Pub Date : 2024-08-01DOI: 10.1038/d41586-024-02416-3
Katherine Bourzac
{"title":"Heaviest element yet within reach after major breakthrough.","authors":"Katherine Bourzac","doi":"10.1038/d41586-024-02416-3","DOIUrl":"10.1038/d41586-024-02416-3","url":null,"abstract":"","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752157","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 : 2024-08-01Epub Date: 2024-07-10DOI: 10.1038/s41586-024-07635-2
S Fava, G De Vecchi, G Jotzu, M Buzzi, T Gebert, Y Liu, B Keimer, A Cavalleri
Coherent optical driving in quantum solids is emerging as a research frontier, with many reports of interesting non-equilibrium quantum phases1-4 and transient photo-induced functional phenomena such as ferroelectricity5,6, magnetism7-10 and superconductivity11-14. In high-temperature cuprate superconductors, coherent driving of certain phonon modes has resulted in a transient state with superconducting-like optical properties, observed far above their transition temperature Tc and throughout the pseudogap phase15-18. However, questions remain on the microscopic nature of this transient state and how to distinguish it from a non-superconducting state with enhanced carrier mobility. For example, it is not known whether cuprates driven in this fashion exhibit Meissner diamagnetism. Here we examine the time-dependent magnetic field surrounding an optically driven YBa2Cu3O6.48 crystal by measuring Faraday rotation in a magneto-optic material placed in the vicinity of the sample. For a constant applied magnetic field and under the same driving conditions that result in superconducting-like optical properties15-18, a transient diamagnetic response was observed. This response is comparable in size with that expected in an equilibrium type II superconductor of similar shape and size with a volume susceptibility χv of order -0.3. This value is incompatible with a photo-induced increase in mobility without superconductivity. Rather, it underscores the notion of a pseudogap phase in which incipient superconducting correlations are enhanced or synchronized by the drive.
{"title":"Magnetic field expulsion in optically driven YBa<sub>2</sub>Cu<sub>3</sub>O<sub>6.48</sub>.","authors":"S Fava, G De Vecchi, G Jotzu, M Buzzi, T Gebert, Y Liu, B Keimer, A Cavalleri","doi":"10.1038/s41586-024-07635-2","DOIUrl":"10.1038/s41586-024-07635-2","url":null,"abstract":"<p><p>Coherent optical driving in quantum solids is emerging as a research frontier, with many reports of interesting non-equilibrium quantum phases<sup>1-4</sup> and transient photo-induced functional phenomena such as ferroelectricity<sup>5,6</sup>, magnetism<sup>7-10</sup> and superconductivity<sup>11-14</sup>. In high-temperature cuprate superconductors, coherent driving of certain phonon modes has resulted in a transient state with superconducting-like optical properties, observed far above their transition temperature T<sub>c</sub> and throughout the pseudogap phase<sup>15-18</sup>. However, questions remain on the microscopic nature of this transient state and how to distinguish it from a non-superconducting state with enhanced carrier mobility. For example, it is not known whether cuprates driven in this fashion exhibit Meissner diamagnetism. Here we examine the time-dependent magnetic field surrounding an optically driven YBa<sub>2</sub>Cu<sub>3</sub>O<sub>6.48</sub> crystal by measuring Faraday rotation in a magneto-optic material placed in the vicinity of the sample. For a constant applied magnetic field and under the same driving conditions that result in superconducting-like optical properties<sup>15-18</sup>, a transient diamagnetic response was observed. This response is comparable in size with that expected in an equilibrium type II superconductor of similar shape and size with a volume susceptibility χ<sub>v</sub> of order -0.3. This value is incompatible with a photo-induced increase in mobility without superconductivity. Rather, it underscores the notion of a pseudogap phase in which incipient superconducting correlations are enhanced or synchronized by the drive.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580262","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 : 2024-08-01Epub Date: 2024-07-17DOI: 10.1038/s41586-024-07688-3
