Pub Date : 2026-03-25DOI: 10.1038/s41467-026-71087-7
Hector A. Rubio Rivera, Lilian Neim, Venkatesh Deenadayalan, Stefan Preble
Photonic chips are powerful tools for measuring and analyzing light, but most compact spectrometers face a fundamental trade-off: improving resolution usually requires larger devices or sacrifices in signal quality. Here, we introduce a chip-scale architecture that overcomes this limitation by extracting phase information corresponding to the hidden timing of light waves using only simple intensity measurements. Our method generalizes earlier minimum phase designs to allow sparse and non-sequential optical delays, enabling accurate phase reconstruction on a single circuit. By engineering these delays, the device can determine the wavelength of an unknown laser with sub-picometer precision, all while using just one input and one output. This single-stream design reduces loss, improves robustness, and avoids the complexity of traditional spectrometers. The result is a compact, scalable platform that enables high-accuracy wavelength metrology and opens possibilities for on-chip sensing and computational spectroscopy.
{"title":"Achieving sub-pm wavelength regression via minimum-phase in a single-stream photonic IC","authors":"Hector A. Rubio Rivera, Lilian Neim, Venkatesh Deenadayalan, Stefan Preble","doi":"10.1038/s41467-026-71087-7","DOIUrl":"https://doi.org/10.1038/s41467-026-71087-7","url":null,"abstract":"Photonic chips are powerful tools for measuring and analyzing light, but most compact spectrometers face a fundamental trade-off: improving resolution usually requires larger devices or sacrifices in signal quality. Here, we introduce a chip-scale architecture that overcomes this limitation by extracting phase information corresponding to the hidden timing of light waves using only simple intensity measurements. Our method generalizes earlier minimum phase designs to allow sparse and non-sequential optical delays, enabling accurate phase reconstruction on a single circuit. By engineering these delays, the device can determine the wavelength of an unknown laser with sub-picometer precision, all while using just one input and one output. This single-stream design reduces loss, improves robustness, and avoids the complexity of traditional spectrometers. The result is a compact, scalable platform that enables high-accuracy wavelength metrology and opens possibilities for on-chip sensing and computational spectroscopy.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"20 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506100","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 : 2026-03-25DOI: 10.1038/s41467-026-71037-3
Yichao Gu, Piaopiao Pan, Gang Yu, Ning-Yi Zhou
Plants recruit root-associated bacterial assemblies primarily through the secretion of specialized metabolites, and the resultant rhizospheric microbiota is empirically considered beneficial. However, detrimental effects on plants arising from bacterial colonization that exploits plant-derived metabolites are rarely documented. Here, we demonstrate that the rhizosphere-derived Pseudomonas sp. strain NyZ480 exhibits a versatile capacity to effectively degrade and utilize simple coumarins—a class of root exudates essential for plant iron acquisition and pathogen defense. This robust catabolic capability is mediated by conserved genetic determinants in NyZ480. In particular, redundant degradation-initiating xenA genes confer NyZ480 not only growth using simple coumarins but also resistance to these antimicrobial metabolites. Consequently, NyZ480 significantly colonizes iron-stressed, coumarin-secreting Arabidopsis roots, trapping plants in perpetual iron scarcity and progressively compromising iron acquisition and overall fitness. Bioinformatic analyses indicate that xenA homologs are prevalent and redundant in environmental bacteria. Thus, we reveal a rhizospheric phenomenon where microorganisms opportunistically utilize and detoxify host-secreted specialized metabolites under stress conditions, enhancing colonization and impairing plant fitness.
