Kathleen E. Mandt, Jacob Lustig-Yaeger, Adrienn Luspay-Kuti, Peter Wurz, Dennis Bodewits, Stephen A. Fuselier, Olivier Mousis, Steven M. Petrinec, Karlheinz J. Trattner
Cometary comae are a mixture of gas and ice-covered dust. Processing on the surface and in the coma change the composition of ice on dust grains relative to that of the nucleus. As the ice on dust grains sublimates, the local coma composition changes. Rosetta observations of 67P/Churyumov-Gerasimenko previously reported one of the highest D/H values for a comet. However, reanalysis of more than 4000 water isotope measurements over the full mission shows that dust markedly increases local D/H. The isotope ratio measured at a distance from the nucleus where the gas is well mixed is close to terrestrial, like that of other Jupiter family comets. This lower D/H has implications for understanding comet formation and the role of comets in delivering water to Earth.
{"title":"A nearly terrestrial D/H for comet 67P/Churyumov-Gerasimenko","authors":"Kathleen E. Mandt, Jacob Lustig-Yaeger, Adrienn Luspay-Kuti, Peter Wurz, Dennis Bodewits, Stephen A. Fuselier, Olivier Mousis, Steven M. Petrinec, Karlheinz J. Trattner","doi":"10.1126/sciadv.adp2191","DOIUrl":"10.1126/sciadv.adp2191","url":null,"abstract":"<div >Cometary comae are a mixture of gas and ice-covered dust. Processing on the surface and in the coma change the composition of ice on dust grains relative to that of the nucleus. As the ice on dust grains sublimates, the local coma composition changes. Rosetta observations of 67P/Churyumov-Gerasimenko previously reported one of the highest D/H values for a comet. However, reanalysis of more than 4000 water isotope measurements over the full mission shows that dust markedly increases local D/H. The isotope ratio measured at a distance from the nucleus where the gas is well mixed is close to terrestrial, like that of other Jupiter family comets. This lower D/H has implications for understanding comet formation and the role of comets in delivering water to Earth.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp2191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602009","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}
Early-life experience influences subsequent maturation and function of the adult brain, sometimes even in a sex-specific manner, but underlying molecular mechanisms are poorly understood. We describe here how juvenile experience defines sexually dimorphic synaptic connectivity in the adult Caenorhabditis elegans nervous system. Starvation of juvenile males disrupts serotonin-dependent activation of the CREB transcription factor in a nociceptive sensory neuron, PHB. CREB acts through a cascade of transcription factors to control expression of an atypical cadherin protein, FMI-1/Flamingo/CELSR. During postembryonic development, FMI-1 promotes and maintains synaptic connectivity of PHB to a command interneuron, AVA, in both sexes, but a serotonin-dependent transcriptional regulatory cassette antagonizes FMI-1 expression in males, thereby establishing sexually dimorphic connectivity between PHB and AVA. A critical regulatory node is the CREB-target LIN-29, a Zn finger transcription factor that integrates four layers of information: sexual specificity, past experience, time and cell-type specificity. Our findings provide the mechanistic details of how an early juvenile experience defines sexually dimorphic synaptic connectivity.
早年的生活经历会影响成年大脑随后的成熟和功能，有时甚至会以性别特异性的方式产生影响，但人们对其潜在的分子机制却知之甚少。我们在此描述了幼年经历是如何定义成年秀丽隐杆线虫神经系统中性双态突触连接的。对幼年雄性的饥饿会破坏血清素依赖性地激活痛觉感觉神经元 PHB 中的 CREB 转录因子。CREB通过一系列转录因子控制非典型粘附蛋白FMI-1/Flamingo/CELSR的表达。在胚后发育过程中，FMI-1 可促进和维持两性 PHB 与指令性中间神经元 AVA 的突触连接，但依赖于血清素的转录调控盒可拮抗雄性的 FMI-1 表达，从而在 PHB 和 AVA 之间建立起性双态连接。CREB靶标LIN-29是一个关键的调控节点，它是一种Zn指转录因子，整合了四层信息：性特异性、过去的经验、时间和细胞类型特异性。我们的研究结果提供了幼年经历如何决定性双态突触连接的机制细节。
{"title":"Experience-dependent, sexually dimorphic synaptic connectivity defined by sex-specific cadherin expression","authors":"Chien-Po Liao, Maryam Majeed, Oliver Hobert","doi":"10.1126/sciadv.adq9183","DOIUrl":"10.1126/sciadv.adq9183","url":null,"abstract":"<div >Early-life experience influences subsequent maturation and function of the adult brain, sometimes even in a sex-specific manner, but underlying molecular mechanisms are poorly understood. We describe here how juvenile experience defines sexually dimorphic synaptic connectivity in the adult <i>Caenorhabditis elegans</i> nervous system. Starvation of juvenile males disrupts serotonin-dependent activation of the CREB transcription factor in a nociceptive sensory neuron, PHB. CREB acts through a cascade of transcription factors to control expression of an atypical cadherin protein, FMI-1/Flamingo/CELSR. During postembryonic development, FMI-1 promotes and maintains synaptic connectivity of PHB to a command interneuron, AVA, in both sexes, but a serotonin-dependent transcriptional regulatory cassette antagonizes FMI-1 expression in males, thereby establishing sexually dimorphic connectivity between PHB and AVA. A critical regulatory node is the CREB-target LIN-29, a Zn finger transcription factor that integrates four layers of information: sexual specificity, past experience, time and cell-type specificity. Our findings provide the mechanistic details of how an early juvenile experience defines sexually dimorphic synaptic connectivity.