Pub Date : 2026-02-12DOI: 10.1038/s41467-026-69090-z
Schuyler M. Melore, Christian D. McRoberts Amador, Marisa C. Hamilton, Charles A. Gersbach, Timothy E. Reddy
Interactions between genes or cis-regulatory elements (CREs) underlie many biological processes. High-throughput CRISPR screens have allowed researchers to assess the impact of activation or repression of gene and regulatory elements on many phenotypes. However, assessment of interactions between those genes or elements remains limited. To enable efficient highly-multiplexed control of regulatory element activity, we combine a hyper-efficient version of Lachnospiraceae bacterium dCas12a (dHyperLbCas12a) with RNA Polymerase II expression of long CRISPR RNA (crRNA) arrays. We demonstrate this system with several activation and repression domains, in cultured primary immune cells, and to differentiate induced pluripotent stem cells. We also develop approaches to use dCas12a for simultaneous activation and repression. Lastly, we demonstrate that dHyperLbCas12a effectors can be used to dissect the independent and combinatorial contributions of CREs to gene expression. These tools create possibilities for highly multiplexed control of gene expression in many biological systems.
{"title":"dHyperCas12a enables multiplexed CRISPRi screens","authors":"Schuyler M. Melore, Christian D. McRoberts Amador, Marisa C. Hamilton, Charles A. Gersbach, Timothy E. Reddy","doi":"10.1038/s41467-026-69090-z","DOIUrl":"https://doi.org/10.1038/s41467-026-69090-z","url":null,"abstract":"Interactions between genes or cis-regulatory elements (CREs) underlie many biological processes. High-throughput CRISPR screens have allowed researchers to assess the impact of activation or repression of gene and regulatory elements on many phenotypes. However, assessment of interactions between those genes or elements remains limited. To enable efficient highly-multiplexed control of regulatory element activity, we combine a hyper-efficient version of Lachnospiraceae bacterium dCas12a (dHyperLbCas12a) with RNA Polymerase II expression of long CRISPR RNA (crRNA) arrays. We demonstrate this system with several activation and repression domains, in cultured primary immune cells, and to differentiate induced pluripotent stem cells. We also develop approaches to use dCas12a for simultaneous activation and repression. Lastly, we demonstrate that dHyperLbCas12a effectors can be used to dissect the independent and combinatorial contributions of CREs to gene expression. These tools create possibilities for highly multiplexed control of gene expression in many biological systems.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"242 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152239","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 : 2026-02-12DOI: 10.1038/s41467-026-69175-9
Xiaojie She, Zhihang Xu, Qiang Ma, Qiming Qian, Hui Shi, Molly Meng-Jung Li, Pei Xiong, Ye Zhu, Mengxia Ji, Huaming Li, Hui Xu, Junlin Zheng, Tongwen Xu, Weimin Yang, Jingzheng Ren, Shu Ping Lau
Electrocatalytic CO₂ reduction (ECO₂R) presents a sustainable pathway for industrial decarbonization by converting CO₂ into carbon-neutral fuels and chemicals. Despite progress in catalyst design, industrial scalability is hindered by slow mass-transfer kinetics. Here, we introduce a high-diffusion-flux gas diffusion electrode (HDF-GDE) that overcomes this limitation in alkali-cation-free systems, achieving CO₂ conversion rates at industrial current densities. Kinetic analysis demonstrates that conversion is governed by mass transfer efficiency rather than flow rate. By optimizing the GDE structure to maximize CO₂ diffusion and GDE utilization, we realize a kW-scale ECO₂R system with stability (>1000 hours), producing CO or C₂H₄ depending on the catalyst. Operating with a 3 L/min CO₂ flow rate, the system delivers 144 kg of CO (1.29 kW) or 17 kg of C2H4 (1.95 kW) over 1000 h. The alkali-cation-free ECO2R system, equipped with HDF-GDEs, demonstrates economic viability for large-scale ECO2R-to-CO/C2H4 production. Our findings bridge the gap between lab innovation and real-world deployment, advancing carbon-neutral chemical manufacturing.
