Joshua S. Stoolman, Rogan A. Grant, Leah K. Billingham, Taylor A. Poor, Samuel E. Weinberg, Madeline C. Harding, Ziyan Lu, Jason Miska, Marten Szibor, GR Scott Budinger, Navdeep S. Chandel
Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)–deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow–derived macrophages (BMDMs) isolated from these mitochondria CIII–deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII–generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.
{"title":"Mitochondria complex III–generated superoxide is essential for IL-10 secretion in macrophages","authors":"Joshua S. Stoolman, Rogan A. Grant, Leah K. Billingham, Taylor A. Poor, Samuel E. Weinberg, Madeline C. Harding, Ziyan Lu, Jason Miska, Marten Szibor, GR Scott Budinger, Navdeep S. Chandel","doi":"10.1126/sciadv.adu4369","DOIUrl":"https://doi.org/10.1126/sciadv.adu4369","url":null,"abstract":"Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)–deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow–derived macrophages (BMDMs) isolated from these mitochondria CIII–deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII–generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020239","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}
Amblyopia, a highly prevalent loss of visual acuity, is classically thought to result from cortical plasticity. The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a passive relay for visual information, but recent findings suggest a largely underestimated functional plasticity in the dLGN. However, the cellular mechanisms supporting this plasticity have not yet been explored. We show here that monocular deprivation (MD), an experimental model of amblyopia, reduces the intrinsic excitability of dLGN cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 hertz or when spikes are induced with current injection. LTP-IE is observed after eye opening, requires calcium influx, is expressed through the down-regulation of Kv1 channels, and is altered following MD. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN neurons induced by natural stimuli.
{"title":"Visual activity enhances neuronal excitability in thalamic relay neurons","authors":"Maël Duménieu, Laure Fronzaroli-Molinieres, Loïs Naudin, Cécile Iborra-Bonnaure, Anushka Wakade, Emilie Zanin, Aurore Aziz, Norbert Ankri, Salvatore Incontro, Danièle Denis, Béatrice Marquèze-Pouey, Romain Brette, Dominique Debanne, Michaël Russier","doi":"10.1126/sciadv.adp4627","DOIUrl":"https://doi.org/10.1126/sciadv.adp4627","url":null,"abstract":"Amblyopia, a highly prevalent loss of visual acuity, is classically thought to result from cortical plasticity. The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a passive relay for visual information, but recent findings suggest a largely underestimated functional plasticity in the dLGN. However, the cellular mechanisms supporting this plasticity have not yet been explored. We show here that monocular deprivation (MD), an experimental model of amblyopia, reduces the intrinsic excitability of dLGN cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 hertz or when spikes are induced with current injection. LTP-IE is observed after eye opening, requires calcium influx, is expressed through the down-regulation of Kv1 channels, and is altered following MD. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN neurons induced by natural stimuli.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"15 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020195","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}
Jeremy Demarteau, Alexander R. Epstein, Laura J. Reed, Nicodemo R. Ciccia, John F. Hartwig, Kristin A. Persson, Brett A. Helms
Controlling the reactivity of bonds along polymer chains enables both functionalization and deconstruction with relevance to chemical recycling and circularity. Because the substrate is a macromolecule, however, understanding the effects of chain conformation on the reactivity of polymer bonds emerges as important yet underexplored. Here, we show how oxy-functionalization of chemically recyclable condensation polymers affects acidolysis to monomers through control over distortion and interaction energies in the rate-limiting transition states. Oxy-functionalization of polydiketoenamines at specific sites on either the amine or triketone monomer segments increased acidolysis rates by more than three orders of magnitude, opening the door to efficient deconstruction of linear chain architectures. These insights substantially broaden the scope of applications for polydiketoenamines in a circular manufacturing economy, including chemically recyclable adhesives for a diverse range of surfaces.