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq9183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602022","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}
The discrimination of quantum operations has long been an intriguing challenge, with theoretical research notably advancing our understanding of the quantum features in discriminating quantum objects. This challenge is closely related to the discrimination of quantum states, and proof-of-principle demonstrations of the latter have already been realized using optical photons. However, the experimental demonstration of discriminating general quantum operations, including both unitary and nonunitary operations, has remained elusive. In general quantum systems, especially those with high dimensions, the preparation of arbitrary quantum states and the implementation of arbitrary quantum operations and generalized measurements are nontrivial tasks. Here, we experimentally demonstrate the optimal unambiguous discrimination of up to six displacement operators and the unambiguous discrimination of nonunitary quantum operations. Our results demonstrate powerful tools for experimental research in quantum information processing and are expected to stimulate a wide range of valuable applications in the field of quantum sensing.
{"title":"Unambiguous discrimination of general quantum operations","authors":"Weizhou Cai, Jing-Ning Zhang, Ziyue Hua, Weiting Wang, Xiaoxuan Pan, Xinyu Liu, Yuwei Ma, Ling Hu, Xianghao Mu, Haiyan Wang, Yipu Song, Chang-Ling Zou, Luyan Sun","doi":"10.1126/sciadv.adq2529","DOIUrl":"10.1126/sciadv.adq2529","url":null,"abstract":"<div >The discrimination of quantum operations has long been an intriguing challenge, with theoretical research notably advancing our understanding of the quantum features in discriminating quantum objects. This challenge is closely related to the discrimination of quantum states, and proof-of-principle demonstrations of the latter have already been realized using optical photons. However, the experimental demonstration of discriminating general quantum operations, including both unitary and nonunitary operations, has remained elusive. In general quantum systems, especially those with high dimensions, the preparation of arbitrary quantum states and the implementation of arbitrary quantum operations and generalized measurements are nontrivial tasks. Here, we experimentally demonstrate the optimal unambiguous discrimination of up to six displacement operators and the unambiguous discrimination of nonunitary quantum operations. Our results demonstrate powerful tools for experimental research in quantum information processing and are expected to stimulate a wide range of valuable applications in the field of quantum sensing.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq2529","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602005","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}
Qingzhou Feng, Martin Saladin, Chunxiang Wu, Eason Cao, Wei Zheng, Amy Zhang, Pushpanjali Bhardwaj, Xia Li, Qi Shen, Larisa E. Kapinos, Toshiya Kozai, Malaiyalam Mariappan, C. Patrick Lusk, Yong Xiong, Roderick Y. H. Lim, Chenxiang Lin
Nucleoporins (nups) in the nuclear pore complex (NPC) form a selective barrier that suppresses the diffusion of most macromolecules while enabling rapid transport of nuclear transport receptor (NTR)–bound cargos. Recent studies have shown that the NPC may dilate and constrict, but how altering the NPC diameter affects its selective barrier properties remains unclear. Here, we build DNA nanopores with programmable diameters and nup arrangements to model the constricted and dilated NPCs. We find that Nup62 proteins form a dynamic cross-channel barrier impermeable to hepatitis B virus (HBV) capsids when grafted inside 60-nm-wide nanopores but not in 79-nm pores, where Nup62 cluster locally. Furthermore, importin-β1 substantially changes the dynamics of Nup62 assemblies and facilitates the passage of HBV capsids through the 60-nm NPC mimics containing Nup62 and Nup153. Our study shows that transport channel width is critical to the permeability of nup barriers and underscores NTRs’ role in dynamically remodeling nup assemblies and mediating the nuclear entry of viruses.
