bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2024–08–25
eleven papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals.
  2. Total Antioxidant Status and Oxidative Stress in Patients with COVID-19 Infection.
  3. Non-human primate model of long-COVID identifies immune associates of hyperglycemia.
  4. PRRSV hijacks DDX3X protein and induces ferroptosis to facilitate viral replication.
  5. HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction.
  6. The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication.
  7. Lipidomic and Metabolomic Changes in Community-acquired and COVID-19 Pneumonia.
  8. LC-MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review.
  9. Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism.
  10. Green tea extract reduces viral proliferation and ROS production during Feline Herpesvirus type-1 (FHV-1) infection.
  11. Differential immunometabolic responses to Delta and Omicron SARS-CoV-2 variants in golden syrian hamsters.
  1. Redox Biol. 2024 Aug 19. pii: S2213-2317(24)00288-X. [Epub ahead of print]76 103310
    Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals.
    Larissa E Vlaming-van Eijk, Marian L C Bulthuis, Bernardina T F van der Gun, Karin I Wold, Alida C M Veloo, María F Vincenti González, Martin H de Borst, Wilfred F A den Dunnen, Jan-Luuk Hillebrands, Harry van Goor, Adriana Tami, Arno R Bourgonje.
       BACKGROUND: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R-SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R-SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19.
    METHODS: Baseline serum R-SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R-SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS.
    RESULTS: Baseline albumin-adjusted serum R-SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R-SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = -9.48, p = 0.023).
    CONCLUSION: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R-SH as a monitoring biomarker and a potential therapeutic target in the development of PCS.
    Keywords:  COVID-19; Coronavirus disease 2019; Long COVID-19; Oxidative stress; Post-COVID-19 syndrome; Redox
    DOI:  https://doi.org/10.1016/j.redox.2024.103310
  2. J Assoc Physicians India. 2024 Aug;72(8): 36-39
    Total Antioxidant Status and Oxidative Stress in Patients with COVID-19 Infection.
    Mohit Jindal, Sarabmeet Singh Lehl, Shivani Jaswal, Nidhi Bhardwaj, Monica Gupta.
       INTRODUCTION: Oxidative stress (OS) may have a role in the pathogenesis and severity of the coronavirus disease 2019 (COVID-19) disease. The present study was conducted to estimate the association of inflammatory markers, total antioxidant status (TAS), and malondialdehyde (MDA) levels with the severity of the disease and to identify their trends after recovery.
    MATERIALS AND METHODS: Adult patients admitted with moderate or severe COVID-19 were included after obtaining written informed consent from patient or next of kin. Patients who were critically ill, on ventilator, or in sepsis/septic shock were excluded. Levels of inflammatory markers, TAS, and OS as measured by MDA were estimated within 24 hours of admission and reevaluated at 12 weeks following discharge.
    RESULTS: The mean age of the 40 patients (42.5% females) was 55 ± 15 years. TAS values (in trolox equivalents/L) were significantly reduced in severe compared to moderate COVID-19 patients at admission (7.2 ± 4.19 vs 12.3 ± 5.21). These increased at 12 weeks after discharge. The MDA levels (in nmol/mL) were significantly higher in severe in comparison to moderate disease (7.1 ± 2.68 vs 4.1 ± 1.81). These values showed a downward trend 12 weeks after discharge in severe disease group. Admission levels of interleukin-6 (IL-6), D-dimer, and lactate dehydrogenase (LDH) were statistically higher in severe COVID-19 patients in contrast to moderate disease.
    CONCLUSION: Moderate and severe COVID-19 are associated with a state of high OS and a low total antioxidant levels which tend to recover at 3 months following discharge.
    DOI:  https://doi.org/10.59556/japi.72.0575
  3. Nat Commun. 2024 Aug 20. 15(1): 6664
    Non-human primate model of long-COVID identifies immune associates of hyperglycemia.
