McDonald, Youngjin Park, Gilhyun Kim, Se-Bum Paik, Junho Hur, Joon Kim, Yong-Mahn Han, Seung-Hee Lee, Fred H. Gage, Jong-Seo Kim, Jinju Han","doi":"10.1038/s42003-024-07089-2","DOIUrl":"10.1038/s42003-024-07089-2","url":null,"abstract":"Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions. miR-124 as a driver of metabolic change initiating neurogenesis by governing the mitochondrial oxidative phosphorylation pathway.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496454","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}
Base editors enable the direct conversion of target bases without inducing double-strand breaks, showing great potential for disease modeling and gene therapy. Yet, their applicability has been constrained by the necessity for specific protospacer adjacent motif (PAM). We generate four versions of near-PAMless base editors and systematically evaluate their editing patterns and efficiencies using an sgRNA-target library of 45,747 sequences. Near-PAMless base editors significantly expanded the targeting scope, with both PAM and target flanking sequences as determinants for editing outcomes. We develop BEguider, a deep learning model, to accurately predict editing results for near-PAMless base editors. We also provide experimentally measured editing outcomes of 20,541 ClinVar sites, demonstrating that variants previously inaccessible by NGG PAM base editors can now be precisely generated or corrected. We make our predictive tool and data available online to facilitate development and application of near-PAMless base editors in both research and clinical settings. Systematic evaluation of near-PAMless base editors enables a robust deep learning model for predicting editing outcomes, facilitating broader and more precise targeting of disease-associated variants for research and therapy.
{"title":"Comprehensive evaluation and prediction of editing outcomes for near-PAMless adenine and cytosine base editors","authors":"Xiaoyu Zhou, Jingjing Gao, Liheng Luo, Changcai Huang, Jiayu Wu, Xiaoyue Wang","doi":"10.1038/s42003-024-07078-5","DOIUrl":"10.1038/s42003-024-07078-5","url":null,"abstract":"Base editors enable the direct conversion of target bases without inducing double-strand breaks, showing great potential for disease modeling and gene therapy. Yet, their applicability has been constrained by the necessity for specific protospacer adjacent motif (PAM). We generate four versions of near-PAMless base editors and systematically evaluate their editing patterns and efficiencies using an sgRNA-target library of 45,747 sequences. Near-PAMless base editors significantly expanded the targeting scope, with both PAM and target flanking sequences as determinants for editing outcomes. We develop BEguider, a deep learning model, to accurately predict editing results for near-PAMless base editors. We also provide experimentally measured editing outcomes of 20,541 ClinVar sites, demonstrating that variants previously inaccessible by NGG PAM base editors can now be precisely generated or corrected. We make our predictive tool and data available online to facilitate development and application of near-PAMless base editors in both research and clinical settings. Systematic evaluation of near-PAMless base editors enables a robust deep learning model for predicting editing outcomes, facilitating broader and more precise targeting of disease-associated variants for research and therapy.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496431","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 : 2024-10-25DOI: 10.1038/s42003-024-07063-y
Debashree Goswami, Silvia A. Arredondo, William Betz, Janna Armstrong, Sudhir Kumar, Gigliola Zanghi, Hardik Patel, Nelly Camargo, Kenza M. Z. Oualim, Annette M. Seilie, Sophia Schneider, Sean C. Murphy, Stefan H. I. Kappe, Ashley M. Vaughan
Malaria, caused by Plasmodium parasites, imposes a significant health burden and live-attenuated parasites are being pursued as vaccines. Here, we report on the creation of a genetically attenuated parasite by the deletion of Plasmodium LINUP, encoding a liver stage nuclear protein. In the rodent parasite Plasmodium yoelii, LINUP expression was restricted to liver stage nuclei after the onset of liver stage schizogony. Compared to wildtype P. yoelii, P. yoelii LINUP gene deletion parasites (linup—) exhibited no phenotype in blood stages and mosquito stages but suffered developmental arrest late in liver stage schizogony with a pronounced defect in exo-erythrocytic merozoite formation. This defect caused severe attenuation of the liver stage-to-blood stage transition and immunization of mice with linup — parasites conferred robust protection against infectious sporozoite challenge. LINUP gene deletion in the human parasite Plasmodium falciparum also caused a severe defect in late liver stage differentiation. Importantly, P. falciparum linup — liver stages completely failed to transition from the liver stage to a viable blood stage infection in a humanized mouse model. These results suggest that P. falciparum LINUP is an ideal target for late liver stage attenuation that can be incorporated into a late liver stage-arresting replication competent whole parasite vaccine. A conserved Plasmodium protein, specific to the liver stage and localized in the nucleus of liver stage schizonts, plays a critical role in liver stage development and differentiation.
