Journal of Pineal Research最新文献

{"title":"Criticism on the Incorrect Use of Oxygen–Ozone Therapy in Medicine","authors":"Marianno Franzini, Luigi Valdenassi, Francesco Vaiano, Tommaso Richelmi, Umberto Tirelli, Salvatore Chirumbolo","doi":"10.1111/jpi.13005","DOIUrl":"10.1111/jpi.13005","url":null,"abstract":"","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 6","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “PP2C1 Fine-Tunes Melatonin Biosynthesis and Phytomelatonin Receptor PMTR1 Binding to Melatonin in Cassava”","authors":"","doi":"10.1111/jpi.12983","DOIUrl":"10.1111/jpi.12983","url":null,"abstract":"<p>Y. Bai, Y. Wei, H. Yin, et al., “PP2C1 Fine-Tunes Melatonin Biosynthesis and Phytomelatonin Receptor PMTR1 Binding to Melatonin in Cassava,” <i>Journal of Pineal Research</i> 73, no. 1 (2022): e12804. https://doi.org/10.1111/jpi.12804</p><p>After publication of the article, the authors identified inaccuracies in images in Figure 3A, namely SD-Trp-Leu-Ade-His for MePP2C1 and MeWRKY20 interaction. The authors have found the original data and corrected this error, which was due to the oversight during combing and dragging different figures in Photoshop software. It is important to emphasize that this correction does not compromise the scientific integrity of the study's conclusions. The authors sincerely apologize for any inconvenience caused by this oversight. The accurate images, obtained during the original experimental procedures, are provided below.</p><p>In addition, the authors also found inaccuracies in images in Figure 6B, namely Vector+Vector, MePMTR1+Vector, Vector+MePP2C1. The authors have found the original data and corrected these errors, which was due to the oversight that the adjacent figures were only labeled by number and stored in the same files during combing and dragging different figures in Photoshop software. It is important to emphasize that this correction does not compromise the scientific integrity of the study's conclusions. The authors sincerely apologize for any inconvenience caused by this oversight. The accurate images, obtained during the original experimental procedures, are provided below.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12983","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Melatonin mediates selenium-induced tolerance to cadmium stress in tomato plants”","authors":"","doi":"10.1111/jpi.12982","DOIUrl":"10.1111/jpi.12982","url":null,"abstract":"<p>Li M-Q, Hasan MK, Li C-X, et al. Melatonin mediates selenium-induced tolerance to cadmium stress in tomato plants. <i>J Pineal Res</i>. 2016;61(3):291-302. https://doi.org/10.1111/jpi.12346</p><p>After the publication of the article, the authors identified inaccuracies in chlorophyll fluorescence images in Figure 4C, namely Water treatment of TRV (1st row, panel 1 from the left), Water treatment of TRV-<i>TDC</i> (1st row, panel 4 from the left), and Se treatment of TRV-<i>TDC</i> (1st row, panel 5 from the left). The accurate images, obtained during the original experimental procedures, are provided below. These corrections do not compromise the scientific integrity of the study's conclusions.</p><p>We apologize for this error.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12982","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Protocol to Determine Circadian Phase by At-Home Salivary Dim Light Melatonin Onset Assessment","authors":"Jade M. Murray,&nbsp;Julia E. Stone,&nbsp;Sabra M. Abbott,&nbsp;Bjorn Bjorvatn,&nbsp;Helen J. Burgess,&nbsp;Christian Cajochen,&nbsp;Jip J. Dekker,&nbsp;Jeanne F. Duffy,&nbsp;Lawrence J. Epstein,&nbsp;Corrado Garbazza,&nbsp;John Harsh,&nbsp;Elizabeth B. Klerman,&nbsp;Jacqueline M. Lane,&nbsp;Steven W. Lockley,&nbsp;Milena K. Pavlova,&nbsp;Stuart F. Quan,&nbsp;Kathryn J. Reid,&nbsp;Frank A. J. L. Scheer,&nbsp;Tracey L. Sletten,&nbsp;Kenneth P. Wright Jr.,&nbsp;Phyllis C. Zee,&nbsp;Andrew J. K. Phillips,&nbsp;Charles A. Czeisler,&nbsp;Shantha M. W. Rajaratnam,&nbsp;International Association of Circadian