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Exploring the Resistance Mechanisms of Distal D835V Mutation in FLT3 to Inhibitors

Zhiwei Wang, Baichun Hu, Yu An, Jian Wang, Imtaiyaz Hassan
2022 Oxidative Medicine and Cellular Longevity  
Objective. FMS-like tyrosine kinase 3 (FLT3) is an attractive therapeutic target in acute myeloid leukemia. Unfortunately, secondary FLT3 mutations that developed resistance to inhibitors have become a severe problem. Specifically, ASP-835 (D835F/H/V/Y) mutant within the activation loop of FLT3 is the most commonly encountered drug-resistant and observed secondary FLT3 mutations. In this study, we carried out a set of computational approaches to explore how this mutation influenced the
more » ... ion and dynamics of DFG motif in a manner altered inhibitors' susceptibility. Methods. Molecular dynamics (MD) simulation, dynamic cross-correlation (DCC) analysis, surface area (SASA), binding free energy (MM-GBSA), and structural analysis were used to compare the severe and minor D835V mutation-induced impact to sorafenib and crenolanib, respectively. Results. The A-loop of the FLT3 protein may experience conformational change in the presence of the resistant mutation, which were mainly positioned at PHE-830. The protein-inhibitor interactions displayed that the motions of PHE-830 influenced that of sorafenib, but not to crenolanib. Conclusions. These findings indicated that the structural impact brought by D835V mutation should be considered in designing novel drugs to overcome resistance to FLT3-D835V.
doi:10.1155/2022/3720026 pmid:35387260 pmcid:PMC8979743 fatcat:62rqgqzjqfetnoir3ituoslnwe

Compound Mutations of the COL4A3 including a Novel Allele Identified in a Patient with Alport Syndrome

Zhendong Wang, Baichun Jiang, Shiqi Jin, Zhao Hu, Guangyi Liu, Yoshiyuki Morishita
2020 BioMed Research International  
Authors' Contributions Zhendong Wang and Baichun Jiang contributed equally to this work.  ... 
doi:10.1155/2020/1626378 pmid:33524082 pmcid:PMC7673930 fatcat:mmumn3wugvg27l3plhxkurgibq

CUL4B contributes to cancer stemness by repressing tumor suppressor miR34a in colorectal cancer

Yanjun Li, Huili Hu, Yuxing Wang, Yujia Fan, Yang Yang, Beibei Guo, Xueyong Xie, Jiabei Lian, Baichun Jiang, Bo Han, Yanlei Wang, Changshun Shao (+1 others)
2020 Oncogenesis  
Given that colorectal cancer stem cells (CCSCs) play key roles in the tumor dormancy, metastasis, and relapse, targeting CCSCs is a promising strategy in cancer therapy. Here, we aimed to identify the new regulators of CCSCs and found that Cullin 4B (CUL4B), which possesses oncogenic properties in multiple solid tumors, drives the development and metastasis of colon cancer by sustaining cancer stem-like features. Elevated expression of CUL4B was confirmed in colon tumors and was associated with
more » ... poor overall survival. Inhibition of CUL4B in cancer cell lines and patient-derived tumor organoids led to reduced sphere formation, proliferation and metastasis capacity. Mechanistically, CUL4B coordinates with PRC2 complex to repress miR34a expression, thus upregulates oncogenes including MYCN and NOTCH1, which are targeted by miR34a. Furthermore, we found that elevated CUL4B expression is associated with miR34a downregulation and upregulation of miR34a target genes in colon cancer specimens. Collectively, our findings demonstrate that CUL4B functions to repress miR34a in maintaining cancer stemness in CRC and provides a potential therapeutic target.
doi:10.1038/s41389-020-0206-3 pmid:32054830 fatcat:eyyiajogh5hr3cnkjgp7mijgku

Zebrafish cul4a, but not cul4b, modulates cardiac and forelimb development by upregulating tbx5a expression