Arvind F Gupta, Sarah C Millholland, Haedam Im, Jiayin Dong, Jonathan M Jackson, Ilaria Carleo, Jessica Libby-Roberts, Megan Delamer, Mark R Giovinazzi, Andrea S J Lin, Shubham Kanodia, Xian-Yu Wang, Keivan Stassun, Thomas Masseron, Diana Dragomir, Suvrath Mahadevan, Jason Wright, Jaime A Alvarado-Montes, Chad Bender, Cullen H Blake, Douglas Caldwell, Caleb I Cañas, William D Cochran, Paul Dalba, Mark E Everett, Pipa Fernandez, Eli Golub, Bruno Guillet, Samuel Halverson, Leslie Hebb, Jesus Higuera, Chelsea X Huang, Jessica Klusmeyer, Rachel Knight, Liouba Leroux, Sarah E Logsdon, Margaret Loose, Michael W McElwain, Andrew Monson, Joe P Ninan, Grzegorz Nowak, Enric Palle, Yatrik Patel, Joshua Pepper, Michael Primm, Jayadev Rajagopal, Paul Robertson, Arpita Roy, Donald P Schneider, Christian Schwab, Heidi Schweiker, Lauren Sgro, Masao Shimizu, Georges Simard, Guðmundur Stefánsson, Daniel J Stevens, Steven Villanueva, John Wisniewski, Stefan Will, Carl Ziegler
Giant exoplanets orbiting close to their host stars are unlikely to have formed in their present configurations1. These 'hot Jupiter' planets are instead thought to have migrated inward from beyond the ice line and several viable migration channels have been proposed, including eccentricity excitation through angular-momentum exchange with a third body followed by tidally driven orbital circularization2,3. The discovery of the extremely eccentric (e = 0.93) giant exoplanet HD 80606 b (ref. 4) provided observational evidence that hot Jupiters may have formed through this high-eccentricity tidal-migration pathway5. However, no similar hot-Jupiter progenitors have been found and simulations predict that one factor affecting the efficacy of this mechanism is exoplanet mass, as low-mass planets are more likely to be tidally disrupted during periastron passage6-8. Here we present spectroscopic and photometric observations of TIC 241249530 b, a high-mass, transiting warm Jupiter with an extreme orbital eccentricity of e = 0.94. The orbit of TIC 241249530 b is consistent with a history of eccentricity oscillations and a future tidal circularization trajectory. Our analysis of the mass and eccentricity distributions of the transiting-warm-Jupiter population further reveals a correlation between high mass and high eccentricity.
在接近宿主恒星的轨道上运行的巨型系外行星不太可能以目前的构型形成1。人们认为这些 "热木星 "行星是从冰线以外向内迁移的,并提出了几种可行的迁移途径,包括通过与第三体进行角动量交换激发偏心,然后进行潮汐驱动的轨道环化2,3。极偏心(e = 0.93)巨型系外行星 HD 80606 b(参考文献 4)的发现为热木星可能通过这种高偏心潮汐迁移途径形成提供了观测证据5。然而,目前还没有发现类似的热木星原生体,而且模拟预测影响这一机制有效性的一个因素是系外行星的质量,因为低质量行星更有可能在近地轨道通过期间受到潮汐干扰6-8。在这里,我们展示了对 TIC 241249530 b 的光谱和光度观测结果,这是一颗高质、凌日暖木星,其轨道偏心率极高,为 e = 0.94。TIC 241249530 b的轨道与偏心率振荡的历史和未来潮汐圆化的轨迹相一致。我们对凌日暖木星群体的质量和偏心率分布的分析进一步揭示了高质和高偏心率之间的相关性。
{"title":"A hot-Jupiter progenitor on a super-eccentric retrograde orbit.","authors":"Arvind F Gupta, Sarah C Millholland, Haedam Im, Jiayin Dong, Jonathan M Jackson, Ilaria Carleo, Jessica Libby-Roberts, Megan Delamer, Mark R Giovinazzi, Andrea S J Lin, Shubham Kanodia, Xian-Yu Wang, Keivan Stassun, Thomas Masseron, Diana Dragomir, Suvrath Mahadevan, Jason Wright, Jaime A Alvarado-Montes, Chad Bender, Cullen H Blake, Douglas Caldwell, Caleb I Cañas, William D Cochran, Paul Dalba, Mark E Everett, Pipa Fernandez, Eli Golub, Bruno Guillet, Samuel Halverson, Leslie Hebb, Jesus Higuera, Chelsea X Huang, Jessica Klusmeyer, Rachel Knight, Liouba Leroux, Sarah E Logsdon, Margaret Loose, Michael W McElwain, Andrew Monson, Joe P Ninan, Grzegorz Nowak, Enric Palle, Yatrik Patel, Joshua Pepper, Michael Primm, Jayadev Rajagopal, Paul Robertson, Arpita Roy, Donald P Schneider, Christian Schwab, Heidi Schweiker, Lauren Sgro, Masao Shimizu, Georges Simard, Guðmundur Stefánsson, Daniel J Stevens, Steven Villanueva, John Wisniewski, Stefan