Pub Date : 2024-09-19DOI: 10.1186/s13148-024-01743-6
Bingbing Shen, Yusheng Pu, Xiaofeng Zheng, Yang Liu, Lin Yang, Jiaye Liu, Zhihui Li
Epigenetic age accelerations (EAAs) are a promising new avenue of research, yet their investigation in subacute thyroiditis (SAT) remains scarce. Our study endeavors to fill this void by exploring the potential causal association between EAAs and SAT. Our study utilized publicly available genome-wide association study (GWAS) data of European ancestry to conduct a bidirectional Mendelian randomization (MR) study. Five MR methods were employed to measure causal association between EAAs and SAT multiple analyses were utilized to perform quality control. Our study evaluated causal association between SAT and four EAAs, included GrimAge acceleration (GrimAA), Hannum age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), intrinsic epigenetic age acceleration (IEAA). Results showed that there is a significant causal association between PhenoAA and SAT (OR 1.109, 95% CI 1.000–1.228, p = 0.049, by IVW method). On the contrary, SAT was associated with IEAA (OR 0.933, 95% CI 0.884–0.984, p = 0.011, by IVW method; OR 0.938, 95% CI 0.881–0.998, p = 0.043, by weighted median method). Leave-one-out sensitivity analysis, heterogeneity test, pleiotropy test, and MR-PRESSO analysis provide good quality control. The bidirectional MR analysis concluded that an increase in PhenoAA was correlated with a higher risk of SAT, indicating a potential causal relationship between PhenoAA and risk of SAT. Conversely, SAT was found to be closely associated with IEAA, suggesting that SAT may accelerate the aging process. Slowing down biological aging has emerged as a new research direction in curbing SAT.
表观遗传年龄加速（EAAs）是一个很有前途的新研究方向，但对其在亚急性甲状腺炎（SAT）中的应用的研究仍然很少。我们的研究试图通过探讨EAAs与亚急性甲状腺炎之间的潜在因果关系来填补这一空白。我们的研究利用公开的欧洲血统全基因组关联研究（GWAS）数据开展了一项双向孟德尔随机化（MR）研究。我们采用了五种 MR 方法来测量 EAAs 与 SAT 之间的因果关系，并利用多重分析来进行质量控制。我们的研究评估了 SAT 与四种 EAA 之间的因果关系，包括 GrimAge 加速（GrimAA）、Hannum Age 加速（HannumAA）、PhenoAge 加速（PhenoAA）和内在表观遗传年龄加速（IEAA）。结果显示，PhenoAA 与 SAT 之间存在明显的因果关系（OR 1.109，95% CI 1.000-1.228，P = 0.049，采用 IVW 法）。相反，SAT 与 IEAA 相关（IVW 法，OR 0.933，95% CI 0.884-0.984，p = 0.011；加权中值法，OR 0.938，95% CI 0.881-0.998，p = 0.043）。留空敏感性分析、异质性检验、多向性检验和 MR-PRESSO 分析提供了良好的质量控制。双向 MR 分析得出结论，PhenoAA 的增加与 SAT 风险的增加相关，表明 PhenoAA 与 SAT 风险之间存在潜在的因果关系。相反，研究发现 SAT 与 IEAA 密切相关，这表明 SAT 可能会加速衰老过程。延缓生物衰老已成为遏制 SAT 的一个新的研究方向。
{"title":"Causal association of epigenetic age acceleration and risk of subacute thyroiditis: a bidirectional Mendelian randomization study","authors":"Bingbing Shen, Yusheng Pu, Xiaofeng Zheng, Yang Liu, Lin Yang, Jiaye Liu, Zhihui Li","doi":"10.1186/s13148-024-01743-6","DOIUrl":"https://doi.org/10.1186/s13148-024-01743-6","url":null,"abstract":"Epigenetic age accelerations (EAAs) are a promising new avenue of research, yet their investigation in subacute thyroiditis (SAT) remains scarce. Our study endeavors to fill this void by exploring the potential causal association between EAAs and SAT. Our study utilized publicly available genome-wide association study (GWAS) data of European ancestry to conduct a bidirectional Mendelian randomization (MR) study. Five MR methods were employed to measure causal association between EAAs and SAT multiple analyses were utilized to perform quality control. Our study evaluated causal association between SAT and four EAAs, included GrimAge acceleration (GrimAA), Hannum age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), intrinsic epigenetic age acceleration (IEAA). Results showed that there is a significant causal association between PhenoAA and SAT (OR 1.109, 95% CI 1.000–1.228, p = 0.049, by IVW method). On the contrary, SAT was associated with IEAA (OR 0.933, 95% CI 0.884–0.984, p = 0.011, by IVW method; OR 0.938, 95% CI 0.881–0.998, p = 0.043, by weighted median method). Leave-one-out sensitivity analysis, heterogeneity test, pleiotropy test, and MR-PRESSO analysis provide good quality control. The bidirectional MR analysis concluded that an increase in PhenoAA was correlated with a higher risk of SAT, indicating a potential causal relationship between PhenoAA and risk of SAT. Conversely, SAT was found to be closely associated with IEAA, suggesting that SAT may accelerate the aging process. Slowing down biological aging has emerged as a new research direction in curbing SAT.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254174","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}
Pub Date : 2024-09-18DOI: 10.1186/s13148-024-01739-2
