Han Yang, Chen Nie, Yingyu Qin, Xinxin Liang, Yifan Chen, Zenan Zhou, Tao Zhou, Tao Zhang, Yilin Cui, Ming Pang, Jiadong Wang, Weibin Wang
R-loop metabolism is closely associated with genome stability and tumors. Here, we identify an exonuclease REXO4, which collaborates with RNaseH1 endonuclease to degrade R-loops in an “endo/exo-cleavage coupling” manner. Specifically, REXO4 directly degrades the RNA strand in R-loops from the end or internal nick through its 3′-5′ exonuclease activity and stimulates RNaseH1 endonuclease activity. The genome-wide R-loop regions regulated by REXO4 highly overlap with those regulated by RNaseH1, and REXO4 overexpression counteracts genome-wide R-loop accumulation caused by RNaseH1 deficiency. Furthermore, REXO4-deficient tumors display elevated R-loop mutation burden, and tumor patient-derived mutations in REXO4 enzymatic region all impair R-loop cleavage activity. Besides, we identify a compound 17 (named REXO4-IN-17) capable of inhibiting REXO4 nuclease activity. Interfering with REXO4 increases the sensitivity of tumor cells to alkylating and G4 stabilizing chemotherapeutic drugs and activates cGAS-mediated antitumor immunity. Therefore, our study proposes an endo/exo-cleavage coupling the R-loop processing model, which provides additional insights into the link between R-loop–associated genome instability, antitumor immunity, and tumors.
R-loop代谢与基因组稳定性和肿瘤密切相关。在这里，我们鉴定了一个外切酶REXO4，它与RNaseH1内切酶合作，以“内/外切偶联”的方式降解r -环。具体来说，REXO4通过其3 ‘ -5 ’外切酶活性直接从末端或内部缺口降解r -环中的RNA链，并刺激RNaseH1内切酶活性。REXO4调控的全基因组R-loop区域与RNaseH1调控的区域高度重叠，REXO4过表达抵消了RNaseH1缺失引起的全基因组R-loop积累。此外，缺乏REXO4的肿瘤表现出更高的r环突变负担，肿瘤患者衍生的REXO4酶区突变都损害了r环切割活性。此外，我们还鉴定出一种能够抑制REXO4核酸酶活性的化合物17（命名为REXO4- in -17）。干扰REXO4可增加肿瘤细胞对烷基化和G4稳定化疗药物的敏感性，激活cgas介导的抗肿瘤免疫。因此，我们的研究提出了一个内切/外切耦合r环加工模型，这为r环相关的基因组不稳定性、抗肿瘤免疫和肿瘤之间的联系提供了额外的见解。
{"title":"R-loop processing via REXO4-RNaseH1–mediated endo- and exo-cleavage coupling mode prevents genome instability and antitumor immunity","authors":"Han Yang, Chen Nie, Yingyu Qin, Xinxin Liang, Yifan Chen, Zenan Zhou, Tao Zhou, Tao Zhang, Yilin Cui, Ming Pang, Jiadong Wang, Weibin Wang","doi":"","DOIUrl":"","url":null,"abstract":"<div >R-loop metabolism is closely associated with genome stability and tumors. Here, we identify an exonuclease REXO4, which collaborates with RNaseH1 endonuclease to degrade R-loops in an “endo/exo-cleavage coupling” manner. Specifically, REXO4 directly degrades the RNA strand in R-loops from the end or internal nick through its 3′-5′ exonuclease activity and stimulates RNaseH1 endonuclease activity. The genome-wide R-loop regions regulated by REXO4 highly overlap with those regulated by RNaseH1, and REXO4 overexpression counteracts genome-wide R-loop accumulation caused by RNaseH1 deficiency. Furthermore, REXO4-deficient tumors display elevated R-loop mutation burden, and tumor patient-derived mutations in REXO4 enzymatic region all impair R-loop cleavage activity. Besides, we identify a compound 17 (named REXO4-IN-17) capable of inhibiting REXO4 nuclease activity. Interfering with REXO4 increases the sensitivity of tumor cells to alkylating and G4 stabilizing chemotherapeutic drugs and activates cGAS-mediated antitumor immunity. Therefore, our study proposes an endo/exo-cleavage coupling the R-loop processing model, which provides additional insights into the link between R-loop–associated genome instability, antitumor immunity, and tumors.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211395","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}
Jiayi Wang, Fan Wang, Jingwen Liu, Yao Xiao, Zhaoyang Li, Xiaonan Liu, Peilin Zhang, Fei Wang, Wenguo Cui, Shen Liu