Will, Carl Ziegler","doi":"10.1038/s41586-024-07688-3","DOIUrl":"10.1038/s41586-024-07688-3","url":null,"abstract":"<p><p>Giant exoplanets orbiting close to their host stars are unlikely to have formed in their present configurations<sup>1</sup>. These 'hot Jupiter' planets are instead thought to have migrated inward from beyond the ice line and several viable migration channels have been proposed, including eccentricity excitation through angular-momentum exchange with a third body followed by tidally driven orbital circularization<sup>2,3</sup>. The discovery of the extremely eccentric (e = 0.93) giant exoplanet HD 80606 b (ref. <sup>4</sup>) provided observational evidence that hot Jupiters may have formed through this high-eccentricity tidal-migration pathway<sup>5</sup>. However, no similar hot-Jupiter progenitors have been found and simulations predict that one factor affecting the efficacy of this mechanism is exoplanet mass, as low-mass planets are more likely to be tidally disrupted during periastron passage<sup>6-8</sup>. Here we present spectroscopic and photometric observations of TIC 241249530 b, a high-mass, transiting warm Jupiter with an extreme orbital eccentricity of e = 0.94. The orbit of TIC 241249530 b is consistent with a history of eccentricity oscillations and a future tidal circularization trajectory. Our analysis of the mass and eccentricity distributions of the transiting-warm-Jupiter population further reveals a correlation between high mass and high eccentricity.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633960","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 : 2024-08-01Epub Date: 2024-07-17DOI: 10.1038/s41586-024-07701-9
Anissa A Widjaja, Wei-Wen Lim, Sivakumar Viswanathan, Sonia Chothani, Ben Corden, Cibi Mary Dasan, Joyce Wei Ting Goh, Radiance Lim, Brijesh K Singh, Jessie Tan, Chee Jian Pua, Sze Yun Lim, Eleonora Adami, Sebastian Schafer, Benjamin L George, Mark Sweeney, Chen Xie, Madhulika Tripathi, Natalie A Sims, Norbert Hübner, Enrico Petretto, Dominic J Withers, Lena Ho, Jesus Gil, David Carling, Stuart A Cook
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
{"title":"Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.","authors":"Anissa A Widjaja, Wei-Wen Lim, Sivakumar Viswanathan, Sonia Chothani, Ben Corden, Cibi Mary Dasan, Joyce Wei Ting Goh, Radiance Lim, Brijesh K Singh, Jessie Tan, Chee Jian Pua, Sze Yun Lim, Eleonora Adami, Sebastian Schafer, Benjamin L George, Mark Sweeney, Chen Xie, Madhulika Tripathi, Natalie A Sims, Norbert Hübner, Enrico Petretto, Dominic J Withers, Lena Ho, Jesus Gil, David Carling, Stuart A Cook","doi":"10.1038/s41586-024-07701-9","DOIUrl":"10.1038/s41586-024-07701-9","url":null,"abstract":"<p><p>For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark<sup>1-7</sup>. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633970","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 : 2024-08-01DOI: 10.1038/d41586-024-02522-2
Ewen Callaway
{"title":"Is that a durian? No, it's a weird ancient mollusc.","authors":"Ewen Callaway","doi":"10.1038/d41586-024-02522-2","DOIUrl":"https://doi.org/10.1038/d41586-024-02522-2","url":null,"abstract":"","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875299","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 : 2024-08-01Epub Date: 2024-07-31DOI: 10.1038/s41586-024-07742-0
Tsung-Han Chou, Max Epstein, Russell G Fritzemeier, Nicholas S Akins, Srinu Paladugu, Elijah Z Ullman, Dennis C Liotta, Stephen F Traynelis, Hiro Furukawa
Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity1. The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands-glutamate and glycine-for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively2,3. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1-GluN2B (GluN1-2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1-2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1-2B dimer arrangements but insufficient tension in the LBD-TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity.
