Proceedings of the National Academy of Sciences of the United States of America最新文献

{"title":"Summer solstice optimizes the thermal growing season","authors":"Victor Van der Meersch, E. M. Wolkovich","doi":"10.1073/pnas.2506796122","DOIUrl":"https://doi.org/10.1073/pnas.2506796122","url":null,"abstract":"Multiple studies have recently proposed the summer solstice as a universal cue for major plant physiological processes. While this would have strong implications for fundamental plant biology and climate change forecasting, we currently have no clear mechanisms to explain the emergence and importance of solstice as a cue. Here, we analyze temperature accumulation patterns in relation to the summer solstice across Europe and North America—in past, historical, and projected future climates. We show that, on average, the summer solstice coincides with a thermal optimum during the growing season. However, we also find significant local variation in the timing of this optimum across different climates—suggesting the potential of alternative cues.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"8 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201871","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":"MyD88 knockdown by RNAi prevents bacterial stimulation of tubeworm metamorphosis","authors":"Emily Darin, Morgan V. Farrell, Tatyana N. Ali, Josefa Rivera Alfaro, Kyle E. Malter, Nicholas J. Shikuma","doi":"10.1073/pnas.2505805122","DOIUrl":"https://doi.org/10.1073/pnas.2505805122","url":null,"abstract":"Diverse animals across the tree of life undergo the life-history transition of metamorphosis in response to bacteria. Although immunity has been implicated in this metamorphosis in response to bacteria, no functional connection has yet been demonstrated between immunity and metamorphosis. We investigated a host–microbe interaction involving a marine tubeworm, <jats:italic toggle=\"yes\">Hydroides elegans</jats:italic> , that undergoes metamorphosis in response to <jats:italic toggle=\"yes\">Pseudoalteromonas luteoviolacea</jats:italic> , a metamorphosis-inducing marine bacterium. By creating a marine bacteria–mediated RNA interference approach, we show that myeloid differentiation factor 88 (MyD88), a critical immune adaptor for Toll-like receptor and interleukin pathways, is necessary for the stimulation of metamorphosis in response to bacteria. In addition to a developmental role, we show that MyD88 is necessary for survival during exposure to the bacterial pathogen <jats:italic toggle=\"yes\">Pseudomonas aeruginosa</jats:italic> , showing that <jats:italic toggle=\"yes\">Hydroides</jats:italic> utilizes MyD88 during both development and an immune response. These results provide a functional characterization of the innate immune system involved in an animal's metamorphosis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"59 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201909","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":"Structure and organization of full-length epidermal growth factor receptor in extracellular vesicles by cryo-electron tomography","authors":"Monica Gonzalez-Magaldi, Anuradha Gullapalli, Ophelia Papoulas, Chang Liu, Adelaide Y.-H. Leung, Luqiang Guo, Axel F. Brilot, Edward M. Marcotte, Zunlong Ke, Daniel J. Leahy","doi":"10.1073/pnas.2424678122","DOIUrl":"https://doi.org/10.1073/pnas.2424678122","url":null,"abstract":"We report here transport of full-length epidermal growth factor receptor (EGFR), Insulin Receptor, 7-pass transmembrane receptor Smoothened, and 13-pass Sodium-iodide symporter to extracellular vesicles (EVs) for structural and functional studies. Mass spectrometry confirmed the transported proteins are the most abundant in EV membranes, and the presence of many receptor-interacting proteins in EVs demonstrates their utility for characterizing membrane protein interactomes. Cryo-electron tomography of EGFR-containing EVs reveals that EGFR forms clusters in both the presence and absence of EGF with a ~3 nm gap between the inner membrane and cytoplasmic density. EGFR extracellular region (ECR) dimers do not form regular arrays in these clusters. Subtomogram averaging of the 150 kDa EGF-bound EGFR ECR dimer yielded a 15 Å map into which the crystal structure of the ligand-bound EGFR ECR dimer fits well. These findings refine our understanding of EGFR activation, clustering, and signaling and establish EVs as a versatile platform for structural and functional characterization of human membrane proteins in cell-derived membranes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"117 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201920","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":"Suborbital- and millennial-scale monsoon variability during Pleistocene