{"title":"A conserved Plasmodium nuclear protein is critical for late liver stage development","authors":"Debashree Goswami, Silvia A. Arredondo, William Betz, Janna Armstrong, Sudhir Kumar, Gigliola Zanghi, Hardik Patel, Nelly Camargo, Kenza M. Z. Oualim, Annette M. Seilie, Sophia Schneider, Sean C. Murphy, Stefan H. I. Kappe, Ashley M. Vaughan","doi":"10.1038/s42003-024-07063-y","DOIUrl":"10.1038/s42003-024-07063-y","url":null,"abstract":"Malaria, caused by Plasmodium parasites, imposes a significant health burden and live-attenuated parasites are being pursued as vaccines. Here, we report on the creation of a genetically attenuated parasite by the deletion of Plasmodium LINUP, encoding a liver stage nuclear protein. In the rodent parasite Plasmodium yoelii, LINUP expression was restricted to liver stage nuclei after the onset of liver stage schizogony. Compared to wildtype P. yoelii, P. yoelii LINUP gene deletion parasites (linup—) exhibited no phenotype in blood stages and mosquito stages but suffered developmental arrest late in liver stage schizogony with a pronounced defect in exo-erythrocytic merozoite formation. This defect caused severe attenuation of the liver stage-to-blood stage transition and immunization of mice with linup — parasites conferred robust protection against infectious sporozoite challenge. LINUP gene deletion in the human parasite Plasmodium falciparum also caused a severe defect in late liver stage differentiation. Importantly, P. falciparum linup — liver stages completely failed to transition from the liver stage to a viable blood stage infection in a humanized mouse model. These results suggest that P. falciparum LINUP is an ideal target for late liver stage attenuation that can be incorporated into a late liver stage-arresting replication competent whole parasite vaccine. A conserved Plasmodium protein, specific to the liver stage and localized in the nucleus of liver stage schizonts, plays a critical role in liver stage development and differentiation.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496424","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 : 2024-10-25DOI: 10.1038/s42003-024-07087-4
Shashank Gupta, Arturo Vera-Ponce de León, Miyako Kodama, Matthias Hoetzinger, Cecilie G. Clausen, Louisa Pless, Ana R. A. Verissimo, Bruno Stengel, Virginia Calabuig, Renate Kvingedal, Stanko Skugor, Bjørge Westereng, Thomas Nelson Harvey, Anna Nordborg, Stefan Bertilsson, Morten T. Limborg, Turid Mørkøre, Simen R. Sandve, Phillip B. Pope, Torgeir R. Hvidsten, Sabina Leanti La Rosa
Microbiome-directed dietary interventions such as microbiota-directed fibers (MDFs) have a proven track record in eliciting responses in beneficial gut microbes and are increasingly being promoted as an effective strategy to improve animal production systems. Here we used initial metataxonomic data on fish gut microbiomes as well as a wealth of a priori mammalian microbiome knowledge on α-mannooligosaccharides (MOS) and β-mannan-derived MDFs to study effects of such feed supplements in Atlantic salmon (Salmo salar) and their impact on its gut microbiome composition and functionalities. Our multi-omic analysis revealed that the investigated MDFs (two α-mannans and an acetylated β-galactoglucomannan), at a dose of 0.2% in the diet, had negligible effects on both host gene expression, and gut microbiome structure and function under the studied conditions. While a subsequent trial using a higher (4%) dietary inclusion of β-mannan significantly shifted the gut microbiome composition, there were still no biologically relevant effects on salmon metabolism and physiology. Only a single Burkholderia-Caballeronia-Paraburkholderia (BCP) population demonstrated consistent and significant abundance shifts across both feeding trials, although with no evidence of β-mannan utilization capabilities or changes in gene transcripts for producing metabolites beneficial to the host. In light of these findings, we revisited our omics data to predict and outline previously unreported and potentially beneficial endogenous lactic acid bacteria that should be targeted with future, conceivably more suitable, MDF strategies for salmon. A multi-omic approach enables the reconstruction of microbial metabolic dynamics in the salmon gut in response to feed and feed supplements, outlining novel and potentially beneficial strategies to manipulate the salmon gut microbiota.
{"title":"The need for high-resolution gut microbiome characterization to design efficient strategies for sustainable aquaculture production","authors":"Shashank Gupta, Arturo Vera-Ponce de León, Miyako Kodama, Matthias Hoetzinger, Cecilie G. Clausen, Louisa Pless, Ana R. A. Verissimo, Bruno Stengel, Virginia Calabuig, Renate Kvingedal, Stanko Skugor, Bjørge Westereng, Thomas Nelson Harvey, Anna Nordborg, Stefan Bertilsson, Morten T. Limborg, Turid Mørkøre, Simen R. Sandve, Phillip B. Pope, Torgeir R. Hvidsten, Sabina Leanti La Rosa","doi":"10.1038/s42003-024-07087-4","DOIUrl":"10.1038/s42003-024-07087-4","url":null,"abstract":"Microbiome-directed dietary interventions such as microbiota-directed fibers (MDFs) have a proven track record in eliciting responses in beneficial gut microbes and are increasingly being promoted as an effective strategy to improve animal production systems. Here we used initial metataxonomic data on fish gut microbiomes as well as a wealth of a priori mammalian microbiome knowledge on α-mannooligosaccharides (MOS) and β-mannan-derived MDFs to study effects of such feed supplements in Atlantic salmon (Salmo salar) and their impact on its gut microbiome composition and functionalities. Our multi-omic analysis revealed that the investigated MDFs (two α-mannans and an acetylated β-galactoglucomannan), at a dose of 0.2% in the diet, had negligible effects on both host gene expression, and gut microbiome structure and function under the studied conditions. While a subsequent trial using a higher (4%) dietary inclusion of β-mannan significantly shifted the gut microbiome composition, there were still no biologically relevant effects on salmon metabolism and physiology. Only a single Burkholderia-Caballeronia-Paraburkholderia (BCP) population demonstrated consistent and significant abundance shifts across both feeding trials, although with no evidence of β-mannan utilization capabilities or changes in gene transcripts for producing metabolites beneficial to the host. In light of these findings, we revisited our omics data to predict and outline previously unreported and potentially beneficial endogenous lactic acid bacteria that should be targeted with future, conceivably more suitable, MDF strategies for salmon. A multi-omic approach enables the reconstruction of microbial metabolic dynamics in the salmon gut in response to feed and feed supplements, outlining novel and potentially beneficial strategies to manipulate the salmon gut microbiota.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496476","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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