{"title":"Molecular mechanism of ligand gating and opening of NMDA receptor.","authors":"Tsung-Han Chou, Max Epstein, Russell G Fritzemeier, Nicholas S Akins, Srinu Paladugu, Elijah Z Ullman, Dennis C Liotta, Stephen F Traynelis, Hiro Furukawa","doi":"10.1038/s41586-024-07742-0","DOIUrl":"10.1038/s41586-024-07742-0","url":null,"abstract":"<p><p>Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity<sup>1</sup>. The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands-glutamate and glycine-for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively<sup>2,3</sup>. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1-GluN2B (GluN1-2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1-2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1-2B dimer arrangements but insufficient tension in the LBD-TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860318","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 : 2024-08-01DOI: 10.1038/d41586-024-02427-0
Sumeet Kulkarni
{"title":"Three ways AI is changing the 2024 Olympics for athletes and fans.","authors":"Sumeet Kulkarni","doi":"10.1038/d41586-024-02427-0","DOIUrl":"10.1038/d41586-024-02427-0","url":null,"abstract":"","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759813","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 : 2024-08-01Epub Date: 2024-07-03DOI: 10.1038/s41586-024-07611-w
Shefeeq M Theparambil, Olga Kopach, Alice Braga, Shereen Nizari, Patrick S Hosford, Virag Sagi-Kiss, Anna Hadjihambi, Christos Konstantinou, Noemi Esteras, Ana Gutierrez Del Arroyo, Gareth L Ackland, Anja G Teschemacher, Nicholas Dale, Tobias Eckle, Petros Andrikopoulos, Dmitri A Rusakov, Sergey Kasparov, Alexander V Gourine
Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.
{"title":"Adenosine signalling to astrocytes coordinates brain metabolism and function.","authors":"Shefeeq M Theparambil, Olga Kopach, Alice Braga, Shereen Nizari, Patrick S Hosford, Virag Sagi-Kiss, Anna Hadjihambi, Christos Konstantinou, Noemi Esteras, Ana Gutierrez Del Arroyo, Gareth L Ackland, Anja G Teschemacher, Nicholas Dale, Tobias Eckle, Petros Andrikopoulos, Dmitri A Rusakov, Sergey Kasparov, Alexander V Gourine","doi":"10.1038/s41586-024-07611-w","DOIUrl":"10.1038/s41586-024-07611-w","url":null,"abstract":"<p><p>Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply<sup>1,2</sup>. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism<sup>3,4</sup>, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood<sup>5,6</sup>. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498468","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 : 2024-08-01Epub Date: 2024-07-17DOI: 10.1038/s41586-024-07692-7
G Maddaloni, Y J Chang, R A Senft, S M Dymecki
Changes in the amount of daylight (photoperiod) alter physiology and behaviour1,2. Adaptive responses to seasonal photoperiods are vital to all organisms-dysregulation associates with disease, including affective disorders3 and metabolic syndromes4. The circadian rhythm circuitry is implicated in such responses5,6, yet little is known about the precise cellular substrates that underlie phase synchronization to photoperiod change. Here we identify a brain circuit and system of axon branch-specific and reversible neurotransmitter deployment that are critical for behavioural and sleep adaptation to photoperiod. A type of neuron called mrEn1-Pet17 in the mouse brainstem median raphe nucleus segregates serotonin from VGLUT3 (also known as SLC17A8, a proxy for glutamate) to different axonal branches that innervate specific brain regions involved in circadian rhythm and sleep-wake timing8,9. This branch-specific neurotransmitter deployment did not distinguish between daylight and dark phase; however, it reorganized with change in photoperiod. Axonal boutons, but not cell soma, changed neurochemical phenotype upon a shift away from equinox light/dark conditions, and these changes were reversed upon return to equinox conditions. When we genetically disabled Vglut3 in mrEn1-Pet1 neurons, sleep-wake periods, voluntary activity and clock gene expression did not synchronize to the new photoperiod or were delayed. Combining intersectional rabies virus tracing and projection-specific neuronal silencing, we delineated a preoptic area-to-mrEn1Pet1 connection that was responsible for decoding the photoperiodic inputs, driving the neurotransmitter reorganization and promoting behavioural synchronization. Our results reveal a brain circuit and periodic, branch-specific neurotransmitter deployment that regulates organismal adaptation to photoperiod change.