{"title":"Circularity in polydiketoenamine thermoplastics via control over reactive chain conformation","authors":"Jeremy Demarteau, Alexander R. Epstein, Laura J. Reed, Nicodemo R. Ciccia, John F. Hartwig, Kristin A. Persson, Brett A. Helms","doi":"10.1126/sciadv.ads8444","DOIUrl":"https://doi.org/10.1126/sciadv.ads8444","url":null,"abstract":"Controlling the reactivity of bonds along polymer chains enables both functionalization and deconstruction with relevance to chemical recycling and circularity. Because the substrate is a macromolecule, however, understanding the effects of chain conformation on the reactivity of polymer bonds emerges as important yet underexplored. Here, we show how oxy-functionalization of chemically recyclable condensation polymers affects acidolysis to monomers through control over distortion and interaction energies in the rate-limiting transition states. Oxy-functionalization of polydiketoenamines at specific sites on either the amine or triketone monomer segments increased acidolysis rates by more than three orders of magnitude, opening the door to efficient deconstruction of linear chain architectures. These insights substantially broaden the scope of applications for polydiketoenamines in a circular manufacturing economy, including chemically recyclable adhesives for a diverse range of surfaces.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"24 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020238","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}
Changhong Linghu, Yangchengyi Liu, Xudong Yang, Zhou Chen, Jin Feng, Yiyuan Zhang, Yan Li, Zhao Zhao, Young-Jae Seo, Junwei Li, Haoyu Jiang, Jiangtao Su, Yin Fang, Yuhang Li, Xiufeng Wang, Yifan Wang, Huajian Gao, K. Jimmy Hsia
Electronic skins endow robots with sensory functions but often lack the multifunctionality of natural skin, such as switchable adhesion. Current smart adhesives based on elastomers have limited adhesion tunability, which hinders their effective use for both carrying heavy loads and performing dexterous manipulations. Here, we report a versatile, one-size-fits-all robotic adhesive skin using shape memory polymers with tunable rubber-to-glass phase transitions. The adhesion strength of our adhesive skin can be changed from minimal (~1 kilopascal) for sensing and handling ultralightweight objects to ultrastrong (>1 megapascal) for picking up and lifting heavy objects. Our versatile adhesive skin is expected to greatly enhance the ability of intelligent robots to interact with their environment.
{"title":"Versatile adhesive skin enhances robotic interactions with the environment","authors":"Changhong Linghu, Yangchengyi Liu, Xudong Yang, Zhou Chen, Jin Feng, Yiyuan Zhang, Yan Li, Zhao Zhao, Young-Jae Seo, Junwei Li, Haoyu Jiang, Jiangtao Su, Yin Fang, Yuhang Li, Xiufeng Wang, Yifan Wang, Huajian Gao, K. Jimmy Hsia","doi":"10.1126/sciadv.adt4765","DOIUrl":"https://doi.org/10.1126/sciadv.adt4765","url":null,"abstract":"Electronic skins endow robots with sensory functions but often lack the multifunctionality of natural skin, such as switchable adhesion. Current smart adhesives based on elastomers have limited adhesion tunability, which hinders their effective use for both carrying heavy loads and performing dexterous manipulations. Here, we report a versatile, one-size-fits-all robotic adhesive skin using shape memory polymers with tunable rubber-to-glass phase transitions. The adhesion strength of our adhesive skin can be changed from minimal (~1 kilopascal) for sensing and handling ultralightweight objects to ultrastrong (>1 megapascal) for picking up and lifting heavy objects. Our versatile adhesive skin is expected to greatly enhance the ability of intelligent robots to interact with their environment.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"14 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987288","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}
Youngmin Jo, Youngoh Lee, Jimin Kwon, Seongju Kim, Gyungin Ryu, Soyoung Yun, Sanghoon Baek, Hyunhyub Ko, Sungjune Jung
Pressure and temperature sensing simultaneously and independently is crucial for creating electronic skin that replicates complex sensory functions of human skin. Thin-film transistor (TFT) arrays with sensors have enabled cross-talk–free spatial sensing. However, the thermal dependence of charge transport in semiconductors has resulted in interference between thermal and pressure stimuli. We develop multimodal sensor arrays based on three-dimensional integration of an active matrix to detect temperature and pressure independently. Our approach includes a calibrated compensation to decouple temperature and pressure signals. An individual pixel device consists of a TFT-based pressure sensor layered above a TFT-based temperature sensor. The detected temperature is used to compensate for the thermal effect on TFT-based pressure sensors. We develop large-area sensor arrays to enable accurate detection of two-dimensional pressure and temperature, leveraging these technologies to demonstrate advanced robotic grippers. The grippers stably grasp and lift a cup regardless of temperature, proving their possibility in skin-like electronic applications.
