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Correction to: Regulation of TrkB receptor translocation to lipid rafts by adenosine A2A receptors and its functional implications for BDNF-induced regulation of synaptic plasticity. 更正:腺苷 A2A 受体对 TrkB 受体向脂质筏转运的调控及其对 BDNF 诱导的突触可塑性调控的功能性影响。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-01 DOI: 10.1007/s11302-024-10011-4
Natália Assaife-Lopes, Vasco C Sousa, Daniela B Pereira, Joaquim A Ribeiro, Ana M Sebastião
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引用次数: 0
ENTPD1 (CD39) and NT5E (CD73) expression in human glioblastoma: an in silico analysis. ENTPD1(CD39)和 NT5E(CD73)在人类胶质母细胞瘤中的表达:一项硅学分析。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-01 Epub Date: 2023-07-04 DOI: 10.1007/s11302-023-09951-0
Elizandra Braganhol, Guilherme Pamplona Bueno de Andrade, Guilherme Tomasi Santos, Marco Antônio Stefani

Glioblastoma (GB) is the most common primary brain tumor in adults and carries a dismal prognosis, despite the best available treatment. The 2021 WHO Classification of CNS tumors incorporated molecular profiling to better define the characteristics and prognosis of tumor types and subtypes. These recent advances in diagnosis have not yet resulted in breakthrough therapies capable of shifting the treatment paradigm. NT5E/CD73 is a cell surface enzyme that participates in a complex purinergic pathway in synergy with ENTPD1/CD39 producing extracellular adenosine (ADO) from ATP. ADO promotes tumor progression by inducing immunosuppression, stimulating adhesion, invasion, and angiogenesis. In this study, we performed an in silico analysis of 156 human glioblastoma samples in an unexplored public database to investigate the transcriptional levels of NT5E and ENTPD1. The analysis revealed a significant increase in transcription levels of the genes under study in GB samples versus non-tumor brain tissue samples, in concordance with previous studies. High transcriptional levels of NT5E or ENTPD1 were independently related to a decrease in overall survival (p = 5.4e-04; 1.1e-05), irrespective of the IDH mutation status. NT5E transcriptional levels were significantly higher in GB IDH wild-type patients compared to GB IDH-mutant; however, ENTPD1 levels showed no significant difference, p ≤ 0.001. This in silico study indicates the need for a deeper understanding of the purinergic pathway relation to GB development, also inspiring future population studies that could explore ENTPD1 and NT5E not only as prognostic markers but also as potential therapeutic targets.

胶质母细胞瘤(GB)是成人中最常见的原发性脑肿瘤,尽管有最好的治疗方法,但预后很差。2021 年世界卫生组织中枢神经系统肿瘤分类纳入了分子图谱分析,以更好地界定肿瘤类型和亚型的特征和预后。最近在诊断方面取得的这些进展尚未带来能够改变治疗模式的突破性疗法。NT5E/CD73 是一种细胞表面酶,与 ENTPD1/CD39 协同参与复杂的嘌呤能途径,从 ATP 生成细胞外腺苷 (ADO)。ADO 通过诱导免疫抑制、刺激粘附、侵袭和血管生成来促进肿瘤进展。在这项研究中,我们对未开发的公共数据库中的 156 个人类胶质母细胞瘤样本进行了硅分析,以研究 NT5E 和 ENTPD1 的转录水平。分析结果显示,与非肿瘤脑组织样本相比,GB样本中研究基因的转录水平明显升高,这与之前的研究结果一致。无论IDH突变状态如何,NT5E或ENTPD1的高转录水平都与总生存率的下降独立相关(p = 5.4e-04; 1.1e-05)。GB IDH野生型患者的NT5E转录水平明显高于GB IDH突变型患者;然而,ENTPD1水平没有明显差异,p ≤ 0.001。这项硅学研究表明,需要更深入地了解嘌呤能通路与 GB 发展的关系,这也启发了未来的人群研究,不仅可以将 ENTPD1 和 NT5E 作为预后标志物,还可以将其作为潜在的治疗靶点。
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引用次数: 0
Correction to: A1R-A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes. 更正:与 Gs 和 Gi/0 蛋白耦合的 A1R-A2AR 异构体调节 GABA 向星形胶质细胞的转运
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-01 DOI: 10.1007/s11302-024-10012-3
Sofia Cristóvão-Ferreira, Gemma Navarro, Marc Brugarolas, Kamil Pérez-Capote, Sandra H Vaz, Giorgia Fattorini, Fiorenzo Conti, Carmen Lluis, Joaquim A Ribeiro, Peter J McCormick, Vicent Casadó, Rafael Franco, Ana M Sebastião
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引用次数: 0
ADP as a novel stimulus for NLRP3-inflammasome activation in mice fails to translate to humans. ADP 作为激活小鼠 NLRP3-炎症小体的一种新型刺激物未能转化为人类的刺激物。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-01 Epub Date: 2023-07-06 DOI: 10.1007/s11302-023-09953-y
Julius Wissemann, Adrian Heidenreich, Helene Zimmermann, Juliane Engelmann, Jasper Jansen, Dymphie Suchanek, Dirk Westermann, Dennis Wolf, Peter Stachon, Julian Merz