Xiaohan Zhao, Baichun Jiang, Huili Hu, Fei Mao, Jun Mi, Zhaohui Li, Qiji Liu, Changshun Shao, Yaoqin Gong
2014 Human Molecular Genetics  
CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disrupted in mammals. We here investigated the roles of cul4a and cul4b during zebrafish embryogenesis by using the morpholino knockdown approach. We found that cul4a is essential for
more » ... rdiac development as well as for pectoral fin development. Whereas cul4a morphants appeared to be unperturbed in chamber specification, they failed to undergo heart looping. The failures in heart looping and pectoral fin formation in cul4a morphants were accompanied by greatly reduced proliferation of cardiac cells and pectoral fin-forming cells. We demonstrated that tbx5a, a transcription factor essential for heart and limb development, is transcriptionally upregulated by cul4a and mediates the function of cul4a in cardiac and pectoral fin development. In contrast to the critical importance of cul4a, cul4b appeared to be dispensable for zebrafish development and was incapable of compensating for the loss of cul4a. This work provides the first demonstration of an essential role of cul4a, but not cul4b, in cardiac development and in the regulation of tbx5a in zebrafish. These findings justify exploring the functional role of CUL4A in human cardiac development.
doi:10.1093/hmg/ddu503 pmid:25274780 fatcat:q5nlidvbqjbhhlo5kogaplvada

Computational investigation reveals Picrasidine C as selective PPARα lead: binding pattern, selectivity mechanism and ADME/tox profile

Fangfei Li, Hanxun Wang, Ying Wang, Shasha Feng, Baichun Hu, Xiangyu Zhang, Jian Wang, Wei Li, Maosheng Cheng
2019 Figshare  
Natural products and their derivatives have been recognized as an important source of therapeutic agents for many years. Previously we isolated a dimeric β-carboline-type alkaloid Picrasidine C from the root of Picrasma quassioides as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonist. In order to modify this natural product for better affinity and druggability, we investigated a series of properties exhibited by Picrasidine C, such as its binding mode with PPARα,
more » ... selectivity mechanism over PPARγ, as well as ADME/Tox profile through computational methods including sequence alignment, molecular docking, pharmacophore modeling and molecular dynamics simulations. The detailed information of binding pattern and affinity for Picrasidine C elucidated here will be valuable for chemical modification. Besides, the steric hindrance of residue Phe363 in PPARγ pocket was speculated as the main isoform selectivity mechanism for Picrasidine C, which would be helpful for the design of selective derivatives. ADME/Tox prediction was conducted to avoid potential undesirable pharmacokinetic properties for reducing the risk of failure. Finally, novel skeletons were derived from lead compound by core hopping method, validated through molecular dynamic simulations and MM-GBSA calculation. In short, the information obtained from computational strategy would be valuable for us to find more potent, safe and selective PPARα agonists during structural optimization. HighlightsThe interactions between PPARα and Picrasidine C was thoroughly investigated by means of molecular docking, binding free energy calculation, molecular dynamics simulation.Selectivity mechanism between PPAR isoforms was analyzed with the aim to maintain or improve the selectivity of Picrasidine C depending on the difference between PPARα/γ cavities.The feasibility of Picrasidine C as a subtype-selective lead targeting PPARα was investigate to promote the further development of subtype-selective PPARα agonists.New analogs of Picrasidine C [...]
doi:10.6084/m9.figshare.11302316.v2 fatcat:xhue4efh2zhafpvvm5lmkwbtk4

