综合性期刊最新文献

{"title":"Junctional force patterning drives both positional order and planar polarity in the auditory epithelia","authors":"Anubhav Prakash, Julian Weninger, Nishant Singh, Sukanya Raman, Madan Rao, Karsten Kruse, Raj K. Ladher","doi":"10.1038/s41467-025-58557-0","DOIUrl":"https://doi.org/10.1038/s41467-025-58557-0","url":null,"abstract":"<p>Tissue function depends on the precise organisation of the constituent cells. In the cochlea, the fidelity of hearing depends on mechanosensory hair cells being consistently surrounded by supporting cells. In addition to this positional order, auditory sensitivity depends crucially on planar cell polarity. This is characterised by the alignment of the orientation of eccentrically placed hair bundles on each hair cell. These two levels of order emerge simultaneously despite the cellular fluxes that occur during cochlear development. However, the link between tissue-scale cellular rearrangements and intrinsic cellular mechanisms remains unknown. By combining experimental and theoretical approaches, we find a precise force patterning underpinning positional order and planar cell polarity. This occurs through the modulation of the levels and phospho-type of the regulatory light chain of non-muscle myosin II at specific cell-cell junctions of the auditory epithelium. We propose that the control of junctional mechanics is vital for the organisation of multi-cell-type epithelia.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"33 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer","authors":"Irene Herranz-Montoya, Mariana Angulo-Aguado, Cristian Perna, Sladjana Zagorac, Luis García-Jimeno, Solip Park, Nabil Djouder","doi":"10.1038/s41467-025-59282-4","DOIUrl":"https://doi.org/10.1038/s41467-025-59282-4","url":null,"abstract":"<p>Incidence of colorectal cancer (CRC) is increasing likely due to different mechanisms driving initiation and progression. The initial model proposed by Fearon and Vogelstein posits it as a multi-hit neoplasia, originating from adenomatous-polyps induced by WNT activation, ultimately progressing to aggressiveness through p53 loss. Integrating human data with mouse genetics, we redefine this paradigm, highlighting pivotal roles of MYC, oncogenic URI and p53 degradation to initiate CRC. Early APC loss activates MYC to transcriptionally upregulate URI, which modulates MDM2 activity, triggering p53 proteasomal degradation, essential for tumour initiation and mutation burden accrual in CRC mice. Remarkably, reinstating p53 levels via genetic URI depletion or p53 super-expression in CRC mice with WNT pathway activation prevents tumour initiation and extends lifespan. Our data reveal a “two-hit” genetic model central to APC loss-driven CRC initiation, wherein MYC/URI axis intricately controls p53 degradation, offering mechanistic insights into transitional mutation acquisition essential for CRC progression.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"5 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice","authors":"Marion Müller, Torben Schubert, Cornelius Welke, Tibor Maske, Thomas Patschkowski, Elfi Donhauser, Jacqueline Heinen-Weiler, Felix-Levin Hormann, Sven Heiles, Tina Johanna Schulz, Luisa Andrea Lengenfelder, Lucia Landwehrjohann, Elisa Theres Vogt, Bernd Stratmann, Jurek Hense, Simon Lüdtke, Martina Düfer, Elena Tolstik, Johann Dierks, Kristina Lorenz, Tamino Huxohl, Jan-Christian Reil, Vasco Sequeira, Francisco Jose Schopfer, Bruce A. Freeman, Volker Rudolph, Uwe Schlomann, Anna Klinke","doi":"10.1038/s41467-025-59192-5","DOIUrl":"https://doi.org/10.1038/s41467-025-59192-5","url":null,"abstract":"<p>The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunction contribute to HFpEF. Nitro-oleic acid (NO₂-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO₂-OA ameliorates diastolic dysfunction and heart failure symptoms in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. Proteomic analysis of left ventricular tissue reveals that one-third of identified proteins, predominantly mitochondrial, are upregulated in hearts of NO₂-OA-treated HFpEF mice compared to naïve and vehicle-treated HFpEF mice. Increased mitochondrial mass and numbers, and enhanced mitochondrial respiration are linked with this response, as assessed by transmission electron microscopy and high-resolution respirometry. Activation of the 5’-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediates the enhancement of mitochondrial dynamics in hearts of NO₂-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO₂-OA may represent a promising therapeutic strategy for HFpEF.