Chemotactic migration of peritendinous nerves is essential for tendon regeneration, yet the underlying neuroelectrical mechanisms remain unclear. Here, we identify an electrically responsive yes-associated protein 1 (YAP1)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/neuropilin-1 (NRP1) signaling axis in sensory neurons. Electrical stimulation enhances YAP1-pSTAT3 interaction, promotes pSTAT3 nuclear translocation and transcriptional activity, and up-regulates NRP1 to support growth of calcitonin gene-related peptide (CGRP)–positive sensory fibers. Guided by these findings, we engineered a bifunctional piezoelectric patch composed of poly(vinylidene difluoride-trifluoroethylene) [P(VDF-TrFE)] and regenerated silk fibroin@poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (RSF@P:P), coupling mechanically induced electrical cues with dynamic lubrication. Under ultrasound activation, the P(VDF-TrFE) layer generates localized electrical signals that facilitate sensory-nerve and vascular ingrowth, while the RSF@P:P layer undergoes piezoelectric-triggered gel-sol transition to form a low-friction interface and reduce adhesion. In rat and Bama minipig models, the patch markedly enhanced tendon regeneration and decreased adhesion scores by ~50%. These findings establish a neuroelectrically guided strategy for enhancing tendon healing.
{"title":"Activation of the YAP1/pSTAT3/NRP1 axis in peritendinous sensory nerves promotes tendon healing","authors":"Jiayi Wang, Fan Wang, Jingwen Liu, Yao Xiao, Zhaoyang Li, Xiaonan Liu, Peilin Zhang, Fei Wang, Wenguo Cui, Shen Liu","doi":"","DOIUrl":"","url":null,"abstract":"<div >Chemotactic migration of peritendinous nerves is essential for tendon regeneration, yet the underlying neuroelectrical mechanisms remain unclear. Here, we identify an electrically responsive yes-associated protein 1 (YAP1)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/neuropilin-1 (NRP1) signaling axis in sensory neurons. Electrical stimulation enhances YAP1-pSTAT3 interaction, promotes pSTAT3 nuclear translocation and transcriptional activity, and up-regulates NRP1 to support growth of calcitonin gene-related peptide (CGRP)–positive sensory fibers. Guided by these findings, we engineered a bifunctional piezoelectric patch composed of poly(vinylidene difluoride-trifluoroethylene) [P(VDF-TrFE)] and regenerated silk fibroin@poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (RSF@P:P), coupling mechanically induced electrical cues with dynamic lubrication. Under ultrasound activation, the P(VDF-TrFE) layer generates localized electrical signals that facilitate sensory-nerve and vascular ingrowth, while the RSF@P:P layer undergoes piezoelectric-triggered gel-sol transition to form a low-friction interface and reduce adhesion. In rat and Bama minipig models, the patch markedly enhanced tendon regeneration and decreased adhesion scores by ~50%. These findings establish a neuroelectrically guided strategy for enhancing tendon healing.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211413","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}
Max O. Kluger, Richard A. Melchert, José M. Moratalla, Tehnuka Ilanko, David J. Lowe, Vicki G. Moon, Pilar Villamor, Jordanka Chaneva, Nic Ross, Rolando P. Orense
Assessing seismic hazards in regions with hidden or poorly expressed faults is one of the major challenges in paleoseismology today. Here, we used computed tomography imaging to quantify the dimensions and distribution of liquefaction structures in ≤17.5–thousand-year-old tephra layers in 18 lakes scattered across the poorly expressed Hamilton Basin fault system in northern New Zealand. These “tephra seismites,” embedded in unconsolidated, organic-bearing lake sediment, increase in occurrence and dimensions toward known faults and indicate the occurrence of a local hidden fault segment. Through incorporating peak ground acceleration modeling, we found that the spatial distribution of tephra seismites directly relates to the ground shaking induced by near-field fault ruptures. We used the variability in tephra seismites within the stratigraphic record and tephrochronology to better constrain the recurrence intervals and magnitudes of paleoearthquakes from both the Hamilton Basin and adjacent Hauraki Basin fault systems. Our methodology is globally applicable in volcanic and tectonic regions where liquefaction structures are preserved among (hidden) faults.