{"title":"Channel width modulates the permeability of DNA origami–based nuclear pore mimics","authors":"Qingzhou Feng, Martin Saladin, Chunxiang Wu, Eason Cao, Wei Zheng, Amy Zhang, Pushpanjali Bhardwaj, Xia Li, Qi Shen, Larisa E. Kapinos, Toshiya Kozai, Malaiyalam Mariappan, C. Patrick Lusk, Yong Xiong, Roderick Y. H. Lim, Chenxiang Lin","doi":"10.1126/sciadv.adq8773","DOIUrl":"10.1126/sciadv.adq8773","url":null,"abstract":"<div >Nucleoporins (nups) in the nuclear pore complex (NPC) form a selective barrier that suppresses the diffusion of most macromolecules while enabling rapid transport of nuclear transport receptor (NTR)–bound cargos. Recent studies have shown that the NPC may dilate and constrict, but how altering the NPC diameter affects its selective barrier properties remains unclear. Here, we build DNA nanopores with programmable diameters and nup arrangements to model the constricted and dilated NPCs. We find that Nup62 proteins form a dynamic cross-channel barrier impermeable to hepatitis B virus (HBV) capsids when grafted inside 60-nm-wide nanopores but not in 79-nm pores, where Nup62 cluster locally. Furthermore, importin-β1 substantially changes the dynamics of Nup62 assemblies and facilitates the passage of HBV capsids through the 60-nm NPC mimics containing Nup62 and Nup153. Our study shows that transport channel width is critical to the permeability of nup barriers and underscores NTRs’ role in dynamically remodeling nup assemblies and mediating the nuclear entry of viruses.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq8773","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602010","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}
Emily Carlisle, Zongjun Yin, Davide Pisani, Philip C. J. Donoghue
The timescale of animal diversification has been a focus of debate over how evolutionary history should be calibrated to geologic time. Molecular clock analyses have invariably estimated a Cryogenian or Tonian origin of animals while unequivocal animal fossils first occur in the Ediacaran. However, redating of key Ediacaran biotas and the discovery of several Ediacaran crown-Metazoa prompt recalibration of molecular clock analyses. We present revised fossil calibrations and use them in molecular clock analyses estimating the timescale of metazoan evolutionary history. Integrating across uncertainties including phylogenetic relationships, clock model, and calibration strategy, we estimate Metazoa to have originated in the early Ediacaran, Eumetazoa in the middle Ediacaran, and Bilateria in the upper Ediacaran, with many crown-phyla originating across the Ediacaran-Cambrian interval or elsewise fully within the Cambrian. These results are in much closer accord with the fossil record, coinciding with marine oxygenation, but they reject a literal reading of the fossil record.
{"title":"Ediacaran origin and Ediacaran-Cambrian diversification of Metazoa","authors":"Emily Carlisle, Zongjun Yin, Davide Pisani, Philip C. J. Donoghue","doi":"10.1126/sciadv.adp7161","DOIUrl":"10.1126/sciadv.adp7161","url":null,"abstract":"<div >The timescale of animal diversification has been a focus of debate over how evolutionary history should be calibrated to geologic time. Molecular clock analyses have invariably estimated a Cryogenian or Tonian origin of animals while unequivocal animal fossils first occur in the Ediacaran. However, redating of key Ediacaran biotas and the discovery of several Ediacaran crown-Metazoa prompt recalibration of molecular clock analyses. We present revised fossil calibrations and use them in molecular clock analyses estimating the timescale of metazoan evolutionary history. Integrating across uncertainties including phylogenetic relationships, clock model, and calibration strategy, we estimate Metazoa to have originated in the early Ediacaran, Eumetazoa in the middle Ediacaran, and Bilateria in the upper Ediacaran, with many crown-phyla originating across the Ediacaran-Cambrian interval or elsewise fully within the Cambrian. These results are in much closer accord with the fossil record, coinciding with marine oxygenation, but they reject a literal reading of the fossil record.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp7161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602017","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}
Cameron D. Griffiths, Millie Shah, William Shao, Cheryl A. Borgman, Kevin A. Janes
Viruses elicit long-term adaptive responses in the tissues they infect. Understanding viral adaptions in humans is difficult in organs such as the heart, where primary infected material is not routinely collected. In search of asymptomatic infections with accompanying host adaptions, we mined for cardio-pathogenic viruses in the unaligned reads of nearly 1000 human hearts profiled by RNA sequencing. Among virus-positive cases (~20%), we identified three robust adaptions in the host transcriptome related to inflammatory nuclear factor κB (NF-κB) signaling and posttranscriptional regulation by the p38-MK2 pathway. The adaptions are not determined by the infecting virus, and they recur in infections of human or animal hearts and cultured cardiomyocytes. Adaptions switch states when NF-κB or p38-MK2 is perturbed in cells engineered for chronic infection by the cardio-pathogenic virus, coxsackievirus B3. Stratifying viral responses into reversible adaptions adds a targetable systems-level simplification for infections of the heart and perhaps other organs.
