Bi-Wen Wang, Qian W. L. Zhang, Yi Chen, Wenhao Zhao, Yu Liu, Guo-Qiang Tang, Hong-Xia Ma, Bin Su, Hejiu Hui, John W. Delano, Fu-Yuan Wu, Xian-Hua Li, Yuyang He, Qiu-Li Li
There is extensive geologic evidence of ancient volcanic activity on the Moon, but it is unclear how long that volcanism persisted. Magma fountains produce volcanic glasses, which have previously been found in samples of the Moon’s surface. We investigated ~3000 glass beads in lunar soil samples collected by the Chang’e-5 mission and identified three as having a volcanic origin on the basis of their textures, chemical compositions, and sulfur isotopes. Uranium-lead dating of the three volcanic glass beads shows that they formed 123 ± 15 million years ago. We measured high abundances of rare earth elements and thorium in these volcanic glass beads, which could indicate that such recent volcanism was related to local enrichment of heat-generating elements in the mantle sources of the magma.
{"title":"Returned samples indicate volcanism on the Moon 120 million years ago","authors":"Bi-Wen Wang, Qian W. L. Zhang, Yi Chen, Wenhao Zhao, Yu Liu, Guo-Qiang Tang, Hong-Xia Ma, Bin Su, Hejiu Hui, John W. Delano, Fu-Yuan Wu, Xian-Hua Li, Yuyang He, Qiu-Li Li","doi":"10.1126/science.adk6635","DOIUrl":"10.1126/science.adk6635","url":null,"abstract":"<div >There is extensive geologic evidence of ancient volcanic activity on the Moon, but it is unclear how long that volcanism persisted. Magma fountains produce volcanic glasses, which have previously been found in samples of the Moon’s surface. We investigated ~3000 glass beads in lunar soil samples collected by the Chang’e-5 mission and identified three as having a volcanic origin on the basis of their textures, chemical compositions, and sulfur isotopes. Uranium-lead dating of the three volcanic glass beads shows that they formed 123 ± 15 million years ago. We measured high abundances of rare earth elements and thorium in these volcanic glass beads, which could indicate that such recent volcanism was related to local enrichment of heat-generating elements in the mantle sources of the magma.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140997","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}
{"title":"Roots in Brazil’s Amazon mangroves","authors":"Celso H. L. Silva-Junior","doi":"10.1126/science.adr3073","DOIUrl":"10.1126/science.adr3073","url":null,"abstract":"","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140999","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}
Sarah Mondoloni, Patricia Molina, Salvatore Lecca, Cheng-Hsi Wu, Léo Michel, Denys Osypenko, Fanchon Cachin, Meghan Flanigan, Mauro Congiu, Arnaud L. Lalive, Thomas Kash, Fei Deng, Yulong Li, Manuel Mameli
Negative emotional contagion—witnessing others in distress—affects an individual’s emotional responsivity. However, whether it shapes coping strategies when facing future threats remains unknown. We found that mice that briefly observe a conspecific being harmed become resilient, withstanding behavioral despair after an adverse experience. Photometric recordings during negative emotional contagion revealed increased serotonin (5-HT) release in the lateral habenula. Whereas 5-HT and emotional contagion reduced habenular burst firing, limiting 5-HT synthesis prevented burst plasticity. Enhancing raphe-to-habenula 5-HT was sufficient to recapitulate resilience. In contrast, reducing 5-HT release in the habenula made witnessing a conspecific in distress ineffective to promote the resilient phenotype after adversity. These findings reveal that 5-HT supports vicarious emotions and leads to resilience by tuning definite patterns of habenular neuronal activity.