{"title":"Tephra seismites—Understanding seismic hazard of hidden faults by analyzing liquefied tephra layers in lakes","authors":"Max O. Kluger, Richard A. Melchert, José M. Moratalla, Tehnuka Ilanko, David J. Lowe, Vicki G. Moon, Pilar Villamor, Jordanka Chaneva, Nic Ross, Rolando P. Orense","doi":"","DOIUrl":"","url":null,"abstract":"<div >Assessing seismic hazards in regions with hidden or poorly expressed faults is one of the major challenges in paleoseismology today. Here, we used computed tomography imaging to quantify the dimensions and distribution of liquefaction structures in ≤17.5–thousand-year-old tephra layers in 18 lakes scattered across the poorly expressed Hamilton Basin fault system in northern New Zealand. These “tephra seismites,” embedded in unconsolidated, organic-bearing lake sediment, increase in occurrence and dimensions toward known faults and indicate the occurrence of a local hidden fault segment. Through incorporating peak ground acceleration modeling, we found that the spatial distribution of tephra seismites directly relates to the ground shaking induced by near-field fault ruptures. We used the variability in tephra seismites within the stratigraphic record and tephrochronology to better constrain the recurrence intervals and magnitudes of paleoearthquakes from both the Hamilton Basin and adjacent Hauraki Basin fault systems. Our methodology is globally applicable in volcanic and tectonic regions where liquefaction structures are preserved among (hidden) faults.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211414","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 scale and timing of genetic contributions from ancient millet- and rice-farming populations in China to Southeast Asian populations remain incompletely understood, particularly concerning Y-chromosome diversity. Here, a comprehensive dataset of Chinese Y-chromosome variations, including 1507 high-coverage sequences from ethnolinguistically diverse groups, was analyzed alongside 780 ancient genomes from eastern Eurasia and 1748 low-coverage sequences from Southeast Asia. We reconstructed a high-resolution, time-calibrated Y-chromosome phylogeny, revealing multiple male-biased expansions associated with Neolithic cultural innovations in South China. These expansions markedly shaped the paternal ancestry of both South China and mainland Southeast Asia. Founding lineages linked to Hmong-Mien and Tai-Kadai speakers were traced, revealing notable growth during the Middle Neolithic. Phylogeographic structure, network analyses, and haplogroup distributions indicate complex demographic interactions that established the genetic legacy of Neolithic farmers in Southeast Asia. These findings highlight recurrent southward migrations of Chinese farmer-related groups and their enduring influence on the paternal genetic landscape of ancient and present-day Southeast Asians.
