eLife最新文献

{"title":"Quantification of the effect of hemodynamic occlusion in two-photon imaging of mouse cortex.","authors":"Baba Yogesh, Matthias Heindorf, Rebecca Jordan, Georg B Keller","doi":"10.7554/eLife.104914","DOIUrl":"10.7554/eLife.104914","url":null,"abstract":"<p><p>The last few years have seen an explosion in the number of tools available to measure neuronal activity using fluorescence imaging (Chen et al., 2013; Feng et al., 2019; Jing et al., 2019; Sun et al., 2018; Wan et al., 2021). When performed in vivo, these measurements are invariably contaminated by hemodynamic occlusion artifacts. In widefield calcium imaging, this problem is well recognized. For two-photon imaging, however, the effects of hemodynamic occlusion have only been sparsely characterized. Here, we perform a quantification of hemodynamic occlusion effects using measurements of fluorescence changes observed with GFP expression using both widefield and two-photon imaging in mouse cortex. We find that in many instances the magnitude of signal changes attributable to hemodynamic occlusion is comparable to that observed with activity sensors. Moreover, we find that hemodynamic occlusion effects were spatially heterogeneous, both over cortical regions and across cortical depth, and exhibited a complex relationship with behavior. Thus, hemodynamic occlusion is an important caveat to consider when analyzing and interpreting not just widefield but also two-photon imaging data.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural mechanisms of PIP₂ activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.","authors":"Jing Xue, Weizhong Zeng, Scott John, Nicole Attiq, Michela Ottolia, Youxing Jiang","doi":"10.7554/eLife.105396","DOIUrl":"10.7554/eLife.105396","url":null,"abstract":"<p><p>Na⁺/Ca²⁺ exchangers (NCXs) transport Ca²⁺ across the plasma membrane in exchange for Na⁺ and play a vital role in maintaining cellular Ca²⁺ homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na⁺-dependent inactivation and Ca²⁺ activation of NCX1. Here, we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP₂), or pharmacological inhibitor SEA0400, that enhances the inactivation of the exchanger. We demonstrate that PIP₂ binding stimulates NCX1 activity by inducing a conformational change at the interface between the transmembrane (TM) and cytosolic domains that destabilizes the inactivation assembly. In contrast, SEA0400 binding in the TM domain of NCX1 stabilizes the exchanger in an inward-facing conformation that facilitates the formation of the inactivation assembly, thereby promoting the Na⁺-dependent inactivation of NCX1. Thus, this study reveals the structural basis of PIP₂ activation and SEA0400 inhibition of NCX1 and provides some mechanistic understandings of cellular regulation and pharmacology of NCX family proteins.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Criterion placement threatens the construct validity of neural measures of consciousness.","authors":"Johannes Jacobus Fahrenfort, Philippa A Johnson, Niels A Kloosterman, Timo Stein, Simon van Gaal","doi":"10.7554/eLife.102335","DOIUrl":"10.7554/eLife.102335","url":null,"abstract":"<p><p>How consciousness arises from brain activity has been a topic of intense scientific research for decades. But how does one identify the neural basis of something that is intrinsically personal and subjective? A hallmark approach has been to ask human observers to judge stimuli as 'seen' (conscious) and 'unseen' (unconscious) and use post hoc sorting of neural measurements based these judgments. Unfortunately, cognitive and response biases are known to strongly affect how observers place their criterion for judging stimuli as 'seen' versus 'unseen', thereby confounding neural measures of consciousness. Surprisingly however, the effect of conservative and liberal criterion placement on neural measures of unconscious and conscious processing has never been explicitly investigated. Here, we use simulations and electrophysiological brain measurements to show that conservative criterion placement has an unintuitive consequence: rather than selectively providing a cautious estimate of conscious processing, it inflates effect sizes in neural measures of both conscious