    Clovis S Palmer, Chrysostomos Perdios, Mohamed Abdel-Mohsen, Joseph Mudd, Prasun K Datta, Nicholas J Maness, Gabrielle Lehmicke, Nadia Golden, Linh Hellmers, Carol Coyne, Kristyn Moore Green, Cecily Midkiff, Kelsey Williams, Rafael Tiburcio, Marissa Fahlberg, Kyndal Boykin, Carys Kenway, Kasi Russell-Lodrigue, Angela Birnbaum, Rudolf Bohm, Robert Blair, Jason P Dufour, Tracy Fischer, Ahmad A Saied, Jay Rappaport.
      Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys. Using this model, we identify a dysregulated blood chemokine signature during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. Hyperglycemia also correlates with liver glycogen levels, but there is no evidence of substantial long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the African green monkey model exhibits important similarities to humans and can be utilized to assess therapeutic candidates to combat COVID-related metabolic defects.
    DOI:  https://doi.org/10.1038/s41467-024-50339-4
  4. Vet Res. 2024 Aug 18. 55(1): 103
    PRRSV hijacks DDX3X protein and induces ferroptosis to facilitate viral replication.
    Qian Mao, Shengming Ma, Shuangyu Li, Yuhua Zhang, Shanshan Li, Wenhui Wang, Fang Wang, Zekun Guo, Chengbao Wang.
      Porcine reproductive and respiratory syndrome virus (PRRSV) is a severe disease with substantial economic consequences for the swine industry. The DEAD-box helicase 3 (DDX3X) is an RNA helicase that plays a crucial role in regulating RNA metabolism, immunological response, and even RNA virus infection. However, it is unclear whether it contributes to PRRSV infection. Recent studies have found that the expression of DDX3X considerably increases in Marc-145 cells when infected with live PRRSV strains Ch-1R and SD16; however, it was observed that inactivated viruses did not lead to any changes. By using the RK-33 inhibitor or DDX3X-specific siRNAs to reduce DDX3X expression, there was a significant decrease in the production of PRRSV progenies. In contrast, the overexpression of DDX3X in host cells substantially increased the proliferation of PRRSV. A combination of transcriptomics and metabolomics investigations revealed that in PRRSV-infected cells, DDX3X gene silencing severely affected biological processes such as ferroptosis, the FoxO signalling pathway, and glutathione metabolism. The subsequent transmission electron microscopy (TEM) imaging displayed the typical ferroptosis features in PRRSV-infected cells, such as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and cytoplasmic membrane rupture. Conversely, the mitochondrial morphology was unchanged in DDX3X-inhibited cells. Furthermore, silencing of the DDX3X gene changed the expression of ferroptosis-related genes and inhibited the virus proliferation, while the drug-induced ferroptosis inversely promoted PRRSV replication. In summary, these results present an updated perspective of how PRRSV infection uses DDX3X for self-replication, potentially leading to ferroptosis via various mechanisms that promote PRRSV replication.
    Keywords:  DDX3X; PRRSV; ferroptosis; metabolome; transcriptome
    DOI:  https://doi.org/10.1186/s13567-024-01358-y
  5. NeuroImmune Pharm Ther. 2024 Jun;3(2): 139-154
    HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction.
    Jessica M Proulx, In-Woo Park, Kathleen Borgmann.
       Objectives: Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one's risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction.
    Methods: Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression.
    Results: Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression.
    Conclusion: Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.
    Keywords:  HIV-associated neurocognitive disorders (HAND); astrocytes; calcium signaling; methamphetamine (METH); mitochondria-associated ER membranes (MAMs); unfolded protein response (UPR)
    DOI:  https://doi.org/10.1515/nipt-2023-0020
  6. Adv Sci (Weinh). 2024 Aug 19. e2404365
    The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication.
    Aotian Ouyang, Tong Chen, Yi Feng, Jiahui Zou, Shaoyu Tu, Meijun Jiang, Huimin Sun, Hongbo Zhou.