电催化CO₂还原（ECO₂R）通过将CO₂转化为碳中性燃料和化学品，为工业脱碳提供了一条可持续的途径。尽管催化剂设计取得了进展，但缓慢的传质动力学阻碍了工业可扩展性。在这里，我们介绍了一种高扩散通量气体扩散电极（HDF-GDE），克服了无碱阳离子系统中的这一限制，实现了工业电流密度下的CO 2转换率。动力学分析表明，转化是由传质效率而不是流量决定的。通过优化GDE结构，最大限度地提高CO₂的扩散和GDE的利用率，我们实现了一个kw级的ECO₂R系统，稳定（>1000小时），根据催化剂的不同产生CO或C₂H₄。在3l /min的CO₂流量下，该系统在1000小时内可输出144kg CO （1.29 kW）或17kg C2H4 （1.95 kW）。配备HDF-GDEs的无碱离子ECO2R系统证明了大规模ECO2R- co /C2H4生产的经济可行性。我们的发现弥合了实验室创新与现实世界部署之间的差距，推动了碳中和化学品制造。
{"title":"Kilowatt-scale alkali-cation-free CO2 electrolysis via accelerating mass transfer","authors":"Xiaojie She, Zhihang Xu, Qiang Ma, Qiming Qian, Hui Shi, Molly Meng-Jung Li, Pei Xiong, Ye Zhu, Mengxia Ji, Huaming Li, Hui Xu, Junlin Zheng, Tongwen Xu, Weimin Yang, Jingzheng Ren, Shu Ping Lau","doi":"10.1038/s41467-026-69175-9","DOIUrl":"https://doi.org/10.1038/s41467-026-69175-9","url":null,"abstract":"Electrocatalytic CO₂ reduction (ECO₂R) presents a sustainable pathway for industrial decarbonization by converting CO₂ into carbon-neutral fuels and chemicals. Despite progress in catalyst design, industrial scalability is hindered by slow mass-transfer kinetics. Here, we introduce a high-diffusion-flux gas diffusion electrode (HDF-GDE) that overcomes this limitation in alkali-cation-free systems, achieving CO₂ conversion rates at industrial current densities. Kinetic analysis demonstrates that conversion is governed by mass transfer efficiency rather than flow rate. By optimizing the GDE structure to maximize CO₂ diffusion and GDE utilization, we realize a kW-scale ECO₂R system with stability (>1000 hours), producing CO or C₂H₄ depending on the catalyst. Operating with a 3 L/min CO₂ flow rate, the system delivers 144 kg of CO (1.29 kW) or 17 kg of C2H4 (1.95 kW) over 1000 h. The alkali-cation-free ECO2R system, equipped with HDF-GDEs, demonstrates economic viability for large-scale ECO2R-to-CO/C2H4 production. Our findings bridge the gap between lab innovation and real-world deployment, advancing carbon-neutral chemical manufacturing.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"47 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152240","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 : 2026-02-11DOI: 10.1038/s41467-026-68610-1
Verena van der Heide, Sara McArdle, Michael S. Nelson, Karen Cerosaletti, Sacha Gnjatic, Zbigniew Mikulski, Amanda L. Posgai, Irina Kusmartseva, Mark A. Atkinson, Dirk Homann
Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation/progression yet an integrated perspective onto in situ pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~25,000 islets effectively contextualizes previously established and additional pancreatic hallmarks in health and T1D. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities.