and unconscious processing, while liberal criterion placement does the reverse. After showing this in simulation, we performed decoding analyses on two electroencephalography studies that employ common subjective indicators of conscious awareness, in which we experimentally manipulated the response criterion. The results confirm that the predicted confounding effects of criterion placement on neural measures of unconscious and conscious processing occur in empirical data, while further showing that the most widely used subjective scale, the Perceptual Awareness Scale (PAS), does not guard against criterion confounds. Follow-up simulations explicate how the experimental context determines whether the relative confounding effect of criterion placement is larger in neural measures of either conscious or unconscious processing. We conclude that criterion placement threatens the construct validity of neural measures of conscious and unconscious processing.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates.","authors":"Elizabeth J Fay, Kolya Isterabadi, Charles M Rezanka, Jessica Le, Matthew D Daugherty","doi":"10.7554/eLife.102301","DOIUrl":"10.7554/eLife.102301","url":null,"abstract":"<p><p>Receptor interacting protein kinases (RIPK) RIPK1 and RIPK3 play important roles in diverse innate immune pathways. Despite this, some RIPK1/3-associated proteins are absent in specific vertebrate lineages, suggesting that some RIPK1/3 functions are conserved, while others are more evolutionarily labile. Here, we perform comparative evolutionary analyses of RIPK1-5 and associated proteins in vertebrates to identify lineage-specific rapid evolution of RIPK3 and RIPK1 and recurrent loss of RIPK3-associated proteins. Despite this, diverse vertebrate RIPK3 proteins are able to activate NF-κB and cell death in human cells. Additional analyses revealed a striking conservation of the RIP homotypic interaction motif (RHIM) in RIPK3, as well as other human RHIM-containing proteins. Interestingly, diversity in the RIPK3 RHIM can tune activation of NF-κB while retaining the ability to activate cell death. Altogether, these data suggest that NF-κB activation is a core, conserved function of RIPK3, and the RHIM can tailor RIPK3 function to specific needs within and between species.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome.","authors":"Pratibha Thakur, Martin Lackinger, Anastasia Diamantopoulou, Sneha Rao, Yijing Chen, Khakima Khalizova, Annie Ferng, Curt Mazur, Holly Kordasiewicz, Robert J Shprintzen, Sander Markx, Bin Xu, Joseph A Gogos","doi":"10.7554/eLife.103328","DOIUrl":"10.7554/eLife.103328","url":null,"abstract":"<p><p>Adults and children with the 22q11.2 Deletion Syndrome demonstrate cognitive, social, and emotional impairments and high risk for schizophrenia. Work in mouse model of the 22q11.2 deletion provided compelling evidence for abnormal expression and processing of microRNAs. A major transcriptional effect of the microRNA dysregulation is upregulation of <i>Emc10,</i> a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. We previously uncovered a key contribution of EMC10 in mediating the behavioral phenotypes observed in 22q11.2 deletion mouse models. Here, we show that expression and processing of miRNAs is abnormal and <i>EMC10</i> expression is elevated in neurons derived from 22q11.2 deletion carriers. Reduction of <i>EMC10 levels</i> restores defects in neurite outgrowth and calcium signaling in patient neurons. Furthermore, antisense oligonucleotide administration and normalization of <i>Emc10</i> in the adult mouse brain not only alleviates cognitive deficits in social and spatial memory but remarkably sustains these improvements for over 2 months post-injection, indicating its therapeutic potential. Broadly, our study integrates findings from both animal models and human neurons to elucidate the translational potential of modulating <i>EMC10</i> levels and downstream targets as a specific venue to ameliorate disease progression in 22q11.2 Deletion Syndrome.