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"42 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactive symbolic regression with co-design mechanism through offline reinforcement learning","authors":"Yuan Tian, Wenqi Zhou, Michele Viscione, Hao Dong, David S. Kammer, Olga Fink","doi":"10.1038/s41467-025-59288-y","DOIUrl":"https://doi.org/10.1038/s41467-025-59288-y","url":null,"abstract":"<p>Symbolic Regression holds great potential for uncovering underlying mathematical and physical relationships from observed data. However, the vast combinatorial space of possible expressions poses significant challenges for previous online search methods and pre-trained transformer models, which mostly do not consider the integration of domain experts’ prior knowledge. To address these challenges, we propose the Symbolic Q-network, an advanced interactive framework for large-scale symbolic regression. Unlike previous transformer-based SR approaches, Symbolic Q-network leverages reinforcement learning without relying on a transformer-based decoder. Furthermore, we propose a co-design mechanism, where the Symbolic Q-network facilitates effective interaction with domain experts at any stage of the equation discovery process. Our extensive experiments demonstrate Sym-Q performs comparably to existing pretrained models across multiple benchmarks. Furthermore, our experiments on real-world cases demonstrate that the interactive co-design mechanism significantly enhances Symbolic Q-network’s performance, achieving greater performance gains than standard autoregressive models.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"49 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying the global climate feedback from energy-based adaptation","authors":"Alexander C. Abajian, Tamma Carleton, Kyle C. Meng, Olivier Deschênes","doi":"10.1038/s41467-025-59201-7","DOIUrl":"https://doi.org/10.1038/s41467-025-59201-7","url":null,"abstract":"<p>Many behavioral responses to climate change are carbon-intensive, raising concerns that adaptation may cause additional warming. The sign and magnitude of this feedback depend on how increased emissions from cooling balance against reduced emissions from heating across space and time. We present an empirical approach that forecasts the effect of future adaptive energy use on global average temperature over the 21^st century. We estimate that energy-based adaptation will lower global mean surface temperature in 2099 by 0.07 to 0.12 °C relative to baseline projections under Representative Concentration Pathways 4.5 and 8.5. This cooling avoids 0.6 to 1.8 trillion U.S. Dollars ($2019) in damages, depending on the baseline emissions scenario. Energy-based adaptation lowers business-as-usual emissions for 85% of countries, reducing the mitigation required to meet their unilateral Nationally Determined Contributions by 20% on average. These findings indicate that while business-as-usual adaptive energy use is unlikely to accelerate warming, it raises important implications for countries’ existing mitigation commitments.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"29 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2","authors":"Zongyang Lyu, Xiaoxuan Lyu, Andrey G. Malyutin, Guliang Xia, Daniel Carney, Vinicius M. Alves, Matthew Falk, Nidhi Arora, Hua Zou, Aaron P. McGrath, Yanyong Kang","doi":"10.1038/s41467-025-59138-x","DOIUrl":"https://doi.org/10.1038/s41467-025-59138-x","url":null,"abstract":"<p>Members of the proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) play critical roles in processes like hemostasis, thrombosis, development, wound healing, inflammation, and cancer progression. Comprising PAR1-PAR4, these receptors are specifically activated by protease cleavage at their extracellular amino terminus, revealing a ‘tethered ligand’ that self-activates the receptor. This triggers complex intracellular signaling via G proteins and beta-arrestins, linking external protease signals to cellular functions. To date, direct structural visualization of these ligand-receptor complexes has been limited. Here, we present structural snapshots of activated PAR1 and PAR2 bound to their endogenous tethered ligands, revealing a shallow and constricted orthosteric binding pocket. Comparisons with antagonist-bound structures show minimal conformational changes in the TM6 helix and larger movements of TM7 upon activation. These findings reveal a common activation mechanism for PAR1 and PAR2, highlighting critical residues involved in ligand recognition. Additionally, the structure of PAR2 bound to a pathway selective antagonist, GB88, demonstrates how potent orthosteric engagement can be achieved by a small molecule mimicking the endogenous tethered ligand’s interactions.