{"title":"Adaptation to photoperiod via dynamic neurotransmitter segregation.","authors":"G Maddaloni, Y J Chang, R A Senft, S M Dymecki","doi":"10.1038/s41586-024-07692-7","DOIUrl":"10.1038/s41586-024-07692-7","url":null,"abstract":"<p><p>Changes in the amount of daylight (photoperiod) alter physiology and behaviour<sup>1,2</sup>. Adaptive responses to seasonal photoperiods are vital to all organisms-dysregulation associates with disease, including affective disorders<sup>3</sup> and metabolic syndromes<sup>4</sup>. The circadian rhythm circuitry is implicated in such responses<sup>5,6</sup>, yet little is known about the precise cellular substrates that underlie phase synchronization to photoperiod change. Here we identify a brain circuit and system of axon branch-specific and reversible neurotransmitter deployment that are critical for behavioural and sleep adaptation to photoperiod. A type of neuron called mrEn1-Pet1<sup>7</sup> in the mouse brainstem median raphe nucleus segregates serotonin from VGLUT3 (also known as SLC17A8, a proxy for glutamate) to different axonal branches that innervate specific brain regions involved in circadian rhythm and sleep-wake timing<sup>8,9</sup>. This branch-specific neurotransmitter deployment did not distinguish between daylight and dark phase; however, it reorganized with change in photoperiod. Axonal boutons, but not cell soma, changed neurochemical phenotype upon a shift away from equinox light/dark conditions, and these changes were reversed upon return to equinox conditions. When we genetically disabled Vglut3 in mrEn1-Pet1 neurons, sleep-wake periods, voluntary activity and clock gene expression did not synchronize to the new photoperiod or were delayed. Combining intersectional rabies virus tracing and projection-specific neuronal silencing, we delineated a preoptic area-to-mrEn1Pet1 connection that was responsible for decoding the photoperiodic inputs, driving the neurotransmitter reorganization and promoting behavioural synchronization. Our results reveal a brain circuit and periodic, branch-specific neurotransmitter deployment that regulates organismal adaptation to photoperiod change.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633873","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 : 2024-08-01Epub Date: 2024-07-17DOI: 10.1038/s41586-024-07708-2
Dylan J Taylor, Surya B Chhetri, Michael G Tassia, Arjun Biddanda, Stephanie M Yan, Genevieve L Wojcik, Alexis Battle, Rajiv C McCoy
Genetic variation that influences gene expression and splicing is a key source of phenotypic diversity1-5. Although invaluable, studies investigating these links in humans have been strongly biased towards participants of European ancestries, which constrains generalizability and hinders evolutionary research. Here to address these limitations, we developed MAGE, an open-access RNA sequencing dataset of lymphoblastoid cell lines from 731 individuals from the 1000 Genomes Project6, spread across 5 continental groups and 26 populations. Most variation in gene expression (92%) and splicing (95%) was distributed within versus between populations, which mirrored the variation in DNA sequence. We mapped associations between genetic variants and expression and splicing of nearby genes (cis-expression quantitative trait loci (eQTLs) and cis-splicing QTLs (sQTLs), respectively). We identified more than 15,000 putatively causal eQTLs and more than 16,000 putatively causal sQTLs that are enriched for relevant epigenomic signatures. These include 1,310 eQTLs and 1,657 sQTLs that are largely private to underrepresented populations. Our data further indicate that the magnitude and direction of causal eQTL effects are highly consistent across populations. Moreover, the apparent 'population-specific' effects observed in previous studies were largely driven by low resolution or additional independent eQTLs of the same genes that were not detected. Together, our study expands our understanding of human gene expression diversity and provides an inclusive resource for studying the evolution and function of human genomes.
{"title":"Sources of gene expression variation in a globally diverse human cohort.","authors":"Dylan J Taylor, Surya B Chhetri, Michael G Tassia, Arjun Biddanda, Stephanie M Yan, Genevieve L Wojcik, Alexis Battle, Rajiv C McCoy","doi":"10.1038/s41586-024-07708-2","DOIUrl":"10.1038/s41586-024-07708-2","url":null,"abstract":"<p><p>Genetic variation that influences gene expression and splicing is a key source of phenotypic diversity<sup>1-5</sup>. Although invaluable, studies investigating these links in humans have been strongly biased towards participants of European ancestries, which constrains generalizability and hinders evolutionary research. Here to address these limitations, we developed MAGE, an open-access RNA sequencing dataset of lymphoblastoid cell lines from 731 individuals from the 1000 Genomes Project<sup>6</sup>, spread across 5 continental groups and 26 populations. Most variation in gene expression (92%) and splicing (95%) was distributed within versus between populations, which mirrored the variation in DNA sequence. We mapped associations between genetic variants and expression and splicing of nearby genes (cis-expression quantitative trait loci (eQTLs) and cis-splicing QTLs (sQTLs), respectively). We identified more than 15,000 putatively causal eQTLs and more than 16,000 putatively causal sQTLs that are enriched for relevant epigenomic signatures. These include 1,310 eQTLs and 1,657 sQTLs that are largely private to underrepresented populations. Our data further indicate that the magnitude and direction of causal eQTL effects are highly consistent across populations. Moreover, the apparent 'population-specific' effects observed in previous studies were largely driven by low resolution or additional independent eQTLs of the same genes that were not detected. Together, our study expands our understanding of human gene expression diversity and provides an inclusive resource for studying the evolution and function of human genomes.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633990","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}