Tatiana Nazarenko, Charlotte Dafni Vavourakis, Allison Jones, Iona Evans, Lena Schreiberhuber, Christine Kastner, Isma Ishaq-Parveen, Elisa Redl, Anthony W. Watson, Kirsten Brandt, Clive Carter, Alexey Zaikin, Chiara Maria Stella Herzog, Martin Widschwendter
The Illumina Methylation array platform has facilitated countless epigenetic studies on DNA methylation (DNAme) in health and disease, yet relatively few studies have so studied its reliability, i.e., the consistency of repeated measures. Here we investigate the reliability of both type I and type II Infinium probes. We propose a method for excluding unreliable probes based on dynamic thresholds for mean intensity (MI) and ‘unreliability’, estimated by probe-level simulation of the influence of technical noise on methylation β values using the background intensities of negative control probes. We validate our method in several datasets, including newly generated Illumina MethylationEPIC BeadChip v1.0 data from paired whole blood samples taken six weeks apart and technical replicates spanning multiple sample types. Our analysis revealed that specifically probes with low MI exhibit higher β value variability between repeated samples. MI was associated with the number of C-bases in the respective probe sequence and correlated negatively with unreliability scores. The unreliability scores were substantiated through validation in a new EPIC v1.0 (blood and cervix) and a publicly available 450k (blood) dataset, as they effectively captured the variability observed in β values between technical replicates. Finally, despite promising higher robustness, the newer version v2.0 of the MethylationEPIC BeadChip retained a substantial number of probes with poor unreliability scores. To enhance current pre-processing pipelines, we developed an R package to calculate MI and unreliability scores and provide guidance on establishing optimal dynamic score thresholds for a given dataset.
Illumina甲基化阵列平台促进了无数有关健康和疾病中DNA甲基化（DNAme）的表观遗传学研究，但对其可靠性（即重复测量的一致性）的研究却相对较少。在这里，我们研究了 I 型和 II 型 Infinium 探针的可靠性。我们提出了一种排除不可靠探针的方法，该方法基于平均强度（MI）和 "不可靠 "的动态阈值，通过使用阴性对照探针的背景强度对技术噪音对甲基化β值的影响进行探针级模拟来估算。我们在多个数据集中验证了我们的方法，包括新生成的 Illumina MethylationEPIC BeadChip v1.0 数据，这些数据来自相隔六周的配对全血样本和跨越多种类型样本的技术重复数据。我们的分析表明，MI 低的探针在重复样本间表现出更高的β值变异性。MI 与相应探针序列中的 C 碱基数量相关，并与不可靠评分呈负相关。通过在新的 EPIC v1.0（血液和宫颈）和公开的 450k （血液）数据集中进行验证，不可靠分数得到了证实，因为它们有效地捕捉了技术重复样本之间观察到的β值变异性。最后，尽管MethylationEPIC BeadChip的最新版本v2.0具有更高的鲁棒性，但仍保留了大量不可靠评分较低的探针。为了加强当前的预处理管道，我们开发了一个 R 软件包来计算 MI 和不可靠度得分，并为给定数据集建立最佳动态得分阈值提供指导。
{"title":"Technical and biological sources of unreliability of Infinium probes on Illumina methylation microarrays","authors":"Tatiana Nazarenko, Charlotte Dafni Vavourakis, Allison Jones, Iona Evans, Lena Schreiberhuber, Christine Kastner, Isma Ishaq-Parveen, Elisa Redl, Anthony W. Watson, Kirsten Brandt, Clive Carter, Alexey Zaikin, Chiara Maria Stella Herzog, Martin Widschwendter","doi":"10.1186/s13148-024-01739-2","DOIUrl":"https://doi.org/10.1186/s13148-024-01739-2","url":null,"abstract":"The Illumina Methylation array platform has facilitated countless epigenetic studies on DNA methylation (DNAme) in health and disease, yet relatively few studies have so studied its reliability, i.e., the consistency of repeated measures. Here we investigate the reliability of both type I and type II Infinium probes. We propose a method for excluding unreliable probes based on dynamic thresholds for mean intensity (MI) and ‘unreliability’, estimated by probe-level simulation of the influence of technical noise on methylation β values using the background intensities of negative control probes. We validate our method in several datasets, including newly generated Illumina MethylationEPIC BeadChip v1.0 data from paired whole blood samples taken six weeks apart and technical replicates spanning multiple sample types. Our analysis revealed that specifically probes with low MI exhibit higher β value variability between repeated samples. MI was associated with the number of C-bases in the respective probe sequence and correlated negatively with unreliability scores. The unreliability scores were substantiated through validation in a new EPIC v1.0 (blood and cervix) and a publicly available 450k (blood) dataset, as they effectively captured the variability observed in β values between technical replicates. Finally, despite promising higher robustness, the newer version v2.0 of the MethylationEPIC BeadChip retained a substantial number of probes with poor unreliability scores. To enhance current pre-processing pipelines, we developed an R package to calculate MI and unreliability scores and provide guidance on establishing optimal dynamic score thresholds for a given dataset.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254177","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}
