Aging and Disease最新文献

{"title":"Coronary Artery Disease Is Linked with Demyelination and Iron Deposition in White Matter Watershed Areas.","authors":"Ali Rezaei, Zacharie Potvin-Jutras, Stefanie A Tremblay, Safa Sanami, Dalia Sabra, Julia Huck, Christine Gagnon, Lindsay Wright, Ilana R Leppert, Christine L Tardif, Josep Iglesies-Grau, Anil Nigam, Louis Bherer, Claudine J Gauthier","doi":"10.14336/AD.2026.0252","DOIUrl":"https://doi.org/10.14336/AD.2026.0252","url":null,"abstract":"<p><p>Coronary artery disease is associated with white matter alterations. However, the biological basis of these changes remains unclear, specifically in normal-appearing white matter. Myelin and iron content are crucial measures of white matter health and can be measured with quantitative MRI. This study investigated whether myelin and iron alterations occur in coronary artery disease, and their relationship with cognition. In this cross-sectional study, 46 individuals with coronary artery disease and 40 healthy controls aged > 50 years, with normal cognition underwent 3T MRI and cognitive assessments. Quantitative MRI metrics (susceptibility, magnetization transfer saturation (MTsat), R2* and R1 relaxation rates) were calculated in the border zones between adjacent arterial territories (watershed regions) and in the areas outside these borders (non-watershed regions) in normal-appearing white matter. Relative to controls, the coronary artery disease group showed lower myelin and higher iron content, as measured by lower MTsat and R1, and higher susceptibility specifically in watershed regions. Importantly, these microstructural alterations were associated with poorer cognitive performance in the coronary artery disease group with lower MTsat and R1 related to poorer global cognition and with higher magnetic susceptibility with poorer verbal memory. These findings suggest that coronary artery disease is associated with demyelination and iron deposition in normal-appearing white matter, most prominently in watershed regions, which are known for their susceptibility to stroke. The association of these microstructural alterations with cognition highlights the role of normal-appearing white matter as a key vulnerable region and a promising focus for future mechanistic and therapeutic studies.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stagnation and Progression: How Glymphatic Failure Promotes Meningioma Malignancy in Aging.","authors":"Wenfei Zhou, Naili Wei, Feng Xu, Chenrui Li, Ruiting Deng, Yuanfeng Yu, Yue Qiu, Yefei Lv, Hao Meng, Jiading Lu, Haojun Li, Yixuan Hao, Ronghua Huang, Xiaoyu Ji, Hailiang Tang, Jian Chen","doi":"10.14336/AD.2026.0116","DOIUrl":"https://doi.org/10.14336/AD.2026.0116","url":null,"abstract":"<p><p>Meningiomas in the elderly present a clinical paradox: despite typically benign histology, they frequently manifest disproportionate peritumoral brain edema (PTBE) and aggressive behavior. Traditional hormonal hypotheses fail to explain this age-specific malignancy. This review articulates a \"Neuro-Glymphatic-Tumor Axis\" as a working hypothesis, proposing that the senescent collapse of brain clearance infrastructure, rather than tumor genetics alone, may be a key driver of this progression. Specifically, the loss of astrocytic aquaporin-4 (AQP4) polarity and the atrophy of meningeal lymphatic vessels are hypothesized to create a critical \"hydrodynamic mismatch.\" This systemic failure may trap oncogenic toxins, specifically HMGB1 and S100A4, potentially activating RAGE signaling, while simultaneously blocking antigen drainage, which could induce a state of \"immunological ignorance.\" Consequently, the tumor microenvironment may become physically congested and immunologically suppressed. Translating this framework into practice, we suggest that assessing \"glymphatic frailty\" via functional MRI and exploring microenvironment-targeted strategies, including lymphatic-sparing surgery and AQP4 modulation, represent promising future directions for dismantling the cycle of edema and recurrence in the vulnerable geriatric population.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming Extracellular Matrix Barriers: Biomaterial-Assisted microRNA Delivery for Fibrous Musculoskeletal Regeneration.","authors":"Ashish Ranjan Sharma, Yeon-Hee Lee, Garima Sharma, Jae Gyu Kim, Jin-Chul Kim, Holger Jahr, Sang-Soo Lee","doi":"10.14336/AD.2026.0343","DOIUrl":"https://doi.org/10.14336/AD.2026.0343","url":null,"abstract":"<p><p>Fibrous musculoskeletal tissues, including tendons, ligaments, fascia, entheses, and aponeuroses, are strengthened by densely organized collagenous extracellular matrix (ECM) but have limited regenerative capacity. The largely avascular, glycosaminoglycan (GAG)-rich ECM restricts cellular entry, slows matrix turnover, and creates substantial barriers to local therapeutic delivery. Within this setting, a subset of microRNAs (miRNAs) coordinates central aspects of degeneration and repair, including inflammation, angiogenesis, apoptosis, matrix synthesis, and mechanotransduction, making them attractive yet incompletely leveraged therapeutic targets. Clinical translation of miRNA-based approaches, however, is hindered by rapid nuclease degradation, limited penetration into dense collagen networks, electrostatic trapping within the ECM, and inefficient endosomal escape after cellular uptake. Recent advances in biomaterials directly address these challenges by designing carriers that are tailored to the structural and biochemical features of fibrous connective tissues. Approaches such as collagen-binding nanoparticles, mechano- and enzyme-responsive systems, injectable hydrogels with programmable release profiles, and exosome-mimetic vesicles have demonstrated improved miRNA stability, tissue retention, and intracellular delivery in preclinical models. However, the absence of cell-specific targeting ligands, pronounced heterogeneity within and across tendons and ligaments, and pathological matrix stiffening in long-term injuries remain major unresolved issues. The review explores how integrating mechanobiology, RNA engineering, and hierarchical biomaterial design could yield delivery platforms with true spatiotemporal control over miRNA activity, aiming to restore structural integrity in musculoskeletal regions where conventional surgical and pharmacological interventions have repeatedly fallen short.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Copper-Gut-Brain Axis: A Triple Inflammatory Pathway Driving Neuroinflammation in Alzheimer's Disease.","authors":"Ashwin Ambi","doi":"10.14336/AD.2026.0375","DOIUrl":"https://doi.org/10.14336/AD.2026.0375","url":null,"abstract":"<p><p>Serum copper increases progressively with normal aging, yet its downstream consequences for the gut microbiome and neuroinflammation remain unexplored. Gut microbiota dysbiosis and elevated lipopolysaccharide levels are established features of Alzheimer's disease, and growing evidence indicates that this dysbiosis drives neuroinflammatory disease progression. Yet the upstream trigger initiating this dysbiosis remains unknown. We propose that age-related copper dyshomeostasis serves as this missing trigger. The redox-active copper content of ceruloplasmin increases across the adult lifespan, and copper is selectively toxic to anaerobic bacteria, preferentially affecting butyrate-producing genera including Faecalibacterium, Roseburia, and Coprococcus while sparing copper-resistant species. This selective toxicity is supported by animal studies demonstrating copper-induced elimination of butyrate producers with reversible gut barrier damage and by Wilson's disease cohorts showing consistent depletion of butyrate-producing genera due to elevated copper levels. The resulting dysbiosis creates a triple inflammatory pathway: butyrate loss compromises gut barrier integrity and removes histone deacetylase-mediated suppression of neuroinflammation; the increase of Gram-negative bacteria elevates lipopolysaccharide translocation through the compromised barrier; and impaired blood-brain barrier integrity reduces amyloid-β clearance. These three insults trigger microglial activation through NF-κB signaling, creating a 'triple hit' on a single transcription factor that may explain the magnitude of neuroinflammatory effects observed in Alzheimer's disease. This mechanism explains the increased acetate/butyrate ratio recently identified as a biomarker distinguishing Alzheimer's-related from non-Alzheimer's cognitive impairment (AUC 0.951), since copper disrupts microbial metabolic cross-feeding networks that convert acetate to butyrate. We present specific, falsifiable predictions that can be tested in human cohorts and propose copper as a novel upstream therapeutic target for Alzheimer's disease prevention.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HFpEF, Aging, Inflammaging, and the Future of Anti-Inflammatory: Therapy in Heart Failure with Preserved Ejection Fraction.","authors":"Arkadiusz Grzeczka, Szymon Graczyk, Jan Gröschel, Sebastian Spethmann, Pawel Kordowitzki","doi":"10.14336/AD.2026.0265","DOIUrl":"https://doi.org/10.14336/AD.2026.0265","url":null,"abstract":"<p><p>Aging is the dominant risk factor for heart failure with preserved ejection fraction (HFpEF), a condition increasingly recognized as a manifestation of maladaptive cardiovascular aging. This review summarizes current evidence linking inflammaging, a chronic, low-grade inflammatory state driven by immunosenescence, mitochondrial dysfunction, and cellular senescence, to progressive myocardial fibrosis, diastolic stiffness, and HFpEF development. We discuss mechanistic pathways connecting fibroblast activation, extracellular matrix remodeling, adipose tissue-driven inflammation, and phenotype-specific inflammatory signatures, as well as the role of multimodality imaging in detecting early fibrotic and inflammatory changes. Finally, we critically evaluate emerging immunometabolic therapies, highlighting the limitations of single-cytokine blockade and the disease-modifying potential of SGLT2 inhibitors and GLP-1 receptor agonists in targeting HFpEF.