Journal of Neurology and Experimental Neural Science

What’s in my BAG-1? The Various and Complex Roles of the Co-Chaperone

by Sandra C Signore1*, Pawel Kermer2

1Department of Neurology, University Medical Center Goettingen, Goettingen, Germany

2Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany

*Corresponding author: Sandra C Signore, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany

Received Date: 11 September, 2024

Accepted Date: 18 September, 2024

Published Date: 20 September, 2024

Citation: Signore SC, Kermer P (2024) What’s in my BAG-1? The Various and Complex Roles of the Co-Chaperone. J Neurol Exp Neural Sci 6: 153. https://doi.org/10.29011/2577-1442.100053

Abstract

The Bcl-2-associated anthanogene-1 (BAG-1) is a multifaceted pro-survival co-chaperone possessing critical functions in cellular pathways. In recent years the interaction potential of BAG-1 with the family of Heat Shock Protein 70 (Hsp70) has been documented. The BAG family provides important functions, given its impact on many different disease models, which are described in the recent literature. Neuroprotective BAG-1 effects have been shown in disease models for Parkinson’s disease, Huntington’s disease and frontotemporal lobar degeneration. But reality is much more complex than theory. Contemporary publications show another side of this co-chaperone: In models for Alzheimer‘s disease, BAG-1 leads to enhanced tau pathology and thus to a deterioration of the disease. Thinking outside the box, BAG-1 is also an important player in hematology and oncology. Given all the information so far, is BAG-1 friend or foe in terms of neurodegenerative as well as hematological and oncological disease models? What conclusions can be drawn for a potential role for BAG-1 as biomarker or even as therapeutic agent?

Keywords: BAG-1; Chaperone; Tau pathology; Neurology, Hematology, Oncology

Introduction

Have you ever wondered where the name “chaperone” comes from?

Based on the etymology, the word “chaperone” characterizing a woman accompanying and guiding a younger, unmarried lady in public has evolved in the 18th century in France. The French word “chaperone” also means “protector” [1].

Molecular co-chaperones are proteins which regulate chaperones by binding to specific sites leading to activation or inhibition. Thus, they assist proteins for appropriate folding which is the basis for their specific functionality [2]. Molecular chaperones are protectors because they prevent protein aggregation. Aggregation can be caused by intracellular stress like toxic chemicals, inflammation, oxidative stress and even induced by heat-shock [3].

BAG-1 A Molecular Co-chaperone with an Antiapoptotic Function

Bcl-2-associated athanogene-1 (BAG-1) is an antiapoptotic protein. It was the first identified member of the BAG family which consists of six members (BAG 1-6). With exception of BAG-5, all BAG family members share the evolutionary highly conserved BAG domain near the C terminus [4-6].

Through this BAG domain it binds to the ATPase domain of Hsp70, stimulating its ATPase activity [7-9]. BAG-1 contains an N-terminal ubiquitin-like motif and was found to bind to the proteasome and to the E3 ligase carboxyl terminus of Hsc70interacting protein (CHIP) [6,10,11].

BAG-1 exerts Neuroprotective Functions in Neurological Disease Models

The function of BAG-1 has been investigated in several disease models and its neuroprotectivity is of particular interest as different outcomes have been shown. In Table 1, studies reporting a neuroprotective effect of the molecular co-chaperone BAG-1 are listed.

Disease model

Reference

Notes

n/a

Over-expression of

BAG-1 in immortalized neuronal CSM14.1 cell

[12,13]

BAG-1 stimulates neuronal differentiation and fosters neuronal survival

Stroke

[12]

BAG-1 is neuroprotective against stroke induced by middle cerebral artery occlusion in transgenic mice overexpressing BAG-1

Ischemia

[14-16]

BAG-1 overexpression protects against various apoptotic insults

Axonal lesion

[17]

BAG-1 enhances axonal regeneration in mice

Huntington’s disease

[9]

BAG-1 overexpression prevents protein aggregation

Parkinson’s disease

[18,19]

BAG-1 overexpression prevents protein aggregation

Table 1: The protective role of BAG-1 in neurological disease models.