Pub Date : 2024-09-18DOI: 10.1186/s13148-024-01738-3
Xuwei Wang, Yunyun Liu, Yuying Wu, Chunxi Lin, Si Yang, Yuhan Yang, Dunjin Chen, Bolan Yu
Imprinted genes play important functions in placentation and pregnancy; however, research on their roles in different placental diseases is limited. It is believed that epigenetic alterations, such as DNA methylation, of placental imprinting genes may contribute to the different pathological features of severe placental diseases, such as pre-eclampsia (PE) and placenta accreta spectrum disorders (PAS). In this study, we conducted a comparative analysis of the methylation and expression of placental imprinted genes between PE and PAS using bisulfite sequencing polymerase chain reaction (PCR) and quantitative PCR, respectively. Additionally, we assessed oxidative damage of placental DNA by determining 8-hydroxy-2′-deoxyguanosine levels and fetal growth by determining insulin-like growth factor 2 (IGF2) and cortisol levels in the umbilical cord blood using enzyme-linked immunosorbent assay. Our results indicated that methylation and expression of potassium voltage-gated channel subfamily Q member 1, GNAS complex locus, mesoderm specific transcript, and IGF2 were significantly altered in both PE and PAS placentas. Additionally, our results revealed that the maternal imprinted genes were significantly over-expressed in PE and significantly under-expressed in PAS compared with a normal pregnancy. Moreover, DNA oxidative damage was elevated and positively correlated with IGF2 DNA methylation in both PE and PAS placentas, and cortisol and IGF2 levels were significantly decreased in PE and PAS. This study suggested that DNA methylation and expression of imprinted genes are aberrant in both PE and PAS placentas and that PE and PAS have different methylation profiles, which may be linked to their unique pathogenesis.
印迹基因在胎盘和妊娠过程中发挥着重要的功能，但有关它们在不同胎盘疾病中作用的研究却很有限。有研究认为，胎盘印记基因的表观遗传学改变（如DNA甲基化）可能导致严重胎盘疾病（如子痫前期（PE）和胎盘早剥谱系障碍（PAS））的不同病理特征。在这项研究中，我们分别采用亚硫酸氢盐测序聚合酶链反应（PCR）和定量 PCR 对 PE 和 PAS 胎盘印迹基因的甲基化和表达进行了比较分析。此外，我们还通过测定脐带血中8-羟基-2′-脱氧鸟苷水平来评估胎盘DNA的氧化损伤，并通过酶联免疫吸附测定法测定脐带血中胰岛素样生长因子2（IGF2）和皮质醇水平来评估胎儿的生长情况。结果表明，在 PE 胎盘和 PAS 胎盘中，钾电压门通道 Q 亚家族成员 1、GNAS 复合基因座、中胚层特异性转录本和 IGF2 的甲基化和表达均发生了显著变化。此外，我们的研究结果表明，与正常妊娠相比，母体印记基因在 PE 胎盘中明显表达过高，而在 PAS 胎盘中则明显表达过低。此外，在 PE 胎盘和 PAS 胎盘中，DNA 氧化损伤均升高，且与 IGF2 DNA 甲基化呈正相关，皮质醇和 IGF2 水平在 PE 胎盘和 PAS 胎盘中均显著下降。这项研究表明，PE 和 PAS 胎盘中 DNA 甲基化和印记基因的表达均存在异常，PE 和 PAS 有不同的甲基化特征，这可能与其独特的发病机制有关。
{"title":"Methylation alterations of imprinted genes in different placental diseases","authors":"Xuwei Wang, Yunyun Liu, Yuying Wu, Chunxi Lin, Si Yang, Yuhan Yang, Dunjin Chen, Bolan Yu","doi":"10.1186/s13148-024-01738-3","DOIUrl":"https://doi.org/10.1186/s13148-024-01738-3","url":null,"abstract":"Imprinted genes play important functions in placentation and pregnancy; however, research on their roles in different placental diseases is limited. It is believed that epigenetic alterations, such as DNA methylation, of placental imprinting genes may contribute to the different pathological features of severe placental diseases, such as pre-eclampsia (PE) and placenta accreta spectrum disorders (PAS). In this study, we conducted a comparative analysis of the methylation and expression of placental imprinted genes between PE and PAS using bisulfite sequencing polymerase chain reaction (PCR) and quantitative PCR, respectively. Additionally, we assessed oxidative damage of placental DNA by determining 8-hydroxy-2′-deoxyguanosine levels and fetal growth by determining insulin-like growth factor 2 (IGF2) and cortisol levels in the umbilical cord blood using enzyme-linked immunosorbent assay. Our results indicated that methylation and expression of potassium voltage-gated channel subfamily Q member 1, GNAS complex locus, mesoderm specific transcript, and IGF2 were significantly altered in both PE and PAS placentas. Additionally, our results revealed that the maternal imprinted genes were significantly over-expressed in PE and significantly under-expressed in PAS compared with a normal pregnancy. Moreover, DNA oxidative damage was elevated and positively correlated with IGF2 DNA methylation in both PE and PAS placentas, and cortisol and IGF2 levels were significantly decreased in PE and PAS. This study suggested that DNA methylation and expression of imprinted genes are aberrant in both PE and PAS placentas and that PE and PAS have different methylation profiles, which may be linked to their unique pathogenesis.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268903","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}