      Ferroptosis is a novel form of cell death caused by the accumulation of lipid peroxides in an iron-dependent manner. However, the precise mechanism underlying the exploitation of ferroptosis by influenza A viruses (IAV) remains unclear. The results demonstrate that IAV promotes its own replication through ferritinophagy by sensitizing cells to ferroptosis, with hemagglutinin identified as a key trigger in this process. Hemagglutinin interacts with autophagic receptors nuclear receptor coactivator 4 (NCOA4) and tax1-binding protein 1 (TAX1BP1), facilitating the formation of ferritin-NCOA4 condensates and inducing ferritinophagy. Further investigation shows that hemagglutinin-induced ferritinophagy causes cellular lipid peroxidation, inhibits aggregation of mitochondrial antiviral signaling protein (MAVS), and suppresses the type I interferon response, thereby contributing to viral replication. Collectively, a novel mechanism by which IAV hemagglutinin induces ferritinophagy resulting in cellular lipid peroxidation, consequently impairing MAVS-mediated antiviral immunity, is revealed.
    Keywords:  autophagy; ferroptosis; influenza a virus; innate immunity; mitochondrial antiviral signaling protein (MAVS)
    DOI:  https://doi.org/10.1002/advs.202404365
  7. J Lipid Res. 2024 Aug 16. pii: S0022-2275(24)00127-5. [Epub ahead of print] 100622
    Lipidomic and Metabolomic Changes in Community-acquired and COVID-19 Pneumonia.
    S M Saballs, S Parra, N Martínez, N Amigó, L Cabau, S Iftimie, R Pavón, X Gavaldó, X Correig, S Paredes, J C Vallvé, A Castro.
      This prospective observational study compared the 1H NMR blood lipidomes and metabolomes of 71 community-acquired pneumonia (CAP) patients, 75 COVID-19 pneumonia patients, and 75 healthy controls (matched by age and sex) to identify potential biomarkers and pathways associated with respiratory infections. Both pneumonia groups had comparable severity indices, including mortality, invasive mechanical ventilation, and intensive care unit admission rates. COVID-19 pneumonia patients exhibited more pronounced hypolipidemia, with significantly lower levels of total cholesterol and LDL-c compared to CAP patients. Atherogenic lipoprotein subclasses (VLDL-cholesterol, IDL-cholesterol, IDL-triglyceride, and LDL-triglyceride/LDL-cholesterol) were significantly increased in severe cases of both pneumonia types, while lower HDL-c and small, dense HDL particles were associated with more severe illness. Both infected groups showed decreased esterified cholesterol and increased triglycerides, along with reduced phosphatidylcholine, lysophosphatidylcholine, PUFA, omega-3 fatty acids, and DHA. Additionally, infected patients had elevated levels of glucose, lactate, 3-hydroxybutyrate, and acetone, which are linked to inflammation, hypoxemia, and sepsis. Increased levels of branched-chain amino acids, alanine, glycine, and creatine, which are involved in energy metabolism and protein catabolism, were also observed. Neurotransmitter synthesis metabolites like histidine and glutamate were higher in infected patients, especially those with COVID-19. Notably, severe infections showed a significant decrease in glutamine, essential for lymphocyte and macrophage energy. Severity in COVID-19 pneumonia was also associated with elevated glycoprotein levels (glycoprotein A, glycoprotein B, glycoprotein F), indicating an inflammatory state. These findings suggest that metabolomic and lipidomic changes in pneumonia are connected to bioenergetic pathways regulating the immune response.
    Keywords:  COVID-19; HDL; NMR; lipidomics; metabolomics; pneumonia
    DOI:  https://doi.org/10.1016/j.jlr.2024.100622
  8. Front Neurol. 2024 ;15 1403312
    LC-MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review.
    Ontefetse Neo Plaatjie, A Marceline Tutu van Furth, Martijn van der Kuip, Shayne Mason.
      There is compelling evidence that a dysregulated immune inflammatory response in neuroinfectious diseases results in modifications in metabolic processes and altered metabolites, directly or indirectly influencing lipid metabolism within the central nervous system (CNS). The challenges in differential diagnosis and the provision of effective treatment in many neuroinfectious diseases are, in part, due to limited understanding of the pathophysiology underlying the disease. Although there are numerous metabolomics studies, there remains a deficit in neurolipidomics research to provide a comprehensive understanding of the connection between altered metabolites and changes in lipid metabolism. The brain is an inherently high-lipid organ; hence, understanding neurolipidomics is the key to future breakthroughs. This review aims to provide an integrative summary of altered cerebrospinal fluid (CSF) metabolites associated with neurolipid metabolism in bacterial and viral CNS infections, with a particular focus on studies that used liquid chromatography-mass spectrometry (LC-MS). Lipid components (phospholipids) and metabolites (carnitine and tryptophan) appear to be the most significant indicators in both bacterial and viral infections. On the basis of our analysis of the literature, we recommend employing neurolipidomics in conjunction with existing neurometabolomics data as a prospective method to enhance our understanding of the cross link between dysregulated metabolites and lipid metabolism in neuroinfectious diseases.