{"title":"Integrated histopathology of the human pancreas throughout stages of type 1 diabetes progression","authors":"Verena van der Heide, Sara McArdle, Michael S. Nelson, Karen Cerosaletti, Sacha Gnjatic, Zbigniew Mikulski, Amanda L. Posgai, Irina Kusmartseva, Mark A. Atkinson, Dirk Homann","doi":"10.1038/s41467-026-68610-1","DOIUrl":"https://doi.org/10.1038/s41467-026-68610-1","url":null,"abstract":"Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation/progression yet an integrated perspective onto in situ pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~25,000 islets effectively contextualizes previously established and additional pancreatic hallmarks in health and T1D. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"31 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152282","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 : 2026-02-11DOI: 10.1038/s41467-026-68865-8
Simeng Lu, Zhenzhen Yin, Limeng Wu, Yao Sun, Jie Chen, Lai Man Natalie Wu, Janet L. Oblinger, Day C. Blake, Bingyu Xiu, Lukas D. Landegger, Richard Seist, William Ho, Adam P. Jones, Alona Muzikansky, Konstantina M. Stankovic, Scott R. Plotkin, Long-Sheng Chang, Lei Xu
NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.
{"title":"NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss","authors":"Simeng Lu, Zhenzhen Yin, Limeng Wu, Yao Sun, Jie Chen, Lai Man Natalie Wu, Janet L. Oblinger, Day C. Blake, Bingyu Xiu, Lukas D. Landegger, Richard Seist, William Ho, Adam P. Jones, Alona Muzikansky, Konstantina M. Stankovic, Scott R. Plotkin, Long-Sheng Chang, Lei Xu","doi":"10.1038/s41467-026-68865-8","DOIUrl":"https://doi.org/10.1038/s41467-026-68865-8","url":null,"abstract":"NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"69 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152260","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 : 2026-02-11DOI: 10.1038/s41467-026-69158-w
Rasmus Magnusson, Carl Söderberg, Liam J. Ward, Jenny Arpe, Fredrik C. Kugelberg, Albert Elmsjö, Henrik Green, Elin Nyman
An accurate prediction of the time since death, known as the post-mortem interval, remains a critical research question in forensic and police investigations. Current methods, such as rectal temperature and vitreous potassium levels, only provide reliable post-mortem interval estimations up to 1–3 days. In this study, we use metabolomic data from routine toxicological screenings using femoral whole blood samples (n=4876 individuals) with known post-mortem interval of 1–67 days. We develop a neural network model that predicts the post-mortem interval with a mean/median absolute error of 1.45/1.03 days in unseen test cases, outperforming six other machine learning architectures. Pseudo-time series clustering of important model features reveals distinct metabolite dynamics, including markers of lipid degradation, mitochondrial dysfunction, and proteolysis. To assess generalizability, we apply the trained model to independent test data (n = 512 individuals) collected in a different year and analyzed on a separate mass spectrometry platform. Despite cross-platform variability, the model retains predictive performance (mean/median absolute error 1.78/1.29 days). We further show that robust models can be trained using only a few hundred cases, supporting scalability. Our findings demonstrate that post-mortem metabolomics, even when derived from routine toxicological workflows, can enable accurate post-mortem interval predictions and may offer a transferable framework for future forensic applications.