interglacials","authors":"Youbin Sun, Ting Wang, Qiuzhen Yin, Steven C. Clemens, Xingxing Liu, Li Ai, Zhipeng Wu, Xiaoke Qiang, Xulong Wang, Hong Chang, Yougui Song, Hendrik Vogel, John Dodson, Andre Berger, Zhisheng An","doi":"10.1073/pnas.2426353122","DOIUrl":"https://doi.org/10.1073/pnas.2426353122","url":null,"abstract":"Observational and modeling results show that the frequency and amplitude of extreme climatic events have increased significantly in the context of global warming. However, whether abrupt climate changes intensified during past warm periods remains poorly constrained due to the lack of high-resolution geological records. Here, we report a 512-m predominantly lacustrine sedimentary record from the Weihe Basin (North China), revealing that lake levels fluctuated significantly on suborbital (half- and quarter-precession) and millennial timescales over the last 2 Ma. Grain-size results reveal that magnitudes of rapid lake level fluctuations increased dramatically during Pleistocene interglacials, differing from glacial amplification of abrupt climate events recorded in North Atlantic marine sediments. Model results indicate that summer insolation maxima in low-latitude region of both hemispheres can lead to intensified monsoon precipitation in East Asia. Our proxy-model comparison highlights the importance of low-latitude bihemispheric insolation maxima in driving millennial-scale hydroclimatic variability in a warming future.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"38 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201910","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":"A mouse model of Jansen’s metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics","authors":"Jakob Höppner, Damla Firat, Mohd Parvez-Khan, Monica Reyes, Patrick Hanna, Prem Swaroop Yadav, Thomas Dean, Karla M. Ramos-Torres, Pedro Brugarolas, Michael T. Collins, Marc N. Wein, Shi Liu, Samuel H. Gellman, Ernestina Schipani, Henry M. Kronenberg, Thomas J. Gardella, Harald Jüppner","doi":"10.1073/pnas.2500176122","DOIUrl":"https://doi.org/10.1073/pnas.2500176122","url":null,"abstract":"Jansen’s metaphyseal chondrodysplasia (JMC) is a rare disorder caused by activating mutations in the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R). Patients exhibit short stature, dysmorphic bones, and severe growth plate abnormalities, as well as hypercalcemia, hypercalciuria, hypophosphatemia, and reduced plasma PTH levels. Humanized PTH1R (hPTH1R) mice expressing the H223R-hPTH1R JMC mutation die early without breeding. We therefore generated and characterized a stable mouse line expressing the T410R-hPTH1R allele, which confers a milder disease phenotype in patients. Mutant mice show near-normal longevity and reproductive capacity yet exhibit a profound skeletal phenotype characteristic of the disease. The long bones of T410R mice are markedly misshapen and have expanded metaphyses with disarrayed chondrocyte zones in growth plates and reduced primary spongiosa. PET/CT scanning revealed diminished uptake of [ <jats:sup>18</jats:sup> F]-sodium fluoride in the growth plate area, consistent with reduced mineralization and vascularization. Genetic ablation of <jats:italic toggle=\"yes\">Hdac4</jats:italic> rescued the growth plate abnormalities in T410R mice, thereby establishing the PTH1R-Gαs-cAMP-PKA-SIK3-HDAC4/5 pathway as the main mediator of growth plate abnormalities in JMC. Serum calcium was elevated and endogenous PTH was suppressed in T410R mice, and both parameters could be normalized by acute injection of an optimized PTH inverse agonist peptide. The T410R mouse thus represents a stable animal model of JMC that recapitulates the abnormalities in skeletal development and mineral ion homeostasis which characterize this disease. The mice should help efforts to further define the cellular and molecular mechanisms underlying the JMC phenotype and to develop a potential mode of therapy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201911","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":"Structure–function coupling in the first month of life: Associations with age and attention","authors":"Ursula A. Tooley, Jeanette K. Kenley, M. Catalina Camacho, Aidan Latham, Dimitrios Alexopoulos, Ashley N. Nielsen, Tara A. Smyser, Barbara B. Warner, Joshua S. Shimony, Jeffrey J. Neil, Joan L. Luby, Deanna M. Barch, Cynthia E. Rogers, Christopher D. Smyser","doi":"10.1073/pnas.2412729122","DOIUrl":"https://doi.org/10.1073/pnas.2412729122","url":null,"abstract":"How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure–function coupling, capturing the degree to which a cortical region’s structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates ( <jats:italic toggle=\"yes\">n</jats:italic> = 239). Regional structure–function coupling is