Health Clinics","doi":"10.1111/jpi.12994","DOIUrl":"10.1111/jpi.12994","url":null,"abstract":"<p>Internal circadian phase assessment is increasingly acknowledged as a critical clinical tool for the diagnosis, monitoring, and treatment of circadian rhythm sleep−wake disorders and for investigating circadian timing in other medical disorders. The widespread use of <i>in-laboratory</i> circadian phase assessments in routine practice has been limited, most likely because circadian phase assessment is not required by formal diagnostic nosologies, and is not generally covered by insurance. At-home assessment of salivary dim light melatonin onset (DLMO, a validated circadian phase marker) is an increasingly accepted approach to assess circadian phase. This approach may help meet the increased demand for assessments and has the advantages of lower cost and greater patient convenience. We reviewed the literature describing at-home salivary DLMO assessment methods and identified factors deemed to be important to successful implementation. Here, we provide specific protocol recommendations for conducting at-home salivary DLMO assessments to facilitate a standardized approach for clinical and research purposes. Key factors include control of lighting, sampling rate, and timing, and measures of patient compliance. We include findings from implementation of an optimization algorithm to determine the most efficient number and timing of samples in patients with Delayed Sleep−Wake Phase Disorder. We also provide recommendations for assay methods and interpretation. Providing definitive criteria for each factor, along with detailed instructions for protocol implementation, will enable more widespread adoption of at-home circadian phase assessments as a standardized clinical diagnostic, monitoring, and treatment tool.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12994","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Priming Promotes Crop Seed Germination and Seedling Establishment Under Flooding Stress by Mediating ABA, GA, and ROS Cascades","authors":"Xiaofeng Luo,&nbsp;Xiaojing Xu,&nbsp;Jiahui Xu,&nbsp;Xiaoting Zhao,&nbsp;Ranran Zhang,&nbsp;Yiping Shi,&nbsp;Mingyu Xia,&nbsp;Baoshan Xian,&nbsp;Wenguan Zhou,&nbsp;Chuan Zheng,&nbsp;Shaowei Wei,&nbsp;Lei Wang,&nbsp;Junbo Du,&nbsp;Weiguo Liu,&nbsp;Kai Shu","doi":"10.1111/jpi.13004","DOIUrl":"10.1111/jpi.13004","url":null,"abstract":"<div>\u0000 \u0000 <p>Both seed germination and subsequent seedling establishment are key checkpoints during the life cycle of seed plants, yet flooding stress markedly inhibits both processes, leading to economic losses from agricultural production. Here, we report that melatonin (MT) seed priming treatment enhances the performance of seeds from several crops, including soybean, wheat, maize, and alfalfa, under flooding stress. Transcriptome analysis revealed that MT priming promotes seed germination and seedling establishment associated with changes in abscisic acid (ABA), gibberellin (GA), and reactive oxygen species (ROS) biosynthesis and signaling pathways. Real-time quantitative RT-PCR (qRT-PCR) analysis confirmed that MT priming increases the expression levels of GA biosynthesis genes, ABA catabolism genes, and ROS biosynthesis genes while decreasing the expression of positive ABA regulatory genes. Further, measurements of ABA and GA concentrations are consistent with these trends. Following MT priming, quantification of ROS metabolism-related enzyme activities and the concentrations of H₂O₂ and superoxide anions (O₂⁻) after MT priming were consistent with the results of transcriptome analysis and qRT-PCR. Finally, exogenous application of GA, fluridone (an ABA biosynthesis inhibitor), or H₂O₂ partially rescued the poor germination of non-primed seeds under flooding stress. Collectively, this study uncovers the application and molecular mechanisms underlying MT priming in modulating crop seed vigor under flooding stress.