{"title":"The human metabolome and machine learning improves predictions of the post-mortem interval","authors":"Rasmus Magnusson, Carl Söderberg, Liam J. Ward, Jenny Arpe, Fredrik C. Kugelberg, Albert Elmsjö, Henrik Green, Elin Nyman","doi":"10.1038/s41467-026-69158-w","DOIUrl":"https://doi.org/10.1038/s41467-026-69158-w","url":null,"abstract":"An accurate prediction of the time since death, known as the post-mortem interval, remains a critical research question in forensic and police investigations. Current methods, such as rectal temperature and vitreous potassium levels, only provide reliable post-mortem interval estimations up to 1–3 days. In this study, we use metabolomic data from routine toxicological screenings using femoral whole blood samples (n=4876 individuals) with known post-mortem interval of 1–67 days. We develop a neural network model that predicts the post-mortem interval with a mean/median absolute error of 1.45/1.03 days in unseen test cases, outperforming six other machine learning architectures. Pseudo-time series clustering of important model features reveals distinct metabolite dynamics, including markers of lipid degradation, mitochondrial dysfunction, and proteolysis. To assess generalizability, we apply the trained model to independent test data (n = 512 individuals) collected in a different year and analyzed on a separate mass spectrometry platform. Despite cross-platform variability, the model retains predictive performance (mean/median absolute error 1.78/1.29 days). We further show that robust models can be trained using only a few hundred cases, supporting scalability. Our findings demonstrate that post-mortem metabolomics, even when derived from routine toxicological workflows, can enable accurate post-mortem interval predictions and may offer a transferable framework for future forensic applications.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"8 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The formation of stable amorphous phases in rigid organic small molecules is fundamentally hindered by their pronounced crystallization tendency. This challenge is particularly acute in energetic materials, in which the amorphous phase must be stabilized without inert additives to preserve high energy density. Here, we overcome this longstanding obstacle by realising a stable amorphous energetic material based on the small molecule explosive (4,4′,5,5′-tetranitro-1H,1′H-2,2′-biimidazole-1,1′-diamine, DATNBI). The amorphous DATNBI (AEM-DATNBI) prepared via a melt quenching process, exhibits a glass transition temperature of 59.67 °C and demonstrates remarkable structural stability below this threshold, maintaining its integrity for over 24 hours at 60 °C. This stability originates from a synergistic interaction between the non-planar molecular framework and a three-dimensional hydrogen-bond network formed by -NH₂/-NO₂ groups. This unique amorphous structure not only enhances safety by suppressing hotspot formation but also accelerates energy release, leading to faster combustion and more complete decomposition. This study demonstrates a general strategy leveraging steric hindrance and intermolecular interactions, thereby extending the realm of amorphous materials to energetic compounds and other functional rigid organic small molecules.
{"title":"Entropy-mediated solidification stabilizes and enhances energetic release in amorphous energetic materials","authors":"Xu Zhou, Zhiqiang Wang, Hui Huang, Yu Liu, Shichun Li, Wen Qian, Shiliang Huang, Jinjiang Xu","doi":"10.1038/s41467-026-69256-9","DOIUrl":"https://doi.org/10.1038/s41467-026-69256-9","url":null,"abstract":"The formation of stable amorphous phases in rigid organic small molecules is fundamentally hindered by their pronounced crystallization tendency. This challenge is particularly acute in energetic materials, in which the amorphous phase must be stabilized without inert additives to preserve high energy density. Here, we overcome this longstanding obstacle by realising a stable amorphous energetic material based on the small molecule explosive (4,4′,5,5′-tetranitro-1H,1′H-2,2′-biimidazole-1,1′-diamine, DATNBI). The amorphous DATNBI (AEM-DATNBI) prepared via a melt quenching process, exhibits a glass transition temperature of 59.67 °C and demonstrates remarkable structural stability below this threshold, maintaining its integrity for over 24 hours at 60 °C. This stability originates from a synergistic interaction between the non-planar molecular framework and a three-dimensional hydrogen-bond network formed by -NH₂/-NO₂ groups. This unique amorphous structure not only enhances safety by suppressing hotspot formation but also accelerates energy release, leading to faster combustion and more complete decomposition. This study demonstrates a general strategy leveraging steric hindrance and intermolecular interactions, thereby extending the realm of amorphous materials to energetic compounds and other functional rigid organic small molecules.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"31 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152294","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 : 2026-02-11DOI: 10.1038/s41467-026-69325-z
Yan Liang, Yi Xia
The influence of genetic variation on alternative splicing (AS) across immune cell types and demographic strata in European populations remains poorly understood. Here, we leveraged the OneK1K cohort, comprising 980 individuals of European ancestry with matched genotyping and single-cell RNA sequencing (scRNA-seq) data, to systematically investigate splicing variation at single-cell resolution. Across 13 immune cell types, we identified extensive cell-type-specific AS events and independent cis-splicing quantitative trait loci (cis-sQTLs), with subsets showing distinct sex- and age-biased patterns. Colocalization analysis identified numerous shared signals between cell-type-specific cis-sQTLs and GWAS loci for 30 polygenic traits, demonstrating that splicing regulation represents an important mechanism through which susceptibility loci influence complex traits. Through trans-sQTL analysis, we found that genetic variants exert distal effects on RPS24 splicing via proximal regulation of IVNS1ABP expression, a splicing regulator that interacts with the splicing factor HNRNPK. Collectively, our findings provide new insights into how genetic variation shapes splicing programs across cellular and demographic contexts in European populations, establishing a mechanistic framework for splicing-mediated regulation of complex traits.