{"title":"Serotonin release in the habenula during emotional contagion promotes resilience","authors":"Sarah Mondoloni, Patricia Molina, Salvatore Lecca, Cheng-Hsi Wu, Léo Michel, Denys Osypenko, Fanchon Cachin, Meghan Flanigan, Mauro Congiu, Arnaud L. Lalive, Thomas Kash, Fei Deng, Yulong Li, Manuel Mameli","doi":"10.1126/science.adp3897","DOIUrl":"10.1126/science.adp3897","url":null,"abstract":"<div >Negative emotional contagion—witnessing others in distress—affects an individual’s emotional responsivity. However, whether it shapes coping strategies when facing future threats remains unknown. We found that mice that briefly observe a conspecific being harmed become resilient, withstanding behavioral despair after an adverse experience. Photometric recordings during negative emotional contagion revealed increased serotonin (5-HT) release in the lateral habenula. Whereas 5-HT and emotional contagion reduced habenular burst firing, limiting 5-HT synthesis prevented burst plasticity. Enhancing raphe-to-habenula 5-HT was sufficient to recapitulate resilience. In contrast, reducing 5-HT release in the habenula made witnessing a conspecific in distress ineffective to promote the resilient phenotype after adversity. These findings reveal that 5-HT supports vicarious emotions and leads to resilience by tuning definite patterns of habenular neuronal activity.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141002","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}
Lea Dietrich, Ahmed-Noor A. Agip, Christina Kunz, Andre Schwarz, Werner Kühlbrandt
Cells depend on a continuous supply of adenosine triphosphate (ATP), the universal energy currency. In mitochondria, ATP is produced by a series of redox reactions, whereby an electrochemical gradient is established across the inner mitochondrial membrane. The ATP synthase harnesses the energy of the gradient to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. We determined the structure of ATP synthase within mitochondria of the unicellular flagellate Polytomella by electron cryo-tomography and subtomogram averaging at up to 4.2-angstrom resolution, revealing six rotary positions of the central stalk, subclassified into 21 substates of the F1 head. The Polytomella ATP synthase forms helical arrays with multiple adjacent rows defining the cristae ridges. The structure of ATP synthase under native operating conditions in the presence of a membrane potential represents a pivotal step toward the analysis of membrane protein complexes in situ.
细胞依赖于三磷酸腺苷（ATP）这种通用能源货币的持续供应。在线粒体中，ATP 通过一系列氧化还原反应产生，在线粒体内膜上形成电化学梯度。ATP 合成酶利用梯度的能量，从二磷酸腺苷（ADP）和无机磷酸生成 ATP。我们通过电子低温断层扫描和子图平均法，以高达4.2埃的分辨率测定了单细胞鞭毛虫多角体线粒体内ATP合成酶的结构，揭示了中央柄的六个旋转位置，细分为F1头的21个亚态。多瘤病毒的 ATP 合酶形成螺旋阵列，多个相邻行定义了嵴脊。在膜电位存在的原生工作条件下的 ATP 合成酶结构是原位分析膜蛋白复合物的关键一步。
{"title":"In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells","authors":"Lea Dietrich, Ahmed-Noor A. Agip, Christina Kunz, Andre Schwarz, Werner Kühlbrandt","doi":"10.1126/science.adp4640","DOIUrl":"10.1126/science.adp4640","url":null,"abstract":"<div >Cells depend on a continuous supply of adenosine triphosphate (ATP), the universal energy currency. In mitochondria, ATP is produced by a series of redox reactions, whereby an electrochemical gradient is established across the inner mitochondrial membrane. The ATP synthase harnesses the energy of the gradient to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. We determined the structure of ATP synthase within mitochondria of the unicellular flagellate <i>Polytomella</i> by electron cryo-tomography and subtomogram averaging at up to 4.2-angstrom resolution, revealing six rotary positions of the central stalk, subclassified into 21 substates of the F<sub>1</sub> head. The <i>Polytomella</i> ATP synthase forms helical arrays with multiple adjacent rows defining the cristae ridges. The structure of ATP synthase under native operating conditions in the presence of a membrane potential represents a pivotal step toward the analysis of membrane protein complexes in situ.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140982","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}
Duccio Conti, Arianna Esposito Verza, Marion E. Pesenti, Verena Cmentowski, Ingrid R. Vetter, Dongqing Pan, Andrea Musacchio
The centromere, a chromosome locus defined by the histone H3–like protein centromeric protein A (CENP-A), promotes assembly of the kinetochore to bind microtubules during cell division. Centromere maintenance requires CENP-A to be actively replenished by dedicated protein machinery in the early G1 phase of the cell cycle to compensate for its dilution after DNA replication. Cyclin-dependent kinases (CDKs) limit CENP-A deposition to once per cell cycle and function as negative regulators outside of early G1. Antithetically, Polo-like kinase 1 (PLK1) promotes CENP-A deposition in early G1, but the molecular details of this process are still unknown. We reveal here a phosphorylation network that recruits PLK1 to the deposition machinery to control a conformational switch required for licensing the CENP-A deposition reaction. Our findings clarify how PLK1 contributes to the epigenetic maintenance of centromeres.