{"title":"3D active-matrix multimodal sensor arrays for independent detection of pressure and temperature","authors":"Youngmin Jo, Youngoh Lee, Jimin Kwon, Seongju Kim, Gyungin Ryu, Soyoung Yun, Sanghoon Baek, Hyunhyub Ko, Sungjune Jung","doi":"10.1126/sciadv.ads4516","DOIUrl":"https://doi.org/10.1126/sciadv.ads4516","url":null,"abstract":"Pressure and temperature sensing simultaneously and independently is crucial for creating electronic skin that replicates complex sensory functions of human skin. Thin-film transistor (TFT) arrays with sensors have enabled cross-talk–free spatial sensing. However, the thermal dependence of charge transport in semiconductors has resulted in interference between thermal and pressure stimuli. We develop multimodal sensor arrays based on three-dimensional integration of an active matrix to detect temperature and pressure independently. Our approach includes a calibrated compensation to decouple temperature and pressure signals. An individual pixel device consists of a TFT-based pressure sensor layered above a TFT-based temperature sensor. The detected temperature is used to compensate for the thermal effect on TFT-based pressure sensors. We develop large-area sensor arrays to enable accurate detection of two-dimensional pressure and temperature, leveraging these technologies to demonstrate advanced robotic grippers. The grippers stably grasp and lift a cup regardless of temperature, proving their possibility in skin-like electronic applications.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"29 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987725","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}
Haoyuan Shi, Ismayn A. Ditter, Adam C. Oken, Steven E. Mansoor
P2X receptors (P2XRs) are adenosine 5′-triphosphate (ATP)–gated ion channels comprising homomeric and heteromeric trimers of seven subtypes (P2X1–P2X7) that confer different rates of desensitization. The helical recoil model of P2XR desensitization proposes stability of the cytoplasmic cap sets the rate of desensitization, but timing of its formation is unclear for slow-desensitizing P2XRs. We report cryo–electron microscopy structures of full-length wild-type human P2X4 receptor in apo closed, antagonist-bound inhibited, and ATP-bound desensitized states. Because the apo closed and antagonist-bound inhibited state structures of this slow-desensitizing P2XR include an intact cytoplasmic cap while the ATP-bound desensitized state structure does not, the cytoplasmic cap is formed before agonist binding. Furthermore, structural and functional data suggest the cytoplasmic cap is stabilized by lipids to modulate desensitization, and P2X4 is modified by glycosylation and palmitoylation. Last, our antagonist-bound inhibited state structure reveals features specific to the allosteric ligand-binding pocket in human receptors that facilitates development of small-molecule modulators.
{"title":"Human P2X4 receptor gating is modulated by a stable cytoplasmic cap and a unique allosteric pocket","authors":"Haoyuan Shi, Ismayn A. Ditter, Adam C. Oken, Steven E. Mansoor","doi":"10.1126/sciadv.adr3315","DOIUrl":"https://doi.org/10.1126/sciadv.adr3315","url":null,"abstract":"P2X receptors (P2XRs) are adenosine 5′-triphosphate (ATP)–gated ion channels comprising homomeric and heteromeric trimers of seven subtypes (P2X1–P2X7) that confer different rates of desensitization. The helical recoil model of P2XR desensitization proposes stability of the cytoplasmic cap sets the rate of desensitization, but timing of its formation is unclear for slow-desensitizing P2XRs. We report cryo–electron microscopy structures of full-length wild-type human P2X4 receptor in apo closed, antagonist-bound inhibited, and ATP-bound desensitized states. Because the apo closed and antagonist-bound inhibited state structures of this slow-desensitizing P2XR include an intact cytoplasmic cap while the ATP-bound desensitized state structure does not, the cytoplasmic cap is formed before agonist binding. Furthermore, structural and functional data suggest the cytoplasmic cap is stabilized by lipids to modulate desensitization, and P2X4 is modified by glycosylation and palmitoylation. Last, our antagonist-bound inhibited state structure reveals features specific to the allosteric ligand-binding pocket in human receptors that facilitates development of small-molecule modulators.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"30 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute alcohol intoxication could cause multiorgan damage, including nervous, digestive, and cardiovascular systems, and in particular, irreversible damage to the brain and liver. Emerging studies have revealed that the endogenous multienzymatic antioxidant defense system (MEAODS) plays a central role in preventing oxidative stress and other toxicological compounds produced by alcohol. However, few available drugs could quickly regulate MEAODS. Herein, we report a nanosized iron sulfide (nFeS) that can rapidly release polysulfide species in gastric juice. The released hydrogen polysulfide activates the Keap1/Nrf2 pathway via S-persulfidation of cysteine residues in Keap1, which promotes the expression of antioxidant enzymes and glutathione synthesis–related enzymes, thus potentiating MEAODS. Results indicate that the activated MEAODS not only alleviates oxidative stress and inflammation in the brain and liver but also mitigates movement dysfunction after only 2.5 hours of oral nFeS treatment. Collectively, this study provides a MEAODS-regulated strategy with nFeS and may aid the prevention of acute alcoholic injury.