The neuroprotective role of the co-chaperone even goes far beyond: Götz et al. described in 2005 that BAG-1 is essential for differentiation and survival of hematopoietic and neuronal cells and a lack of this co-chaperone leads to cell death [20]. BAG-1 overexpression leads to deterioration of tau levels and tau aggregates in Alzheimer’s disease models [21-22]. In a comparative study, BAG-1 likely acts as protective factor for sporadic frontotemporal lobar degeneration (FTLD), but not for Alzheimer’s disease (AD), suggesting its specific role in tau pathology in this disease model [23]. These results were quite surprising and contrasting other disease models in which BAG1 appears to act as neuroprotective factor.

Is the Dichotomous Role of BAG-1 just found in Tau Pathology Models?

Tau inclusions are classic hallmarks of many neurodegenerative diseases including Alzheimer’s disease [24]. Since Elliott et al. and our group investigated the influence of BAG-1 in a model for Alzheimer’s disease focusing on tau pathology the question arose whether BAG-1 does lead to deterioration in a disease model where tau is involved [6,21]. Conflicting results could be found in the forementioned study by Venturelli et al. who examined the role of BAG-1 in a comparative study on two models of tau pathology. The protective role could be seen in sporadic FTLD while deteriorating effects had to be documented in AD [23].

BAG-1 influences crucial intracellular pathways in Alzheimer’s disease models leading to increased toxicity

Recently it has been shown that there is an increase in levels of the BAG-1M isoform in the hippocampus of AD patients. The colocalization of BAG-1 with both tau tangles and intracellular amyloid underlines the hypothesis that BAG-1 may play a significant role in the pathology of AD [22]. In table 2, the non-protective function of BAG-1 are summarized.

Disease model

Reference

Notes

Alzheimer’s disease

[21]

BAG-1 overexpression induced increased tau levels, which is shown to be due to an inhibition of protein degradation

Alzheimer’s disease

[23]

BAG-1M is up-regulated in hippocampus of Alzheimer’s disease patients and associates with tau and APP proteins

Alzheimer’s disease

[6]

BAG-1 stabilizes high molecular tau fragments and enhances the formation of tau aggregates

Table 2: The non-protective role of BAG-1 in Alzheimer’s disease models.

Does BAG-1 act like a molecular switch in tau pathology?

Since we work back from effect to cause – what exactly does BAG-1 in tau pathology? In the AD disease model this has not been found yet since its overexpression led to an increased amount of intracellular high molecular tau protein in timeline experiments where the expression of high molecular tau protein could be detected after a few hours and was increasing by time [6]. Thus, this effect of BAG-1 is not based on a certain time point or to a distinct amount of tau protein. This proves that the co-chaperone BAG-1 is not a molecular switch in tau pathology. Given all the published studies on BAG-1-tau interaction, the deterioration of tau pathology is its originally function. Can at al. already pointed out the potential role of BAG-1 in the funneling of chaperone clients into the proteasome for degradation [25].

BAG-1 is a Potential Biomarker for Early AD and Hematological/Oncological diseases

Biomarkers in neurodegenerative diseases are becoming increasingly important for differential diagnosis. Nowadays, the levels of analysis of beta-Amyloid-1-42, Tau, beta-Amyloid-1-42, phospho-Tau, Huntingtin and alpha-Synuclein are analyzed in cerebrospinal fluid and more recently in serum as biomarkers reflecting neuronal damage and loss [26]. The search for early biomarkers not only in AD is still ongoing. Currently, neurofilaments as well as glial markers like the Glial Fibrillary Acid Protein (GFAP) are discussed vividly as indicators for early neuronal loss [27]. The fact that the isoform BAG-1M is upregulated in the hippocampus of Alzheimer’s disease patients [22] could be used for further studies. While BAG-1 has been proven to accelerate tau aggregation from the beginning, the question remains if the co-chaperone can be detected in early AD stages. Investigations of cerebrospinal fluid levels of BAG-1M in predementia and dementia patients would be the next step.