{"title":"Role of protein kinase PLK1 in the epigenetic maintenance of centromeres","authors":"Duccio Conti, Arianna Esposito Verza, Marion E. Pesenti, Verena Cmentowski, Ingrid R. Vetter, Dongqing Pan, Andrea Musacchio","doi":"10.1126/science.ado5178","DOIUrl":"10.1126/science.ado5178","url":null,"abstract":"<div >The centromere, a chromosome locus defined by the histone H3–like protein centromeric protein A (CENP-A), promotes assembly of the kinetochore to bind microtubules during cell division. Centromere maintenance requires CENP-A to be actively replenished by dedicated protein machinery in the early G<sub>1</sub> phase of the cell cycle to compensate for its dilution after DNA replication. Cyclin-dependent kinases (CDKs) limit CENP-A deposition to once per cell cycle and function as negative regulators outside of early G<sub>1</sub>. Antithetically, Polo-like kinase 1 (PLK1) promotes CENP-A deposition in early G<sub>1</sub>, but the molecular details of this process are still unknown. We reveal here a phosphorylation network that recruits PLK1 to the deposition machinery to control a conformational switch required for licensing the CENP-A deposition reaction. Our findings clarify how PLK1 contributes to the epigenetic maintenance of centromeres.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140998","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}
Ervin Ascic, Fritiof Åkerström, Malavika Sreekumar Nair, André Rosa, Ilia Kurochkin, Olga Zimmermannova, Xavier Catena, Nadezhda Rotankova, Charlotte Veser, Michal Rudnik, Tommaso Ballocci, Tiffany Schärer, Xiaoli Huang, Maria de Rosa Torres, Emilie Renaud, Marta Velasco Santiago, Özcan Met, David Askmyr, Malin Lindstedt, Lennart Greiff, Laure-Anne Ligeon, Irina Agarkova, Inge Marie Svane, Cristiana F Pires, Fábio F Rosa, Carlos-Filipe Pereira
Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced tumor regressions, and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.