The NLRP3-inflammasome is a cytosolic multiprotein complex that triggers an inflammatory response to certain danger signals. Recently adenosine diphosphate (ADP) was found to activate the NLRP3-inflammasome in murine macrophages via the P2Y1 receptor. Blockade of this signaling pathway reduced disease severity in a murine colitis-model. However, the role of the ADP/P2Y1-axis has not yet been studied in humans. This present study confirmed ADP-dependent NLRP3-inflammasome activation in murine macrophages, but found no evidence for a role of ADP in inflammasome activation in humans. We investigated the THP1 cell line as well as primary monocytes and further looked at macrophages. Although all cells express the three human ADP-receptors P2Y1, P2Y12 and P2Y13, independent of priming, neither increased ASC-speck formation could be detected with flow cytometry nor additional IL-1β release be found in the culture supernatant of ADP stimulated cells. We now show for the first time that the responsiveness of monocytes and macrophages to ADP as well as the regulation of its purinergic receptors is very much dependent on the species. Therefore the signaling pathway found to contribute to colitis in mice is likely not applicable to humans.

NLRP3-炎症小体是一种细胞膜多蛋白复合物,可触发对某些危险信号的炎症反应。最近发现,二磷酸腺苷(ADP)可通过 P2Y1 受体激活小鼠巨噬细胞中的 NLRP3-炎症体。在小鼠结肠炎模型中,阻断这一信号通路可减轻疾病的严重程度。然而,ADP/P2Y1 轴在人体中的作用尚未得到研究。本研究证实了小鼠巨噬细胞中依赖 ADP 的 NLRP3-炎症小体活化,但没有发现 ADP 在人类炎症小体活化中发挥作用的证据。我们研究了 THP1 细胞系和原代单核细胞,并进一步研究了巨噬细胞。虽然所有细胞都表达了三种人类 ADP 受体 P2Y1、P2Y12 和 P2Y13,但与引物无关,流式细胞术既不能检测到 ASC 斑形成的增加,也不能在 ADP 刺激细胞的培养上清液中发现 IL-1β 的额外释放。我们现在首次证明,单核细胞和巨噬细胞对 ADP 的反应性及其嘌呤能受体的调节在很大程度上取决于物种。因此,在小鼠体内发现的导致结肠炎的信号通路很可能不适用于人类。
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引用次数: 0
Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived astrocytes. ATP 门控 P2X7 受体在人 iPSC 衍生星形胶质细胞中的功能表达。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-01 Epub Date: 2023-07-15 DOI: 10.1007/s11302-023-09957-8
Jaideep Kesavan, Orla Watters, Laura de Diego-Garcia, Aida Menéndez Méndez, Mariana Alves, Klaus Dinkel, Michael Hamacher, Jochen H M Prehn, David C Henshall, Tobias Engel

