Biogerontology最新文献

{"title":"Phase-transition failure in aged skeletal muscle regeneration.","authors":"Bo Zhang, Haijiao Shi, Xiaojing Guo, Yan Wang","doi":"10.1007/s10522-026-10500-6","DOIUrl":"https://doi.org/10.1007/s10522-026-10500-6","url":null,"abstract":"<p><p>Aged skeletal muscle is impaired at every phase of post-injury repair that has been examined, with myeloid recruitment delayed and skewed in composition, debris degradation lagging behind uptake, and muscle stem cell (MuSC) activation following a conserved trajectory at delayed kinetics. Deficits inside a phase may be differences of degree that a longer window absorbs, whereas the transition between phases offers no comparable slack. Each transition is triggered by a defined switch in signal, either the fall in damage input after debris degradation, the TNF/TGF-β balance that permits fibro-adipogenic progenitor (FAP) apoptosis, or the Ly6C^high→Ly6C^low monocyte conversion. Because positive feedback operates beyond each switch, a compartment arriving late meets a microenvironment already committed to a self-maintaining alternative state that its later output appears unable to reverse. Retained mitochondrial lesions in postmitotic myofibers are one proposed input holding the first switch open. MuSCs face pool contraction, skewed fate allocation, and cell-autonomous defects uncorrected by a young host. FAPs resist clearance past their support phase while a stiffening matrix keeps them fibrogenic, and aged myeloid cells reach the pro-repair switch late and with attenuated output. None of these lesions need be primary for the sequence to fail. Interventions should instead be judged on whether inflammation declines, matrix remodeling closes, myogenic output yields mature fibers, and reserve survives repeated injury. Aging may therefore be read as a loss of temporal coordination, in which sub-threshold delays accumulate between compartments that must act in sequence, until a failed transition settles the tissue into an inflammatory-fibrotic endpoint.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-related biochemical profiling reveals multi-system physiological decline in the annual fish Nothobranchius guentheri.","authors":"Ravindra Pawar, Shicui Zhang","doi":"10.1007/s10522-026-10493-2","DOIUrl":"https://doi.org/10.1007/s10522-026-10493-2","url":null,"abstract":"<p><p>Annual killifishes of the genus Nothobranchius compress a vertebrate life cycle into a few months, which is what makes them useful in aging research, yet no broad biochemical description of ageing exists for N. guentheri. In a cross-sectional design, we measured 27 clinical chemistry analytes in whole-body homogenates of male and female fish sampled at 3, 6 and 9 months of age (20 analytical samples). Age trends were assessed by Spearman rank correlation, and age, sex and their interaction by two-way ANOVA. Twenty-four of the 27 analytes fell with age. Calcium declined most steeply (r = - 0.573, p = 0.008), followed by fructose (r = - 0.507, p = 0.023), albumin (r = - 0.486, p = 0.030) and magnesium (r = - 0.479, p = 0.033); potassium fell just short of significance (r = - 0.422, p = 0.064). Only adenosine deaminase, C-reactive protein and HDL cholesterol trended upward, none of them significantly. Males had higher creatinine, carbon dioxide and HDL cholesterol than females. The picture is one of generalised decline rather than the selective elevations of glucose, lipids and nitrogenous waste seen in long-lived mammals, and is most simply read as progressive loss of metabolically active tissue. We suggest, as a hypothesis for testing, that the abrupt terminal mortality familiar to killifish keepers follows the crossing of a threshold after months of subclinical decline. Sample sizes were small and p-values uncorrected, so individual associations need confirmation, but the panel offers endpoints that can be read out within one generation of this species.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammaging and cytokine-driven cardiovascular senescence in age-related myocardial infarction: mechanisms, biomarkers, and precision immunotherapy strategies.","authors":"Sithu Aung, Soe Ei Phyu, Nelli Giribabu, Naguib Salleh","doi":"10.1007/s10522-026-10482-5","DOIUrl":"https://doi.org/10.1007/s10522-026-10482-5","url":null,"abstract":"<p><p>Ageing is an independent, non-modifiable risk factor for myocardial infarction (MI). It is also characterized by chronic, low-grade inflammation (inflammaging) and progressive cardiovascular senescence. These ageing-associated processes alter cytokine networks and innate and adaptive immune-cell function, promote endothelial dysfunction, and compromise post-infarction repair, thereby increasing myocardial susceptibility to ischaemia and adverse cardiac remodelling in the elderly. Lifestyle modifications, including regular physical activity, reduce inflammaging by facilitating the release of anti-inflammatory cytokines and counteract cellular senescence. This review compiles current mechanistic and translational evidence connecting inflammaging