{"title":"Three modes of viral adaption by the heart","authors":"Cameron D. Griffiths, Millie Shah, William Shao, Cheryl A. Borgman, Kevin A. Janes","doi":"10.1126/sciadv.adp6303","DOIUrl":"10.1126/sciadv.adp6303","url":null,"abstract":"<div >Viruses elicit long-term adaptive responses in the tissues they infect. Understanding viral adaptions in humans is difficult in organs such as the heart, where primary infected material is not routinely collected. In search of asymptomatic infections with accompanying host adaptions, we mined for cardio-pathogenic viruses in the unaligned reads of nearly 1000 human hearts profiled by RNA sequencing. Among virus-positive cases (~20%), we identified three robust adaptions in the host transcriptome related to inflammatory nuclear factor κB (NF-κB) signaling and posttranscriptional regulation by the p38-MK2 pathway. The adaptions are not determined by the infecting virus, and they recur in infections of human or animal hearts and cultured cardiomyocytes. Adaptions switch states when NF-κB or p38-MK2 is perturbed in cells engineered for chronic infection by the cardio-pathogenic virus, coxsackievirus B3. Stratifying viral responses into reversible adaptions adds a targetable systems-level simplification for infections of the heart and perhaps other organs.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp6303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602001","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}
Tatsuaki Kurata, Masaki Takegawa, Takayuki Ohira, Egor A. Syroegin, Gemma C. Atkinson, Marcus J.O. Johansson, Yury S. Polikanov, Abel Garcia-Pino, Tsutomu Suzuki, Vasili Hauryliuk
Translation-targeting toxic small alarmone synthetases (toxSAS) are effectors of bacterial toxin-antitoxin systems that pyrophosphorylate the 3′-CCA end of transfer RNA (tRNA) to prevent aminoacylation. toxSAS are implicated in antiphage immunity: Phage detection triggers the toxSAS activity to shut down viral production. We show that the toxSAS FaRel2 inspects the tRNA acceptor stem to specifically select tRNAGly and tRNAThr. The first, second, fourth, and fifth base pairs of the stem act as the specificity determinants. We show that the toxSASs PhRel2 and CapRelSJ46 differ in tRNA specificity from FaRel2 and rationalize this through structural modeling: While the universal 3′-CCA end slots into a highly conserved CCA recognition groove, the acceptor stem recognition region is variable across toxSAS diversity. As phages use tRNA isoacceptors to overcome tRNA-targeting defenses, we hypothesize that highly evolvable modular tRNA recognition allows for the escape of viral countermeasures through tRNA substrate specificity switching.
{"title":"Toxic small alarmone synthetase FaRel2 inhibits translation by pyrophosphorylating tRNAGly and tRNAThr","authors":"Tatsuaki Kurata, Masaki Takegawa, Takayuki Ohira, Egor A. Syroegin, Gemma C. Atkinson, Marcus J.O. Johansson, Yury S. Polikanov, Abel Garcia-Pino, Tsutomu Suzuki, Vasili Hauryliuk","doi":"10.1126/sciadv.adr9624","DOIUrl":"10.1126/sciadv.adr9624","url":null,"abstract":"<div >Translation-targeting toxic small alarmone synthetases (toxSAS) are effectors of bacterial toxin-antitoxin systems that pyrophosphorylate the 3′-CCA end of transfer RNA (tRNA) to prevent aminoacylation. toxSAS are implicated in antiphage immunity: Phage detection triggers the toxSAS activity to shut down viral production. We show that the toxSAS FaRel2 inspects the tRNA acceptor stem to specifically select tRNA<sup>Gly</sup> and tRNA<sup>Thr</sup>. The first, second, fourth, and fifth base pairs of the stem act as the specificity determinants. We show that the toxSASs PhRel2 and CapRel<sup>SJ46</sup> differ in tRNA specificity from FaRel2 and rationalize this through structural modeling: While the universal 3′-CCA end slots into a highly conserved CCA recognition groove, the acceptor stem recognition region is variable across toxSAS diversity. As phages use tRNA isoacceptors to overcome tRNA-targeting defenses, we hypothesize that highly evolvable modular tRNA recognition allows for the escape of viral countermeasures through tRNA substrate specificity switching.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr9624","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602018","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}
Anna Nespolo, Linda Stefenatti, Ilenia Pellarin, Alice Gambelli, Gian Luca Rampioni Vinciguerra, Javad Karimbayli, Sara Barozzi, Fabrizio Orsenigo, Riccardo Spizzo, Milena S. Nicoloso, Ilenia Segatto, Sara D’Andrea, Michele Bartoletti, Emilio Lucia, Giorgio Giorda, Vincenzo Canzonieri, Fabio Puglisi, Barbara Belletti, Monica Schiappacassi, Gustavo Baldassarre, Maura Sonego
PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)–based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.