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionary unique <i>N</i>-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in <i>Cryptococcus neoformans</i>.","authors":"Catia Mota, Kiseung Kim, Ye Ji Son, Eun Jung Thak, Su-Bin Lee, Ju-El Kim, Jeong-Kee Yoon, Min-Ho Kang, Heeyoun Hwang, Yong-Sun Bahn, J Andrew Alspaugh, Hyun Ah Kang","doi":"10.7554/eLife.103729","DOIUrl":"10.7554/eLife.103729","url":null,"abstract":"<p><p>A conserved <i>N</i>-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system has evolved in eukaryotes to ensure accuracy during glycoprotein folding. The human pathogen <i>Cryptococcus neoformans</i> possesses a unique <i>N</i>-glycosylation pathway that affects microbial physiology and interactions with the infected host. To investigate the molecular features and functions of the ERQC system in <i>C. neoformans,</i> we characterized a set of mutants with deletion of genes coding for the ERQC sensor UDP-glucose:glycoprotein glucosyltransferase (<i>UGG1</i>) and putative α1,2-mannose-trimming enzymes (<i>MNS1</i>, <i>MNS101</i>, <i>MNL1</i>, and <i>MNL2</i>). The <i>ugg1</i>Δ, <i>mns1</i>Δ, <i>mns101</i>Δ, and <i>mns1</i>Δ<i>101</i>Δ mutants showed alterations in <i>N</i>-glycan profiles, defective cell surface organization, decreased survival in host cells, and varying degrees of reduced <i>in vivo</i> virulence. The <i>ugg1</i>Δ strain exhibited severely impaired extracellular secretion of capsular polysaccharides and virulence-related enzymes. Comparative transcriptome analysis showed the upregulation of protein folding, proteolysis, and cell wall remodeling genes, indicative of induced endoplasmic reticulum stress. However, no apparent changes were observed in the expression of genes involved in protein secretion or capsule biosynthesis. Additionally, extracellular vesicle (EV) analysis combined with proteomic analysis showed significant alterations in the number, size distribution, and cargo composition of EVs in <i>ugg1</i>Δ. These findings highlight the essential role of the functional ERQC system for cellular fitness under adverse conditions and proper EV-mediated transport of virulence factors, which are crucial for the full fungal pathogenicity of <i>C. neoformans</i>.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of <i>Leishmania donovani</i>.","authors":"Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee","doi":"10.7554/eLife.102857","DOIUrl":"10.7554/eLife.102857","url":null,"abstract":"<p><p>The management of <i>Leishmania donovani</i> (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-R's heightened reliance on host lipids. Here, we report that LD-R-infection in mice promotes fluid-phase endocytosis in the host macrophages, selectively accumulating neutral lipids while excluding oxidized-low-density lipoprotein (LDL). LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness toward Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reliable protein-protein docking with AlphaFold, Rosetta, and replica exchange.","authors":"Ameya Harmalkar, Sergey Lyskov, Jeffrey J Gray","doi":"10.7554/eLife.94029","DOIUrl":"10.7554/eLife.94029","url":null,"abstract":"<p><p>Despite the recent breakthrough of AlphaFold (AF) in the field of protein sequence-to-structure prediction, modeling protein interfaces and predicting protein complex structures remains challenging, especially when there is a significant conformational change in one or both binding partners. Prior studies have demonstrated that AF-multimer (AFm) can predict accurate protein complexes in only up to 43% of cases (Yin et al., 2022). In this work, we combine AF as a structural template generator with a physics-based replica exchange docking algorithm to better sample conformational changes. Using a curated collection of 254 available protein targets with both unbound and bound structures, we first demonstrate that AF confidence measures (pLDDT) can be repurposed for estimating protein flexibility and docking accuracy for multimers. We incorporate these metrics within our ReplicaDock 2.0 protocol to complete a robust in silico pipeline for accurate protein complex structure prediction. AlphaRED (AlphaFold-initiated Replica Exchange Docking) successfully docks failed AF predictions, including 97 failure cases in Docking Benchmark Set 5.5. AlphaRED generates CAPRI acceptable-quality or better predictions for 63% of benchmark targets. Further, on a subset of antigen-antibody targets, which is challenging for AFm (20% success rate), AlphaRED demonstrates a success rate of 43%. This new strategy demonstrates the success possible by integrating deep learning-based architectures trained on evolutionary information with physics-based enhanced sampling. The pipeline is available at https://github.com/Graylab/AlphaRED.