to age-related myocardial infarction, focusing on cytokine-mediated immune interactions. Additionally, this review also examines age-related cytokine dysregulation in myocardial infarction, pro-inflammatory and anti-inflammatory cytokine networks, inflammasome-mediated pyroptosis, senescence-associated secretory phenotypes, and emerging cytokine and extracellular vesicle-based biomarkers. It further discusses translational advances in cytokine-targeted, senescence-directed, and precision immunology-guided therapeutic strategies for the ageing population. In conclusion, inflammaging is closely linked to age-related myocardial infarction, with the IL-6/IL-1 signalling axis supported by the most direct interventional evidence to date including outcome evidence from canakinumab (CANTOS) and phase 2 STEMI myocardial-salvage evidence from tocilizumab (ASSAIL-MI). Cytokine-based immunotherapies targeting this axis represent a promising therapeutic approach for age-related myocardial infarction, although their efficacy and safety in older populations remain to be established in dedicated clinical trials.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hardened ground: ECM stiffness as a unifying biomechanical driver of reproductive stem cell aging.","authors":"Onder Celik, Nur Dokuzeylul Gungor, Aynur Ersahin, Nilufer Celik, Aziz Ihsan Tavuz, Yasemin Kizilkaya, Sudenaz Celik, Kagan Gungor","doi":"10.1007/s10522-026-10498-x","DOIUrl":"https://doi.org/10.1007/s10522-026-10498-x","url":null,"abstract":"<p><p>Reproductive aging in the ovary, endometrium, and testis is characterized by progressive decline in regenerative capacity, yet the upstream mechanisms coordinating stem cell dysfunction across these tissues remain incompletely understood. Emerging evidence suggests that alterations in extracellular matrix (ECM) mechanics, particularly age and disease associated increases in tissue stiffness, may contribute to impaired stem cell function through mechanotransductive signaling pathways. In the testis, increased matrix stiffness has been associated with activation of mechanosensitive pathways such as Piezo1, leading to calcium influx, mitochondrial stress, and downstream effects on steroidogenic and stem cell populations. In the ovary, age-related fibrosis and cortical stiffening correlate with disrupted follicular development and altered signaling through Hippo-YAP/TAZ pathways. Similarly, the endometrium exhibits stiffness-dependent functional changes, where excessive ECM remodeling is associated with impaired decidualization and reduced regenerative potential. Across these reproductive tissues, mechanotransduction pathways involving calcium signaling, reactive oxygen species generation, and YAP/TAZ activity appear to integrate biomechanical cues with cellular stress responses, potentially contributing to stem cell exhaustion. However, current evidence remains largely correlative, and direct causal links between tissue stiffness and stem cell failure in human reproductive tissues are still limited. We propose the \"Hardened Ground\" framework as a unifying working model suggesting that increased ECM stiffness may represent a contributory biomechanical factor influencing stem cell function across the reproductive axis. Importantly, this model does not replace established molecular and hormonal mechanisms of aging but instead integrates mechanical properties of the tissue microenvironment as an additional regulatory layer. Notably, clinical observations such as preserved follicular reserve in polycystic ovary syndrome despite increased ovarian stiffness, and dynamic changes in endometrial stiffness across the menstrual cycle, indicate that mechanotransduction outcomes are context-dependent and influenced by hormonal and inflammatory states. Future studies integrating quantitative elastography with stem cell and molecular markers in human tissues are needed to clarify the causal role of stiffness in reproductive aging. This framework generates testable predictions and highlights potential therapeutic avenues targeting extracellular matrix remodeling and mechanosensitive signaling pathways to preserve reproductive tissue function.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lifelong dietary interventions selectively reverse age-associated circulating microRNA upregulation in a time-dependent manner in female MMTV-TGF-α mice.","authors":"Bilge Guvenc Tuna, Nazim Arda Keles, Munevver Burcu Cicekdal, Umit Ozorhan, Pınar Buket Thomas, Aysegul Kuskucu, Omer Faruk Bayrak, Bayram Yilmaz, Soner Dogan","doi":"10.1007/s10522-026-10469-2","DOIUrl":"10.1007/s10522-026-10469-2","url":null,"abstract":"<p><p>Breast cancer is among the leading causes of cancer mortality worldwide, with aging as a major risk factor. Caloric restriction (CR) is a well-established non-pharmaceutical intervention that extends healthspan and delays tumorigenesis, yet the systemic molecular mechanisms remain elusive. Both chronic and intermittent CR influence metabolic homeostasis, but their long-term effects on circulating miRNAs in breast cancer