Pub Date : 2024-09-16DOI: 10.1186/s13148-024-01741-8
Kristen M. Kocher, Julius Ngwa, Kushal J. Kapse, Surajit Bhattacharya, Christopher Rossi, Emmanuele Delot, Adre duPlessis, Catherine Limperopoulos, Nickie Andescavage
To assess the impact of postnatal processing on placental DNA methylation, array data from flash-frozen placental tissue was compared to perfluorocarbon-immersed and formalin-fixed paraffin-embedded placental tissue. We observed that tissue exposed to perfluorocarbon showed no significant DNA methylation differences when compared to unprocessed tissue, while formalin processing altered the quality and reliability of the data produced on the DNA methylation array platform. Placental DNA methylation allows for the study of gene–environment interactions that influence the fetal environment and development. Our study highlights that placental post-processing techniques must be considered in the evaluation and interpretation of epigenetic studies.
为了评估产后处理对胎盘DNA甲基化的影响，我们将速冻胎盘组织的阵列数据与全氟浸泡胎盘组织和福尔马林固定石蜡包埋胎盘组织进行了比较。我们观察到，与未经处理的组织相比，浸泡在全氟碳化物中的组织没有显示出明显的DNA甲基化差异，而福尔马林处理则改变了DNA甲基化阵列平台上产生的数据的质量和可靠性。胎盘 DNA 甲基化有助于研究影响胎儿环境和发育的基因与环境之间的相互作用。我们的研究强调，在评估和解释表观遗传学研究时必须考虑胎盘后处理技术。
{"title":"Technical considerations for placental tissue processing and the subsequent impact on genome-wide DNA methylation analysis","authors":"Kristen M. Kocher, Julius Ngwa, Kushal J. Kapse, Surajit Bhattacharya, Christopher Rossi, Emmanuele Delot, Adre duPlessis, Catherine Limperopoulos, Nickie Andescavage","doi":"10.1186/s13148-024-01741-8","DOIUrl":"https://doi.org/10.1186/s13148-024-01741-8","url":null,"abstract":"To assess the impact of postnatal processing on placental DNA methylation, array data from flash-frozen placental tissue was compared to perfluorocarbon-immersed and formalin-fixed paraffin-embedded placental tissue. We observed that tissue exposed to perfluorocarbon showed no significant DNA methylation differences when compared to unprocessed tissue, while formalin processing altered the quality and reliability of the data produced on the DNA methylation array platform. Placental DNA methylation allows for the study of gene–environment interactions that influence the fetal environment and development. Our study highlights that placental post-processing techniques must be considered in the evaluation and interpretation of epigenetic studies.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268902","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}
Pub Date : 2024-09-16DOI: 10.1186/s13148-024-01742-7
Lanfei Bi, Jialie Jin, Yao Fan, Yu Liu, Haifeng Xu, Mengxia Li, Changying Chen, Chong Shen, Rongxi Yang
Coronary heart disease (CHD) and stroke have become the leading cause of premature mortality and morbidity worldwide. Therefore, sensitive and accurate biomarkers for early detection of CHD and stroke are urgently needed for effective prevention and treatment. We aim to investigate the association between blood-based HYAL2 methylation and the risk of CHD and stroke in Chinese population. In a prospective nested case–control study comprising 171 CHD cases, 139 stroke cases, who developed the diseases after recruitment and 356 controls who remained healthy during the 2.5 years of follow-up time, the methylation level of HYAL2 in the peripheral blood was quantified using mass spectrometry, and the association was calculated by logistic regression adjusted for covariant. Significant association between HYAL2 methylation in the peripheral blood and increased risk of preclinical CHD and stroke were identified [odds ratios (ORs) per − 10% methylation: 1.35–1.64, p ≤ 0.045 for HYAL2_CpG_1, HYAL2_CpG_2 and HYAL2_CpG_3 in CHD; ORs per − 10% methylation: 0.76–1.64, p ≤ 0.033 for HYAL2_CpG_2 and HYAL2_CpG_4 in stroke]. The association in CHD was further enhanced by female gender, younger age (< 70 years old), without the history of hypertension and cancer. The combination of four HYAL2 methylation sites showed an effective discrimination of CHD and stroke cases without hypertension from controls [area under curve (AUC) = 0.78 and 0.75, respectively]. This study presents a strong association of altered HYAL2 methylation in peripheral blood with preclinical CHD and stroke, providing a novel biomarker for risk assessment and early detection of cardiovascular diseases.