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Kv2 inhibitor combination reveals native neuronal conductances consistent with Kv2/KvS heteromers.","authors":"Robert G Stewart, Matthew James Marquis, Sooyeon Jo, Brandon J Harris, Aman S Aberra, Verity Cook, Zachary Whiddon, Vladimir Yarov-Yarovoy, Michael Ferns, Jon T Sack","doi":"10.7554/eLife.99410","DOIUrl":"10.7554/eLife.99410","url":null,"abstract":"<p><p>KvS proteins are voltage-gated potassium channel subunits that form functional channels when assembled into heteromers with Kv2.1 (<i>KCNB1</i>) or Kv2.2 (<i>KCNB2</i>). Mammals have 10 KvS subunits: Kv5.1 (<i>KCNF1</i>), Kv6.1 (<i>KCNG1</i>), Kv6.2 (<i>KCNG2</i>), Kv6.3 (<i>KCNG3</i>), Kv6.4 (<i>KCNG4</i>), Kv8.1 (<i>KCNV1</i>), Kv8.2 (<i>KCNV2</i>), Kv9.1 (<i>KCNS1</i>), Kv9.2 (<i>KCNS2</i>), and Kv9.3 (<i>KCNS3</i>). Electrically excitable cells broadly express channels containing Kv2 subunits and most neurons have substantial Kv2 conductance. However, whether KvS subunits contribute to these conductances has not been clear, leaving the physiological roles of KvS subunits poorly understood. Here, we identify that two potent Kv2 inhibitors, used in combination, can distinguish conductances of Kv2/KvS heteromers and Kv2-only channels. We find that Kv5, Kv6, Kv8, or Kv9-containing channels are resistant to the Kv2-selective pore-blocker RY785 yet remain sensitive to the Kv2-selective voltage sensor modulator guangxitoxin-1E (GxTX). Using these inhibitors in mouse superior cervical ganglion neurons, we find predominantly RY785-sensitive conductances consistent with channels composed entirely of Kv2 subunits. In contrast, RY785-resistant but GxTX-sensitive conductances consistent with Kv2/KvS heteromeric channels predominate in mouse and human dorsal root ganglion neurons. These results establish an approach to pharmacologically distinguish conductances of Kv2/KvS heteromers from Kv2-only channels, enabling investigation of the physiological roles of endogenous KvS subunits. These findings suggest that drugs which distinguish KvS subunits could modulate electrical activity of subsets of Kv2-expressing cell types.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing.","authors":"Madeline M Keenen, Liheng Yang, Huan Liang, Veronica J Farmer, Rizban E Worota, Rohit Singh, Amy S Gladfelter, Carolyn B Coyne","doi":"10.7554/eLife.101170","DOIUrl":"10.7554/eLife.101170","url":null,"abstract":"<p><p>The syncytiotrophoblast (STB) is a multinucleated cell layer that forms the outer surface of human chorionic villi. Its unusual structure, with billions of nuclei in a single cell, makes it difficult to resolve using conventional single-cell methods. To better understand STB differentiation, we performed single-nucleus and single-cell RNA sequencing on placental tissue and trophoblast organoids (TOs). Single-nucleus RNA-seq was essential for capturing STB populations, revealing three nuclear subtypes: a juvenile subtype co-expressing CTB and STB markers, one enriched in oxygen sensing genes, and another in transport and GTPase signaling. Organoids grown in suspension culture (STBout) showed higher expression of STB markers, hormones, and a greater proportion of the transport-associated nuclear subtype while TOs grown with an inverted polarity (STBin) exhibited a higher proportion of the oxygen sensing nuclear subtype. Gene regulatory analysis identified conserved STB markers, including the chromatin remodeler RYBP. Although RYBP knockout did not impair fusion, it downregulated CSH1 and upregulated oxygen-sensing genes. Comparing STB expression in first trimester, term, and TOs revealed shared features but context-dependent variability. These findings establish TOs as a robust platform to model STB differentiation and nuclear heterogeneity, providing insight into the regulatory networks that shape placental development and function.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}