免疫疗法可使一些癌症患者长期存活，但由于抗原呈递不足以及免疫原细胞被排除在肿瘤微环境之外，免疫疗法的普遍成功一直受到阻碍。在这里，我们开发了一种方法，通过腺病毒递送转录因子PU.1、IRF8和BATF3，在体内对肿瘤细胞进行重编程，使它们能像1型常规树突状细胞一样呈递抗原。重编程的肿瘤细胞重塑了肿瘤微环境，招募并扩增了多克隆细胞毒性 T 细胞，诱导了肿瘤消退，并在多种小鼠黑色素瘤模型中建立了长期的全身免疫力。在人类肿瘤球体和异种移植物中，重编程为免疫原性树突状细胞的过程不受免疫抑制的影响，而免疫抑制通常会限制免疫疗法。我们的研究为体内免疫细胞重编程用于癌症免疫疗法的人体临床试验铺平了道路。
{"title":"In vivo dendritic cell reprogramming for cancer immunotherapy.","authors":"Ervin Ascic, Fritiof Åkerström, Malavika Sreekumar Nair, André Rosa, Ilia Kurochkin, Olga Zimmermannova, Xavier Catena, Nadezhda Rotankova, Charlotte Veser, Michal Rudnik, Tommaso Ballocci, Tiffany Schärer, Xiaoli Huang, Maria de Rosa Torres, Emilie Renaud, Marta Velasco Santiago, Özcan Met, David Askmyr, Malin Lindstedt, Lennart Greiff, Laure-Anne Ligeon, Irina Agarkova, Inge Marie Svane, Cristiana F Pires, Fábio F Rosa, Carlos-Filipe Pereira","doi":"10.1126/science.adn9083","DOIUrl":"https://doi.org/10.1126/science.adn9083","url":null,"abstract":"<p><p>Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced tumor regressions, and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.</p>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140970","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}
The Moon is the extraterrestrial body that is not only the closest to Earth, but also the best sampled and best explored celestial object. Analyses of rocks and soils delivered by the Apollo and Luna missions have established that the Moon is ancient, dry, and depleted of volatile elements. Studies also have indicated that early in its history, the Moon was covered with molten rock. This magma ocean eventually cooled and produced a compositionally diverse surface crust (1). How long the Moon produced magma has been an open question. On page 1077 of this issue, Wang et al. (2) report that volcanism on the Moon occurred as recently as 120 million years ago (Ma). This implies that the Moon may still be able to produce magma.
火山玻璃珠可追溯到 1.2 亿年前的月球岩浆活动。
{"title":"How young is volcanism on the Moon?","authors":"Yuri Amelin, Qing-Zhu Yin","doi":"10.1126/science.adr9336","DOIUrl":"10.1126/science.adr9336","url":null,"abstract":"<div >The Moon is the extraterrestrial body that is not only the closest to Earth, but also the best sampled and best explored celestial object. Analyses of rocks and soils delivered by the Apollo and Luna missions have established that the Moon is ancient, dry, and depleted of volatile elements. Studies also have indicated that early in its history, the Moon was covered with molten rock. This magma ocean eventually cooled and produced a compositionally diverse surface crust (<i>1</i>). How long the Moon produced magma has been an open question. On page 1077 of this issue, Wang <i>et al</i>. (<i>2</i>) report that volcanism on the Moon occurred as recently as 120 million years ago (Ma). This implies that the Moon may still be able to produce magma.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140980","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}
Differences between skin in different parts of the body are well recognized, but exploiting those differences to benefit the millions of people worldwide with prosthetic limbs is a new prospect. The skin of the palms and soles, known as volar skin, is specialized to withstand physical and mechanical forces, such as friction, shear stress, and pressure. Limb prostheses come into close contact with stump skin that is not adapted to these forces. As a result, the skin can break down, resulting in pain, ulceration, and infection (1). On page 1059 of this issue, Lee et al. (2) describe the distinctive properties of fibroblasts from volar skin and demonstrate, in a clinical trial of healthy volunteers, that injecting autologous volar fibroblasts (derived from the volunteers’ own tissue) confers volar features on nonvolar skin that persist for several months. This is a promising step toward improved quality of life for prosthesis wearers.