{"title":"USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity","authors":"Anna Nespolo, Linda Stefenatti, Ilenia Pellarin, Alice Gambelli, Gian Luca Rampioni Vinciguerra, Javad Karimbayli, Sara Barozzi, Fabrizio Orsenigo, Riccardo Spizzo, Milena S. Nicoloso, Ilenia Segatto, Sara D’Andrea, Michele Bartoletti, Emilio Lucia, Giorgio Giorda, Vincenzo Canzonieri, Fabio Puglisi, Barbara Belletti, Monica Schiappacassi, Gustavo Baldassarre, Maura Sonego","doi":"10.1126/sciadv.adp6567","DOIUrl":"10.1126/sciadv.adp6567","url":null,"abstract":"<div >PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)–based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp6567","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602008","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}
Marcos Quijal-Zamorano, Desislava Petrova, Èrica Martínez-Solanas, François R. Herrmann, Xavier Rodó, Jean-Marie Robine, Marc Marí-Dell’Olmo, Hicham Achebak, Joan Ballester
More than 110,000 Europeans died as a result of the record-breaking temperatures of 2022 and 2023. A new generation of impact-based early warning systems, using epidemiological models to transform weather forecasts into health forecasts for targeted population subgroups, is an essential adaptation strategy to increase resilience against climate change. Here, we assessed the skill of an operational continental heat-cold-health forecasting system. We used state-of-the-art temperature-lag-mortality epidemiological models to transform bias-corrected ensemble weather forecasts into daily temperature-related mortality forecasts. We found that temperature forecasts can be used to issue skillful forecasts of temperature-related mortality. However, the forecast skill varied by season and location, and it was different for temperature and temperature-related mortality due to the use of epidemiological models. Overall, our study demonstrates and quantifies the forecast skill horizon of heat-cold-health forecasting systems, which is a necessary step toward generating trust among public health authorities and end users.
{"title":"Forecast skill assessment of an operational continental heat-cold-health forecasting system: New avenues for health early warning systems","authors":"Marcos Quijal-Zamorano, Desislava Petrova, Èrica Martínez-Solanas, François R. Herrmann, Xavier Rodó, Jean-Marie Robine, Marc Marí-Dell’Olmo, Hicham Achebak, Joan Ballester","doi":"10.1126/sciadv.ado5286","DOIUrl":"10.1126/sciadv.ado5286","url":null,"abstract":"<div >More than 110,000 Europeans died as a result of the record-breaking temperatures of 2022 and 2023. A new generation of impact-based early warning systems, using epidemiological models to transform weather forecasts into health forecasts for targeted population subgroups, is an essential adaptation strategy to increase resilience against climate change. Here, we assessed the skill of an operational continental heat-cold-health forecasting system. We used state-of-the-art temperature-lag-mortality epidemiological models to transform bias-corrected ensemble weather forecasts into daily temperature-related mortality forecasts. We found that temperature forecasts can be used to issue skillful forecasts of temperature-related mortality. However, the forecast skill varied by season and location, and it was different for temperature and temperature-related mortality due to the use of epidemiological models. Overall, our study demonstrates and quantifies the forecast skill horizon of heat-cold-health forecasting systems, which is a necessary step toward generating trust among public health authorities and end users.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado5286","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602013","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}
Alexander J. Dimitri, Amy E. Baxter, Gregory M. Chen, Caitlin R. Hopkins, Geoffrey T. Rouin, Hua Huang, Weimin Kong, Christopher H. Holliday, Volker Wiebking, Robert Bartoszek, Sydney Drury, Katherine Dalton, Owen M. Koucky, Zeyu Chen, Josephine R. Giles, Alexander T. Dils, In-Young Jung, Roddy O’Connor, Sierra Collins, John K. Everett, Kevin Amses, Scott Sherrill-Mix, Aditi Chandra, Naomi Goldman, Golnaz Vahedi, Julie K. Jadlowsky, Regina M. Young, Jan Joseph Melenhorst, Shannon L. Maude, Bruce L. Levine, Noelle V. Frey, Shelley L. Berger, Stephan A. Grupp, David L. Porter, Friederike Herbst, Matthew H. Porteus, Shannon A. Carty, Frederic D. Bushman, Evan W. Weber, E. John Wherry, Martha S. Jordan, Joseph A. Fraietta
CD8+ T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting TET2 in CAR T cells provides therapeutic benefit; however, TET2’s role in exhausted T cell (TEX) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell–like TEX progenitors toward terminally differentiated and effector (TEFF)–like TEX. TET2 also enforced a terminally differentiated state in the early bifurcation between TEFF and TEX, indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable TET2-targeted CAR T cells by disrupting TET2 via knock-in of a safety switch alongside CAR knock-in at the TRAC locus. TET2-targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in TEX differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.