On the contrary, the relevance of BAG-1 as a biomarker has already been established in hematology and oncology [25,28-32]. Xerri et al. already described in 1999, that apoptotic factors like BAG-1 are expressed in human biopsy samples from patients suffering from B cell non-Hodgkin’s lymphoma [33]. Deregulation of the molecular co-chaperone BAG-1 also plays an important part in acute myeloid leukemia (AML) where it acts like a sentinel for apoptosis [34]. In B-cell acute lymphoblastic leukemia (B-ALL), BAG-1 isoform expression and intracellular localization were investigated. Interestingly, BAG1 levels decreased during disease remission, and showed a drastic increase at relapse [35].

Kitada et al. made a similar observation as they stated that BAG1 may provide prognostic information about clinical responses to chemotherapy in previously untreated B-CLL (B-cell chronic lymphocytic leukemia) patients. Higher levels of BAG-1 were associated with failure to achieve complete remission [36]. Besides blood cancer, the role of the co-chaperone BAG-1 has also been investigated in various solid tumors. A special role of BAG-1 as biomarker has been described in breast cancer. Namely, the prognostic value of the BAG-1L isoform specifically binding to the transcriptional activity of estrogen in breast cancer cells has been pointed out in a recent meta-analysis [37]. In a current publication, BAG-1 has additionally been identified as one of five autophagy-related genes that are of substantial prognostic value in breast cancer [38].

Moreover, expression of BAG-1 has been identified in primary and metastatic human melanoma cells. These findings indicate not only a diagnostic but also prognostic potential for BAG-1. Analyzing the HPA database [39] resulted in a higher survival probability of patients showing low BAG-1 expression in their melanoma cells [40]. The interaction of the BAG1S isoform with the HSP70 chaperone complex selectively mediated cell survival in MYC overexpressing osteosarcoma cells. The authors stated the high importance due to the fact that most human cancers show a MYC overexpression indicating a possible treatment option [41]. There is also a role for BAG-1 in lung cancer [42-44]. Silencing of BAG1 may lead to sensitized cisplatin-induced apoptosis [45]. BAG-1 polymorphisms might even act as important predictive markers for platinum-based chemotherapy efficacy, indicating a crucial role for sensitivity and survival in patients with advanced non-small cell lung cancer (NSCLC) [46]. The effects of apoptotic factors on prostate cancer have been recently explored, Intriguingly, BAG-1 can alter the function of the androgen receptor via nuclear signaling [47]. Further encouraging results for an important role of BAG1 in solid malignancies are described in the entities renal cancer [48], esophageal cancer [49], colon cancer [50], glioblastoma [51,52] and soft-tissue sarcoma [53].

Discussion

BAG-1 – Even a Potential Treatment Strategy?

Besides its role as biomarker for diagnosis and prognosis in hematological/oncological diseases, its role as a target for potential treatment options has been discussed for neurological indications. The wide landscape with different functions of the co-chaperone BAG-1 are summed up in Figure 1.

 

Figure 1: Multiple functions of the co-chaperone BAG-1.

 

Therapies involving molecular co-chaperones which induce refolding of misfolded proteins have already been established and approved for Gaucher’s disease [54] and transthyretin-mediated amyloidosis [55]. Recently, small molecules are attracting increasing attention because they are able to pass the blood-brain barrier and represent novel and promising treatment approaches. Small molecules with chaperone/co-chaperone interactions are currently investigated as therapeutic approach in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis [56,57].

