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A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression. 膜1型基质金属蛋白酶在致癌炎性小体基因表达中的转录调控作用。
Pub Date : 2017-06-08 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017713996
Samuel Sheehy, Borhane Annabi

Signal-transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-associated cancer cell functions including migration, proliferation, and survival. Aside from upregulation of the inflammation biomarker cyclooxygenase-2 (COX-2) expression, MT1-MMP's role in relaying intracellular signals triggered by extracellular pro-inflammatory cues remains poorly understood. Here, we triggered inflammation in HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), an inducer of COX-2 and of MT1-MMP. To assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens with a transient MT1-MMP gene silencing strategy. Expression of MT1-MMP was found to exert both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as interleukin (IL)-1B, IL-6, IL-12A, and IL-33, as well as of transcription factors such as EGR1, ELK1, and ETS1/2 in PMA-treated cells. Among the signal-transducing pathways explored, the silencing of MT1-MMP prevented PMA from phosphorylating extracellular signal-regulated kinase, inhibitor of κB, and p105 nuclear factor κB (NF-κB) intermediates. We also found a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. Altogether, our data indicate a significant involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution to signal transduction functions in addition to its classical hydrolytic activity.

细胞膜1型基质金属蛋白酶(MT1-MMP)胞质结构域驱动的信号转导功能被认为调节许多炎症相关的癌细胞功能,包括迁移、增殖和存活。除了炎症生物标志物环氧化酶-2 (COX-2)表达上调外,MT1-MMP在传递细胞外促炎线索触发的细胞内信号中的作用仍然知之甚少。在这里,我们用phorpol -12-肉豆蔻酸-13-乙酸酯(PMA)触发HT1080纤维肉瘤细胞的炎症,PMA是COX-2和MT1-MMP的诱诱剂。为了评估MT1-MMP可能对炎症生物标志物发挥的全局转录调控作用,我们将基因阵列筛选与MT1-MMP基因瞬时沉默策略相结合。研究发现,在pma处理的细胞中,MT1-MMP的表达对几种炎症小体相关的生物标志物(如白细胞介素(IL)-1B、IL-6、IL- 12a和IL-33)以及转录因子(如EGR1、ELK1和ETS1/2)发挥刺激和抑制的转录控制作用。在所探索的信号转导途径中,MT1-MMP的沉默阻止了PMA磷酸化细胞外信号调节激酶、κB抑制剂和p105核因子κB (NF-κB)中间体。我们还发现了一个连接MT1-MMP和MMP-9转录调控的信号轴。总之,我们的数据表明MT1-MMP在炎症生物标志物的转录调节中有重要的参与,巩固了它在信号转导功能中的贡献,以及它的经典水解活性。
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引用次数: 7
Overexpression and Knockdown of Hypoxia-Inducible Factor 1 Disrupt the Expression of Steroidogenic Enzyme Genes and Early Embryonic Development in Zebrafish. 低氧诱导因子1的过表达和敲低干扰斑马鱼体内类固醇生成酶基因的表达和早期胚胎发育。
Pub Date : 2017-06-08 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017713193
Tianfeng Tan, Richard Man Kit Yu, Rudolf Shiu Sun Wu, Richard Yuen Chong Kong

Hypoxia is an important environmental stressor leading to endocrine disruption and reproductive impairment in fish. Although the hypoxia-inducible factor 1 (HIF-1) is known to regulate the transcription of various genes mediating oxygen homeostasis, its role in modulating steroidogenesis-related gene expression remains poorly understood. In this study, the regulatory effect of HIF-1 on the expression of 9 steroidogenic enzyme genes was investigated in zebrafish embryos using a "gain-of-function and loss-of-function" approach. Eight of the genes, CYP11a, CYP11b2, 3β-HSD, HMGCR, CYP17a1, 17β-HSD2, CYP19a, and CYP19b, were found to be differentially upregulated at 24 and 48 hpf following zHIF-1α-ΔODD overexpression (a mutant zebrafish HIF-1α protein with proline-414 and proline-557 deleted). Knockdown of zHIF-1α also affected the expression pattern of the steroidogenic enzyme genes. Overexpression of zHIF-1α and hypoxia exposure resulted in downregulated StAR expression but upregulated CYP11a and 3β-HSD expression in zebrafish embryos. Conversely, the expression patterns of these 3 genes were reversed in embryos in which zHIF-1α was knocked down under normoxia, suggesting that these 3 genes are regulated by HIF-1. Overall, the findings from this study indicate that HIF-1-mediated mechanisms are likely involved in the regulation of specific steroidogenic genes.