Activation of the ATP-gated P2X7 receptor (P2X7R), implicated in numerous diseases of the brain, can trigger diverse responses such as the release of pro-inflammatory cytokines, modulation of neurotransmission, cell proliferation or cell death. However, despite the known species-specific differences in its pharmacological properties, to date, most functional studies on P2X7R responses have been analyzed in cells from rodents or immortalised cell lines. To assess the endogenous and functional expression of P2X7Rs in human astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into GFAP and S100 β-expressing astrocytes. Immunostaining revealed prominent punctate P2X7R staining. P2X7R protein expression was also confirmed by Western blot. Importantly, stimulation with the potent non-selective P2X7R agonist 2',3'-O-(benzoyl-4-benzoyl)-adenosine 5'- triphosphate (BzATP) or endogenous agonist ATP induced robust calcium rises in hiPSC-derived astrocytes which were blocked by the selective P2X7R antagonists AFC-5128 or JNJ-47965567. Our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived astrocytes and support their in vitro utility in investigating the role of the P2X7R and drug screening in disorders of the central nervous system (CNS).

ATP 门控 P2X7 受体(P2X7R)与多种脑部疾病有关,激活 P2X7R 可引发多种反应,如释放促炎细胞因子、调节神经传递、细胞增殖或细胞死亡。然而,尽管其药理特性存在已知的物种特异性差异,但迄今为止,有关 P2X7R 反应的大多数功能研究都是在啮齿动物细胞或永生细胞系中进行分析的。为了评估 P2X7R 在人类星形胶质细胞中的内源性和功能性表达,我们将人类诱导多能干细胞(hiPSCs)分化为表达 GFAP 和 S100 β 的星形胶质细胞。免疫染色显示了明显的点状P2X7R染色。P2X7R 蛋白表达也得到了 Western 印迹的证实。重要的是,强效非选择性 P2X7R 激动剂 2',3'-O-(苯甲酰基-4-苯甲酰基)-腺苷 5'- 三磷酸(BzATP)或内源性激动剂 ATP 可诱导 hiPSC 衍生星形胶质细胞中的钙离子强劲上升,而选择性 P2X7R 拮抗剂 AFC-5128 或 JNJ-47965567 可阻断这种上升。我们的研究结果为 P2X7R 在 hiPSC 衍生的星形胶质细胞中的功能表达提供了证据,并支持其在体外研究 P2X7R 的作用和中枢神经系统(CNS)疾病的药物筛选中的实用性。
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引用次数: 0
Potential role of the P2X7 receptor in the proliferation of human diffused large B-cell lymphoma. P2X7 受体在人类弥漫大 B 细胞淋巴瘤增殖中的潜在作用。
IF 3 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-06-01 Epub Date: 2023-05-24 DOI: 10.1007/s11302-023-09947-w
Xiao Yang, Yuanyuan Ji, Lin Mei, Wenwen Jing, Xin Yang, Qianwei Liu

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin lymphoma. 60-70% of patients are curable with current chemoimmunotherapy, whereas the rest are refractory or relapsed. Understanding of the interaction between DLBCL cells and tumor microenvironment raises the hope of improving overall survival of DLBCL patients. P2X7, a member of purinergic receptors P2X family, is activated by extracellular ATP and subsequently promotes the progression of various malignancies. However, its role in DLBCL has not been elucidated. In this study, the expression level of P2RX7 in DLBCL patients and cell lines was analyzed. MTS assay and EdU incorporation assay were carried out to study the effect of activated/inhibited P2X7 signaling on the proliferation of DLBCL cells. Bulk RNAseq was performed to explore potential mechanism. The results demonstrated high level expression of P2RX7 in DLBCL patients, typically in patients with relapse DLBCL. 2'(3')-O-(4-benzoylbenzoyl) adenosine 5-triphosphate (Bz-ATP), an agonist of P2X7, significantly accelerated the proliferation of DLBCL cells, whereas delayed proliferation was detected when administrated with antagonist A740003. Furthermore, a urea cycle enzyme named CPS1 (carbamoyl phosphate synthase 1), which up-regulated in P2X7-activated DLBCL cells while down-regulated in P2X7-inhibited group, was demonstrated to involve in such process. Our study reveals the role of P2X7 in the proliferation of DLBCL cells and implies that P2X7 may serve as a potential molecular target for the treatment of DLBCL.