{"title":"Blood-based HYAL2 methylation as a potential marker for the preclinical detection of coronary heart disease and stroke","authors":"Lanfei Bi, Jialie Jin, Yao Fan, Yu Liu, Haifeng Xu, Mengxia Li, Changying Chen, Chong Shen, Rongxi Yang","doi":"10.1186/s13148-024-01742-7","DOIUrl":"https://doi.org/10.1186/s13148-024-01742-7","url":null,"abstract":"Coronary heart disease (CHD) and stroke have become the leading cause of premature mortality and morbidity worldwide. Therefore, sensitive and accurate biomarkers for early detection of CHD and stroke are urgently needed for effective prevention and treatment. We aim to investigate the association between blood-based HYAL2 methylation and the risk of CHD and stroke in Chinese population. In a prospective nested case–control study comprising 171 CHD cases, 139 stroke cases, who developed the diseases after recruitment and 356 controls who remained healthy during the 2.5 years of follow-up time, the methylation level of HYAL2 in the peripheral blood was quantified using mass spectrometry, and the association was calculated by logistic regression adjusted for covariant. Significant association between HYAL2 methylation in the peripheral blood and increased risk of preclinical CHD and stroke were identified [odds ratios (ORs) per − 10% methylation: 1.35–1.64, p ≤ 0.045 for HYAL2_CpG_1, HYAL2_CpG_2 and HYAL2_CpG_3 in CHD; ORs per − 10% methylation: 0.76–1.64, p ≤ 0.033 for HYAL2_CpG_2 and HYAL2_CpG_4 in stroke]. The association in CHD was further enhanced by female gender, younger age (< 70 years old), without the history of hypertension and cancer. The combination of four HYAL2 methylation sites showed an effective discrimination of CHD and stroke cases without hypertension from controls [area under curve (AUC) = 0.78 and 0.75, respectively]. This study presents a strong association of altered HYAL2 methylation in peripheral blood with preclinical CHD and stroke, providing a novel biomarker for risk assessment and early detection of cardiovascular diseases.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254175","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}
Pub Date : 2024-09-16DOI: 10.1186/s13148-024-01733-8
Vibha Patil, Patricia Perez-Carpena, Jose A. Lopez-Escamez
<p><b>Correction: Clinical Epigenetics (2024) 16:88</b> <b>https://doi.org/10.1186/s13148-024-01697-9</b></p><br/><p>Following publication of the original article [1], the authors noticed the error in Fig. 1. The typesetter has inadvertently processed the flowchart with a missing box in the figure. The correct Fig. 1 has been presented with this erratum.</p><figure><figcaption><b data-test="figure-caption-text">Fig. 1</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13148-024-01733-8/MediaObjects/13148_2024_1733_Fig1_HTML.png?as=webp" type="image/webp"/><img alt="figure 1" aria-describedby="Fig1" height="805" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13148-024-01733-8/MediaObjects/13148_2024_1733_Fig1_HTML.png" width="685"/></picture><p>Flow diagram for the DNA methylation study selection</p><span>Full size image</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure><p>The original article has been corrected.</p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>Patil V, Perez-Carpena P, Lopez-Escamez JA. A systematic review on the contribution of DNA methylation to hearing loss. Clin Epigenet. 2024;16:88.</p><p>Article CAS Google Scholar </p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Meniere’s Disease Neuroscience Research Program, Faculty of Medicine and Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Rm 611024, Level 11 Kolling Institute | 10 Westbourne St, St Leonards, Sydney, NSW, 2064, Australia</p><p>Vibha Patil & Jose A. Lopez-Escamez</p></li><li><p>Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, Ibs.Granada, Universidad de Granada, Granada, Spain</p><p>Patricia Perez-Carpena & Jose A. Lopez-Escamez</p></li><li><p>Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, Ibs.GRANADA, Universidad de Granada, Granada, Spain</p><p>Patricia Perez-Carpena & Jose A. Lopez-Escamez</p></li><li><p>Sensorineural Pathology Program, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER, Madrid, Spain</p><p>Patricia Perez-Carpena & Jose A. Lopez-Escamez</p></li><li><p>Department of Otolaryngology, Hospital Universitario San Cecilio, Instituto de Investigacion Biosanitaria, Ibs.GRANADA, Granada, Spain</p><p>Patricia Perez-Carpena</p></li></ol><span>Authors</span><ol><li><span>Vibha Patil</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</s