{"title":"Multiple southward migrations of Neolithic Chinese farmers into Southeast Asia revealed from large-scale Y-chromosome sequences","authors":"Mengge Wang, Yunhui Liu, Lintao Luo, Zhiyong Wang, Yuhang Feng, Ting Yang, Jing Chen, Yufeng Liu, Yuguo Huang, Qiuxia Sun, Shuhan Duan, Xinyu Lin, Jie Zhong, Bowen Li, Kaijun Liu, Haibing Yuan, Chao Liu, Renkuan Tang, Guanglin He","doi":"","DOIUrl":"","url":null,"abstract":"<div >The scale and timing of genetic contributions from ancient millet- and rice-farming populations in China to Southeast Asian populations remain incompletely understood, particularly concerning Y-chromosome diversity. Here, a comprehensive dataset of Chinese Y-chromosome variations, including 1507 high-coverage sequences from ethnolinguistically diverse groups, was analyzed alongside 780 ancient genomes from eastern Eurasia and 1748 low-coverage sequences from Southeast Asia. We reconstructed a high-resolution, time-calibrated Y-chromosome phylogeny, revealing multiple male-biased expansions associated with Neolithic cultural innovations in South China. These expansions markedly shaped the paternal ancestry of both South China and mainland Southeast Asia. Founding lineages linked to Hmong-Mien and Tai-Kadai speakers were traced, revealing notable growth during the Middle Neolithic. Phylogeographic structure, network analyses, and haplogroup distributions indicate complex demographic interactions that established the genetic legacy of Neolithic farmers in Southeast Asia. These findings highlight recurrent southward migrations of Chinese farmer-related groups and their enduring influence on the paternal genetic landscape of ancient and present-day Southeast Asians.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211415","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}
Kyle W. Cuklanz, Abigail Stein, Virginie-Anne Chouinard, Dost Ongur, Fei Du
Redox dysregulation, characterized by an imbalance in the NAD + [nicotinamide adenine dinucleotide (oxidized form)]/NADH (reduced form of NAD + ) ratio, is implicated in neurodegenerative and psychiatric disorders such as Alzheimer’s disease and schizophrenia. This imbalance contributes to mitochondrial dysregulation, oxidative stress, and inflammation. Despite promising preclinical studies supporting therapeutic strategies aimed at restoring redox balance and thereby rescuing brain bioenergetic deficits, clinical outcomes and efficacy remain limited. Progress has been hindered by the incomplete understanding of NAD + subcellular cycling, as well as a lack of in vivo biomarkers measuring target engagement of redox status and mitochondrial function. Thus, this review examines molecular mechanisms of NAD (nicotinamide adenine dinucleotide)–related bioenergetic deficits, current and emerging NAD-targeted therapies, and recent advances in the development of neuroimaging biomarkers, emphasizing personalized and mechanism-driven approaches.
{"title":"Redox therapy for neuropsychiatric disorders: Molecular mechanisms and biomarker development","authors":"Kyle W. Cuklanz, Abigail Stein, Virginie-Anne Chouinard, Dost Ongur, Fei Du","doi":"10.1126/sciadv.aea9014","DOIUrl":"https://doi.org/10.1126/sciadv.aea9014","url":null,"abstract":"Redox dysregulation, characterized by an imbalance in the NAD <jats:sup>+</jats:sup> [nicotinamide adenine dinucleotide (oxidized form)]/NADH (reduced form of NAD <jats:sup>+</jats:sup> ) ratio, is implicated in neurodegenerative and psychiatric disorders such as Alzheimer’s disease and schizophrenia. This imbalance contributes to mitochondrial dysregulation, oxidative stress, and inflammation. Despite promising preclinical studies supporting therapeutic strategies aimed at restoring redox balance and thereby rescuing brain bioenergetic deficits, clinical outcomes and efficacy remain limited. Progress has been hindered by the incomplete understanding of NAD <jats:sup>+</jats:sup> subcellular cycling, as well as a lack of in vivo biomarkers measuring target engagement of redox status and mitochondrial function. Thus, this review examines molecular mechanisms of NAD (nicotinamide adenine dinucleotide)–related bioenergetic deficits, current and emerging NAD-targeted therapies, and recent advances in the development of neuroimaging biomarkers, emphasizing personalized and mechanism-driven approaches.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"40 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210013","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}
Tianchen Li, Yuchen Yue, Hui Li, Ning Guo, Fengmian Li, Hanfei Gao, Lei Jiang, Yuchen Wu
AgInGaS (AIGS) quantum dots (QDs) are promising for displays due to their narrow full width at half maximum (FWHM) and tunable emission. However, nonuniform silver vacancy ( VAg ) distribution causes emission broadening and hinders device performance improvement. Here, we present a multistep temperature control strategy that precisely regulates reaction temperature to control nucleation, cation exchange, and defect reconstruction, thereby enabling uniform VAg distribution in AIGS QDs. Simultaneously, we construct a dual-layer shell structure (AgGaS 2 /GaS x ), which efficiently passivates surface defects. The synthesized red, green, and blue AIGS QDs achieve photoluminescence quantum yields (92.6, 98.5, and 53.3%) and narrow FWHMs (32, 29, and 21 nm). On the basis of these materials, we fabricated red, green, and blue QD light-emitting diodes that demonstrate external quantum efficiencies of 13.2, 8.0, and 2.9%. Moreover, the interfacial confinement self-assembly strategy enables the fabrication of full-color QD pixel arrays with resolutions up to 2032 pixels per inch, further highlighting the potential of AIGS QDs for near-eye displays.