弥漫大B细胞淋巴瘤(DLBCL)是侵袭性非霍奇金淋巴瘤中最常见的亚型。60%-70%的患者可通过目前的化学免疫疗法治愈,而其他患者则是难治或复发。了解 DLBCL 细胞与肿瘤微环境之间的相互作用为提高 DLBCL 患者的总体生存率带来了希望。P2X7是嘌呤能受体P2X家族的成员,它被细胞外ATP激活,随后促进各种恶性肿瘤的进展。然而,它在DLBCL中的作用尚未阐明。本研究分析了 P2RX7 在 DLBCL 患者和细胞系中的表达水平。采用 MTS 检测法和 EdU 结合检测法研究 P2X7 信号激活/抑制对 DLBCL 细胞增殖的影响。为了探索潜在的机制,还进行了大量的 RNAseq 研究。结果表明,P2RX7在DLBCL患者中高水平表达,尤其是在复发的DLBCL患者中。P2X7的激动剂2'(3')-O-(4-苯甲酰基苯甲酰基)腺苷-5-三磷酸(Bz-ATP)能显著加速DLBCL细胞的增殖,而使用拮抗剂A740003则会导致增殖延迟。此外,一种名为 CPS1(氨基甲酰磷酸合成酶 1)的尿素循环酶被证实参与了上述过程,该酶在 P2X7 激活的 DLBCL 细胞中上调,而在 P2X7 抑制组中下调。我们的研究揭示了 P2X7 在 DLBCL 细胞增殖中的作用,并暗示 P2X7 可作为治疗 DLBCL 的潜在分子靶点。
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引用次数: 0
Caffeine: a potential mechanism for anti-obesity. 咖啡因:抗肥胖的潜在机制。
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-28 DOI: 10.1007/s11302-024-10022-1
Meng Wang, Wei Guo, Jiang-Fan Chen

Obesity refers to the excessive accumulation of fat caused by a long-term imbalance between energy intake (EI) and energy expenditure (EE). Over recent years, obesity has become a major public health challenge. Caffeine is a natural product that has been demonstrated to exert anti-obesity effects; however, the mechanisms responsible for the effect of caffeine on weight loss have yet to be fully elucidated. Most obesity-related deaths are due to cardiovascular disease. Recent research has demonstrated that caffeine can reduce the risk of death from cardiovascular disease; thus, it can be hypothesized that caffeine may represent a new therapeutic agent for weight loss. In this review, we synthesize data arising from clinical and animal studies over the last decade and discuss the potential mechanisms by which caffeine may induce weight loss, focusing particularly on increasing energy consumption, suppressing appetite, altering lipid metabolism, and influencing the gut microbiota. Finally, we summarize the major challenges associated with caffeine and anti-obesity research and highlight possible directions for future research and development.