负重皮肤细胞显示出良好的治疗潜力。
{"title":"Transplanted fibroblasts take the pressure","authors":"Fiona M. Watt","doi":"10.1126/science.adr9294","DOIUrl":"10.1126/science.adr9294","url":null,"abstract":"<div >Differences between skin in different parts of the body are well recognized, but exploiting those differences to benefit the millions of people worldwide with prosthetic limbs is a new prospect. The skin of the palms and soles, known as volar skin, is specialized to withstand physical and mechanical forces, such as friction, shear stress, and pressure. Limb prostheses come into close contact with stump skin that is not adapted to these forces. As a result, the skin can break down, resulting in pain, ulceration, and infection (<i>1</i>). On page 1059 of this issue, Lee <i>et al</i>. (<i>2</i>) describe the distinctive properties of fibroblasts from volar skin and demonstrate, in a clinical trial of healthy volunteers, that injecting autologous volar fibroblasts (derived from the volunteers’ own tissue) confers volar features on nonvolar skin that persist for several months. This is a promising step toward improved quality of life for prosthesis wearers.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141010","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}
Melody Di Bona, Yanyang Chen, Albert S. Agustinus, Alice Mazzagatti, Mercedes A. Duran, Matthew Deyell, Daniel Bronder, James Hickling, Christy Hong, Lorenzo Scipioni, Giulia Tedeschi, Sara Martin, Jun Li, Aušrinė Ruzgaitė, Nadeem Riaz, Parin Shah, Edridge K. D’Souza, D. Zack Brodtman, Simone Sidoli, Bill Diplas, Manisha Jalan, Nancy Y. Lee, Alban Ordureau, Benjamin Izar, Ashley M. Laughney, Simon Powell, Enrico Gratton, Stefano Santaguida, John Maciejowski, Peter Ly, Thomas M. Jeitner, Samuel F. Bakhoum
Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.
{"title":"Micronuclear collapse from oxidative damage","authors":"Melody Di Bona, Yanyang Chen, Albert S. Agustinus, Alice Mazzagatti, Mercedes A. Duran, Matthew Deyell, Daniel Bronder, James Hickling, Christy Hong, Lorenzo Scipioni, Giulia Tedeschi, Sara Martin, Jun Li, Aušrinė Ruzgaitė, Nadeem Riaz, Parin Shah, Edridge K. D’Souza, D. Zack Brodtman, Simone Sidoli, Bill Diplas, Manisha Jalan, Nancy Y. Lee, Alban Ordureau, Benjamin Izar, Ashley M. Laughney, Simon Powell, Enrico Gratton, Stefano Santaguida, John Maciejowski, Peter Ly, Thomas M. Jeitner, Samuel F. Bakhoum","doi":"10.1126/science.adj8691","DOIUrl":"10.1126/science.adj8691","url":null,"abstract":"<div >Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100565","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}
Michael P. Fatt, Ming-Dong Zhang, Jussi Kupari, Müge Altınkök, Yunting Yang, Yizhou Hu, Per Svenningsson, Patrik Ernfors
Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels of abuse. While these compounds act on numerous central and peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means of single-cell transcriptomics and manipulation of morphine-responsive neurons, we have identified an ensemble of neurons in the rostral ventromedial medulla (RVM) that regulates mechanical nociception in mice. Among these, forced activation or silencing of excitatory RVMBDNF projection neurons mimicked or completely reversed morphine-induced mechanical antinociception, respectively, via a brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)–dependent mechanism and activation of inhibitory spinal galanin-positive neurons. Our results reveal a specific RVM-spinal circuit that scales mechanical nociception whose function confers the antinociceptive properties of morphine.
{"title":"Morphine-responsive neurons that regulate mechanical antinociception","authors":"Michael P. Fatt, Ming-Dong Zhang, Jussi Kupari, Müge Altınkök, Yunting Yang, Yizhou Hu, Per Svenningsson, Patrik Ernfors","doi":"10.1126/science.ado6593","DOIUrl":"10.1126/science.ado6593","url":null,"abstract":"<div >Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels of abuse. While these compounds act on numerous central and peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means of single-cell transcriptomics and manipulation of morphine-responsive neurons, we have identified an ensemble of neurons in the rostral ventromedial medulla (RVM) that regulates mechanical nociception in mice. Among these, forced activation or silencing of excitatory RVM<sup>BDNF</sup> projection neurons mimicked or completely reversed morphine-induced mechanical antinociception, respectively, via a brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)–dependent mechanism and activation of inhibitory spinal galanin-positive neurons. Our results reveal a specific RVM-spinal circuit that scales mechanical nociception whose function confers the antinociceptive properties of morphine.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":null,"pages":null},"PeriodicalIF":44.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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