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Transition Windows in Tissue Repair: Timing, Boundary Conditions and Resolution.","authors":"Fangyuan Zhu, Feixin Liang, Sijia Song","doi":"10.14336/AD.2026.0204","DOIUrl":"https://doi.org/10.14336/AD.2026.0204","url":null,"abstract":"<p><p>Regenerative repair is accompanied by extensive cellular remodeling, with metabolic reprogramming frequently observed across injury models. Glycolytic upregulation is commonly reported early after tissue damage, yet similar metabolic shifts have also been described in settings that progress toward functional regeneration or fibrotic remodeling. These observations indicate that pathway enrichment alone provides an incomplete explanation for divergent repair trajectories. Accumulating studies are consistent with a time-resolved perspective in which outcomes may depend on the onset, magnitude, and reversibility of metabolic remodeling, together with spatial and niche-derived boundary conditions. This review synthesizes recent work linking metabolic flux to chromatin regulation and cell-state plasticity. Metabolites such as acetyl-CoA, α-ketoglutarate, and lactate have been associated with chromatin remodeling and changes in epigenetic constraints in multiple contexts, although their necessity and directionality remain model dependent. We discuss evidence that immune microenvironments can shape metabolic boundary conditions by modulating oxygenation, inflammatory cues, and debris clearance, thereby influencing when reparative programs are engaged and whether tissues transition toward maturation and oxidative recovery. Comparative analysis across the heart, nervous system, lung, and liver supports the concept of organ-specific bottlenecks that may limit repair at distinct stages, including constrained entry into reparative states, impaired maintenance of rebuilding programs, or delayed resolution that coincides with persistent inflammation and scarring. We highlight methodological challenges that complicate causal interpretation, including reliance on transcript-level proxies and incomplete temporal sampling. We propose that advancing the field will require longitudinal and stage-resolved analyses coupled with functional repair endpoints, with explicit consideration of tissue microenvironmental context.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular Senescence Drives Diabetic Atherosclerosis: Aging Mechanisms and Integrative Therapeutic Implications.","authors":"Yu Deng, Guangtao Pan, Shanyan Chen, Xiang Jia, Xu Zhang, Tianle Wang, Aochuan Sun, Zhengtang Liu, Mishan Wu, Chaojun Chen","doi":"10.14336/AD.2026.0182","DOIUrl":"https://doi.org/10.14336/AD.2026.0182","url":null,"abstract":"<p><p>Cellular senescence is increasingly recognized as a key mechanism linking aging to chronic disease. Diabetic atherosclerosis (DAS), a major macrovascular complication of type 2 diabetes, often progresses despite standard metabolic and lipid-lowering therapies, highlighting the involvement of aging-related processes beyond classical metabolic and inflammatory pathways. This review synthesizes evidence to propose a conceptual framework in which stress-induced senescence is a key disease-oriented aging mechanism contributing to DAS initiation and progression. Hyperglycemia and lipotoxicity induce premature senescence in endothelial cells, vascular smooth muscle cells, and macrophages through oxidative stress, mitochondrial dysfunction, and activation of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. Senescent cells secrete a senescence-associated secretory phenotype (SASP), which amplifies chronic vascular inflammation, promotes plaque instability, and facilitates systemic propagation of senescence, thereby contributing to multi-organ dysfunction in the heart, brain, and kidneys. Together, these features position DAS as a representative model of stress-accelerated vascular aging. From a therapeutic perspective, we discuss emerging senescence-targeted strategies, including senolytics, senomorphics, and multi-target interventions derived from integrative medicine, with emphasis on their potential to modulate the aging tissue microenvironment and delay disease progression. By framing diabetic atherosclerosis within the context of aging biology, this review provides a disease-focused perspective on mechanisms and therapeutic opportunities underlying age-associated vascular disorders.