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"8 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Macrophage ferroptosis under the guide of infrared thermography promotes the healing of pressure injuries","authors":"Xiaoqiong Jiang, Xuanlong Zhang, Huiming Deng, Lulu Lin, Yu Wang, Yuqi Wang, Jiayi Huang, Ningning Yang, Shi Xu, Jian Wang, Keqing Shi, Ke Tao, Zimiao Chen, Fuman Cai, Kailiang Zhou, Jian Xiao","doi":"10.1016/j.jare.2025.04.039","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.039","url":null,"abstract":"<h3>Background</h3>Accurately recognizing and regulating the transition time of macrophages to a pro- (M1-like) or anti-inflammatory (M2-like) state is essential for improving chronic inflammation in pressure injuries (PIs).<h3>Objective</h3>This study aimed to evaluate the effectiveness of infrared thermography (IRT) in measuring wound temperature of PIs for the purpose of guiding treatment in regulating chronic inflammation.<h3>Methods</h3>The healing process of 21 patients with PIs was monitored using IRT prospectively followed for 30 days. The wound temperature changing pattern of different healing outcomes were analyzed and calculated the optimal wound temperature range to guide the treatment time of anti-inflammation for 100 patients with PIs accurately. Additionally, the molecular mechanisms underlying the observed temperature changes in a mouse model of PI were investigated, and the effect of IRT-guided chronic inflammation targeting ferroptosis modulation on PIs was validated.<h3>Results</h3>The application of IRT to monitor PIs temperatures outside the 36.23 °C to 37.37 °C range is indicative of a potential risk indicator, which allows for the timely guidance of treatment to markedly enhance the efficacy of PIs healing outcomes. This wound temperature change was also observed during the process of PIs healing in mice, as a result of the imbalance of M1-like/M2-like macrophages and the subsequent chronic inflammation. Mechanically, evidence indicates that ferroptosis is hyperactivated in PIs, and the enrichment of M1-like macrophages with iNOS/NO• can enhance their resistance to ferroptosis compared with M2-like macrophages, resulting in the imbalance of M1-like/M2-like macrophages and subsequent alteration of wound temperature.<h3>Conclusions</h3>The modulation of M2-like macrophage resistance to ferroptosis in PIs by NO• donors, suggesting by IRT-monitored temperature changes, has been demonstrated to significantly improve chronic inflammation. This establishes a foundation for the application of IRT to direct a therapeutic strategy for the precise promotion of PIs healing.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"6 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasensitive detection of clinical pathogens through a target-amplification-free collateral-cleavage-enhancing CRISPR-CasΦ tool","authors":"Huiyou Chen, Fengge Song, Buhua Wang, Hui Huang, Yanchi Luo, Xiaosheng Han, Hewen He, Shaolu Lin, Liudang Wan, Zhengliang Huang, Zhaoyong Fu, Rodrigo Ledesma-Amaro, Dapeng Yin, Haimei Mao, Linwen He, Tao Yang, Zijing Chen, Yubin Ma, Evelyn Y. Xue, Yi Wan, Chuanbin Mao","doi":"10.1038/s41467-025-59219-x","DOIUrl":"https://doi.org/10.1038/s41467-025-59219-x","url":null,"abstract":"<p>Clinical pathogen diagnostics detect targets by qPCR (but with low sensitivity) or blood culturing (but time-consuming). Here we leverage a dual-stem-loop DNA amplifier to enhance non-specific collateral enzymatic cleavage of an oligonucleotide linker between a fluophore and its quencher by CRISPR-CasΦ, achieving ultrasensitive target detection. Specifically, the target pathogens are lysed to release DNA, which binds its complementary gRNA in CRISPR-CasΦ to activate the collateral DNA-cleavage capability of CasΦ, enabling CasΦ to cleave the stem-loops in the amplifier. The cleavage product binds its complementary gRNA in another CRISPR-CasΦ to activate more CasΦ. The activated CasΦ collaterally cleaves the linker, releasing the fluophore to recover its fluorescent signal. The cycle of stem-loop-cleavage/CasΦ-activation/fluorescence-recovery amplifies the detection signal. Our target amplification-free collateral-cleavage-enhancing CRISPR-CasΦ method (TCC), with a detection limit of 0.11 copies/μL, demonstrates enhanced sensitivity compared to qPCR. It can detect pathogenic bacteria as low as 1.2 CFU/mL in serum within 40 min.