{"title":"Efficient AgInGaS-based QLEDs and full-color displays via uniform silver vacancy distribution","authors":"Tianchen Li, Yuchen Yue, Hui Li, Ning Guo, Fengmian Li, Hanfei Gao, Lei Jiang, Yuchen Wu","doi":"10.1126/sciadv.aea0753","DOIUrl":"https://doi.org/10.1126/sciadv.aea0753","url":null,"abstract":"AgInGaS (AIGS) quantum dots (QDs) are promising for displays due to their narrow full width at half maximum (FWHM) and tunable emission. However, nonuniform silver vacancy ( <jats:italic toggle=\"yes\">V</jats:italic> <jats:sub>Ag</jats:sub> ) distribution causes emission broadening and hinders device performance improvement. Here, we present a multistep temperature control strategy that precisely regulates reaction temperature to control nucleation, cation exchange, and defect reconstruction, thereby enabling uniform <jats:italic toggle=\"yes\">V</jats:italic> <jats:sub>Ag</jats:sub> distribution in AIGS QDs. Simultaneously, we construct a dual-layer shell structure (AgGaS <jats:sub>2</jats:sub> /GaS <jats:sub>x</jats:sub> ), which efficiently passivates surface defects. The synthesized red, green, and blue AIGS QDs achieve photoluminescence quantum yields (92.6, 98.5, and 53.3%) and narrow FWHMs (32, 29, and 21 nm). On the basis of these materials, we fabricated red, green, and blue QD light-emitting diodes that demonstrate external quantum efficiencies of 13.2, 8.0, and 2.9%. Moreover, the interfacial confinement self-assembly strategy enables the fabrication of full-color QD pixel arrays with resolutions up to 2032 pixels per inch, further highlighting the potential of AIGS QDs for near-eye displays.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"325 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210019","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}
Max O. Kluger, Richard A. Melchert, José M. Moratalla, Tehnuka Ilanko, David J. Lowe, Vicki G. Moon, Pilar Villamor, Jordanka Chaneva, Nic Ross, Rolando P. Orense
Assessing seismic hazards in regions with hidden or poorly expressed faults is one of the major challenges in paleoseismology today. Here, we used computed tomography imaging to quantify the dimensions and distribution of liquefaction structures in ≤17.5–thousand-year-old tephra layers in 18 lakes scattered across the poorly expressed Hamilton Basin fault system in northern New Zealand. These “tephra seismites,” embedded in unconsolidated, organic-bearing lake sediment, increase in occurrence and dimensions toward known faults and indicate the occurrence of a local hidden fault segment. Through incorporating peak ground acceleration modeling, we found that the spatial distribution of tephra seismites directly relates to the ground shaking induced by near-field fault ruptures. We used the variability in tephra seismites within the stratigraphic record and tephrochronology to better constrain the recurrence intervals and magnitudes of paleoearthquakes from both the Hamilton Basin and adjacent Hauraki Basin fault systems. Our methodology is globally applicable in volcanic and tectonic regions where liquefaction structures are preserved among (hidden) faults.