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YTHDF3 Regulates the Degradation and Stability of m6A-Enriched Transcripts to Facilitate the Progression of Castration-Resistant Prostate Cancer","authors":"Juanjuan Duan,&nbsp;Daogui Fan,&nbsp;Pingping Chen,&nbsp;Jie Xiang,&nbsp;Xin Xie,&nbsp;Yuhui Peng,&nbsp;Jingdi Bai,&nbsp;Tao Li,&nbsp;Yi Li,&nbsp;Hui Song,&nbsp;Wenli Fu,&nbsp;Ting Zhang,&nbsp;Yan Xiao,&nbsp;Xiaolan Qi,&nbsp;Wei Hong,&nbsp;Jing Zhou,&nbsp;Yan He,&nbsp;ChangXue Wu,&nbsp;Hongmei Zeng,&nbsp;Hua Bai,&nbsp;Tengxiang Chen,&nbsp;Wenfeng Yu,&nbsp;Qifang Zhang","doi":"10.1111/jpi.13003","DOIUrl":"10.1111/jpi.13003","url":null,"abstract":"<div>\u0000 \u0000 <p>RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of <i>SPOP</i> and <i>NXK3.1</i> but stabilized RNA expressions of <i>TWIST1</i> and <i>SNAI2</i> dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading <i>SPOP</i> in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin and Seasonal Synchrony in Mammals","authors":"David G. Hazlerigg,&nbsp;Valérie Simonneaux,&nbsp;Hugues Dardente","doi":"10.1111/jpi.12996","DOIUrl":"10.1111/jpi.12996","url":null,"abstract":"<p>In mammals, seasonal opportunities and challenges are anticipated through programmed changes in physiology and behavior. Appropriate anticipatory timing depends on synchronization to the external solar year, achieved through the use of day length (photoperiod) as a synchronizing signal. In mammals, nocturnal production of melatonin by the pineal gland is the key hormonal mediator of photoperiodic change, exerting its effects via the hypothalamopituitary axis. In this review/perspective, we consider the key developments during the history of research into the seasonal synchronizer effect of melatonin, highlighting the role that the <i>pars tuberalis</i>–tanycyte module plays in this process. We go on to consider downstream pathways, which include discrete hypothalamic neuronal populations. Neurons that express the neuropeptides kisspeptin and (Arg)(Phe)–related peptide-3 (RFRP-3) govern seasonal reproductive function while neurons that express somatostatin may be involved in seasonal metabolic adaptations. Finally, we identify several outstanding questions, which need to be addressed to provide a much thorough understanding of the deep impact of melatonin upon seasonal synchronization.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12996","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship Between Melatonin Receptor Agonists and Parkinson's Disease","authors":"Yoshihiro Noguchi,&nbsp;Rikuto Masuda,&nbsp;Haruka Aizawa,&nbsp;Tomoaki Yoshimura","doi":"10.1111/jpi.13002","DOIUrl":"10.1111/jpi.13002","url":null,"abstract":"<p>Parkinson's disease affects millions of people worldwide, and without significant progress in disease prevention and treatment, its incidence and prevalence could increase by more than 30% by 2030. Researchers have focused on targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease. This study investigated the association between melatonin receptor agonists and Parkinson's disease, using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS). The target drugs were melatonin receptor agonists including ramelteon, tasimelteon, and agomelatine. Parkinson's disease cases were defined according to the Medical Dictionary for Regulatory Activities (MedDRA) 25.0; Standardized MedDRA Query (SMQ) using both the “narrow” and “broad” preferred terms (PTs) associated with Parkinson's disease. The association between melatonin receptor agonists (ramelteon, tasimelteon, and agomelatine) and Parkinson's disease was evaluated by the reporting odds ratio. Upon analyzing the data from all patients registered in the FAERS, ramelteon (ROR: 0.66, 95% confidence interval [95% CI]: 0.51–0.84) and tasimelteon (ROR: 0.49, 95% CI: 0.38–0.62) showed negative correlations with Parkinson's disease. Conversely, only agomelatine was positively correlated with Parkinson's disease (ROR: 2.63, 95% CI: 2.04–3.40). These results suggest that among the melatonin receptor agonists, ramelteon and tasimelteon are negatively correlated with Parkinson's disease. In contrast, agomelatine was shown to be positively correlated with Parkinson's disease. These results should be used in research to develop drugs for the treatment of Parkinson's disease, fully considering the limitations of the spontaneous reporting system.