The interaction of BAG-1 with Hsp70 requires an intact C-terminal domain. We showed in vitro in an AD model that the deletion mutant BAGΔC was not capable of stabilizing high-molecular tau fragments [6]. Specifically blocking the C-terminal domain of BAG-1 with a small molecule would be an interesting approach. Moreover, it would not restrict the physiological function of Hsp70 and thus the physiological degradation of other proteins. BAG-1 expression is frequently altered in human cancers. Reduced BAG1 expression specifically targets tumor cells to apoptosis and impairs tumorigenesis suggesting BAG-1 as a potential molecular target for cancer treatment [43].

Conclusion

Let’s resume: Is BAG-1 friend or foe?

Further investigations in neurological, hematological and oncological diseases are necessary to answer the question above. Certainly, BAG-1 can be seen as “foe” in the reviewed AD disease models because of increased toxicity. However, supposing BAG-1 as a potential biomarker puts into perspective the term “foe” and should foster further research dealing with BAG-1 as prognostic and therapeutic agent.

Acknowledgments: None.

Ethical Considerations: Not applicable.

Conflict of Interest: The authors have no relevant financial or non-financial interests to disclose.

Funding: The authors declare that there is no funding for this publication.

References

  1. Online Etymology Dictionary (2024) Chaperone.
  2. Bohush A, Bieganowski P, Filipek A (2019) Hsp90 and Its CoChaperones in Neurodegenerative Diseases. Int J Mol Sci 20(20):
  3. Garrido C, Gurbuxani S, Ravagnan L, Kroemer G (2001) Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem. Biophys Res Commun 286(3): 433-442.
  4. Takayama S, Reed JC (2001) Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol 3(10): E237-E241.
  5. Liman J, Ganesan S, Dohm CP, Krajewski S, Reed JC, et al. (2005) Interaction of BAG1 and Hsp70 mediates neuroprotectivity and increases chaperone activity. Mol Cell Biol 25(9): 3715-3725.
  6. Signore SC, Wouters FS, Schmitz M, Baehr M, Kermer P (2021) BAG1 Overexpression Stabilizes High Molecular Tau Protein-a Crucial Role of the Co-chaperone in Tau Pathology. American Journal of Psychiatry and Neuroscience 9(2): 77-85.
  7. Hohfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16(20): 6209
  8. Takayama S, Bimston DN, Matsuzawa S, Freeman BC, Aime-Sempe C, et al. (1997) BAG-1 modulates the chaperone activity of Hsp70/ EMBO J 16(16): 4887-4896.
  9. Sroka K, Voigt A, Deeg S, Reed JC, Schulz JB, et al. (2009) BAG1 modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution. J Neurochem 111(3): 801-807.
  10. Lueders J, Demand J, Höhfeld J (2000) The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem 275(7): 4613-4617.
  11. Demand J, Alberti S, Patterson C (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/ proteasome coupling. Curr Biol 11(20): 1569-1577.
  12. Kermer P, Krajewska M, Zapata JM, Takayama S, Mai J, et al. (2002) Bag1 is a regulator and marker of neuronal differentiation. Cell Death Differ 9(4): 405-413.
  13. Götz J, Faida L, Dohm CP, Reed JC, Bähr M, et al. (2008) Subcellular distribution affects BAG1 function. Brain Res 1198: 21-26.
  14. Takayama S, Sato T, Krajewski S, Kochel K, Irie S, et al. (1995) Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 80(2): 279-284.
  15. Kermer P, Digicaylioglu MH, Kaul M, Zapata JM, Krajewska M, et al.(2003) BAG1 over-expression in brain protects against stroke. Brain Pathol 13(4): 495-506.