CUL4B facilitates HBV replication by promoting HBx stabilization

Haixia Shan, Bo Wang, Xiaodong Zhang, Hui Song, Xi Li, Yongxin Zou, Baichun Jiang, Huili Hu, Hao Dou, Changshun Shao, Lifen Gao, Chunhong Ma (+3 others)
2021 Cancer Biology and Medicine  
Hepatitis B virus (HBV) infection is a major public health problem worldwide. However, the regulatory mechanisms underlying HBV replication remain unclear. Cullin 4B-RING ubiquitin E3 ligase (CRL4B) is involved in regulating diverse physiological and pathophysiological processes. In our study, we aimed to explain the role of CUL4B in HBV infection. Cul4b transgenic mice or conditional knockout mice, as well as liver cell lines with CUL4B overexpression or knockdown, were used to assess the role
more » ... of CUL4B in HBV replication. Immunoprecipitation assays and immunofluorescence staining were performed to study the interaction between CUL4B and HBx. Cycloheximide chase assays and in vivo ubiquitination assays were performed to evaluate the half-life and the ubiquitination status of HBx. The hydrodynamics-based hepatitis B model in Cul4b transgenic or conditional knockout mice indicated that CUL4B promoted HBV replication (P < 0.05). Moreover, the overexpression or knockdown system in human liver cell lines validated that CUL4B increased HBV replication in an HBx-dependent manner. Importantly, immunoprecipitation assays and immunofluorescence staining showed an interaction between CUL4B and HBx. Furthermore, CUL4B upregulated HBx protein levels by inhibiting HBx ubiquitination and proteasomal degradation (P < 0.05). Finally, a positive correlation between CUL4B expression and HBV pgRNA level was observed in liver tissues from HBV-positive patients and HBV transgenic mice. CUL4B enhances HBV replication by interacting with HBx and disrupting its ubiquitin-dependent proteasomal degradation. CUL4B may therefore be a potential target for anti-HBV therapy.
doi:10.20892/j.issn.2095-3941.2020.0468 pmid:33969670 pmcid:PMC8763003 fatcat:fewelsasorhajon6ctp7qczff4

Revealing the interaction modes of 5-HT2A receptor antagonists and the Structure-Based virtual screening from FDA and TCMNP database

Ying Wang, Johnson Joseph, Yinli Gao, Baichun Hu, Xiaohui Geng, Di Wu, Jian Wang, Fengjiao Zhang
2020 Figshare  
5-hydroxytryptamine 2A (5-HT2A) receptor is emerging as an important target for numerous psychoactive drugs due to its imperative roles in psychological diseases. In fact, multiple 5-HT2A receptor antagonists were developed to treat numerous psychiatric disorders, however, their clinical outcome was far from ideal probably due to a blurry information of the exact interaction modes between the receptor and its antagonists. Impressively, with a recent release of its crystal structure, we
more » ... analyzed the receptor-ligand interactions with Protein Contacts Atlas, structure-based pharmacophore models, and molecular dynamics (MD) simulations to sum up the chemical features for antagonists interacting with 5-HT2A receptor. Moreover, the molecular docking-based virtual screening was applied to discover potential 5-HT2A receptor antagonists from FDA and TCMNP databases. Intriguingly, after a systematic assessment of the docking scores, binding modes and free energies, as well as their MD simulations performances, three compounds in TCMNP database were highlighted to be potential 5-HT2A receptor antagonists. Fascinatedly, these three hits also exhibited highly binding affinities with dopamine D2 receptor (D2R) due to the similarity of the ligand binding pockets of the receptors, indicating them to be promising dual target molecules that are of great benefit for anti-psychotic-drug research and development. In addition, ADME/Tox predictions were conducted for a primary evaluation of their developing potential. Together, this study not only revealed the exact interaction modes between 5-HT2A receptor and its antagonists, which shed a light on a better access for developing its novel antagonists, but also provided promising dual D2 and 5-HT2A receptor antagonists. Communicated by Ramaswamy H. Sarma
doi:10.6084/m9.figshare.12301310.v2 fatcat:gyafm3i5avhlrdwwrxvhuzxuzm

CRL4B Catalyzes H2AK119 Monoubiquitination and Coordinates with PRC2 to Promote Tumorigenesis