heterogeneously patterned across the cortex, with higher coupling in the auditory, lateral prefrontal, and inferior parietal cortices. Average structure–function coupling is negatively associated with age during the first month of life, with age-associated decreases seen in primary sensory systems, specifically in auditory and somatomotor regions. Age-associated “decoupling” of structure and function reflects increasingly segregated patterns of functional connectivity and increasingly integrated patterns of white matter connectivity with age. Notably, higher structure–function coupling after accounting for age in the dorsal attention, cingulo-opercular, and visual systems at birth is associated with faster visuospatial attention to faces at one year of age. These results yield valuable insight into the development of structural and functional connectivity across the cortex, including how interregional variation in structure–function coupling during the first month of life might shape later attention.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"52 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201915","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":"Concerted transport and phosphorylation of diacylglycerol at ER–PM contact sites regulate phospholipid dynamics during stress","authors":"Selene Garcia-Hernandez, Jorge Morello-López, Richard Haslam, Vitor Amorim-Silva, José Moya-Cuevas, Rafael Catalá, Louise Michaelson, Jessica Pérez-Sancho, Vedrana Marković, Julio Salinas, Johnathan Napier, Yvon Jaillais, Noemí Ruiz-Lopez, Miguel A. Botella","doi":"10.1073/pnas.2421334122","DOIUrl":"https://doi.org/10.1073/pnas.2421334122","url":null,"abstract":"A universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C, which hydrolyzes phosphoinositides to produce soluble inositol phosphate and diacylglycerol (DAG). Because of their conical shape, DAG amounts have to be tightly regulated or they can destabilize membranes. We previously showed that upon stress, Synaptotagmin1 (SYT1) transports DAG from the PM to the endoplasmic reticulum (ER) at ER–PM Contact Sites (CS). Here, we addressed the fate of the incoming DAG in the ER. We show that diacylglycerol kinases (DGKs) DGK1 and DGK2 form a module with SYT1 functionally coupling DAG transport and phosphorylation at ER–PM CS. Although SYT1 and DGK1/DGK2 do not show exclusive ER–PM CS localization, their interaction occurs specifically at ER–PM CS and the removal of ER–PM CS abolishes the interaction. Lipidomic analysis of a <jats:italic toggle=\"yes\">dgk1dgk2</jats:italic> double mutant supports that DGK1 and DGK2 phosphorylate DAG at the ER and transcriptomic and phenotypic analyses indicate that SYT1 and DGK1/DGK2 are functionally related. Taken together, our results highlight a mechanism at ER–PM CS that coordinates the transfer of DAG from the PM to the ER by SYT1 upon stress and the concomitant phosphorylation of DAG by DGK1 and DGK2 at the ER. These findings underscore the critical role of spatial coordination in lipid metabolism during stress-induced membrane remodeling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"5 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201919","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":"The cell-permeable iron chelator M606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response","authors":"Ruby Pandher, Chengyuan Xue, Laura D. Gamble, Giorgio Milazzo, Simone Di Giacomo, Jayne Murray, Leanna Cheung, Francesca Ferrucci, Marta Palombo, Stefania Purgato, Catherine A. Burkhart, Natalia Fedtsova, Anatoli S. Gleiberman, Andrei A. Purmal, Lioubov Korotchkina, Mikhail A. Nikiforov, Sergei S. Makarov, Thomas J. Telfer, Rachel Codd, Glenn M. Marshall, David A. Scott, Andrei L. Osterman, Andrei V. Gudkov, Giovanni Perini, Michelle Haber, Murray D. Norris","doi":"10.1073/pnas.2420011122","DOIUrl":"https://doi.org/10.1073/pnas.2420011122","url":null,"abstract":"Despite Myc oncoproteins being major causal factors in human cancer, they remain “undruggable.” The <jats:italic toggle=\"yes\">MYCN</jats:italic> oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library. M606 reduced MYCN protein levels in neuroblastoma cell lines and upregulated hypoxia-inducible factor 1 alpha (HIF1A). Using siRNA-mediated knockdown of <jats:italic toggle=\"yes\">MYCN</jats:italic> , <jats:italic toggle=\"yes\">c-Myc</jats:italic> , or <jats:italic toggle=\"yes\">HIF1A</jats:italic> in HepG2 and BE(2)-C cells followed by M606 treatment, we demonstrated that Myc downregulation and HIF1A upregulation were two independent effects of M606 treatment. M606 selectively targeted neuroblastoma cell lines expressing higher levels of MYCN protein and delayed neuroblastoma development in the <jats:italic toggle=\"yes\">TH-MYCN</jats:italic> transgenic mouse