  16. Townsend PA, Cutress RI, Sharp A, Brimmell M, Packham G (2003) BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway. Cancer Res 63(14): 4150-4157.
  17. Planchamp V, Bermel C, Tönges L, Ostendorf T, Kügler S, et al. (2008) BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1and reduction of ROCK activity. Brain 131(Pt 10): 2606-2619.
  18. Deeg S, Gralle M, Sroka K, Bähr M, Wouters FS, et al. (2010) BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity. J Cell Biol 188(4): 505-513.
  19. Kermer P, Köhn A, Schnieder M, Lingor P, Bähr M, et al. (2015) BAG1 is neuroprotective in in vivo and in vitro models of Parkinson’s disease. J Mol Neurosci 55(3): 587-595.
  20. Götz R, Wiese S, Takayama S, Camarero GC, Rossoll W, et al. (2005) Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells. Nat Neurosci 8(9): 1169-1178.
  21. Elliott E, Tsvetkov P, Ginzburg I (2007) BAG-1 associates with Hsc70. Tau complex and regulates the proteasomal degradation of Tau J Biol Chem 282(51): 37276-37284.
  22. Elliott E, Laufer O, Ginzburg I (2009) BAG-1M is up-regulated in hippocampus of Alzheimer’s disease patients and associates with tau and APP proteins. J Neurochem 109(4): 1168-1178.
  23. Venturelli E, Villa C, Fenoglio C, Clerici F, Marcone A, et al. (2011) BAG1is a protective factor for sporadic frontotemporal lobar degeneration but not for Alzheimer’s disease. J Alzheimers Dis 23(4): 701-707.
  24. Fontaine SN, Sabbagh JJ, Baker J, Martinez-Licha CR, Darling A, et (2015) Cellular factors modulating the mechanism of tau protein aggregation. Cell Mol Life Sci 72(10): 1863-1879.
  25. Can ND, Basturk E, Kizilboga T, Akcay IM, Dingiloglu B, et al. (2021) Interactome analysis of Bag-1 isoforms reveals novel interaction partners in endoplasmic reticulum-associated degradation. PLoS One 16(8): e0256640.
  26. NIH National Instutite of Aging (2024) How Biomarkers Help Diagnose
  27. Mattsson-Carlgren N, Salvadó G, Ashton NJ, Tideman P, Stomrud E, et al. (2023) Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers. JAMA Neurol 80(4): 360-369.
  28. Alberti S, Esser C, Hoehfeld J (2003) BAG-1-a nucleotide exchange factor of Hsc70 with multiple cellular functions. Cell Stress Chaperones 8(3): 225-231.
  29. Da Costa CR, Villadiego J, Sancho R, Fontana X, Packham G, et al.(2010) Bag1-L is a phosphorylation-dependent coactivator of c-Jun during neuronal apoptosis. Mol Cell Biol 30(15): 3842-3852.
  30. Mariotto E, Viola G, Zanon C, Aveic S (2020) A BAG’s life: Everyconnection matters in cancer Pharmacol Ther 209: 107498.
  31. Sharp A, Crabb SJ, Townsend PA, Cutress RI, Brimmell M, et al.(2004) BAG-1 in carcinogenesis. Expert Rev Mol Med 6(7): 1-15.
  32. Galmiche A, Fueller J (2007) RAF kinases and mitochondria. Biochim Biophys Acta 1773(8): 1256-1262.
  33. Xerri L, Devilard E, Bouabdallah R, Hassoun J, Chaperot L, et (1999) Quantitative analysis detects ubiquitous expression of apoptotic regulators in B cell non-Hodgkin’s lymphomas. Leukemia 13(10): 1548-1553.
  34. Aveic S, Pigazzi M, Basso G (2011) BAG1: the guardian of antiapoptotic proteins in acute myeloid leukemia. PLoS One 6(10):
  35. Mariotto E, Corallo D, Pantile M, Giarin E, Pigazzi M, et al. (2021) BAG1down-regulation increases chemo-sensitivity of acute lymphoblastic leukaemia cells. J Cell Mol Med 25(18): 9060-9065.
  36. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, et al. (1998) Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo Blood 91(9): 3379-3389.