Huili Hu, Yang Yang, Qinghong Ji, Wei Zhao, Baichun Jiang, Ruiqiong Liu, Jupeng Yuan, Qiao Liu, Xi Li, Yongxin Zou, Changshun Shao, Yongfeng Shang (+2 others)
2012 Cancer Cell  
We reported that Cullin4B-Ring E3 ligase complex (CRL4B) is physically associated with Polycomb-repressive complex 2 (PRC2). We showed that CRL4B possesses an intrinsic transcription repressive activity by promoting H2AK119 monoubiquitination. Ablation of Cul4b or depletion of CUL4B, the main component of CRL4B, resulted in loss of not only H2AK119 monoubiquitination but also H3K27 trimethylation, leading to derepression of target genes that are critically involved in cell growth and migration.
more » ... We demonstrated that CUL4B promotes cell proliferation, invasion, and tumorigenesis in vitro and in vivo and found that its expression is markedly upregulated in various human cancers. Our data indicate that CUL4B promotes tumorigenesis, supporting the pursuit of CUL4B as a target for cancer therapy. Cancer Cell CRL4B Catalyzes H2AK119ub1 and Promotes Tumorigenesis 782 Cancer Cell 22, 781-795, December 11, 2012 ª2012 Elsevier Inc.
doi:10.1016/j.ccr.2012.10.024 pmid:23238014 fatcat:smzfqq4menfa3ixbsk4lqz4t7e

Identification of Pyruvate Dehydrogenase E1 as a Potential Target against Magnaporthe oryzae through Experimental and Theoretical Investigation

Yuejuan Li, Baichun Hu, Zhibin Wang, Jianhua He, Yaoliang Zhang, Jian Wang, Lijie Guan
2021 International Journal of Molecular Sciences  
Magnaporthe oryzae (M. oryzae) is a typical cause of rice blast in agricultural production. Isobavachalcone (IBC), an active ingredient of Psoralea corylifolia L. extract, is an effective fungicide against rice blast. To determine the mechanism of IBC against M. oryzae, the effect of IBC on the metabolic pathway of M. oryzae was explored by transcriptome profiling. In M. oryzae, the expression of pyruvate dehydrogenase E1 (PDHE1), part of the tricarboxylic acid (TCA cycle), was significantly
more » ... reased in response to treatment with IBC, which was verified by qPCR and testing of enzyme activity. To further elucidate the interactions between IBC and PDHE1, the 3D structure model of the PDHE1 from M. oryzae was established based on homology modeling. The model was utilized to analyze the molecular interactions through molecular docking and molecular dynamics simulation, revealing that IBC has π-π stacking interactions with residue TYR139 and undergoes hydrogen bonding with residue ASP217 of PDHE1. Additionally, the nonpolar residues PHE111, MET174, ILE 187, VAL188, and MET250 form strong hydrophobic interactions with IBC. The above results reveal that PDHE1 is a potential target for antifungal agents, which will be of great significance for guiding the design of new fungicides. This research clarified the mechanism of IBC against M. oryzae at the molecular level, which will underpin further studies of the inhibitory mechanism of flavonoids and the discovery of new targets. It also provides theoretical guidance for the field application of IBC.
doi:10.3390/ijms22105163 pmid:34068366 fatcat:ceuk75biwffahf23rrcnsyiwyq

CUL4B promotes replication licensing by up-regulating the CDK2–CDC6 cascade

Yongxin Zou, Jun Mi, Wenxing Wang, Juanjuan Lu, Wei Zhao, Zhaojian Liu, Huili Hu, Yang Yang, Xiaoxing Gao, Baichun Jiang, Changshun Shao, Yaoqin Gong
2013 Journal of Cell Biology  
doi:10.1083/jcb.201206065 pmid:23479742 pmcid:PMC3601365 fatcat:o2iz7dzra5hpxcnlxqng4b5gbe

Computational insights into the binding pattern of mitochondrial calcium uniporter inhibitor through homology modeling, molecular dynamics simulation, binding free energy prediction and density functional theory calculation