缺氧是导致鱼类内分泌紊乱和生殖功能障碍的重要环境应激源。虽然已知缺氧诱导因子1 (HIF-1)调节各种介导氧稳态的基因的转录,但其在调节类固醇生成相关基因表达中的作用仍知之甚少。本研究采用“功能获得和功能丧失”的方法,研究了HIF-1对斑马鱼胚胎中9个甾体生成酶基因表达的调控作用。其中8个基因CYP11a、CYP11b2、3β-HSD、HMGCR、CYP17a1、17β-HSD2、CYP19a和CYP19b在zHIF-1α-ΔODD过表达(一种缺失脯氨酸-414和脯氨酸-557的突变斑马鱼HIF-1α蛋白)后,在24和48 hpf时出现差异上调。敲低zHIF-1α也会影响甾体生成酶基因的表达模式。在斑马鱼胚胎中,过表达zHIF-1α和缺氧暴露导致StAR表达下调,而CYP11a和3β-HSD表达上调。相反,在正常缺氧条件下,当HIF-1α被敲低时,这3个基因的表达模式被逆转,表明这3个基因受HIF-1调控。总的来说,本研究的结果表明hif -1介导的机制可能参与了特定类固醇生成基因的调节。
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引用次数: 25
Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses. 药物性肝损伤的机制建模:研究先天免疫反应的作用。
Pub Date : 2017-05-30 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017696074
Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell

Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.

药物性肝损伤(DILI)仍然是药物开发和上市药物关注的重大不良事件,该领域将受益于更好的工具,在开发早期识别肝脏损害和/或减轻其他有希望的药物的潜在DILI风险。DILIsym软件采用定量系统毒理学方法来代表临床前物种和人类中的DILI,用于肝毒性的机制研究。除了肝细胞毒性的多种内在机制(如氧化应激、胆汁酸积累、线粒体功能障碍)外,DILIsym还包括肝细胞与先天免疫反应细胞在肝损伤放大和肝再生中的相互作用。这里详细介绍的先天免疫反应的表现,在一个单一的框架内巩固了DILI中先天免疫反应的许多可用数据,并提供了系统地研究DILI先天反应的贡献的机会。
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引用次数: 22
Effects of High-Fat Feeding on Skeletal Muscle Gene Expression in Diabetic Goto-Kakizaki Rats. 高脂肪喂养对糖尿病后藤- kakizaki大鼠骨骼肌基因表达的影响
Pub Date : 2017-05-29 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017710009
Jing Nie, Debra C DuBois, Bai Xue, William J Jusko, Richard R Almon

In the present report, we examined the responses of diabetic Goto-Kakizaki (GK) rats and control Wistar-Kyoto (WKY) rats fed either a standard chow or high-fat diet (HFD) from weaning to 20 weeks of age. This comparison included gene expression profiling of skeletal muscle using Affymetrix gene array chips. The expression profiling is interpreted within the context of a wide array of physiological measurements. Genes whose expressions are different between the 2 strains regardless of diet, as well as genes that differ between strains only with HFD, were identified. In addition, genes that were regulated by diet in 1 or both strains were identified. The results suggest that both strains respond to HFD by an increased capacity to oxidize lipid fuels in the musculature but that this adaptation occurs more rapidly in WKY rats. The results also demonstrated an impaired cytokine signalling and heightened inflammatory status in the GK rats.