{"title":"Oral iron sulfide prevents acute alcohol intoxication by initiating the endogenous multienzymatic antioxidant defense system","authors":"Heping Wang, Xiaonan Wang, Mingxing Mao, Xi Chen, Ziwei Han, Zengyu Xun, Qian Wang, Yilin Qi, Weitao Zhao, Tianqi Li, Xiyun Yan, Jianfeng Liu, Lizeng Gao, Xue Xue","doi":"10.1126/sciadv.adr4231","DOIUrl":"https://doi.org/10.1126/sciadv.adr4231","url":null,"abstract":"Acute alcohol intoxication could cause multiorgan damage, including nervous, digestive, and cardiovascular systems, and in particular, irreversible damage to the brain and liver. Emerging studies have revealed that the endogenous multienzymatic antioxidant defense system (MEAODS) plays a central role in preventing oxidative stress and other toxicological compounds produced by alcohol. However, few available drugs could quickly regulate MEAODS. Herein, we report a nanosized iron sulfide (nFeS) that can rapidly release polysulfide species in gastric juice. The released hydrogen polysulfide activates the Keap1/Nrf2 pathway via S-persulfidation of cysteine residues in Keap1, which promotes the expression of antioxidant enzymes and glutathione synthesis–related enzymes, thus potentiating MEAODS. Results indicate that the activated MEAODS not only alleviates oxidative stress and inflammation in the brain and liver but also mitigates movement dysfunction after only 2.5 hours of oral nFeS treatment. Collectively, this study provides a MEAODS-regulated strategy with nFeS and may aid the prevention of acute alcoholic injury.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"55 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17Epub Date: 2025-01-15DOI: 10.1126/sciadv.adl5602
Max-Philipp Stenner, Cindy Márquez Nossa, Tino Zaehle, Elena Azañón, Hans-Jochen Heinze, Matthias Deliano, Lars Büntjen
Prior knowledge changes how the brain processes sensory input. Whether knowledge influences initial sensory processing upstream of the brain, in the spinal cord, is unknown. Studying electric potentials recorded invasively and noninvasively from the human spinal cord at millisecond resolution, we find that the cord generates electric potentials at 600 hertz that are modulated by prior knowledge about the time of sensory input, as early as 13 to 16 milliseconds after stimulation. Our results reveal that already in the spinal cord, sensory processing is under top-down, cognitive control, and that 600-hertz signals, which have been identified as a macroscopic marker of population spiking in other regions of the nervous system, play a role in early, context-dependent sensory processing. The possibility to examine these signals noninvasively in humans opens up avenues for research into the physiology of the spinal cord and its interaction with the brain.
{"title":"Prior knowledge changes initial sensory processing in the human spinal cord.","authors":"Max-Philipp Stenner, Cindy Márquez Nossa, Tino Zaehle, Elena Azañón, Hans-Jochen Heinze, Matthias Deliano, Lars Büntjen","doi":"10.1126/sciadv.adl5602","DOIUrl":"https://doi.org/10.1126/sciadv.adl5602","url":null,"abstract":"<p><p>Prior knowledge changes how the brain processes sensory input. Whether knowledge influences initial sensory processing upstream of the brain, in the spinal cord, is unknown. Studying electric potentials recorded invasively and noninvasively from the human spinal cord at millisecond resolution, we find that the cord generates electric potentials at 600 hertz that are modulated by prior knowledge about the time of sensory input, as early as 13 to 16 milliseconds after stimulation. Our results reveal that already in the spinal cord, sensory processing is under top-down, cognitive control, and that 600-hertz signals, which have been identified as a macroscopic marker of population spiking in other regions of the nervous system, play a role in early, context-dependent sensory processing. The possibility to examine these signals noninvasively in humans opens up avenues for research into the physiology of the spinal cord and its interaction with the brain.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 3","pages":"eadl5602"},"PeriodicalIF":11.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17Epub Date: 2025-01-15DOI: 10.1126/sciadv.adq8158
Weihao Zheng, Michael Borja, Leah C Dorman, Jonathan Liu, Andy Zhou, Amanda Seng, Ritwicq Arjyal, Sara Sunshine, Alina Nalyvayko, Angela Oliveira Pisco, Oren S Rosenberg, Norma Neff, Beth Shoshana Zha
Mycobacterium tuberculosis (MTB) ESX-1, a type VII secretion system, is a key virulence determinant contributing to MTB's survival within lung mononuclear phagocytes (MNPs), but its effect on MNP recruitment and differentiation remains unknown. Here, using multiple single-cell RNA sequencing techniques, we studied the role of ESX-1 in MNP heterogeneity and response in mice and murine bone marrow-derived macrophages (BMDM). We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces a transcriptional signature of immune evasion in lung macrophages and BMDM in an ESX-1-dependent manner. Spatial transcriptomics revealed an up-regulation of permissive features within MTB lesions, where monocyte-derived macrophages concentrate near MTB-infected cells. Together, our findings suggest that MTB ESX-1 facilitates the recruitment and differentiation of MNPs, which MTB can infect and manipulate for survival. Our dataset across various models and methods could contribute to the broader understanding of recruited cell heterogeneity during MTB lung infection.