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"5 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division","authors":"Hien Bui, Simon Andersson, Agustin Sola-Carvajal, Tommaso De Marchi, Eliisa Vähäkangas, Minna Holopainen, Andrew H. House, Bohdana M. Rovenko, Johanna I. Englund, Maria Kasper, Emilia Kuuluvainen, Reijo Käkelä, Ville Hietakangas, Emma Niméus, Pekka Katajisto","doi":"10.1038/s41467-025-58752-z","DOIUrl":"https://doi.org/10.1038/s41467-025-58752-z","url":null,"abstract":"<p>Selective inheritance of sub-cellular components has emerged as a mechanism guiding stem cell fate after asymmetric cell divisions. Peroxisomes play a crucial role in multiple metabolic processes such as fatty acid metabolism and reactive oxygen species detoxification, but the apportioning of peroxisomes during stem cell division remains understudied. Here, we develop a mouse model and labeling technique to follow the dynamics of distinct peroxisome age-classes, and find that old peroxisomes are inherited by the daughter cell retaining full stem cell potency in mammary and epidermal stem cell divisions. Old peroxisomes carry Glucose-6-phosphate-dehydrogenase, whose specific location on the peroxisomal membrane promotes stem cell function by facilitating peroxisomal ether lipid synthesis. Our study demonstrates age-selective apportioning of peroxisomes in vivo, and unveils how functional heterogeneity of peroxisomes is utilized by asymmetrically dividing cells to metabolically divert the fate of the two daughter cells.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"37 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmentally endothelial locus-1 facilitates intestinal inflammation resolution by suppressing the Cmpk2-cGAS-STING pathway and promoting reparatory macrophage transition","authors":"Meihui Tao, Li Wang, Chaoyue Chen, Mengfan Tang, Yanping Wang, Jingyue Zhang, Xi Zhao, Qinyu Feng, Junfa Chen, Wei Yan, Rong Lin, Yu Fu","doi":"10.1016/j.jare.2025.04.030","DOIUrl":"https://doi.org/10.1016/j.jare.2025.04.030","url":null,"abstract":"<h3>Introduction</h3>Abnormalities in inflammation resolution function are intimately linked to chronic inflammation, and proresolution therapies may offer novel opportunities for IBD treatment. Developmental endothelial locus 1 (DEL-1), a natural modulator of tissue immunity and inflammation resolution, has not been studied in IBD.<h3>Objectives</h3>We aimed to investigate the expression and functions of DEL-1 in IBD.<h3>Methods</h3>Assessment of DEL-1 expression in patients, murine models, and cellular levels. To explore the effects of DEL-1 in the acute and recovery phases of inflammation, overexpression plasmids, adeno-associated viruses for DEL-1 knockdown, and DEL-1-Fc fusion proteins were administered to cells and mice. Additionally, the potential mechanism of DEL-1 in IBD was demonstrated using flow cytometry, RNA-Seq, ChIP, dual-luciferase reporter assays and 16S rRNA.<h3>Results</h3>DEL-1 levels were significantly reduced in IBD patients, colitis mice and macrophages, while the levels increased with inflammation to resolve. Transfection with DEL-1 overexpression plasmid or DEL-1-Fc intervention reduces levels of inflammatory cytokines in both phases and upregulates reparative gene levels in the recovery phase. DEL-1 knockdown inhibits inflammation resolution of colitis. Mechanistically, we demonstrated that DEL-1 inhibits Cmpk2-dependent mtDNA synthesis, thereby inhibiting the cGAS-STING pathway to ameliorate intestinal inflammation. Moreover, DEL-1 promotes reparative macrophage transition in the repair model of colitis. Spi1 was identified as a transcription factor that regulates Cmpk2 and the reparative gene Il10. Intervention with overexpression plasmid of Spi1 or Cmpk2 or the STING agonist DMXAA reverses the effects of DEL-1. In parallel, DEL-1 also inhibits neutrophil recruitment, repairs the intestinal barrier, and improves intestinal microbiota dysbiosis.<h3>Conclusion</h3>We report the first demonstration that DEL-1 significantly ameliorates colonic inflammation in colitis mice. Our findings elucidate a novel mechanism wherein DEL-1 exerts its protective effects by suppressing the Cmpk2-cGAS-STING pathway and promoting reparative macrophage transition. These results collectively position DEL-1 as a promising therapeutic avenue for IBD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"25 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872464","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}