predisposition are unclear. Here, we examined how chronic and intermittent CR and subsequent refeeding remodel circulating miRNA networks in a tumor-free, female breast cancer-prone transgenic mouse model. Blood samples were collected and circulating miRNA expression levels were determined at weeks 10 (young), 49 (adult), and 81 (old) using GeneChip miRNA 4.1 Array. Differential expression and target enrichment analysis were performed to identify age- and diet-associated modulatory patterns. Aging significantly altered the global circulating miRNA profile and validated targets were enriched in the IL-7 signaling, GPCR signaling, and TCA cycle. Both chronic and intermittent CR reshaped these age-associated alterations, with the consistent target pathways. The effects were most pronounced at adult age rather than old age, while the refeeding phase of the intermittent CR partially preserved the CR-induced miRNA patterns. Integrative analyses identified three key miRNAs (mmu-miR-142-5p, mmu-miR-30e-5p, mmu-miR-494-3p), where CR reversed the expression patterns induced by aging, suggesting a shared molecular mechanism. Our findings demonstrate that chronic and intermittent CR modulate circulating miRNAs in an age-dependent manner in female transgenic breast cancer-prone mice.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An aging essential 8: closing the gap between geroscience and the public it serves.","authors":"Franco Grimolizzi","doi":"10.1007/s10522-026-10497-y","DOIUrl":"10.1007/s10522-026-10497-y","url":null,"abstract":"<p><p>Longevity science has advanced faster than the public's capacity to interpret it. Biological age tests, longevity clinics, and consumer wearables now reach millions of people, yet no shared framework exists to tell an individual what those numbers mean or what to do about them. Cardiovascular medicine encountered a comparable problem and resolved it not with a new therapeutic but with a communication instrument: Life's Essential 8, which distilled a contested risk landscape into eight components scored from 0 to 100, and which has since been shown to track biological aging itself. This Perspective argues that geroscience has assembled much of the material for an equivalent instrument, even while the field continues to disagree about foundational questions. Expert panels have converged on which biomarkers are worth tracking as outcomes in aging intervention trials, and have concluded that no single biomarker suffices, which leaves a composite as the only viable path. What has not happened is the translation of that research-level agreement into a public-facing instrument. A candidate structure is proposed, comprising four behavioral and four biological pillars with explicit scoring thresholds, designed for administration by clinicians in primary care rather than by longevity clinics only, and constructed so that seven of the eight components require only a questionnaire, a bedside test, and routine bloods.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Partial reduction of the mitochondrial lipoyltransferase LipT2 promotes longevity and redox remodeling in Drosophila.","authors":"Yoshihito Kishita, Manabu Tsuda, Yukiko Sato-Miyata, Satomi Takeo, Toshiro Aigaki","doi":"10.1007/s10522-026-10494-1","DOIUrl":"https://doi.org/10.1007/s10522-026-10494-1","url":null,"abstract":"<p><p>Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes, and mutations in the lipoyltransferase LIPT2 cause severe metabolic and neurological defects in humans. In Drosophila, two independent lipT2 loss-of-function alleles cause severe physiological abnormalities in homozygotes. Here, we show that heterozygotes for these same alleles exhibit significantly extended lifespan and delayed age-dependent decline in locomotor performance. Metabolic analysis revealed no major alterations in central carbon metabolites or cellular energy status, indicating that overall metabolic homeostasis is largely preserved. In contrast, LipT2 heterozygosity was associated with reduced DCF fluorescence and selective changes in redox-related metabolites, including glutathione and urate. LipT2 heterozygotes also exhibited enhanced resistance to paraquat-induced oxidative stress without induction of canonical antioxidant genes. These findings indicate that partial reduction of LipT2 activity is associated with selective remodeling of cellular redox homeostasis while preserving metabolic homeostasis, providing a physiological state associated with longevity and enhanced stress resistance. Thus, the effects of LipT2 deficiency are strongly dependent on gene dosage, with moderate reduction being associated with longevity and maintenance of physiological function rather than overt metabolic dysfunction.