肥胖症是指由于能量摄入(EI)和能量消耗(EE)长期失衡而导致的脂肪过度堆积。近年来,肥胖已成为一项重大的公共卫生挑战。咖啡因是一种天然产品,已被证实具有抗肥胖作用;然而,咖啡因对减肥作用的机制尚未完全阐明。大多数与肥胖有关的死亡都是由心血管疾病造成的。最近的研究表明,咖啡因可以降低心血管疾病导致死亡的风险;因此,可以假设咖啡因可能是一种新的减肥治疗药物。在这篇综述中,我们综合了过去十年中临床和动物研究的数据,讨论了咖啡因诱导减肥的潜在机制,尤其侧重于增加能量消耗、抑制食欲、改变脂质代谢和影响肠道微生物群。最后,我们总结了咖啡因和抗肥胖研究面临的主要挑战,并强调了未来研究和发展的可能方向。
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引用次数: 0
Curcumin modulates purinergic signaling and inflammatory response in cutaneous metastatic melanoma cells. 姜黄素调节皮肤转移性黑色素瘤细胞的嘌呤能信号转导和炎症反应
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-27 DOI: 10.1007/s11302-024-10023-0
Daiane Manica, Gilnei Bruno da Silva, Rafael Antônio Narzetti, Paula Dallagnoll, Alana Patrícia da Silva, Filomena Marafon, Joana Cassol, Letícia de Souza Matias, Ariane Zamoner, Sarah Franco Vieira de Oliveira Maciel, Marcelo Moreno, Margarete Dulce Bagatini

Cutaneous melanoma (CM) poses a therapeutic challenge due to its aggressive nature and often limited response to conventional treatments. Exploring novel therapeutic targets is essential, and natural compounds have emerged as potential candidates. This study aimed to elucidate the impact of curcumin, a natural compound known for its anti-inflammatory, antioxidant, and anti-tumor properties, on metastatic melanoma cells, focusing on the purinergic system and immune responses. Human melanoma cell line SK-Mel-28 were exposed to different curcumin concentrations for either 6 or 24 h, after which we assessed components related to the purinergic system and the inflammatory cascade. Using RT-qPCR, we assessed the gene expression of CD39 and CD73 ectonucleotidases, as well as adenosine deaminase (ADA). Curcumin effectively downregulated CD39, CD73, and ADA gene expression. Flow cytometry analysis revealed that curcumin significantly reduced CD39 and CD73 protein expression at specific concentrations. Moreover, the A2A receptor's protein expression decreased across all concentrations. Enzymatic activity assays demonstrated that curcumin modulated CD39, CD73, and ADA activities, with effects dependent on concentration and duration of treatment. Extracellular ATP levels increased after 24 h of curcumin treatment, emphasizing its role in modulating hydrolytic activity. Curcumin also displayed anti-inflammatory properties by reducing NLRP3 gene expression and impacting the levels of key inflammatory cytokines. In conclusion, this study unveils the potential of curcumin as a promising adjuvant in CM treatment. Curcumin modulates the expression and activity of crucial components of the purinergic system and exhibits anti-inflammatory effects, indicating its potential therapeutic role in combating CM. These findings underscore curcumin's promise and warrant further investigation in preclinical and clinical settings for melanoma management.