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Healthy Lifestyles Modify the Association of Melatonin Receptor 1B Gene and Ischemic Stroke: A Family-Based Cohort Study in Northern China","authors":"Huangda Guo,&nbsp;Hexiang Peng,&nbsp;Siyue Wang,&nbsp;Tianjiao Hou,&nbsp;Yixin Li,&nbsp;Hanyu Zhang,&nbsp;Jin Jiang,&nbsp;Bohao Ma,&nbsp;Mengying Wang,&nbsp;Yiqun Wu,&nbsp;Xueying Qin,&nbsp;Xun Tang,&nbsp;Dafang Chen,&nbsp;Jing Li,&nbsp;Yonghua Hu,&nbsp;Tao Wu","doi":"10.1111/jpi.13000","DOIUrl":"10.1111/jpi.13000","url":null,"abstract":"<div>\u0000 \u0000 <p>Limited research has reported the association between <i>MTNR1B</i> gene polymorphisms and ischemic stroke (IS), and there is insufficient evidence on whether adopting a healthy lifestyle can mitigate genetic risks in this context. This study aimed to investigate the associations between <i>MTNR1B</i> gene variants (rs10830963 and rs1387153) and IS, examining the potential effect of gene–lifestyle interactions on IS risk. Conducted in northern China, this family-based cohort study involved 5116 initially IS-free subjects. Genotype data for rs10830963 and rs1387153 in <i>MTNR1B</i> were collected. Eight modifiable lifestyle factors, including body mass index (BMI), smoking, alcohol consumption, dietary habits, physical activity, sedentary time, sleep duration, and chronotype, were considered in calculating healthy lifestyle scores. Multilevel Cox models were used to examine the associations between <i>MTNR1B</i> variants and IS. Participants carrying the rs10830963-G and rs1387153-T alleles exhibited an elevated IS risk. Each additional rs10830963-G allele and rs1387153-T allele increased the IS risk by 36% (HR = 1.36, 95% CI, 1.12–1.65) and 32% (HR = 1.32, 95% CI, 1.09–1.60), respectively. Participants were stratified into low, medium, and high healthy lifestyle score groups (1537, 2188, and 1391 participants, respectively). Genetic–lifestyle interactions were observed for rs10830963 and rs1387153 (<i>p</i> for interaction &lt; 0.001). Notably, as the healthy lifestyle score increased, the effect of <i>MTNR1B</i> gene variants on IS risk diminished (<i>p</i> for trend &lt; 0.001). This study underscores the association between the <i>MTNR1B</i> gene and IS, emphasizing that adherence to a healthy lifestyle can mitigate the genetic predisposition to IS.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141887686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adrenergic Agonists Activate Transcriptional Activity in Immortalized Neuronal Cells From the Mouse Suprachiasmatic Nucleus","authors":"Monica Langiu,&nbsp;Faramarz Dehghani,&nbsp;Urszula Hohmann,&nbsp;Philipp Bechstein,&nbsp;Oliver Rawashdeh,&nbsp;Abdelhaq Rami,&nbsp;Erik Maronde","doi":"10.1111/jpi.12999","DOIUrl":"10.1111/jpi.12999","url":null,"abstract":"<p>The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ-amino-butyric acid, arginine-vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary-derived adenylate cyclase-activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin-releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β-adrenergic receptors in SCN and a mouse SCN-derived immortalized cell line by immunohistochemical, immuno-cytochemical, and pharmacological techniques. We then characterized the effects of β-adrenergic agonists and antagonists on cAMP-regulated element (CRE) signaling. Moreover, we investigated the interaction of β-adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β-blockers applied as anti-hypertensive drugs.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"76 5","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.12999","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}