{"title":"Rhizobacteria opportunistically boost colonization and impair plant fitness by degrading plant-derived coumarins under iron deficiency","authors":"Yichao Gu, Piaopiao Pan, Gang Yu, Ning-Yi Zhou","doi":"10.1038/s41467-026-71037-3","DOIUrl":"https://doi.org/10.1038/s41467-026-71037-3","url":null,"abstract":"Plants recruit root-associated bacterial assemblies primarily through the secretion of specialized metabolites, and the resultant rhizospheric microbiota is empirically considered beneficial. However, detrimental effects on plants arising from bacterial colonization that exploits plant-derived metabolites are rarely documented. Here, we demonstrate that the rhizosphere-derived Pseudomonas sp. strain NyZ480 exhibits a versatile capacity to effectively degrade and utilize simple coumarins—a class of root exudates essential for plant iron acquisition and pathogen defense. This robust catabolic capability is mediated by conserved genetic determinants in NyZ480. In particular, redundant degradation-initiating xenA genes confer NyZ480 not only growth using simple coumarins but also resistance to these antimicrobial metabolites. Consequently, NyZ480 significantly colonizes iron-stressed, coumarin-secreting Arabidopsis roots, trapping plants in perpetual iron scarcity and progressively compromising iron acquisition and overall fitness. Bioinformatic analyses indicate that xenA homologs are prevalent and redundant in environmental bacteria. Thus, we reveal a rhizospheric phenomenon where microorganisms opportunistically utilize and detoxify host-secreted specialized metabolites under stress conditions, enhancing colonization and impairing plant fitness.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"20 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506109","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}
There is a growing necessity for edge training to adapt to dynamically changing environments. Neuromorphic computing represents a significant pathway for highly efficient intelligent computation in energy-constrained edges, but existing neuromorphic architectures lack the ability of directly training spiking neural networks based on backpropagation. We developed a multi-core neuromorphic architecture with Feedforward-Propagation, Back-Propagation, and Weight-Gradient engines in each core, supporting highly efficient parallel computing at both the engine and core levels, achieving 190% ~ 330% performance of Jetson Orin. It combines various data flows and sparse computation optimization by fully leveraging the sparsity in spiking neural network training, obtaining a high energy efficiency of 1.05TFLOPS/W@ FP16 @ 28 nm, 55 ~ 85% reduction of memory access compared to A100 GPU in the training. Additionally, we deployed the architecture on Field Programmable Gate Arrays, successfully demonstrating 20-core deep spiking network training and 5-worker federated learning. Our study develops the first multi-core neuromorphic architecture supporting direct training of spiking neural network, facilitating neuromorphic computing in edge-learnable applications.
{"title":"A highly energy-efficient multi-core neuromorphic architecture for training deep spiking neural networks","authors":"Mingjing Li, Huihui Zhou, Xiaofeng Xu, Zhiwei Zhong, Puli Quan, Xueke Zhu, Yanyu Lin, Wenjie Lin, Xiaosha Li, Dong Wang, Junchao Zhang, Yunhao Ma, Xiaole Cui, Wei Wang, Qingyan Meng, Zhengyu Ma, Guoqi Li, Xiaoxin Cui, Yonghong Tian","doi":"10.1038/s41467-026-70586-x","DOIUrl":"https://doi.org/10.1038/s41467-026-70586-x","url":null,"abstract":"There is a growing necessity for edge training to adapt to dynamically changing environments. Neuromorphic computing represents a significant pathway for highly efficient intelligent computation in energy-constrained edges, but existing neuromorphic architectures lack the ability of directly training spiking neural networks based on backpropagation. We developed a multi-core neuromorphic architecture with Feedforward-Propagation, Back-Propagation, and Weight-Gradient engines in each core, supporting highly efficient parallel computing at both the engine and core levels, achieving 190% ~ 330% performance of Jetson Orin. It combines various data flows and sparse computation optimization by fully leveraging the sparsity in spiking neural network training, obtaining a high energy efficiency of 1.05TFLOPS/W@ FP16 @ 28 nm, 55 ~ 85% reduction of memory access compared to A100 GPU in the training. Additionally, we deployed the architecture on Field Programmable Gate Arrays, successfully demonstrating 20-core deep spiking network training and 5-worker federated learning. Our study develops the first multi-core neuromorphic architecture supporting direct training of spiking neural network, facilitating neuromorphic computing in edge-learnable applications.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"16 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506125","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 : 2026-03-25DOI: 10.1038/s41467-026-71101-y