皮肤黑色素瘤(CM)具有侵袭性,对传统疗法的反应往往有限,因此给治疗带来了挑战。探索新的治疗靶点至关重要,而天然化合物已成为潜在的候选靶点。姜黄素是一种以抗炎、抗氧化和抗肿瘤特性著称的天然化合物,本研究旨在阐明姜黄素对转移性黑色素瘤细胞的影响,重点关注嘌呤能系统和免疫反应。将人类黑色素瘤细胞株 SK-Mel-28 暴露于不同浓度的姜黄素 6 或 24 小时后,我们评估了与嘌呤能系统和炎症级联相关的成分。我们使用 RT-qPCR 评估了 CD39 和 CD73 外切核苷酸酶以及腺苷脱氨酶(ADA)的基因表达。姜黄素能有效下调 CD39、CD73 和 ADA 基因的表达。流式细胞术分析表明,姜黄素在特定浓度下可显著降低 CD39 和 CD73 蛋白表达。此外,A2A受体的蛋白表达在所有浓度下都有所下降。酶活性测定表明,姜黄素能调节 CD39、CD73 和 ADA 的活性,其效果取决于浓度和治疗时间。姜黄素处理 24 小时后,细胞外 ATP 水平升高,强调了姜黄素在调节水解活性方面的作用。姜黄素还通过减少 NLRP3 基因的表达和影响关键炎症细胞因子的水平而显示出抗炎特性。总之,本研究揭示了姜黄素作为一种有前景的辅助药物治疗中风的潜力。姜黄素能调节嘌呤能系统关键成分的表达和活性,并具有抗炎作用,这表明姜黄素具有抗击 CM 的潜在治疗作用。这些研究结果突显了姜黄素的前景,值得在临床前和临床环境中进一步研究它对黑色素瘤的治疗作用。
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引用次数: 0
ATP release mediated by pannexin-3 is required for plasma cell survival via P2X4 receptors in bone marrow. 骨髓中浆细胞通过 P2X4 受体存活需要由 pannexin-3 介导的 ATP 释放。
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-21 DOI: 10.1007/s11302-024-10024-z
Sonia Paz-López
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引用次数: 0
Functional role of P2X7 purinergic receptor in cancer and cancer-related pain. P2X7 嘌呤能受体在癌症和癌症相关疼痛中的功能作用
IF 3.5 4区 医学 Q2 NEUROSCIENCES Pub Date : 2024-05-21 DOI: 10.1007/s11302-024-10019-w
Yong-Sheng Xu, Jun Xiang, Si-Jian Lin

Numerous studies have revealed that the ATP-gated ion channel purinergic 2X7 receptor (P2X7R) plays an important role in tumor progression and the pathogenesis of cancer pain. P2X7R requires activation by extracellular ATP to perform its regulatory role functions. During tumor development or cancer-induced pain, ATP is released from tumor cells or other cells in the tumor microenvironment (such as tumor-associated immune cells), which activates P2X7R, opens ion channels on the cell membrane, affects intracellular molecular metabolism, and regulates the activity of tumor cells. Furthermore, peripheral organs and receptors can be damaged during tumor progression, and P2X7R expression in nerve cells (such as microglia) is significantly upregulated, enhancing sensory afferent information, sensitizing the central nervous system, and inducing or exacerbating pain. These findings reveal that the ATP-P2X7R signaling axis plays a key regulatory role in the pathogenesis of tumors and cancer pain and also has a therapeutic role. Accordingly, in this study, we explored the role of P2X7R in tumors and cancer pain, discussed the pharmacological properties of inhibiting P2X7R activity (such as the use of antagonists) or blocking its expression in the treatment of tumor and cancer pain, and provided an important evidence for the treatment of both in the future.

大量研究表明,ATP 门控离子通道嘌呤能 2X7 受体(P2X7R)在肿瘤进展和癌痛发病机制中发挥着重要作用。P2X7R 需要细胞外 ATP 的激活才能发挥其调节作用。在肿瘤发生发展或癌症诱发疼痛的过程中,肿瘤细胞或肿瘤微环境中的其他细胞(如肿瘤相关免疫细胞)会释放出 ATP,从而激活 P2X7R,打开细胞膜上的离子通道,影响细胞内分子代谢,调节肿瘤细胞的活性。此外,在肿瘤进展过程中,外周器官和受体会受到损伤,神经细胞(如小胶质细胞)中的 P2X7R 表达会显著上调,从而增强感觉传入信息,使中枢神经系统敏感化,诱发或加剧疼痛。这些发现揭示了 ATP-P2X7R 信号轴在肿瘤和癌痛的发病机制中起着关键的调控作用,同时也具有治疗作用。因此,在本研究中,我们探讨了P2X7R在肿瘤和癌痛中的作用,讨论了抑制P2X7R活性(如使用拮抗剂)或阻断其表达在治疗肿瘤和癌痛中的药理特性,为今后治疗这两种疾病提供了重要依据。
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引用次数: 0
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Purinergic Signalling
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