  37. Papadakis ES, Reeves T, Robson NH, Maishman T, Packham G, et (2017) BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses. Br J Cancer 116(12): 15851594.
  38. Du JX, Chen C, Luo YH, Cai JL, Cai CZ, et al. (2020) Establishment and validation of a novel autophagy-related gene signature for patients with breast cancer. Gene 15:762:144974.
  39. H A D b, Human Autophagy Data base (2024) Luxemburg Institute of
  40. D’Arcangelo D, Giampietri C, Muscio M, Scatozza F, Facchiano F, et (2018) WIPI1, BAG1, and PEX3 Autophagy-Related Genes Are Relevant Melanoma Markers. Oxid Med Cell Longev 2018: 1471682.
  41. Gennaro VJ, Wedegaertner H, McMahon SB (2019) Interaction between the BAG1S isoform and HSP70 mediates the stability of antiapoptotic proteins and the survival of osteosarcoma cells expressing oncogenic MYC. BMC Cancer 22 19(1):258.
  42. Rorke S, Murphy S, Khalifa M, Chernenko G, Tang SC (2001) Prognostic significance of BAG-1 expression in nonsmall cell lung Int J Cancer 20 95(5): 317-322.
  43. Götz R, Kramer BW, Camarero G, Rapp U (2004) BAG-1 haploinsufficiency impairs lung tumorigenesis. BMC Cancer 4:85.
  44. Lin PL, Wu TC, Wu DW, Wang L, Chen C-Y, et al. (2017) An increasein BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling. Eur J Cancer 85: 95-105.
  45. Liu H, Liang Y, Li Y, Li Y, Wang J, et al. (2010) Gene silencing of BAG1 modulates apoptotic genes and sensitizes lung cancer cell lines tocisplatin-induced apoptosis. Cancer Biol Ther 9(10): 832-840.
  46. Li P, Wang YD, Cheng J, Chen JC, Ha MW (2015) Association between polymorphisms of BAG-1 and XPD and chemotherapy sensitivity in advanced non-small-cell lung cancer patients treated with vinorelbine combined cisplatin regimen. Tumour Biol 36(12): 9465-9473.
  47. Kuznik NC, Solozobova V, Lee II, Jung N, Yang L, et al. (2022) A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway 25(5): 104175.
  48. Wu H, Liu M, He Y, Meng G, Guo W, et al. (2021) Expression of BAG1 is associated with prognosis in kidney renal clear cell carcinoma based on bioinformatics. BMC Cancer 21(1): 160.
  49. Yoshino K, Motoyama S, Koyota S, Shibuya K, Usami S, et al. (2011)IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells. Biochem Biophys Res Commun 404 (4): 1070-1075.
  50. Bai YX, Yi JL, Li JF, Sui H (2007) Clinicopathologic significance of BAG1and TIMP3 expression in colon carcinoma. World J Gastroenterol 13(28): 3883-5.
  51. Roth W, Grimmel C, Rieger L, Strik H, Takayama S, et al. (2000) Bag-1 and Bcl-2 gene transfer in malignant glioma: modulation of cell cycle regulation and apoptosis. Brain Pathol 10(2): 223-234.
  52. Rocchi A, Wollebo HS, Khalili K (2022) Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets. Int J Mol Sci 23(17): 9734.
  53. Hu F, Yu Y, Chen JS, Hu H, Scheet P, et al. (2021) Integrated casecontrol and somatic-germline interaction analyses of soft-tissue J Med Genet 58(3): 145-153.
  54. Benito JM, García Fernández JM, Ortiz Mellet C (2011) Pharmacological chaperone therapy for Gaucher disease: a patent review. Expert Opin Ther Pat 21(6): 885-903.
  55. NIH National Library of Medicine (2020) Nationale Centre for Biomedical Information. Clinical Review Report: Tafamidis (Vyndaqel).
  56. Wang L, Bergkvist L, Kumar R, Winblad B, Pavlov PF (2021) Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases. Cells 10(10): 2596.
  57. Voronin MV, Abramova EV, Verbovaya ER, Vakhitova YV, Seredenin SB (2023) Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection. Int J Mol Sci 24(1): 823.

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