在本报告中,我们研究了糖尿病大鼠Goto-Kakizaki (GK)和对照组Wistar-Kyoto (WKY)大鼠从断奶到20周龄分别饲喂标准食物或高脂肪饮食(HFD)的反应。该比较包括使用Affymetrix基因阵列芯片对骨骼肌进行基因表达谱分析。表达谱是在广泛的生理测量范围内解释的。发现了两种菌株在不同饮食条件下表达不同的基因,以及仅在HFD条件下表达不同的基因。此外,还鉴定了1株或2株菌株中受饮食调节的基因。结果表明,这两个品系对HFD的反应都是通过增加肌肉组织中氧化脂质燃料的能力,但这种适应在WKY大鼠中发生得更快。结果还表明,GK大鼠的细胞因子信号传导受损,炎症状态升高。
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引用次数: 6
The Synergistic Role of Light-Feeding Phase Relations on Entraining Robust Circadian Rhythms in the Periphery. 取光期关系对外周强生理节律的协同作用。
Pub Date : 2017-04-20 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017702393
Seul-A Bae, Ioannis P Androulakis

The feeding and fasting cycles are strong behavioral signals that entrain biological rhythms of the periphery. The feeding rhythms synchronize the activities of the metabolic organs, such as liver, synergistically with the light/dark cycle primarily entraining the suprachiasmatic nucleus. The likely phase misalignment between the feeding rhythms and the light/dark cycles appears to induce circadian disruptions leading to multiple physiological abnormalities motivating the need to investigate the mechanisms behind joint light-feeding circadian entrainment of peripheral tissues. To address this question, we propose a semimechanistic mathematical model describing the circadian dynamics of peripheral clock genes in human hepatocyte under the control of metabolic and light rhythmic signals. The model takes the synergistically acting light/dark cycles and feeding rhythms as inputs and incorporates the activity of sirtuin 1, a cellular energy sensor and a metabolic enzyme activated by nicotinamide adenine dinucleotide. The clock gene dynamics was simulated under various light-feeding phase relations and intensities, to explore the feeding entrainment mechanism as well as the convolution of light and feeding signals in the periphery. Our model predicts that the peripheral clock genes in hepatocyte can be completely entrained to the feeding rhythms, independent of the light/dark cycle. Furthermore, it predicts that light-feeding phase relationship is a critical factor in robust circadian oscillations.

进食和禁食周期是一种强烈的行为信号,它会影响周围的生物节律。摄食节律与代谢器官(如肝脏)的活动同步,与主要携带视交叉上核的光/暗循环协同作用。摄食节律和光/暗周期之间可能的相位失调似乎会导致昼夜节律中断,导致多种生理异常,这促使人们有必要研究外周组织联合摄食昼夜节律干扰背后的机制。为了解决这个问题,我们提出了一个半机械的数学模型来描述代谢和光节律信号控制下人类肝细胞外周时钟基因的昼夜动力学。该模型以协同作用的光/暗周期和摄食节律为输入,并结合了sirtuin 1的活性,sirtuin 1是一种细胞能量传感器,是一种由烟酰胺腺嘌呤二核苷酸激活的代谢酶。在不同的供光相位关系和强度下,模拟时钟基因的动态,探索供光夹带机制以及光和供光信号在外围的卷积。我们的模型预测,肝细胞中的外周时钟基因可以完全受摄食节律的影响,独立于光/暗周期。此外,它预测了光摄食相位关系是稳健的昼夜节律振荡的关键因素。
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引用次数: 29
Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification. 通过模型简化模拟果糖负荷诱导的肝脏去新生脂肪生成。
Pub Date : 2017-04-12 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017690133
Richard J Allen, Cynthia J Musante

Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing 'transfer function'. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate) of the pathway as a whole.