Junyan Lin, Arantxa Agote-Aran, Yongrong Liao, Mehdi Cloarec, Leonid Andronov, Rafael L. Schoch, Paolo Ronchi, Victor Cochard, Rui Zhu, Erwan Grandgirard, Xiaotian Liu, Marianne Victoria Lemée, Charlotte Kleiss, Christelle Golzio, Marc Ruff, Guillaume Chevreux, Yannick Schwab, Bruno P. Klaholz, Izabela Sumara
Nuclear pore complexes (NPCs) enable nucleocytoplasmic transport. While NPCs primarily localize to the nuclear envelope (NE), they also appear in cytoplasmic endoplasmic reticulum (ER) membranes called annulate lamellae (AL). Though discovered in the mid-20th century, AL’s function and biogenesis remain unclear. Previously considered exclusive to embryonic and malignant cells, we find AL in somatic mammalian cells. Under normal conditions, AL store pre-assembled AL-NPCs that integrate into the NE, producing approximately one-third of newly formed nuclear pores and supporting nuclear expansion during G1. Upon pathological stimuli, AL transfer to the NE is impaired, leading to their cytoplasmic accumulation. RanBP2 (Nup358) is essential for AL biogenesis, with its phenylalanine-glycine repeats promoting AL-NPC scaffold oligomerization. ER-associated Climp63 (CKAP4) directs AL-NPCs to ER sheets and the NE. This AL-driven nuclear pore formation is complementary to the canonical routes, constituting a distinct NPC assembly pathway. Our work uncovers the biogenesis mechanism of AL and the nuclear function of this key cellular organelle.
{"title":"RanBP2-dependent annulate lamellae drive nuclear pore assembly and nuclear expansion","authors":"Junyan Lin, Arantxa Agote-Aran, Yongrong Liao, Mehdi Cloarec, Leonid Andronov, Rafael L. Schoch, Paolo Ronchi, Victor Cochard, Rui Zhu, Erwan Grandgirard, Xiaotian Liu, Marianne Victoria Lemée, Charlotte Kleiss, Christelle Golzio, Marc Ruff, Guillaume Chevreux, Yannick Schwab, Bruno P. Klaholz, Izabela Sumara","doi":"10.1038/s41467-026-71101-y","DOIUrl":"https://doi.org/10.1038/s41467-026-71101-y","url":null,"abstract":"Nuclear pore complexes (NPCs) enable nucleocytoplasmic transport. While NPCs primarily localize to the nuclear envelope (NE), they also appear in cytoplasmic endoplasmic reticulum (ER) membranes called annulate lamellae (AL). Though discovered in the mid-20th century, AL’s function and biogenesis remain unclear. Previously considered exclusive to embryonic and malignant cells, we find AL in somatic mammalian cells. Under normal conditions, AL store pre-assembled AL-NPCs that integrate into the NE, producing approximately one-third of newly formed nuclear pores and supporting nuclear expansion during G1. Upon pathological stimuli, AL transfer to the NE is impaired, leading to their cytoplasmic accumulation. RanBP2 (Nup358) is essential for AL biogenesis, with its phenylalanine-glycine repeats promoting AL-NPC scaffold oligomerization. ER-associated Climp63 (CKAP4) directs AL-NPCs to ER sheets and the NE. This AL-driven nuclear pore formation is complementary to the canonical routes, constituting a distinct NPC assembly pathway. Our work uncovers the biogenesis mechanism of AL and the nuclear function of this key cellular organelle.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"16 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506072","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 : 2026-03-25DOI: 10.1038/s41467-026-70965-4
Marie Rumpler, Guido van Mierlo, Kasper T. Vinten, Maria Pilar Giner, Stefan Christen, Faisal Hayat, Mikhail V. Makarov, Vincent Gardeux, Julie Russeil, Bauke V. Schomakers, Laurine van Gijn, Horia Hashimi, Clémence Steiner, Judith Giroud-Gerbetant, Magali Joffraud, Jose Luis Sanchez Garcia, Sofia Moco, Marie E. Migaud, Riekelt H. Houtkooper, Bart Deplancke, Carles Canto