{"title":"Single-cell analysis reveals <i>Mycobacterium tuberculosis</i> ESX-1-mediated accumulation of permissive macrophages in infected mouse lungs.","authors":"Weihao Zheng, Michael Borja, Leah C Dorman, Jonathan Liu, Andy Zhou, Amanda Seng, Ritwicq Arjyal, Sara Sunshine, Alina Nalyvayko, Angela Oliveira Pisco, Oren S Rosenberg, Norma Neff, Beth Shoshana Zha","doi":"10.1126/sciadv.adq8158","DOIUrl":"https://doi.org/10.1126/sciadv.adq8158","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> (MTB) ESX-1, a type VII secretion system, is a key virulence determinant contributing to MTB's survival within lung mononuclear phagocytes (MNPs), but its effect on MNP recruitment and differentiation remains unknown. Here, using multiple single-cell RNA sequencing techniques, we studied the role of ESX-1 in MNP heterogeneity and response in mice and murine bone marrow-derived macrophages (BMDM). We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces a transcriptional signature of immune evasion in lung macrophages and BMDM in an ESX-1-dependent manner. Spatial transcriptomics revealed an up-regulation of permissive features within MTB lesions, where monocyte-derived macrophages concentrate near MTB-infected cells. Together, our findings suggest that MTB ESX-1 facilitates the recruitment and differentiation of MNPs, which MTB can infect and manipulate for survival. Our dataset across various models and methods could contribute to the broader understanding of recruited cell heterogeneity during MTB lung infection.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 3","pages":"eadq8158"},"PeriodicalIF":11.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17Epub Date: 2025-01-15DOI: 10.1126/sciadv.adq9686
Min Jiao, Wenbo He, Zhenlin Ouyang, Qinyue Yu, Jiaxin Zhang, Qian Qin, Ruochen Wang, Xiaolong Guo, Ruihan Liu, Xiaoyu He, Peter M Hwang, Fang Zheng, Yurong Wen
The rare metal element molybdenum functions as a cofactor in molybdoenzymes that are essential to life in almost all living things. Molybdate can be captured by the periplasmic substrate-binding protein ModA of ModABC transport system in bacteria. We demonstrate that ModA plays crucial roles in growth, multiple metabolic pathways, and ROS tolerance in Acinetobacter baumannii. Crystal structures of molybdate-coordinated A. baumannii ModA show a noncanonical disulfide bond with a conformational change between reduced and oxidized states. Disulfide bond formation reduced binding affinity to molybdate by two orders of magnitude and contributes to its substrate preference. ModA-mediated molybdate binding was important for A. baumannii infection in a murine pneumonia model. Together, our study sheds light on the structural and functional diversity of molybdate uptake and highlights a potential target for antibacterial development.
{"title":"Molybdate uptake interplay with ROS tolerance modulates bacterial pathogenesis.","authors":"Min Jiao, Wenbo He, Zhenlin Ouyang, Qinyue Yu, Jiaxin Zhang, Qian Qin, Ruochen Wang, Xiaolong Guo, Ruihan Liu, Xiaoyu He, Peter M Hwang, Fang Zheng, Yurong Wen","doi":"10.1126/sciadv.adq9686","DOIUrl":"https://doi.org/10.1126/sciadv.adq9686","url":null,"abstract":"<p><p>The rare metal element molybdenum functions as a cofactor in molybdoenzymes that are essential to life in almost all living things. Molybdate can be captured by the periplasmic substrate-binding protein ModA of ModABC transport system in bacteria. We demonstrate that ModA plays crucial roles in growth, multiple metabolic pathways, and ROS tolerance in <i>Acinetobacter baumannii</i>. Crystal structures of molybdate-coordinated <i>A. baumannii</i> ModA show a noncanonical disulfide bond with a conformational change between reduced and oxidized states. Disulfide bond formation reduced binding affinity to molybdate by two orders of magnitude and contributes to its substrate preference. ModA-mediated molybdate binding was important for <i>A. baumannii</i> infection in a murine pneumonia model. Together, our study sheds light on the structural and functional diversity of molybdate uptake and highlights a potential target for antibacterial development.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 3","pages":"eadq9686"},"PeriodicalIF":11.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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