{"title":"Tephra seismites—Understanding seismic hazard of hidden faults by analyzing liquefied tephra layers in lakes","authors":"Max O. Kluger, Richard A. Melchert, José M. Moratalla, Tehnuka Ilanko, David J. Lowe, Vicki G. Moon, Pilar Villamor, Jordanka Chaneva, Nic Ross, Rolando P. Orense","doi":"10.1126/sciadv.ads2015","DOIUrl":"https://doi.org/10.1126/sciadv.ads2015","url":null,"abstract":"Assessing seismic hazards in regions with hidden or poorly expressed faults is one of the major challenges in paleoseismology today. Here, we used computed tomography imaging to quantify the dimensions and distribution of liquefaction structures in ≤17.5–thousand-year-old tephra layers in 18 lakes scattered across the poorly expressed Hamilton Basin fault system in northern New Zealand. These “tephra seismites,” embedded in unconsolidated, organic-bearing lake sediment, increase in occurrence and dimensions toward known faults and indicate the occurrence of a local hidden fault segment. Through incorporating peak ground acceleration modeling, we found that the spatial distribution of tephra seismites directly relates to the ground shaking induced by near-field fault ruptures. We used the variability in tephra seismites within the stratigraphic record and tephrochronology to better constrain the recurrence intervals and magnitudes of paleoearthquakes from both the Hamilton Basin and adjacent Hauraki Basin fault systems. Our methodology is globally applicable in volcanic and tectonic regions where liquefaction structures are preserved among (hidden) faults.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"40 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210296","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}
Wesley B. Fabyan, Chelsea L. Fortin, Dorice L. Goune, Heidi L. Kenerson, Susana P. Simmonds Bohorquez, Jonathan T. C. Liu, Matthew M. Yeh, Rotonya M. Carr, Raymond S. W. Yeung, Kelly R. Stevens
The liver contains an intricate microstructure that is critical for proper liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, two-dimensional (2D) histopathology—the gold standard for pathological understanding of many liver diseases—can misrepresent or leave gaps in our understanding of complex 3D structural features. Here, we used immunostaining, tissue clearing, microscopy, and computational software to create 3D multilobular reconstructions of both nonfibrotic and cirrhotic human liver tissue. We found that spatial architecture in human cirrhotic liver samples with varying etiologies had sinusoid zonal dysregulation, reduction in glutamine synthetase–expressing pericentral hepatocytes, regression of central vein networks, disruption of hepatic arterial networks, and fragmentation of biliary networks, which together suggest a pro-portalization/decentralization phenotype in cirrhotic tissue. Further implementation of 3D pathological analyses may provide a deeper understanding of cirrhotic pathobiology and inspire treatments for liver disease.
{"title":"3D reconstruction of human liver tissue at cellular resolution","authors":"Wesley B. Fabyan, Chelsea L. Fortin, Dorice L. Goune, Heidi L. Kenerson, Susana P. Simmonds Bohorquez, Jonathan T. C. Liu, Matthew M. Yeh, Rotonya M. Carr, Raymond S. W. Yeung, Kelly R. Stevens","doi":"10.1126/sciadv.adz2299","DOIUrl":"https://doi.org/10.1126/sciadv.adz2299","url":null,"abstract":"The liver contains an intricate microstructure that is critical for proper liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, two-dimensional (2D) histopathology—the gold standard for pathological understanding of many liver diseases—can misrepresent or leave gaps in our understanding of complex 3D structural features. Here, we used immunostaining, tissue clearing, microscopy, and computational software to create 3D multilobular reconstructions of both nonfibrotic and cirrhotic human liver tissue. We found that spatial architecture in human cirrhotic liver samples with varying etiologies had sinusoid zonal dysregulation, reduction in glutamine synthetase–expressing pericentral hepatocytes, regression of central vein networks, disruption of hepatic arterial networks, and fragmentation of biliary networks, which together suggest a pro-portalization/decentralization phenotype in cirrhotic tissue. Further implementation of 3D pathological analyses may provide a deeper understanding of cirrhotic pathobiology and inspire treatments for liver disease.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"5 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210441","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}
Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A. Deming, Yue Shu, Akila D. Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C. Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang
Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAB receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an SCN2A nonsense (C959X) mutation associated with profound autism. Microglia displayed heightened calcium responses to SCN2A mutation–mediated neuronal hyperactivity and engaged in excessive synaptic pruning. These pathological effects were reversed not only by pharmacological inhibition of microglial GABAB receptors but also by knockout of the GABBR1 gene in microglia. Collectively, our findings establish an advanced platform that can be used to dissect human neuroimmune interactions in subcortical regions and to evaluate previously undiscovered therapies, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders.