{"title":"Single-cell resolution of splicing regulation in peripheral blood mononuclear cells uncovers heterogeneity-driven mechanisms underlying human complex traits","authors":"Yan Liang, Yi Xia","doi":"10.1038/s41467-026-69325-z","DOIUrl":"https://doi.org/10.1038/s41467-026-69325-z","url":null,"abstract":"The influence of genetic variation on alternative splicing (AS) across immune cell types and demographic strata in European populations remains poorly understood. Here, we leveraged the OneK1K cohort, comprising 980 individuals of European ancestry with matched genotyping and single-cell RNA sequencing (scRNA-seq) data, to systematically investigate splicing variation at single-cell resolution. Across 13 immune cell types, we identified extensive cell-type-specific AS events and independent cis-splicing quantitative trait loci (cis-sQTLs), with subsets showing distinct sex- and age-biased patterns. Colocalization analysis identified numerous shared signals between cell-type-specific cis-sQTLs and GWAS loci for 30 polygenic traits, demonstrating that splicing regulation represents an important mechanism through which susceptibility loci influence complex traits. Through trans-sQTL analysis, we found that genetic variants exert distal effects on RPS24 splicing via proximal regulation of IVNS1ABP expression, a splicing regulator that interacts with the splicing factor HNRNPK. Collectively, our findings provide new insights into how genetic variation shapes splicing programs across cellular and demographic contexts in European populations, establishing a mechanistic framework for splicing-mediated regulation of complex traits.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"9 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152287","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 : 2026-02-11DOI: 10.1038/s41467-026-69338-8
Feng Zhu, Kang Xu, Yuhe Liao, Liyan Chen, Yangsen Xu, Feng Hu, Fan He, Xirui Zhang, Yu Chen
The development of oxygen electrodes with sufficient oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) activity, as well as good tolerance to contaminants, is crucial for promoting the commercialization of reversible solid oxide cells (Re-SOCs) technologies. Herein, we design and synthesize a medium-entropy oxygen electrode with a formula of Pr0.5Ba0.2Sr0.2Ca0.1CoO3-δ (ME-PBSCC). The abundant surface oxygen vacancy concentration, high electrical conductivity, rapid and stable oxygen exchange kinetics, and structural stability of the ME-PBSCC oxygen electrode ensure the efficient and poisoning-tolerant ORR/OER in ambient air and Cr-contaminated atmosphere. Specifically, Re-SOCs incorporating the PBSCC oxygen electrodes exhibit maximum power densities of 2.239 (in ambient air) and 1.859 W cm-2 (in a Cr-contaminated air) at 750 oC in fuel cell (FC) mode, and current densities of 1.10 A cm-2 at 1.3 V and 700 oC under 50% H2O (in a Cr-contaminated air) in electrolysis (EC) mode, demonstrating competitive performance for Re-SOCs. More importantly, the developed ME-PBSCC oxygen electrode has achieved the highly promising stable operation of Re-SOCs in FC, EC, and reversible modes in the presence of Cr contamination.