Na Duan, Zisen Gao, Baichun Hu, Dandan Ge, Wei Li, Tong Ye, Xiaohui Geng, Xiaodong Li
2019 Figshare  
The mitochondrial calcium uniporter (MCU) is the critical protein of the inner mitochondrial membrane that is the primary mediator for calcium uptake into the mitochondrial matrix. Herein we built the optimal homology model of human MCU which was refined through all-atom molecular dynamics simulation. Then, the binding mode of known inhibitor was predicted through molecular docking method, along with molecular dynamics simulation and binding free energy calculation to verify the docking result
more » ... nd stability of the protein-inhibitor complex. Finally, density functional theory (DFT) calculation enhanced our understanding of the molecular interaction of MCU inhibitor. Our research would provide a deeper insight into the interactions between human MCU and its inhibitor, which boosts to develop novel therapy against MCU related disease. Communicated by Ramaswamy H. Sarma
doi:10.6084/m9.figshare.10745594 fatcat:mrhvw64ev5bjzbpqm7bzhg3hfi

Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma

Jun Mi, Yongxin Zou, Xiaohua Lin, Juanjuan Lu, Xiaochen liu, Hui Zhao, Xiang Ye, Huili Hu, Baichun Jiang, Bo Han, Changshun Shao, Yaoqin Gong
2017 Molecular Oncology  
The transwell migration assay was performed as previously described (Hu et al., 2012) .  ...  We previously reported that CUL4B could act in concert with PRC2 to repress target genes (Hu et al., 2012) .  ... 
doi:10.1002/1878-0261.12038 pmid:28164432 pmcid:PMC5527444 fatcat:iwnzl2z765bfta6gmwwinozpay

Bioremediation of Petroleum Hydrocarbons Using Acinetobacter sp. SCYY-5 Isolated from Contaminated Oil Sludge: Strategy and Effectiveness Study

Yiyun Cai, Runkai Wang, Pinhua Rao, Baichun Wu, Lili Yan, Lijiang Hu, Sangsook Park, Moonhee Ryu, Xiaoya Zhou
2021 International Journal of Environmental Research and Public Health  
Biodegradation has been considered as an ideal technique for total petroleum hydrocarbon (TPH) contamination, but its efficiency is limited by its application in the field. Herein, an original TPH-degrading strain, SCYY-5, was isolated from contaminated oil sludge and identified as Acinetobacter sp. by 16S rDNA sequence analysis. The biological function of the isolate was investigated by heavy metal tolerance, carbon, and nitrogen source and degradation tests. To enhance its biodegradation
more » ... iency, the response surface methodology (RSM) based on a function model was adopted to investigate and optimize the strategy of microbial and environmental variables for TPH removal. Furthermore, the performance of the system increased to 79.94% with the further addition of extra nutrients, suggesting that the RSM and added nutrients increased the activity of bacteria to meet the needs of the co-metabolism matrix during growth or degradation. These results verified that it is feasible to adopt the optimal strategy of combining bioremediation with RSM to improve the biodegradation efficiency, for contaminated oil sludge.
doi:10.3390/ijerph18020819 pmid:33477988 fatcat:rms5eoncfrhqvmnvzfmtcth4ia

Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain

Wei Zhao, Baichun Jiang, Huili Hu, Shuqian Zhang, Shuaishuai Lv, Jupeng Yuan, Yanyan Qian, Yongxin Zou, Xi Li, Hong Jiang, Fang Liu, Changshun Shao (+1 others)
2015 Human Molecular Genetics  
Astrocytes are the most abundant cell type in the mammalian brain and are important for the functions of the central nervous system. Glial fibrillary acidic protein (GFAP) is regarded as a hallmark of mature astrocytes, though some GFPA-positive cells may act as neural stem cells. Missense heterozygous mutations in GFAP cause Alexander disease that manifests leukodystrophy and intellectual disability. Here, we show that CUL4B, a scaffold protein that assembles E3 ubiquitin ligase, represses the
more » ... expression of GFAP in neural progenitor cells (NPCs) during brain development. Lack of Cul4b in NPCs in cultures led to increased generation of astrocytes, marked by GFAP and S100β. The GFAP+ cells were also found to be more abundant in the brains of nervous system-specific Cul4b knockout mice in vivo. Moreover, we demonstrated that the increased generation of GFAP+ cells from Cul4b-null NPCs was mediated by an upregulation of prostaglandin D2 synthase PTGDS. We showed that the increased GFAP expression can be attenuated by pharmacological inhibition of the PTGDS enzymatic activity or by shRNA-mediated knockdown of Ptgds. Importantly, exogenously added PTGDS could promote the generation of GFAP+ cells from wild-type NPCs. We further observed that Ptgds is targeted and repressed by the CUL4B/PRC2 complex. Together, our results demonstrate CUL4B as a negative regulator of GFAP expression during neural development. † Co-first authors.
doi:10.1093/hmg/ddv200 pmid:26025376 fatcat:3nxqz37xozc6rh7pmoayncrv3u