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian Rhythm, Clock Genes and Osteoarthritis: The Dream of a Good Night's Sleep.","authors":"Hong Xu, Xinzhan Mao, Qichen Long, Antonia Rujia Sun, Indira Prasadam, Ross Crawford, Yang Chen, Yanping Wang, Xiwei Fan","doi":"10.14336/AD.2026.0105","DOIUrl":"https://doi.org/10.14336/AD.2026.0105","url":null,"abstract":"<p><p>Circadian rhythm is an endogenous 24-hour timing system that coordinates metabolic, inflammatory, and reparative processes required for tissue homeostasis. Disruption of this temporal organization, increasingly common because of shift work, sleep disturbance, and other modern lifestyle factors, has been implicated in chronic inflammatory and metabolic diseases, including osteoarthritis (OA). Experimental studies indicate that circadian dysregulation in joint tissues can alter chondrocyte metabolism, extracellular matrix turnover, synovial inflammatory tone, and subchondral bone remodeling. At the molecular level, perturbation of core clock components such as BMAL1, PER, and CRY is associated with oxidative stress, an imbalance between anabolism and catabolism, and increased sensitivity to inflammatory stimuli. Human evidence currently supports an association between circadian misalignment, disturbed sleep, and greater OA symptom burden, but direct causal inference remains limited. OA-related pain, reduced physical activity, and metabolic dysfunction may, in turn, aggravate sleep and circadian disruption, creating a bidirectional cycle. This review synthesizes mechanistic, animal, and human evidence on circadian regulation of joint homeostasis and discusses translational opportunities, including chronotherapy, rhythm-aligned behavioral interventions, and pharmacological modulation of clock pathways. We also highlight major limitations of the current literature and priorities for future phase-informed precision studies in OA.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peanut Procyanidin A Delays Hematopoietic Stem Cells Aging through Cox5a.","authors":"Ying Wang, Bingzheng Zhang, Junfei Lu, Lin Liu, Xiaoyu Tang, Changzheng Li, Xi Zeng, Chuqing Fan, Yuncong Qiao, Cheng Chen, Yu Zhang, Jiajia Chen, Zhiyi Li, Yucheng Luo, Guizhi Yang, Juan Shen, Bing Liu","doi":"10.14336/AD.2025.1354","DOIUrl":"https://doi.org/10.14336/AD.2025.1354","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) are essential for maintaining blood system homeostasis. Their aging leads to functional decline and increased susceptibility to blood disorders, largely driven by elevated reactive oxygen species (ROS). Here, we identify peanut procyanidin A (PPA) as a potent compound that delays HSC aging by targeting cytochrome c oxidase subunit 5a (Cox5a). Through screening of 234 FDA-approved natural compounds, we found that PPA significantly reduces mitochondrial ROS and improves the function of aged HSCs in mice. Transcriptomic analysis revealed that PPA induces a metabolic shift from oxidative phosphorylation toward glycolysis, reminiscent of a youthful HSC state. Moreover, PPA rescues aging phenotypes in human CD34+ hematopoietic progenitor cells. Our study establishes Cox5a as a druggable target for HSC rejuvenation and highlights PPA as a promising therapeutic candidate for age-related hematopoietic decline.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Potential of Micheliolide and ACT001 in Age-Related Diseases: Molecular Mechanisms and Clinical Prospects.","authors":"Hui Xu, Xin Cong, Lian-Jun Lin","doi":"10.14336/AD.2025.1556","DOIUrl":"https://doi.org/10.14336/AD.2025.1556","url":null,"abstract":"<p><p>Aging is the predominant risk factor for several chronic disorders; therefore, elucidating the molecular and cellular mechanisms underlying age-related pathologies is essential for therapeutic advancement. Micheliolide (MCL), a naturally occurring guaianolide sesquiterpene lactone derived from Michelia champaca and Michelia compressa, has attracted increasing attention for its pharmacological potential. Its derivative, ACT001, enables the sustained release of MCL into the plasma in vivo, thereby enhancing oral bioavailability and improving therapeutic efficacy. ACT001 has recently received orphan drug designation for glioblastoma treatment, highlighting its clinical feasibility and safety profile. Increasing evidence indicates that MCL regulates age-related diseases by modulating inflammation, cell cycle, mitochondrial dysfunction, oxidative stress, and autophagy. By targeting key signaling pathways, including NF-κB, STAT3, NRF2, AMPK, and NLRP3, MCL/ACT001 demonstrated its protective effect against age-related diseases. This paper summarizes the current mechanistic insight and disease-specific evidence regarding MCL/ACT001 and further evaluates their therapeutic repositioning potential for age-related diseases, including cardiovascular and cerebrovascular diseases, fibrotic conditions, immune disorders, metabolic diseases, and tumors. Additionally, we discussed key translational challenges.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}