肝脏de-novo脂肪生成是2型糖尿病发病机制中的一个代谢过程。在临床上,这个过程的速率可以通过使用标记醋酸盐和果糖的刺激来确定。该过程的系统药理学模型是可取的,因为它有助于描述、分析和预测该实验。由于去novo脂肪生成涉及多种酶,且数据有限,因此希望使用单一功能表达来封装多种酶之间的通量。为了实现这一目标,我们开发了一种新的简化技术,该技术利用有关单个酶的特性的可用信息来绑定单个控制“传递函数”的参数。这种方法应该适用于任何具有线性酶链的模型。我们在一个极限情况下用计算模拟和分析论证验证了这种方法。使用这种技术,我们在这些实验条件下生成了一个简单的肝脏去新生脂肪生成模型,与先前的数据相匹配。该模型可用于评估该通路上特定点的药物干预。我们已经通过对乙酰辅酶a羧化酶抑制的前瞻性模拟证明了这一点。这种简化技术表明,酶链反应的组成性质如何引起整个途径(对底物)的敏感性。
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引用次数: 3
Time Course Expression Analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole Induction of Cytoprotection in Human Endothelial Cells. 1[2-氰-3,12-二氧齐烷-1,9(11)-二烯-28-油基]咪唑诱导人内皮细胞保护的时间过程表达分析。
Pub Date : 2017-04-07 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017701106
James A Bynum, Xinyu Wang, Salomon A Stavchansky, Phillip D Bowman

1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a synthetic derivative of oleanolic acid that exhibits antioxidant and anti-inflammatory activity in several animal and in vitro models, has been shown to be beneficial if given after injury. Although induction of heme oxygenase 1 appears to be a major effector of cytoprotection, the mechanism by which the overall effect is mediated is largely unknown. This study evaluated temporal gene expression profiles to better characterize the early transcriptional events and their relationship to the dynamics of the cytoprotective response in human umbilical vein endothelial cells (HUVEC) to CDDO-Im. Time-course gene expression profiling was performed on HUVEC treated with CDDO-Im for 0.5, 1, 3, 6, and 24 hours. More than 10 000 genes were statistically altered in their expression in at least 1 time point across the time course. Large alterations in immediate-early gene expression were readily detectable within 0.5 hour after administration of CDDO-Im.

1[2-氰-3,12-二氧齐墩酸-1,9(11)-二氧齐墩酸-28-油基]咪唑(CDDO-Im)是齐墩果酸的合成衍生物,在几种动物和体外模型中显示出抗氧化和抗炎活性,已被证明在损伤后给予有益。虽然血红素加氧酶1的诱导似乎是细胞保护的主要效应,但其整体效应的介导机制在很大程度上是未知的。本研究评估了时间基因表达谱,以更好地表征人类脐静脉内皮细胞(HUVEC)对CDDO-Im的早期转录事件及其与细胞保护反应动力学的关系。用CDDO-Im处理HUVEC 0.5、1、3、6和24小时,进行时间过程基因表达谱分析。在整个时间过程中,至少有1万个基因的表达在统计上发生了改变。在给药后0.5小时内,立即早期基因表达的大变化很容易检测到。
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引用次数: 3
Use of Biomedical Ontologies for Integration of Biological Knowledge for Learning and Prediction of Adverse Drug Reactions. 利用生物医学本体整合生物知识,以学习和预测药物不良反应。
Pub Date : 2017-03-15 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017696075
Shadia Zaman, Sirarat Sarntivijai, Darrell R Abernethy

Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases. The integration process is accommodated by biomedical ontologies, a set of standardized vocabularies that define terms and logical relationships between them in each vocabulary. We describe a few programs that have used ontologies to address biomedical questions. The PredicTox effort is leveraging the experience gathered from these early initiatives to develop an infrastructure that allows evaluation of the hypothesis that having a mechanistic understanding underlying adverse drug reactions will improve the capacity to understand drug-induced clinical adverse drug reactions.

药物毒性是导致患者发病和死亡的主要公共卫生问题。为了解决这个问题,美国食品和药物管理局正在开展PredicTox计划,这是一个关于酪氨酸激酶抑制剂的试点研究项目,旨在建立药物毒性的机制和预测模型。该项目涉及整合制药公司开发项目中临床前研究和临床试验期间获得的数据,这些数据已同意放入公共领域,并公开提供生物、药理学和化学数据库。生物医学本体是一组标准化词汇表,用于定义术语和每个词汇表中术语之间的逻辑关系。我们描述了一些使用本体来解决生物医学问题的程序。PredicTox项目正在利用从这些早期倡议中收集的经验来开发一个基础设施,该基础设施允许对假设进行评估,即对药物不良反应的机制了解将提高了解药物引起的临床药物不良反应的能力。
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引用次数: 14
Graphical Modeling Meets Systems Pharmacology. 图形建模满足系统药理学。
Pub Date : 2017-03-10 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017691937
Rosario Lombardo, Corrado Priami