CD8 + T细胞衰竭会阻碍癌症和慢性感染的控制，并限制嵌合抗原受体（CAR）T细胞的疗效。以 CAR T 细胞中的 TET2 为靶标可带来治疗效果，但 TET2 在衰竭 T 细胞（T EX）发育过程中的作用尚不清楚。在慢性淋巴细胞性脉络膜炎病毒（LCMV）感染中，TET2促使干细胞样T EX祖细胞向终末分化和效应（T EFF）样T EX转化。TET2 还能在 T EFF 和 T EX 之间的早期分叉中强化终末分化状态，这表明 TET2 在获得效应生物学中发挥着广泛的作用。为了利用 TET2 的治疗潜力，我们通过敲入 TRAC 基因座上的 CAR 基因的同时敲入一个安全开关来破坏 TET2，从而开发出了临床上可行的 TET2 靶向 CAR T 细胞。TET2 靶向 CAR T 细胞在体外表现出抑制性终末衰竭，在体内增强了抗肿瘤反应。因此，TET2调节T EX分化过程中的命运转换，可作为CAR T细胞安全机制的靶点，以改善肿瘤控制。
{"title":"TET2 regulates early and late transitions in exhausted CD8+ T cell differentiation and limits CAR T cell function","authors":"Alexander J. Dimitri, Amy E. Baxter, Gregory M. Chen, Caitlin R. Hopkins, Geoffrey T. Rouin, Hua Huang, Weimin Kong, Christopher H. Holliday, Volker Wiebking, Robert Bartoszek, Sydney Drury, Katherine Dalton, Owen M. Koucky, Zeyu Chen, Josephine R. Giles, Alexander T. Dils, In-Young Jung, Roddy O’Connor, Sierra Collins, John K. Everett, Kevin Amses, Scott Sherrill-Mix, Aditi Chandra, Naomi Goldman, Golnaz Vahedi, Julie K. Jadlowsky, Regina M. Young, Jan Joseph Melenhorst, Shannon L. Maude, Bruce L. Levine, Noelle V. Frey, Shelley L. Berger, Stephan A. Grupp, David L. Porter, Friederike Herbst, Matthew H. Porteus, Shannon A. Carty, Frederic D. Bushman, Evan W. Weber, E. John Wherry, Martha S. Jordan, Joseph A. Fraietta","doi":"10.1126/sciadv.adp9371","DOIUrl":"10.1126/sciadv.adp9371","url":null,"abstract":"<div >CD8<sup>+</sup> T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting <i>TET2</i> in CAR T cells provides therapeutic benefit; however, TET2’s role in exhausted T cell (T<sub>EX</sub>) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell–like T<sub>EX</sub> progenitors toward terminally differentiated and effector (T<sub>EFF</sub>)–like T<sub>EX</sub>. TET2 also enforced a terminally differentiated state in the early bifurcation between T<sub>EFF</sub> and T<sub>EX</sub>, indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable <i>TET2-</i>targeted CAR T cells by disrupting <i>TET2</i> via knock-in of a safety switch alongside CAR knock-in at the <i>TRAC</i> locus. <i>TET2</i>-targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in T<sub>EX</sub> differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp9371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602016","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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