model. Metabolomic analysis showed that M606 modulated glucose metabolism, consistent with a hypoxic response and iron deprivation. Biochemical characterization of M606 not only confirmed its iron-chelating properties but also revealed its ability to downregulate <jats:italic toggle=\"yes\">MYCN</jats:italic> promoter activity, which could be rescued by the addition of iron. Luciferase assays identified the minimal <jats:italic toggle=\"yes\">MYCN</jats:italic> promoter region required for the M606 response, which contained overlapping E2F transcription factor binding sites. Further evaluation defined a key role for E2F3 in the M606-mediated response. The finding of a potent cell-permeable iron chelator that can chelate iron to directly downregulate <jats:italic toggle=\"yes\">MYCN</jats:italic> transcription via an E2F3-mediated response represents a potentially valuable therapeutic approach in the treatment of cancers overexpressing Myc oncoproteins.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"9 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201981","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":"Climate warming increases global oceanic dimethyl sulfide emissions","authors":"Sankirna D. Joge, Karam Mansour, Rafel Simó, Martí Galí, Nadja Steiner, Alfonso Saiz-Lopez, Anoop S. Mahajan","doi":"10.1073/pnas.2502077122","DOIUrl":"https://doi.org/10.1073/pnas.2502077122","url":null,"abstract":"Oceanic dimethyl sulfide (DMS) is the largest natural source of atmospheric sulfur. DMS is biologically produced in seawater and emitted into the atmosphere, where its oxidation products contribute to aerosol formation with consequences for cloud albedo and the Earth’s radiative budget and climate. Climate model projections of how DMS emissions change with global warming are largely uncertain, even contradictory. Here, we use machine-learning models trained with biome-resolved global observations to simulate seawater DMS concentrations (1850 to 2100) using physico-chemical and biological predictors from eight CMIP6 models. The scatter in current projections is largely reduced, and globally averaged seawater DMS concentrations are predicted to decrease in the coming decades. However, global DMS emissions will increase due to rising surface wind speeds and sea surface temperatures which contradicts the current AR6 assessment that the DMS flux will reduce in the future. Concurrence of increasing DMS emissions and declining anthropogenic sulfur dioxide emissions suggests an increase in the relative importance of DMS to sulfate aerosol formation and its climate cooling impact.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"139 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201912","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":"Revealing land control dynamics in emerging agricultural frontiers","authors":"Olivia del Giorgio, Matthias Baumann, Tobias Kuemmerle, Yann le Polain de Waroux","doi":"10.1073/pnas.2407916122","DOIUrl":"https://doi.org/10.1073/pnas.2407916122","url":null,"abstract":"The expansion of commodity agriculture into tropical and subtropical woodlands degrades ecosystem functionality, biodiversity, and the livelihood base of millions of people. Understanding where and how agricultural frontiers emerge is thus important. Yet, existing monitoring approaches typically focus on mapping deforestation and do not capture the shifts in land access and ownership that lay the ground for agricultural expansion, thereby missing early stages of frontier development. We develop an approach that captures these early dynamics and apply it to the entire 1,1 million km <jats:sup>2</jats:sup> of the Chaco, a global deforestation hotspot. Through the detection of linear features indicative of land claims and the analysis of their spatial–temporal dynamics, we reveal that the footprint of agricultural frontiers in the region extends far beyond that of deforestation. Most of the Chaco shows signs of land claiming, and although claiming activity is especially concentrated close to active deforestation, emergent claiming in remote parts of the Bolivian and Paraguayan Chaco indicates rapidly growing interest in land in these regions. Finally, the strong spatial correlation between land claiming and the disappearance of smallholder homesteads points to the social repercussions of early agricultural frontier expansion in the Chaco. By offering a transferable template to map land-control indicators at scale, our approach enables a better understanding of frontier processes and more accurate targeting of policy interventions in emerging agricultural frontiers globally.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"38 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201978","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}