A main source of failures in systems projects (including systems pharmacology) is poor communication level and different expectations among the stakeholders. A common and not ambiguous language that is naturally comprehensible by all the involved players is a boost to success. We present bStyle, a modeling tool that adopts a graphical language close enough to cartoons to be a common media to exchange ideas and data and that it is at the same time formal enough to enable modeling, analysis, and dynamic simulations of a system. Data analysis and simulation integrated in the same application are fundamental to understand the mechanisms of actions of drugs: a core aspect of systems pharmacology.

系统项目(包括系统药理学)失败的主要原因是沟通水平差和涉众之间的不同期望。所有参与者都能自然理解的通用且不模棱两可的语言有助于推动成功。我们介绍了bStyle,这是一种建模工具,它采用了一种与漫画非常接近的图形语言,作为交换思想和数据的通用媒体,同时它也足够正式,可以对系统进行建模、分析和动态模拟。在同一应用程序中集成数据分析和模拟是理解药物作用机制的基础:系统药理学的核心方面。
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引用次数: 4
Identifying Cell Type-Specific Transcription Factors by Integrating ChIP-seq and eQTL Data–Application to Monocyte Gene Regulation 整合ChIP-seq和eQTL数据鉴定细胞类型特异性转录因子-在单核细胞基因调控中的应用
Pub Date : 2016-12-13 DOI: 10.4137/GRSB.S40768
Mudra Choudhury, S. Ramsey
We describe a novel computational approach to identify transcription factors (TFs) that are candidate regulators in a human cell type of interest. Our approach involves integrating cell type-specific expression quantitative trait locus (eQTL) data and TF data from chromatin immunoprecipitation-to-tag-sequencing (ChIP-seq) experiments in cell lines. To test the method, we used eQTL data from human monocytes in order to screen for TFs. Using a list of known monocyte-regulating TFs, we tested the hypothesis that the binding sites of cell type-specific TF regulators would be concentrated in the vicinity of monocyte eQTLs. For each of 397 ChIP-seq data sets, we obtained an enrichment ratio for the number of ChIP-seq peaks that are located within monocyte eQTLs. We ranked ChIP-seq data sets according to their statistical significances for eQTL overlap, and from this ranking, we observed that monocyte-regulating TFs are more highly ranked than would be expected by chance. We identified 27 TFs that had significant monocyte enrichment scores and mapped them into a protein interaction network. Our analysis uncovered two novel candidate monocyte-regulating TFs, BCLAF1 and SIN3A. Our approach is an efficient method to identify candidate TFs that can be used for any cell/tissue type for which eQTL data are available.
我们描述了一种新的计算方法来识别转录因子(TFs),这些转录因子是感兴趣的人类细胞类型的候选调节因子。我们的方法包括整合细胞系中染色质免疫沉淀-标签测序(ChIP-seq)实验的细胞类型特异性表达定量性状位点(eQTL)数据和TF数据。为了验证该方法,我们使用了来自人单核细胞的eQTL数据来筛选tf。使用已知的单核细胞调节TF列表,我们验证了细胞类型特异性TF调节因子的结合位点将集中在单核细胞eqtl附近的假设。对于397个ChIP-seq数据集中的每一个,我们获得了位于单核细胞eqtl内的ChIP-seq峰数量的富集比。我们根据其eQTL重叠的统计意义对ChIP-seq数据集进行排名,从这个排名中,我们观察到单核细胞调节tf的排名比偶然预期的要高。我们确定了27个具有显著单核细胞富集分数的tf,并将它们映射到蛋白质相互作用网络中。我们的分析发现了两个新的候选单核细胞调节tf, BCLAF1和SIN3A。我们的方法是一种有效的方法来鉴定候选tf,可用于任何细胞/组织类型的eQTL数据可用。
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引用次数: 3
期刊
Gene regulation and systems biology
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