J. Neurosci. Neurosci. This dosage was based on indications of literature reviews documenting its efficacy in attenuating stress-induced behavioral and neurochemical abnormalities in a chronic setting39,40. Neurosci. The up-regulation of Actb and Cfl1, its major binding protein, could relate with the coping mechanism under CSIS conditions, since one of the Cfl roles is in mediating synaptic plasticity via regulating actin filament dynamics68. Kim WM, Lee SH, Jeong HJ, Lee HG, Choi JI, Yoon MH. 116 (2010). Several hypotheses have been postulated as a pathophysiological cause of MD. As noted above, similar effect of Tian was seen in controls where expression of Prdx6 was increased thus suggesting on a possible common protective mechanism regardless of the physiological condition. Lee, H. et al. For HSP90 expression changes, two-way ANOVA failed to detect any significant main effects or significant difference in expression changes between the examined groups. Ponceau S staining intensity was analyzed with the use of ImageJ software (Version 1.52i). Mirza, F. J. 2 The understanding that tianeptine bypasses the synapse and acts on the nucleus to exert its effects on restoring neuroplasticity and neurogenesis has direct . Funct. Tonix recently announced that the plastogen anti-depressant tianeptine, a drug marketed outside the U.S. for more than 30 years, acts on nuclear PPAR-/ and PPAR- in neurons and glia to restore neuronal connectivity in depression. The same trend was observed in Tian-treated CSIS rats (*p<0.05). Gombik, K. et al. 5a,b). You are using a browser version with limited support for CSS. Google Scholar. I experimented for a year by using nootropics in place of the 20 mg of Ritalin I had been using 3-times a day for several years. Rev. & Poo, M. M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Lower synaptic density is associated with depression severity and network alterations. A. Depression, anxiety, bipolar disorder, schizophrenia, you name it. PMC Protein Sci. 136, 112 (2002). Full-length blots are presented in Supplementary Figure S1. Syn1 expression change was validated with the use of immunohistochemical procedure in the coronal sections of the dorsal (d) hippocampus. 3, 175190 (2002). Psychopharmacol. In optimizer-brain parlance, sunlight, exercise, and rest are all stackable. U S A. J. Neuropsychopharmacol. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Although doctors still reluctantly prescribe prescription nootropics for these kinds of patients. Pegasus Kratom Alternative Capsules - Earth Grown Wellness Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. Tonix recently announced that the plastogen anti-depressant tianeptine, a drug marketed outside the U.S. for more than 30 years, acts on nuclear PPAR-/ and PPAR- in neurons and glia to . 26, 35093517 (2007). Ultimate Guide To Using Nootropics For Opiate Withdrawal Slowed or stopped breathing. Rev. STRING-based interactome map of interactions among differently regulated proteins in Tian-treated CSIS rats, with the corresponding GO Biological process terms: (a) up-regulated synaptosomal proteins and (b) down-regulated synaptosomal proteins. The increased expression of Cyt c, also aids a significance to the activation i.e. All protein identification experiments were carried out using the corresponding decoy database and a false discovery rate (FDR) of 1%. An increased synaptic energy metabolism of CSIS rats along with up-regulated expression of proteins involved in actin cytoskeleton, signaling transduction and synaptic transmission were revealed. Further, Tian administration for 3weeks resulted in serum concentrations of 121.15ng/ml in Tian-treated controls and 13.400.81ng/ml in Tian-treated CSIS rats. Google Scholar. However, all these proteome changes induced by Tian in normal physiological state could also relate to side effects of its prolonged use as a cognitive enhancer, rather than its antidepressant efficacy. Ferguson, J. On contrary, our previous study showed that Tian causes a decline in Glud1 expression in the NSM14. 1). 16, 289299 (2013). J. Psychopharmacol. Neuropsychopharmacology 33, 88109 (2008). Biol. We performed immunohistochemical (IHC) procedure for validation of observed Synapsin-1 (Syn1) expression changes upon CSIS and/or Tian treatment. Stress 6, 7893 (2017). Filipovi, D. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. The results were presented as averageSEM. The significant main effect of combined impact of TianCSIS was seen in the dCA3 subregion of the hippocampus (F1.17=4.55, p<0.05). Separate batch of animals (n=46 per group) was used for IHC validation purpose. Within each group, both rat hippocampal hemispheres of two hippocampi were pooled and homogenized in cold homogenization buffer (10mM Tris/HCl (SERVA) pH 7.4, 0.25M sucrose (Fisher Scientific)) containing protease inhibitor cocktail tablet (complete tablets, Mini, EASY pack, Roche) by 10 strokes at 800rpm, in the PotterElvehjem homogenizer with Teflon pestle. Our study revealed that Tian treatment boosted the already increased expression of Inositol-1-monophosphatase (Impa1) in the hippocampus of CSIS rats, which is the enzyme responsible for conversion of myo-inositol phosphate to myo-inositol. Tianeptine (AMO-04/REV-001) acts by targeting the glutamate receptor. Back when Nootropics Depot carried tianeptine sulfate, I was using it regularly to treat my OCD, ADHD, and depression. 8600 Rockville Pike A. The https:// ensures that you are connecting to the Biochem. It seems to affect mood when used in low doses. Neurochem. The same trend was confirmed by the Western blot, however lacking the statistical significance (Fig. However, these could also contribute to MDD-related alterations caused by increased level of glutamate, thus leading to structural alterations of neural terminals and subsequent functional alterations in MDD. Regarding Tian treatment of Controls and CSIS rats, 31 proteins were up-regulated, whereby 5 proteins were up- and 26 proteins were down-regulated by Tian in CSIS (Table 2). Long answer 2. Gupta, S. C. et al. Literature also revealed Tian memory enhancing properties in the absence of stress32. Brains were cut into 40m-thick coronal sections with a vibratome (VT 100 S; Leica Bensheim, Germany). 5e). Tianeptine antagonizes the reduction of PV+ and GAD67 cells number in dorsal hippocampus of socially isolated rats. The relative quantification of the proteins in the two subgroups were performed with the label free quantification (LFQ) tool of the Sieve 2.0 software (Thermo Fisher Scientific) using a mass error tolerance of10ppm and a retention time shift of1min. Therefore, in order to understand the organization of the synaptic machinery in health and disease18 intensive research in the field of MDD is increasingly focused on the characterization of synaptosomal proteins, which is an artificial structure constructed from neural terminals, including mitochondria, synaptic vesicles and postsynaptic density17,19. All methods are reported following the recommendations of ARRIVE guidelines. 98, 1279612801 (2001). Read on to find out what the science says. These data are in accordance with the results obtained from the proteomic study. During the second 3weeks of experiment, half of each batch of animals (Controls and CSIS) were treated with intraperitoneal (ip) injections of Tian solution (10mg/kg/day) (Control+Tian and CSIS+Tian), while the rest were treated with vehicle (Veh, physiological saline) (Control+Veh and CSIS+Veh). Frigerio, F., Casimir, M., Carobbio, S. & Maechler, P. Tissue specificity of mitochondrial glutamate pathways and the control of metabolic homeostasis. 209, 577589 (2006). Internet Explorer). The alterations in neurotransmission processes mediated via serotonin, dopamine and gamma-aminobutyric acid (GABA), as well as the reduction in synapse number and their functionality have also been associated with MDD. In vivo studies on the enhancement of serotonin reuptake by tianeptine. 2012 Mar;114(3):683-9. doi: 10.1213/ANE.0b013e31824181e7. Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats. CSIS vs. Controls showed 118 up-regulated proteins (Supplementary Table S2). Best Nootropics for ADHD & ADD - Nootropics Expert It was also observed the impact of Tian on up-regulation of a number of glycolysis-related proteins. Nat. Peri, I. et al. Perspect. Tianeptine - a Paradox to the Current Paradigm of Depression Buy Tianeptine (Sulfate) Capsules 25mg Online | Nootropics.com PubMed Unlike ecstasy, where you get these bursts of good feelings followed by a come down that is depressive in nature, with Tianeptine, the good feelings would pass into a natural feeling. The specificity in studying synaptosomes, as a mean for investigating synaptic transmission, relies on the fact that the entire machinery responsible for neurotransmitter trafficking, mediated by synaptic vesicles as well as the storage, remains intact17. Holmes, S. E. et al. Understanding the basics a. Neurosci. Hence, by stimulating the process of neural transmission in the hippocampus of rats under normal physiological state, Tian may improve cognitive preferences related to its nootropic efficacy. and JavaScript. 