NAD+ is a crucial metabolic cofactor whose intracellular levels can influence the progression of multiple metabolic and age-related complications. There is therefore a strong interest in using NAD+ precursors (vitamin B3s) as therapeutic tools, but most current precursors exhibit either poor bioavailability or adverse effects. This study examines the metabolic impact of chronic dietary supplementation with a newly described NAD+ precursor, dihydronicotinamide riboside (NRH), in mice using a comprehensive approach including phenotyping tests, RNA sequencing in different tissues and microbiome analyses. We show that chronic NRH administration at 100 mg/(kg*day) is well tolerated, yet has minimal metabolic effects in mice on a regular diet. However, NRH mitigates high-fat diet-induced metabolic complications when used as a preventive or as a treatment strategy, including improvements in glucose tolerance, increased hepatic expression of lipid catabolism genes and fat redistribution. These results highlight the potential of NRH as a therapeutic agent, although further studies are needed to optimize its use, as higher doses reveal signs of toxicity.
{"title":"Therapeutic potential of dihydronicotinamide riboside (NRH) on obesity and glucose intolerance in mice","authors":"Marie Rumpler, Guido van Mierlo, Kasper T. Vinten, Maria Pilar Giner, Stefan Christen, Faisal Hayat, Mikhail V. Makarov, Vincent Gardeux, Julie Russeil, Bauke V. Schomakers, Laurine van Gijn, Horia Hashimi, Clémence Steiner, Judith Giroud-Gerbetant, Magali Joffraud, Jose Luis Sanchez Garcia, Sofia Moco, Marie E. Migaud, Riekelt H. Houtkooper, Bart Deplancke, Carles Canto","doi":"10.1038/s41467-026-70965-4","DOIUrl":"https://doi.org/10.1038/s41467-026-70965-4","url":null,"abstract":"NAD+ is a crucial metabolic cofactor whose intracellular levels can influence the progression of multiple metabolic and age-related complications. There is therefore a strong interest in using NAD+ precursors (vitamin B3s) as therapeutic tools, but most current precursors exhibit either poor bioavailability or adverse effects. This study examines the metabolic impact of chronic dietary supplementation with a newly described NAD+ precursor, dihydronicotinamide riboside (NRH), in mice using a comprehensive approach including phenotyping tests, RNA sequencing in different tissues and microbiome analyses. We show that chronic NRH administration at 100 mg/(kg*day) is well tolerated, yet has minimal metabolic effects in mice on a regular diet. However, NRH mitigates high-fat diet-induced metabolic complications when used as a preventive or as a treatment strategy, including improvements in glucose tolerance, increased hepatic expression of lipid catabolism genes and fat redistribution. These results highlight the potential of NRH as a therapeutic agent, although further studies are needed to optimize its use, as higher doses reveal signs of toxicity.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"12 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506075","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}
Protein complexes are fundamental to all biological processes. Public repositories have expanded to include millions of potential protein–protein interactions (PPIs) from human and diverse model organisms. Yet, large-scale structural characterization of these complexes—especially across different biological kingdoms—has lagged far behind, leaving most potential and unidentified interactions unresolved. Here, we present a comprehensive atlas of 1.1 million predicted protein–protein interaction structures generated with the AlphaFold2-based ColabFold framework. This dataset spans proteome-wide interactions from bacteria, archaea, humans, mice, plants, and human–virus pairs. Overall, we identify 181,671 high-confidence protein complex structures, especially 37,855 in the human interactome. Structural clustering revealed numerous conserved protein complex architectures shared across kingdoms, providing insights into previously uncharacterized biological functions. Supported by co-immunoprecipitation experiments, we further identify candidate viral receptors for Human mastadenovirus A and Papiine alphaherpesvirus 2. Comparative analyses integrating our complex structures with the AlphaFold monomeric structure database uncovered widespread gene fusion and fission events during evolution. Finally, we demonstrate how our dataset can enhance protein binding–surface prediction using deep learning approaches, illustrating its broad utility beyond structural modeling alone. Altogether, this atlas to our knowledge, represents one of the most extensive cross-kingdom resources and opens avenues for future discoveries in various biomedical applications.