更正：临床表观遗传学（2024）16:88 https://doi.org/10.1186/s13148-024-01697-9Following 原文[1]发表后，作者注意到图 1 中的错误。排版人员在处理流程图时不慎在图中少了一个方框。图 1：DNA 甲基化研究选择流程图全图原文已更正。关于 DNA 甲基化对听力损失影响的系统综述。Clin Epigenet.2024;16:88.Article CAS Google Scholar Download references作者和工作单位Meniere's Disease Neuroscience Research Program, Faculty of Medicine and Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Rm 611024, Level 11 Kolling Institute | 10 Westbourne St, St Leonards, Sydney, NSW, 2064, AustraliaVibha Patil & Jose A. Lopez-EscamezDivision.Lopez-EscamezDivision of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, Ibs.格拉纳达，格拉纳达大学，西班牙Patricia Perez-Carpena & Jose A. Lopez-EscamezOtology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, Ibs.西班牙格拉纳达，格拉纳达大学Patricia Perez-Carpena & Jose A. Lopez-EscamezSensorineural Pathology Program, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER, Madrid, SpainPatricia Perez-Carpena & Jose A. Lopez-EscamezLopez-EscamezDepartment of Otolaryngology, Hospital Universitario San Cecilio, Instituto de Investigacion Biosanitaria, Ibs.GRANADA, Granada, SpainPatricia Perez-CarpenaAuthorsVibha PatilView author publications您也可以在PubMed Google Scholar中搜索该作者Patricia Perez-CarpenaView author publications您也可以在PubMed Google Scholar中搜索该作者Jose A. Lopez-Escamez查看作者发表的文章Lopez-EscamezView author publications您也可以在PubMed Google Scholar中搜索该作者Corresponding authorCorrespondence to Vibha Patil.开放获取本文采用知识共享署名 4.0 国际许可协议进行许可，该协议允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出许可使用范围，您需要直接从版权所有者处获得许可。要查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明，否则创作共用公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文Patil, V., Perez-Carpena, P. & Lopez-Escamez, J.A. Correction：关于 DNA 甲基化对听力损失影响的系统综述。Clin Epigenet 16, 129 (2024). https://doi.org/10.1186/s13148-024-01733-8Download citationPublished: 16 September 2024DOI: https://doi.org/10.1186/s13148-024-01733-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative
{"title":"Correction: A systematic review on the contribution of DNA methylation to hearing loss","authors":"Vibha Patil, Patricia Perez-Carpena, Jose A. Lopez-Escamez","doi":"10.1186/s13148-024-01733-8","DOIUrl":"https://doi.org/10.1186/s13148-024-01733-8","url":null,"abstract":"<p><b>Correction: Clinical Epigenetics (2024) 16:88</b> <b>https://doi.org/10.1186/s13148-024-01697-9</b></p><br/><p>Following publication of the original article [1], the authors noticed the error in Fig. 1. The typesetter has inadvertently processed the flowchart with a missing box in the figure. The correct Fig. 1 has been presented with this erratum.</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13148-024-01733-8/MediaObjects/13148_2024_1733_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"805\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13148-024-01733-8/MediaObjects/13148_2024_1733_Fig1_HTML.png\" width=\"685\"/></picture><p>Flow diagram for the DNA methylation study selection</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p>The original article has been corrected.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Patil V, Perez-Carpena P, Lopez-Escamez JA. A systematic review on the contribution of DNA methylation to hearing loss. Clin Epigenet. 2024;16:88.</p><p>Article CAS Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Meniere’s Disease Neuroscience Research Program, Faculty of Medicine and Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Rm 611024, Level 11 Kolling Institute | 10 Westbourne St, St Leonards, Sydney, NSW, 2064, Australia</p><p>Vibha Patil & Jose A. Lopez-Escamez</p></li><li><p>Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, Ibs.Granada, Universidad de Granada, Granada, Spain</p><p>Patricia Perez-Carpena & Jose A. Lopez-Escamez</p></li><li><p>Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, Ibs.GRANADA, Universidad de Granada, Granada, Spain</p><p>Patricia Perez-Carpena & Jose A. Lopez-Escamez</p></li><li><p>Sensorineural Pathology Program, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER, Madrid, Spain</p><p>Patricia Perez-Carpena & Jose A. Lopez-Escamez</p></li><li><p>Department of Otolaryngology, Hospital Universitario San Cecilio, Instituto de Investigacion Biosanitaria, Ibs.GRANADA, Granada, Spain</p><p>Patricia Perez-Carpena</p></li></ol><span>Authors</span><ol><li><span>Vibha Patil</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</s","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254176","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}
Pub Date : 2024-09-12DOI: 10.1186/s13148-024-01736-5
Man Tan, Siyi Liu, Lubin Liu
Fibrosis is an abnormal tissue healing process characterized by the excessive accumulation of ECM components, such as COL I and COL III, in response to tissue injury or chronic inflammation. Recent advances in epitranscriptomics have underscored the importance of m6A modification in fibrosis. m6A, the most prevalent modification in eukaryotic RNA, is catalyzed by methyltransferases (e.g., METTL3), removed by demethylases (e.g., FTO), and recognized by reader proteins (e.g., YTHDF1/2). These modifications are crucial in regulating collagen metabolism and associated diseases. Understanding the role of m6A modification in fibrosis and other collagen-related conditions holds promise for developing targeted therapies. This review highlights the latest progress in this area.