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ODC1-associated astrocytic urea cycle dysregulation in age-related memory impairment.","authors":"Mengna Wu, Shengyao Zhang, Xi Zhao, Bingyu Zhang, Guoran Wan, Jie Gui, Meng Zhang, Baoxue Yang, Dilong Chen, Guoli Li, Qiu Chen, Boyue Huang, Jianhua Ran","doi":"10.1007/s10522-026-10483-4","DOIUrl":"https://doi.org/10.1007/s10522-026-10483-4","url":null,"abstract":"<p><p>Aging is an inevitable physiological process characterized by progressive functional decline and degenerative alterations across organ systems. Metabolic disturbance, particularly the disruption of substance and energy metabolism, is increasingly recognized as a central hallmark of aging. Emerging evidence suggests that dysregulation of the urea cycle (UC) contributes to aging-related pathological processes, including cognitive impairment; however, its role in astrocyte-mediated brain aging remains unclear. In this study, we used a D-galactose-induced mouse aging model to investigate the involvement of UC activation in age-related cognitive decline. Aging mice exhibited marked cognitive impairment, accompanied by an increased proportion of reactive astrocytes in the hippocampus, a key pathological feature of brain aging. Metabolic analysis and molecular validation revealed enhanced UC activity and increased urea production in aging mice. Inhibition of UC activation reduced urea production and decreased the proportion of hippocampal reactive astrocytes. Mechanistically, the expression of key UC-related enzymes, including ornithine decarboxylase 1 (ODC1) and arginase 1 (ARG1), was significantly downregulated, accompanied by improved mitochondrial dynamics, particularly the restoration of mitochondrial fusion and fission balance. Furthermore, ODC1 knockdown confirmed its critical role in mediating UC activation in astrocytes and significantly alleviated aging-like cellular phenotypes. Notably, Ganoderma lucidum polysaccharide peptides (GLPs) effectively suppressed UC activation in aging astrocytes by downregulating ODC1 and ARG1. Collectively, this study identifies dysregulated astrocytic UC activity as a novel metabolic mechanism linking astrocyte reactivity, mitochondrial dysfunction, and age-related cognitive decline, suggesting that targeting ODC1-mediated UC activation and mitochondrial dynamics may provide a promising dual strategy for combating brain aging.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging regulation by gut microbiota: molecular insights from Caenorhabditis elegans.","authors":"Qin Liu, Haiqing Tang","doi":"10.1007/s10522-026-10496-z","DOIUrl":"https://doi.org/10.1007/s10522-026-10496-z","url":null,"abstract":"<p><p>Aging is a complex biological process governed by conserved genetic and metabolic pathways. Increasing evidence has identified the gut microbiota as a critical modulator of host aging and healthspan. The Caenorhabditis elegans model provides a powerful system to elucidate the molecular determinants of this cross-kingdom dialogue. Recent advances in this model organism reveal that gut microbes may regulate aging through two distinct yet convergent mechanisms: (i) the production of small-molecule metabolites that modulate conserved host longevity pathways, and (ii) the presentation of structural components that trigger hormetic defense responses via immune recognition. This review synthesizes these findings, offering a framework for understanding microbial contributions to aging and highlighting potential directions for future research aimed at extending healthspan in higher organisms.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formononetin attenuates cellular senescence through a FOS-mediated mechanism.","authors":"Minseon Kim, Kyeong Seon Lee, Jee Hee Yoon, Ji Ho Park, Yoo Jin Lee, Jihyun Song, Hyung Wook Kwon, Youngjoo Byun, Ki Yong Lee, Joon Tae Park","doi":"10.1007/s10522-026-10495-0","DOIUrl":"https://doi.org/10.1007/s10522-026-10495-0","url":null,"abstract":"<p><p>Cellular senescence is characterized by cell cycle arrest accompanied by mitochondrial dysfunction. Despite extensive efforts to overcome this stable state of growth arrest, effective strategies for treating cellular senescence have not been identified. In this study, we screened plant-derived secondary metabolites and confirmed that formononetin is a substance that potently induces the proliferation of senescent fibroblasts. Formononetin-induced proliferation was associated with the suppression of expression of key cell cycle inhibitors, including p53 and Rb-1. This proliferative response was accompanied by the restoration of mitochondrial function. Transcriptome analysis identified the Fos proto-oncogene (FOS) as a downstream regulator, and FOS expression significantly increased after formononetin treatment. Functional verification further confirmed that the increase in FOS expression recapitulates the anti-senescence effects of formononetin. In summary, the results of this study revealed a previously unknown mechanism by which formononetin promotes cell cycle re-entry and restores mitochondrial function through the regulation of FOS expression. These findings suggest that therapeutic strategies regulating formononetin-mediated FOS pathway could be promising treatments for aging and age-related diseases.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":"27 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}