{"title":"Atlas of predicted protein complex structures across kingdoms","authors":"Xianzhi Qi, Cheng Ye, Jianqiang Liang, Shimin Wen, Yuanyuan Li, Kai Ding, Yongfu Hao, Junjie Fei, Weian Mao, Liupeng Li, Zhiyu Lin, Yichong Shen, Hongjie Zhu, Yayun Hu, Rui Zhang, Pengli Ji, Yafei Lu, Bonan Liu, Han Wang, Yuxuan Chen, Zhenguo Ma, Peiyuan Yang, Xinyu Xu, Junlong Wu, Youyuan Zhu, Qiaosha Zou, Wencheng Zhu, Kelu Yao, Shuya Li, Hongyi Xin, Daji Ergu, Jianyang Zeng, Zhi-Xiong Jim Xiao, Chunhua Shen, Ying Cai, Yong Yi, Dacheng Ma","doi":"10.1038/s41467-026-70884-4","DOIUrl":"https://doi.org/10.1038/s41467-026-70884-4","url":null,"abstract":"Protein complexes are fundamental to all biological processes. Public repositories have expanded to include millions of potential protein–protein interactions (PPIs) from human and diverse model organisms. Yet, large-scale structural characterization of these complexes—especially across different biological kingdoms—has lagged far behind, leaving most potential and unidentified interactions unresolved. Here, we present a comprehensive atlas of 1.1 million predicted protein–protein interaction structures generated with the AlphaFold2-based ColabFold framework. This dataset spans proteome-wide interactions from bacteria, archaea, humans, mice, plants, and human–virus pairs. Overall, we identify 181,671 high-confidence protein complex structures, especially 37,855 in the human interactome. Structural clustering revealed numerous conserved protein complex architectures shared across kingdoms, providing insights into previously uncharacterized biological functions. Supported by co-immunoprecipitation experiments, we further identify candidate viral receptors for Human mastadenovirus A and Papiine alphaherpesvirus 2. Comparative analyses integrating our complex structures with the AlphaFold monomeric structure database uncovered widespread gene fusion and fission events during evolution. Finally, we demonstrate how our dataset can enhance protein binding–surface prediction using deep learning approaches, illustrating its broad utility beyond structural modeling alone. Altogether, this atlas to our knowledge, represents one of the most extensive cross-kingdom resources and opens avenues for future discoveries in various biomedical applications.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"16 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506078","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}
Small cell lung cancer (SCLC) is aggressive with limited treatment options, requiring new therapies. Lysine-specific histone demethylase 1 A (LSD1) maintains neuroendocrine state by repressing NOTCH/TGF-β signaling; their reactivation suppresses proliferation and induces differentiation. However, mechanisms of LSD1 inhibition and chemoresistance remain unclear. Here we developed TAS1440, a histone H3-competitive LSD1 inhibitor, using structure-based engineering to improve specificity and reduce off-target effects. Unlike irreversible inhibitors targeting the flavin adenine dinucleotide site, TAS1440 non-covalently targets the H3-binding pocket to enhance safety and efficacy. TAS1440 suppressed proliferation in INSM1/ASCL1-high SCLC-A cells and induced tumor regression in xenografts. TAS1440 acts through dual mechanisms: inhibiting LSD1 activity and disrupting LSD1-repressive complexes, remodeling histone marks and activating transcription factors INSM1 and SMAD2. These actions reprogram tumor-suppressive TGF-β/NOTCH signaling, supporting TAS1440 as epigenetic therapy for SCLC. Loss of LSD1 enzymatic activity or INSM1 knockout abrogated TAS1440 effects, defining its mode of action and chemoresistance. These findings support TAS1440 as a next-generation epigenetic therapy candidate for INSM1-high SCLC-A.