    Keywords:  central nervous system; cerebrospinal fluid; encephalitis; lipidomics; liquid chromatography mass spectrometer; meningitis; metabolomics; neuroinflammation
    DOI:  https://doi.org/10.3389/fneur.2024.1403312
  9. J Virol. 2024 Aug 19. e0063524
    Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism.
    Jiang-Fei Zhou, Meng-Ran Zhang, Qi Wang, Mei-Zhen Li, Ji-Shan Bai, Qi Dai, Yuan-Hang Zhang, Meng-Xue Yan, Xiao-Han Li, Jing Chen, Ya-Yun Liu, Chun-Chun Liu, Jing Ye, Bin Zhou.
      Flavivirus infection capitalizes on cellular lipid metabolism to remodel the cellular intima, creating a specialized lipid environment conducive to viral replication, assembly, and release. The Japanese encephalitis virus (JEV), a member of the Flavivirus genus, is responsible for significant morbidity and mortality in both humans and animals. Currently, there are no effective antiviral drugs available to combat JEV infection. In this study, we embarked on a quest to identify anti-JEV compounds within a lipid compound library. Our research led to the discovery of two novel compounds, isobavachalcone (IBC) and corosolic acid (CA), which exhibit dose-dependent inhibition of JEV proliferation. Time-of-addition assays indicated that IBC and CA predominantly target the late stage of the viral replication cycle. Mechanistically, JEV nonstructural proteins 1 and 2A (NS1 and NS2A) impede 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation by obstructing the liver kinase B1 (LKB1)-AMPK interaction, resulting in decreased p-AMPK expression and a consequent upsurge in lipid synthesis. In contrast, IBC and CA may stimulate AMPK by binding to its active allosteric site, thereby inhibiting lipid synthesis essential for JEV replication and ultimately curtailing viral infection. Most importantly, in vivo experiments demonstrated that IBC and CA protected mice from JEV-induced mortality, significantly reducing viral loads in the brain and mitigating histopathological alterations. Overall, IBC and CA demonstrate significant potential as effective anti-JEV agents by precisely targeting AMPK-associated signaling pathways. These findings open new therapeutic avenues for addressing infections caused by Flaviviruses.
    IMPORTANCE: This study is the inaugural utilization of a lipid compound library in antiviral drug screening. Two lipid compounds, isobavachalcone (IBC) and corosolic acid (CA), emerged from the screening, exhibiting substantial inhibitory effects on the Japanese encephalitis virus (JEV) proliferation in vitro. In vivo experiments underscored their efficacy, with IBC and CA reducing viral loads in the brain and mitigating JEV-induced histopathological changes, effectively shielding mice from fatal JEV infection. Intriguingly, IBC and CA may activate 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) by binding to its active site, curtailing the synthesis of lipid substances, and thus suppressing JEV proliferation. This indicates AMPK as a potential antiviral target. Remarkably, IBC and CA demonstrated suppression of multiple viruses, including Flaviviruses (JEV and Zika virus), porcine herpesvirus (pseudorabies virus), and coronaviruses (porcine deltacoronavirus and porcine epidemic diarrhea virus), suggesting their potential as broad-spectrum antiviral agents. These findings shed new light on the potential applications of these compounds in antiviral research.
    Keywords:  Flavivirus; Japanese encephalitis virus (JEV); antiviral; corosolic acid (CA); isobavachalcone (IBC); lipid metabolism
    DOI:  https://doi.org/10.1128/jvi.00635-24
  10. BMC Vet Res. 2024 Aug 22. 20(1): 374
    Green tea extract reduces viral proliferation and ROS production during Feline Herpesvirus type-1 (FHV-1) infection.