纤维化是一种异常的组织愈合过程，其特点是组织损伤或慢性炎症时 ECM 成分（如 COL I 和 COL III）的过度积累。m6A 是真核 RNA 中最常见的修饰，由甲氧基转移酶（如 METTL3）催化，由去甲基化酶（如 FTO）去除，并由阅读蛋白（如 YTHDF1/2）识别。这些修饰在调节胶原代谢和相关疾病方面至关重要。了解 m6A 修饰在纤维化和其他胶原蛋白相关疾病中的作用为开发靶向疗法带来了希望。本综述重点介绍了这一领域的最新进展。
{"title":"N6-methyladenosine (m6A) RNA modification in fibrosis and collagen-related diseases","authors":"Man Tan, Siyi Liu, Lubin Liu","doi":"10.1186/s13148-024-01736-5","DOIUrl":"https://doi.org/10.1186/s13148-024-01736-5","url":null,"abstract":"Fibrosis is an abnormal tissue healing process characterized by the excessive accumulation of ECM components, such as COL I and COL III, in response to tissue injury or chronic inflammation. Recent advances in epitranscriptomics have underscored the importance of m6A modification in fibrosis. m6A, the most prevalent modification in eukaryotic RNA, is catalyzed by methyltransferases (e.g., METTL3), removed by demethylases (e.g., FTO), and recognized by reader proteins (e.g., YTHDF1/2). These modifications are crucial in regulating collagen metabolism and associated diseases. Understanding the role of m6A modification in fibrosis and other collagen-related conditions holds promise for developing targeted therapies. This review highlights the latest progress in this area.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223417","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}
Pub Date : 2024-09-11DOI: 10.1186/s13148-024-01737-4
Johanna Thomas, Usama-Ur Rehman, Helena Bresser, Olga Grishina, Dietmar Pfeifer, Etienne Sollier, Konstanze Döhner, Christoph Plass, Heiko Becker, Claudia Schmoor, Maike de Wit, Michael Lübbert
DNA-hypomethylating agents (HMAs) induce notable remission rates in AML/MDS patients with TP53 mutations; however, secondary resistance often develops rapidly. In the DECIDER trial (NCT00867672), elderly AML patients (also those with adverse genetics) randomized to all-trans retinoic acid (ATRA) added to decitabine (DEC) attained significantly delayed time-to-resistance. An 82-year-old patient with a non-disruptive, in-frame TP53 mutation (p.Cys238_Asn239delinsTyr, VAF 90%) and complex-monosomal karyotype attained a complete hematologic and cytogenetic remission with DEC + ATRA, with 3.7 years survival after 30 treatment cycles that were well-tolerated. Further HMA + ATRA studies appear warranted in AML/MDS patients of different genetic risk groups ineligible for more intensive treatment. Trial registration: This trial was registered at ClinicalTrials.gov identifier: NCT00867672
{"title":"Continued decitabine/all-trans retinoic acid treatment: extended complete remission in an elderly AML patient with multi-hit TP53 lesions and complex-monosomal karyotype","authors":"Johanna Thomas, Usama-Ur Rehman, Helena Bresser, Olga Grishina, Dietmar Pfeifer, Etienne Sollier, Konstanze Döhner, Christoph Plass, Heiko Becker, Claudia Schmoor, Maike de Wit, Michael Lübbert","doi":"10.1186/s13148-024-01737-4","DOIUrl":"https://doi.org/10.1186/s13148-024-01737-4","url":null,"abstract":"DNA-hypomethylating agents (HMAs) induce notable remission rates in AML/MDS patients with TP53 mutations; however, secondary resistance often develops rapidly. In the DECIDER trial (NCT00867672), elderly AML patients (also those with adverse genetics) randomized to all-trans retinoic acid (ATRA) added to decitabine (DEC) attained significantly delayed time-to-resistance. An 82-year-old patient with a non-disruptive, in-frame TP53 mutation (p.Cys238_Asn239delinsTyr, VAF 90%) and complex-monosomal karyotype attained a complete hematologic and cytogenetic remission with DEC + ATRA, with 3.7 years survival after 30 treatment cycles that were well-tolerated. Further HMA + ATRA studies appear warranted in AML/MDS patients of different genetic risk groups ineligible for more intensive treatment. Trial registration: This trial was registered at ClinicalTrials.gov identifier: NCT00867672","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223416","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}