{"title":"LSD1 inhibitor, TAS1440, disrupts INSM1-LSD1 complex activating tumor-suppressive pathways via transcriptional reprogramming in neuroendocrine SCLC","authors":"Takumitsu Machida, Yingbo Gong, Sayaka Tsukioka, Atsushi Onodera, Akitoshi Nakayama, Naoko Hashimoto, Takahiro Fuchigami, Motoi Nishimura, Tomohiro Ogino, Ryota Kurimoto, Yasufumi Uematsu, Hidemi Suzuki, Hongye Yu, Mingyang Chen, Masataka Yokoyama, Ikki Sakuma, Yuki Taki, Takashi Kono, Takashi Miki, Shinichiro Motohashi, Yusuke Kawashima, Osamu Ohara, Satoshi Yamashita, Tatsuya Suzuki, Ryo Hatanaka, Yasuo Kodama, Shuichi Ohkubo, Tomoaki Tanaka","doi":"10.1038/s41467-026-70984-1","DOIUrl":"https://doi.org/10.1038/s41467-026-70984-1","url":null,"abstract":"Small cell lung cancer (SCLC) is aggressive with limited treatment options, requiring new therapies. Lysine-specific histone demethylase 1 A (LSD1) maintains neuroendocrine state by repressing NOTCH/TGF-β signaling; their reactivation suppresses proliferation and induces differentiation. However, mechanisms of LSD1 inhibition and chemoresistance remain unclear. Here we developed TAS1440, a histone H3-competitive LSD1 inhibitor, using structure-based engineering to improve specificity and reduce off-target effects. Unlike irreversible inhibitors targeting the flavin adenine dinucleotide site, TAS1440 non-covalently targets the H3-binding pocket to enhance safety and efficacy. TAS1440 suppressed proliferation in INSM1/ASCL1-high SCLC-A cells and induced tumor regression in xenografts. TAS1440 acts through dual mechanisms: inhibiting LSD1 activity and disrupting LSD1-repressive complexes, remodeling histone marks and activating transcription factors INSM1 and SMAD2. These actions reprogram tumor-suppressive TGF-β/NOTCH signaling, supporting TAS1440 as epigenetic therapy for SCLC. Loss of LSD1 enzymatic activity or INSM1 knockout abrogated TAS1440 effects, defining its mode of action and chemoresistance. These findings support TAS1440 as a next-generation epigenetic therapy candidate for INSM1-high SCLC-A.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"20 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506111","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 : 2026-03-25DOI: 10.1038/s41467-026-70310-9
Tamires Duarte Afonso Serdan, Heidi Cervantes, Benjamin Frank, Akhil Gargey Iragavarapu, Qiyu Tian, Daniel Hope, Chan Hee J. Choi, Anne Hoffmann, Adhideb Ghosh, Christian Wolfrum, Matthew B. Greenblatt, Paul Cohen, Matthias Blüher, Halil Aydin, Gary J. Schwartz, Farnaz Shamsi
Brown adipose tissue is an evolutionary innovation in placental mammals that regulates body temperature through adaptive thermogenesis. Cold exposure activates brown adipose tissue thermogenesis through coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation; however, how these processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (SLIT3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Adipocyte progenitors secrete SLIT3, which is cleaved into functionally distinct SLIT3-N and SLIT3-C fragments that independently promote angiogenesis and sympathetic innervation. We identify PLXNA1 as a receptor for SLIT3-C and demonstrate its essential role in sympathetic innervation of brown adipose tissue. Moreover, we identify BMP1 as the first SLIT protease described in vertebrates. Coordinated neurovascular expansion mediated by distinct SLIT3 fragments provides a bifurcated yet integrated mechanism that ensures a synchronized brown adipose tissue response to environmental challenges. Finally, this study reveals a previously unrecognized role for adipocyte progenitors in regulating tissue innervation.