    Consiglia Longobardi, Sara Damiano, Gianmarco Ferrara, Riccardo Esposito, Serena Montagnaro, Salvatore Florio, Roberto Ciarcia.
       BACKGROUND: Feline Herpesvirus type-1 (FHV-1) is a worldwide spread pathogen responsible for viral rhinotracheitis and conjunctivitis in cats that, in the most severe cases, can lead to death. Despite the availability of a variety of antiviral medications to treat this illness, mainly characterized by virostatic drugs that alter DNA replication, their use is often debated. Phytotherapeutic treatments are a little-explored field for FHV-1 infections and reactivations. In this scenario, natural compounds could provide several advantages, such as reduced side effects, less resistance and low toxicity. The purpose of this study was to explore the potential inhibitory effects of the green tea extract (GTE), consisting of 50% of polyphenols, on FHV-1 infection and reactive oxygen species (ROS) production.
    RESULTS: Crandell-Reese feline kidney (CRFK) cells were treated with different doses of GTE (10-400 µg/mL) during the viral adsorption and throughout the following 24 h. The MTT and TCID50 assays were performed to determine the cytotoxicity and the EC50 of the extract, determining the amounts of GTE used for the subsequent investigations. The western blot assay showed a drastic reduction in the expression of viral glycoproteins (i.e., gB and gI) after GTE treatment. GTE induced not only a suppression in viral proliferation but also in the phosphorylation of Akt protein, generally involved in viral entry. Moreover, the increase in cell proliferation observed in infected cells upon GTE addition was supported by enhanced expression of Bcl-2 and Bcl-xL anti-apoptotic proteins. Finally, GTE antioxidant activity was evaluated by dichloro-dihydro-fluorescein diacetate (DCFH-DA) and total antioxidant capacity (TAC) assays. The ROS burst observed during FHV-1 infection was mitigated after GTE treatment, leading to a reduction in the oxidative imbalance.
    CONCLUSIONS: Although further clinical trials are necessary, this study demonstrated that the GTE could potentially serve as natural inhibitor of FHV-1 proliferation, by reducing viral entry. Moreover, it is plausible that the extract could inhibit apoptosis by modulating the intrinsic pathway, thus affecting ROS production.
    Keywords:  Antiviral; Feline Herpesvirus type-1; Green tea extract; ROS
    DOI:  https://doi.org/10.1186/s12917-024-04227-0
  11. iScience. 2024 Aug 16. 27(8): 110501
    Differential immunometabolic responses to Delta and Omicron SARS-CoV-2 variants in golden syrian hamsters.
    Rajesh Rajaiah, Kabita Pandey, Arpan Acharya, Anoop Ambikan, Narendra Kumar, Reema Guda, Sean N Avedissian, Luis J Montaner, Samuel M Cohen, Ujjwal Neogi, Siddappa N Byrareddy.
      Delta (B.1.617.2) and Omicron (B.1.1.529) variants of SARS-CoV-2 represents unique clinical characteristics. However, their role in altering immunometabolic regulations during acute infection remains convoluted. Here, we evaluated the differential immunopathogenesis of Delta vs. Omicron variants in Golden Syrian hamsters (GSH). The Delta variant resulted in higher virus titers in throat swabs and the lungs and exhibited higher lung damage with immune cell infiltration than the Omicron variant. The gene expression levels of immune mediators and metabolic enzymes, Arg-1 and IDO1 in the Delta-infected lungs were significantly higher compared to Omicron. Further, Delta/Omicron infection perturbed carbohydrates, amino acids, nucleotides, and TCA cycle metabolites and was differentially regulated compared to uninfected lungs. Collectively, our data provide a novel insight into immunometabolic/pathogenic outcomes for Delta vs. Omicron infection in the GSH displaying concordance with COVID-19 patients associated with inflammation and tissue injury during acute infection that offered possible new targets to develop potential therapeutics.
    Keywords:  Immunology; Public health; Virology
    DOI:  https://doi.org/10.1016/j.isci.2024.110501
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