{"title":"Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation","authors":"Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A. Deming, Yue Shu, Akila D. Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C. Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang","doi":"","DOIUrl":"","url":null,"abstract":"<div >Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABA<sub>B</sub> receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABA<sub>B</sub> receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an <i>SCN2A</i> nonsense (C959X) mutation associated with profound autism. Microglia displayed heightened calcium responses to <i>SCN2A</i> mutation–mediated neuronal hyperactivity and engaged in excessive synaptic pruning. These pathological effects were reversed not only by pharmacological inhibition of microglial GABA<sub>B</sub> receptors but also by knockout of the <i>GABBR1</i> gene in microglia. Collectively, our findings establish an advanced platform that can be used to dissect human neuroimmune interactions in subcortical regions and to evaluate previously undiscovered therapies, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211406","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}
Wesley B. Fabyan, Chelsea L. Fortin, Dorice L. Goune, Heidi L. Kenerson, Susana P. Simmonds Bohorquez, Jonathan T. C. Liu, Matthew M. Yeh, Rotonya M. Carr, Raymond S. W. Yeung, Kelly R. Stevens
The liver contains an intricate microstructure that is critical for proper liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, two-dimensional (2D) histopathology—the gold standard for pathological understanding of many liver diseases—can misrepresent or leave gaps in our understanding of complex 3D structural features. Here, we used immunostaining, tissue clearing, microscopy, and computational software to create 3D multilobular reconstructions of both nonfibrotic and cirrhotic human liver tissue. We found that spatial architecture in human cirrhotic liver samples with varying etiologies had sinusoid zonal dysregulation, reduction in glutamine synthetase–expressing pericentral hepatocytes, regression of central vein networks, disruption of hepatic arterial networks, and fragmentation of biliary networks, which together suggest a pro-portalization/decentralization phenotype in cirrhotic tissue. Further implementation of 3D pathological analyses may provide a deeper understanding of cirrhotic pathobiology and inspire treatments for liver disease.
{"title":"3D reconstruction of human liver tissue at cellular resolution","authors":"Wesley B. Fabyan, Chelsea L. Fortin, Dorice L. Goune, Heidi L. Kenerson, Susana P. Simmonds Bohorquez, Jonathan T. C. Liu, Matthew M. Yeh, Rotonya M. Carr, Raymond S. W. Yeung, Kelly R. Stevens","doi":"","DOIUrl":"","url":null,"abstract":"<div >The liver contains an intricate microstructure that is critical for proper liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, two-dimensional (2D) histopathology—the gold standard for pathological understanding of many liver diseases—can misrepresent or leave gaps in our understanding of complex 3D structural features. Here, we used immunostaining, tissue clearing, microscopy, and computational software to create 3D multilobular reconstructions of both nonfibrotic and cirrhotic human liver tissue. We found that spatial architecture in human cirrhotic liver samples with varying etiologies had sinusoid zonal dysregulation, reduction in glutamine synthetase–expressing pericentral hepatocytes, regression of central vein networks, disruption of hepatic arterial networks, and fragmentation of biliary networks, which together suggest a pro-portalization/decentralization phenotype in cirrhotic tissue. Further implementation of 3D pathological analyses may provide a deeper understanding of cirrhotic pathobiology and inspire treatments for liver disease.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211412","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号