{"title":"SLIT3 fragments orchestrate neurovascular expansion and thermogenesis in brown adipose tissue","authors":"Tamires Duarte Afonso Serdan, Heidi Cervantes, Benjamin Frank, Akhil Gargey Iragavarapu, Qiyu Tian, Daniel Hope, Chan Hee J. Choi, Anne Hoffmann, Adhideb Ghosh, Christian Wolfrum, Matthew B. Greenblatt, Paul Cohen, Matthias Blüher, Halil Aydin, Gary J. Schwartz, Farnaz Shamsi","doi":"10.1038/s41467-026-70310-9","DOIUrl":"https://doi.org/10.1038/s41467-026-70310-9","url":null,"abstract":"Brown adipose tissue is an evolutionary innovation in placental mammals that regulates body temperature through adaptive thermogenesis. Cold exposure activates brown adipose tissue thermogenesis through coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation; however, how these processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (SLIT3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Adipocyte progenitors secrete SLIT3, which is cleaved into functionally distinct SLIT3-N and SLIT3-C fragments that independently promote angiogenesis and sympathetic innervation. We identify PLXNA1 as a receptor for SLIT3-C and demonstrate its essential role in sympathetic innervation of brown adipose tissue. Moreover, we identify BMP1 as the first SLIT protease described in vertebrates. Coordinated neurovascular expansion mediated by distinct SLIT3 fragments provides a bifurcated yet integrated mechanism that ensures a synchronized brown adipose tissue response to environmental challenges. Finally, this study reveals a previously unrecognized role for adipocyte progenitors in regulating tissue innervation.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"33 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506785","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 : 2026-03-25DOI: 10.1038/s41467-026-70107-w
Feng Hong, Hongqiu Chen, Jiawei Chen, Zhehan Ying, Mi Peng, Jingwang Zhang, Zuodong Yang, Guodong Wen, Jiangyong Diao, Bo Sun, Geng Sun, Ding Ma, Hongyang Liu
Acetylene semihydrogenation is a critical process in the polyolefin industry by selectively removing trace acetylene from ethylene-rich reformate. However, this reaction is generally limited by the inherent activity-selectivity trade-off due to the thermodynamic advantage of overhydrogenation. Herein, we develop a facile and straightforward strategy to construct Pd2 dual-atom sites anchored on defect-rich surface-graphitized nanodiamond (ND@G) via the solvent-mediated dispersion of palladium carboxylate driven by the chelation of palladium precursors via carboxylate anion. Cs-corrected HAADF-STEM images coupled with XAS analysis unambiguously manifest the successful architecting of Pd2 dual-atom sites. Compared to Pd1 single-atom sites, the obtained Pd2/ND@G sample demonstrates superior catalytic performance in acetylene semihydrogenation, with the corresponding TOF values increased from 0.151 s−1 to 1.953 s−1, without the obvious decline of ethylene selectivity (93.2%, at full acetylene conversion). C2H2/C2H4-TPD, H2-D2 exchange reaction, isotope-labeled TPSR combined with DFT calculations confirm the effective co-activation of C2H2/H2 on Pd2 dual-atom sites while maintaining the weak adsorption of ethylene similar to that on its single-atom sites, which can break the activity-selectivity trade-off in acetylene semihydrogenation.
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