开发具有足够的氧还原反应（ORR）和氧析反应（OER）活性以及良好的污染物耐受性的氧电极，对于促进可逆固体氧化物电池（re - soc）技术的商业化至关重要。本文设计并合成了一种分子式为Pr0.5Ba0.2Sr0.2Ca0.1CoO3-δ (ME-PBSCC)的中熵氧电极。ME-PBSCC氧电极丰富的表面氧空位浓度、高导电性、快速稳定的氧交换动力学和结构稳定性，保证了其在环境空气和cr污染大气中的高效耐毒ORR/OER。具体来说，含有PBSCC氧电极的re - soc在燃料电池（FC）模式下，在750℃时的最大功率密度为2.239（环境空气中）和1.859 W cm-2 （cr污染空气中），在电解（EC）模式下，在1.3 V和700℃下（在cr污染空气中）电流密度为1.10 a cm-2，展示了re - soc的竞争性能。更重要的是，所开发的ME-PBSCC氧电极在Cr污染下实现了re - soc在FC、EC和可逆模式下的稳定运行。
{"title":"A medium-entropy oxygen electrode enables high-performance and contaminant-tolerant reversible solid oxide cells","authors":"Feng Zhu, Kang Xu, Yuhe Liao, Liyan Chen, Yangsen Xu, Feng Hu, Fan He, Xirui Zhang, Yu Chen","doi":"10.1038/s41467-026-69338-8","DOIUrl":"https://doi.org/10.1038/s41467-026-69338-8","url":null,"abstract":"The development of oxygen electrodes with sufficient oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) activity, as well as good tolerance to contaminants, is crucial for promoting the commercialization of reversible solid oxide cells (Re-SOCs) technologies. Herein, we design and synthesize a medium-entropy oxygen electrode with a formula of Pr0.5Ba0.2Sr0.2Ca0.1CoO3-δ (ME-PBSCC). The abundant surface oxygen vacancy concentration, high electrical conductivity, rapid and stable oxygen exchange kinetics, and structural stability of the ME-PBSCC oxygen electrode ensure the efficient and poisoning-tolerant ORR/OER in ambient air and Cr-contaminated atmosphere. Specifically, Re-SOCs incorporating the PBSCC oxygen electrodes exhibit maximum power densities of 2.239 (in ambient air) and 1.859 W cm-2 (in a Cr-contaminated air) at 750 oC in fuel cell (FC) mode, and current densities of 1.10 A cm-2 at 1.3 V and 700 oC under 50% H2O (in a Cr-contaminated air) in electrolysis (EC) mode, demonstrating competitive performance for Re-SOCs. More importantly, the developed ME-PBSCC oxygen electrode has achieved the highly promising stable operation of Re-SOCs in FC, EC, and reversible modes in the presence of Cr contamination.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"134 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152292","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}
Sexual dimorphism in the incidence and mortality of hepatocellular carcinoma (HCC) has been observed worldwide. Sex hormones play an essential role in determining male predominance in hepatocarcinogenesis. Here we reveal significant sexual dimorphism in regulatory T cells (Tregs). Compared with HCC in female mice/patients, tumours in male mice/patients are more enriched in Tregs. The male sex hormone androgen is shown to activate the NFκB pathway and reinforce the binding of NFκB to Ccl2 promoter loci in HCC cells, thereby promoting Ccl2 production, which facilitates the intratumoral recruitment of Tregs via the Ccl2-Ccr2 axis. Additionally, Treg infiltration shapes the HCC microenvironment through the suppression of the antitumorigenic activity of γδ T cells rather than CD8+T cells. Moreover, intratumoral hypoxia induces the secretion of Treg-derived extracellular vesicle (EV)-S100a4, which serves as a transcriptional corepressor to impede γδ T cell activation in an epigenetic manner. Overall, these results demonstrate that sex-specific differences in Tregs from HCC are related to the ability of androgen-dependent Ccl2 secretion to enable immune evasion through the suppression of γδ T cell activity.