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Qing Li, Min Cui, Fan Yang, Na Li, Baichun Jiang, Zhen Yu, Daolai Zhang, Yijing Wang, Xibin Zhu, Huili Hu, Pei-Shan Li, Shang-Lei Ning (+14 others)
2017 Journal of Clinical Investigation  
Figure 1. CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A and B) Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per
more » ... oup; 4-7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. (D) Confirmation of pancreatic δ cell-specific CUL4B deficiency (Sst-Cre +/-Cul4b fl/Y ) through immunofluorescence. The colocalization of somatostatin (red) and CUL4B (green) in δ cells of WT mice was absent in Sst-Cre +/-Cul4b fl/Y mice. Scale bar: 100 μm. (E) Immunostaining for insulin (red) and somatostatin (green) in WT and Sst-Cre +/-Cul4b fl/Y mice. Scale bar: 50 μm. (F) Quantitative data for islet density, pancreatic δ cell number, and β cell mass. n = 6 mice per group; 4-10 random areas were selected from each section, and 12 sections were randomly selected from each mouse. (G) The fasting and fed blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice and their WT littermates. n = 8 mice per group. (H) Glucose tolerance test for Sst-Cre +/-Cul4b fl/Y mice and their WT littermates (n = 11-12). (I) Insulin tolerance test for Sst-Cre +/-Cul4b fl/Y mice and their WT littermates. Insulininduced decreases in blood glucose levels were significantly lower in Sst-Cre +/-Cul4b fl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9-11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA. Figure 2. Impaired glucose tolerance in Sst-Cre +/-Cul4b fl/Y mice is due to increased somatostatin paracrine signaling. (A and B) Plasma insulin levels (A) and somatostatin levels (B) of WT and Sst-Cre +/-Cul4b fl/Y mice in the fasted and fed states. n = 6-7 mice per group. (C and D) 1 mM, 5.5 mM, and 20 mM glucoseinduced insulin (C) and somatostatin (D) secretion in islets isolated from Sst-Cre +/-Cul4b fl/Y mice and WT littermates after 5 minutes. n = 5 mice per group. (E and F) Glucose-and high KCl-induced insulin secretion (E) or somatostatin secretion (F) of islets isolated from WT and Sst-Cre +/-Cul4b fl/Y mice after 5 minutes. n = 4 mice per group. (G and H) Short-and long-term glucose-induced insulin secretion (G) and somatostatin secretion (H) of islets isolated from WT mice and Sst-Cre +/-Cul4b fl/Y mice. n = 4 mice per group. (I) Effect of the somatostatin receptor antagonist cyclosomatostatin (12 μM) on glucose-induced insulin secretion of islets isolated from Sst-Cre +/-Cul4b fl/Y mice and WT littermates after 5 minutes. n = 4 mice per group. (J) Glucose-or high KCl-induced somatostatin secretion from CUL4B knockdown and control TGP52 cells after 1 hour (n = 5) . A-I, *P < 0.05; **P < 0.01. Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. J, *P < 0.05. CUL4B knockdown cells were compared with control shRNA knockdown cells. Bars represent mean ± SEM. All data were analyzed using 1-way ANOVA.
doi:10.1172/jci91348 pmid:28604389 pmcid:PMC5490770 fatcat:p7c2cf7wnbfonmnf7kx24ckpwq
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