Breast tumorigenesis is a complex and multistep process accompanied by both genetic and epigenetic dysregulation. In contrast to the extensive studies on DNA epigenetic modifications 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in malignant breast tumors, their roles in the early phases of breast tumorigenesis remain ambiguous. DNA 5hmC and 5mC exhibited a consistent and significant decrease from usual ductal hyperplasia to atypical ductal hyperplasia and subsequently to ductal carcinoma in situ (DCIS). However, 5hmC showed a modest increase in invasive ductal breast cancer compared to DCIS. Genomic analyses showed that the changes in 5hmC and 5mC levels occurred around the transcription start sites (TSSs), and the modification levels were strongly correlated with gene expression levels. Meanwhile, it was found that differentially hydroxymethylated regions (DhMRs) and differentially methylated regions (DMRs) were overlapped in the early phases and accompanied by the enrichment of active histone marks. In addition, TET2-related DNA demethylation was found to be involved in breast tumorigenesis, and four transcription factor binding sites (TFs: ESR1, FOXA1, GATA3, FOS) were enriched in TET2-related DhMRs/DMRs. Intriguingly, we also identified a certain number of common DhMRs between tumor samples and cell-free DNA (cfDNA). Our study reveals that dynamic changes in DNA 5hmC and 5mC play a vital role in propelling breast tumorigenesis. Both TFs and active histone marks are involved in TET2-related DNA demethylation. Concurrent changes in 5hmC signals in primary breast tumors and cfDNA may play a promising role in breast cancer screening.
{"title":"Genome-wide characterization of dynamic DNA 5-hydroxymethylcytosine and TET2-related DNA demethylation during breast tumorigenesis","authors":"Shuang-Ling Wu, Lin Yang, Changcai Huang, Qing Li, Chunhui Ma, Fang Yuan, Yinglin Zhou, Xiaoyue Wang, Wei-Min Tong, Yamei Niu, Feng Jin","doi":"10.1186/s13148-024-01726-7","DOIUrl":"https://doi.org/10.1186/s13148-024-01726-7","url":null,"abstract":"Breast tumorigenesis is a complex and multistep process accompanied by both genetic and epigenetic dysregulation. In contrast to the extensive studies on DNA epigenetic modifications 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in malignant breast tumors, their roles in the early phases of breast tumorigenesis remain ambiguous. DNA 5hmC and 5mC exhibited a consistent and significant decrease from usual ductal hyperplasia to atypical ductal hyperplasia and subsequently to ductal carcinoma in situ (DCIS). However, 5hmC showed a modest increase in invasive ductal breast cancer compared to DCIS. Genomic analyses showed that the changes in 5hmC and 5mC levels occurred around the transcription start sites (TSSs), and the modification levels were strongly correlated with gene expression levels. Meanwhile, it was found that differentially hydroxymethylated regions (DhMRs) and differentially methylated regions (DMRs) were overlapped in the early phases and accompanied by the enrichment of active histone marks. In addition, TET2-related DNA demethylation was found to be involved in breast tumorigenesis, and four transcription factor binding sites (TFs: ESR1, FOXA1, GATA3, FOS) were enriched in TET2-related DhMRs/DMRs. Intriguingly, we also identified a certain number of common DhMRs between tumor samples and cell-free DNA (cfDNA). Our study reveals that dynamic changes in DNA 5hmC and 5mC play a vital role in propelling breast tumorigenesis. Both TFs and active histone marks are involved in TET2-related DNA demethylation. Concurrent changes in 5hmC signals in primary breast tumors and cfDNA may play a promising role in breast cancer screening.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178259","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}
Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.
{"title":"Epigenetics and immunotherapy in colorectal cancer: progress and promise","authors":"Tianjiao Dang, Xin Guan, Luying Cui, Yuli Ruan, Zhuo Chen, Haoyi Zou, Ya Lan, Chao Liu, Yanqiao Zhang","doi":"10.1186/s13148-024-01740-9","DOIUrl":"https://doi.org/10.1186/s13148-024-01740-9","url":null,"abstract":"Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178260","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}
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