{"title":"Treg-γδ T cell axis determines sexual dimorphism in hepatocarcinogenesis","authors":"Qing Liang, Qian Zhang, Wei Zhang, Rui Wang, Yinjiang Ma, Xiaoya Mai, Zhenglang Zhang, Bing Liu, Ping Lu, Huijuan Wan, Kejia Wang","doi":"10.1038/s41467-026-69603-w","DOIUrl":"https://doi.org/10.1038/s41467-026-69603-w","url":null,"abstract":"Sexual dimorphism in the incidence and mortality of hepatocellular carcinoma (HCC) has been observed worldwide. Sex hormones play an essential role in determining male predominance in hepatocarcinogenesis. Here we reveal significant sexual dimorphism in regulatory T cells (Tregs). Compared with HCC in female mice/patients, tumours in male mice/patients are more enriched in Tregs. The male sex hormone androgen is shown to activate the NFκB pathway and reinforce the binding of NFκB to Ccl2 promoter loci in HCC cells, thereby promoting Ccl2 production, which facilitates the intratumoral recruitment of Tregs via the Ccl2-Ccr2 axis. Additionally, Treg infiltration shapes the HCC microenvironment through the suppression of the antitumorigenic activity of γδ T cells rather than CD8+T cells. Moreover, intratumoral hypoxia induces the secretion of Treg-derived extracellular vesicle (EV)-S100a4, which serves as a transcriptional corepressor to impede γδ T cell activation in an epigenetic manner. Overall, these results demonstrate that sex-specific differences in Tregs from HCC are related to the ability of androgen-dependent Ccl2 secretion to enable immune evasion through the suppression of γδ T cell activity.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"24 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152293","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 : 2026-02-11DOI: 10.1038/s41467-026-69151-3
Pablo Lechón-Alonso, Srilena Kundu, Paula Lemos-Costa, José A. Capitán, Stefano Allesina
Darwin already recognized that competition is fiercest among conspecifics, a principle that later made intraspecific competition central to ecological theory through concepts such as niche differentiation and limiting similarity. Beyond shaping coexistence, strong intraspecific competition can also stabilize community dynamics by ensuring that populations return to equilibrium after disturbance. Here we investigate a more fundamental question: how intraspecific competition influences the very existence of a steady state (feasibility) in large random ecological communities dominated by competition. We show that, in analogy with classical results on stability, there is a critical level of intraspecific competition above which a feasible steady state is guaranteed to exist. We derive a general expression for the probability of feasibility and prove that, asymptotically (as species number grows), the transition to stability occurs before the transition to feasibility with probability one. Thus, in large competitive communities, any feasible equilibrium is automatically stable. This ordering persists even when many species in the initial pool cannot coexist and extinctions occur: the dynamics prune the community, shifting feasibility and stability thresholds but never reversing their order. These results imply that large competitive communities generically converge to a globally stable equilibrium, making sustained oscillations or chaos unlikely—consistent with experimental observations.
{"title":"Robust coexistence in competitive ecological communities","authors":"Pablo Lechón-Alonso, Srilena Kundu, Paula Lemos-Costa, José A. Capitán, Stefano Allesina","doi":"10.1038/s41467-026-69151-3","DOIUrl":"https://doi.org/10.1038/s41467-026-69151-3","url":null,"abstract":"Darwin already recognized that competition is fiercest among conspecifics, a principle that later made intraspecific competition central to ecological theory through concepts such as niche differentiation and limiting similarity. Beyond shaping coexistence, strong intraspecific competition can also stabilize community dynamics by ensuring that populations return to equilibrium after disturbance. Here we investigate a more fundamental question: how intraspecific competition influences the very existence of a steady state (feasibility) in large random ecological communities dominated by competition. We show that, in analogy with classical results on stability, there is a critical level of intraspecific competition above which a feasible steady state is guaranteed to exist. We derive a general expression for the probability of feasibility and prove that, asymptotically (as species number grows), the transition to stability occurs before the transition to feasibility with probability one. Thus, in large competitive communities, any feasible equilibrium is automatically stable. This ordering persists even when many species in the initial pool cannot coexist and extinctions occur: the dynamics prune the community, shifting feasibility and stability thresholds but never reversing their order. These results imply that large competitive communities generically converge to a globally stable equilibrium, making sustained oscillations or chaos unlikely—consistent with experimental observations.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"91 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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