639, 167170 (1994). 22, 238249 (2016). Zuccoli, G. S., Saia-Cereda, V. M., Nascimento, J. M. & Martins-de-Souza, D. The energy metabolism dysfunction in psychiatric disorders postmortem brains: Focus on proteomic evidence. 4a). Overall, the modulation of synaptic vesicle dynamics and up-regulation of the proteins involved in energy metabolism suggests them as potential targets for Tian treatment and potentially crucial for the effective treatment of stress-related MD. Google Scholar. J. Neurochem. Curr. CSIS led to upregulation of proteins associated with actin cytoskeleton, signaling transduction and glucose metabolism. Biochimica et Biophysica Acta - Bioenergetics 1777, 965972 (2008). But it most often refers to nutritional . De Simoni, M. G., De Luigi, A., Clavenna, A. Accordingly, glycolytic-made NADH produced by up-regulated protein expression of MDH2 and Got1, would have increased entry to synaptic mitochondria for oxidation. Tianeptine by AMO Pharma for Rett Syndrome: Likelihood of Approval 16, 35343540 (1996). ADS sharing sensitive information, make sure youre on a federal It is administered orally and intravenous route. To reveal the molecular basis of MDD and effects of Tian, hippocampal synaptoproteome changes in rats exposed to CSIS with or without antidepressant Tian treatment was done using 1D SDS-PAGE in combination with a nano LCMS/MS system analysis. However, the trend of up-regulated protein expression was observed in Tian-treated CSIS rats. The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: the role of 5-HT receptors. They were housed under standard conditions in groups up to four per cage at a temperature 202C, humidity 5510% with access to water and food (commercial rat pellets) ad libitum. Nat. Anesth Analg. The staining of the immunohistochemical complexes was performed with 3,3'-diaminobenzidine (D5637 Sigma-Aldrich). $ 73.48 - $ 134.98. The validation of the synaptoproteomic data for selected proteins was performed by Western blot on a separate batch of animals (n=46 per group) that underwent the same procedure as explained in the Study design section. Tianeptine affects brain chemicals. 86, 10.8.110.8.11 (2016). PubMedGoogle Scholar. Article Biol. Neuropharmacology 93, 274284 (2015). For people struggling with anxiety or depression, it can have significant mood enhancing effects. Nootropic Source's Tianeptine Sulfate has been lab-tested and verified for both product purity and identity. MeSH When an obscurity becomes a trend: Social-media descriptions of Significance of these pathways represents potential common targets for different types of antidepressant. 1. 6). The pellet containing mitochondria and synaptosomes was processed based on Percoll (GE Healthcare) gradient procedure (15%, 24%, and 40%) in sucrose buffer41, for separation of synaptosomal fraction. [1][2] Nootropics are thought to work by altering the availability of the brain's supply of neurochemicals (i.e. Pittenger, C. & Duman, R. S. Stress, depression, and neuroplasticity: A convergence of mechanisms. Reliable Source. Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats, https://doi.org/10.1038/s41598-021-97186-7. Sci Rep 11, 17747 (2021). Phosphorylation of Syn1 by CaamkI causes a release of synaptic vesicles from the cytoskeleton and increases the number of vesicles available for fusion with plasma membrane. For Tian-treated Controls, significantly more interactions were revealed among up-regulated proteins with enrichment (p<11016). Kasper, S. & McEwen, B. S. Neurobiological and clinical effects of the antidepressant tianeptine. Physiol. Tian increased the expression of several proteins associated with vesicle-mediated transport such as Dnm1, Dpysl2, Hspa8, Pacsin1, Rab3a, Stx1b, Stxbp1, Syt1. Data were expressed as meanSEM, n=46 independent measurements in each group. For Glul expression changes, CSIS showed a significant main effect as revealed by ANOVA (F1.20=9.44, p<0.01). Substances frequently discussed as being co-used with tianeptine were typically referred to as "nootropics" (or "noots," or "cognitive enhancers"). Sanacora, G., Treccani, G. & Popoli, M. Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. All animals were maintained under a 12h light/dark cycle (lights on 07.00 to 19.00h). Psychiatry 52, 175184 (2002). Among main biological processes affected by down-regulated proteins were transport, mainly vesicle mediated and protein transport, cytoskeleton organization with synaptic vesicle cycle and phagosome activated KEGG pathways (Fig. 42 filter paper and Millipore Express PES membrane filter (0.22m). ATP generated by synaptic vesicle-associated pyruvate kinase (Pkm) is harnessed to transport glutamate into synaptic vesicles63. The 6-week experiment was divided into two parts (Fig. Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats. Up-regulated MDH2 has been found in post-mortem brain tissue of MDD patients using proteomic approach66. Best Nootropics (2023 Rankings) Strongest Brain Boosters & Most Life Sci. Tianeptine Sodium Powder. Within an hour of use, it provides mental stability and clarity, functioning as a medium duration productivity tool. However, a similar pattern of action could be related with modulations of synaptic vesicle dynamics. Tianeptine use: Another dangerous substance emerges during opioid crisis As part of its public health mission, FDA has been monitoring for adverse effects from opioids and opioid-like. Hence, our study was conducted on male Wistar rat only, and the results of this study should be interpreted strictly in regard to male rat population. Kole, M. H. P., Swan, L. & Fuchs, E. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. 5bf). Neurobiol. Glul was significantly increased in CSIS rats (1.28 fc, **p<0.01), as detected by proteomic study. Neurosci. Federal government websites often end in .gov or .mil. Yiu Chung Tse, Jolle Lopez, Tak Pan Wong, Tiziana Bonifacino, Jessica Mingardi, Laura Musazzi, Jacopo Lamanna, Francesco Isotti, Antonio Malgaroli, Qiao Deng, Shao-qi Zhang, Jian-guo Chen, Hope Kronman, Anglica Torres-Berro, Eric J. Nestler, Enrica Montalban, Omar Al-Massadi, Albert Giralt, Anne-Kathrin Gellner, Aileen Sitter, Valentin Stein, Scientific Reports Best Nootropics: 11 Dietary Supplements to Boost Your Mental Performance. 1659, 4154 (2017). Social isolation stress-resilient rats reveal energy shift from glycolysis to oxidative phosphorylation in hippocampal nonsynaptic mitochondria. Prevention of stress-induced morphological and cognitive consequences. The actual concentration of Tian in solution (3.94mg/ml) was determined with the use of high-performance liquid chromatography with photodiode array detector. Negative side effects can occur if used carelessly, so make sure you're aware of the risks of Tianeptine. Nature 266, 730732 (1977). Google Scholar. Google Scholar. Med. Epub 2012 Jan 17. Hou, S. T. et al. Proteins and peptides identified according to only one peptide match and/or one unique peptide were excluded from bioinformatics analysis. Protoc. Paxinos, G. & Watson, C. The rat brain in stereotaxic coordinates (Academic Press, 2005). Subcell. 43, 7798 (2007). Careers. Conception and design of experiments: D.F; Performed experiments and data analysis: I.P, V.C, S.Dj, D.F; Interpreted results: I.P, D.F; Wrote, reviewed, and edited the manuscript: I.P, P.F, P.G, D.I, S.B, D.F; Research Funding: P.F, P.G, D.I, S.B, D.F. 33, 1329 (2003). Filipovi, D., Todorovi, N., Bernardi, R. E. & Gass, P. Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms. Chronic stress-induced changes in the rat brain: Role of sex differences and effects of long-term tianeptine treatment. The most frequently mentioned nootropic drug was phenibut (n=35; 4-amino-3-phenul-butyric acid), a GABA B agonist with anxiolytic and putative cognitive-enhancing effects sold online as a dietary supplement, and clinically prescribed . Tian treatment may also exert its role by controlling oxidative stress, given that increased expressions of antioxidant-related enzyme Prdx6, responsible for peroxide removal was found. CAS Tianeptine isn't playing around. Protoc. Nat. Fast and free shipping on orders over $150 (USA ONLY) Tianeptine - PsychonautWiki Literature data have shown that Camk2 could be implicated in the mechanism of antidepressant drug action58,59. Article Deletion of glutamate delta-1 receptor in mouse leads to aberrant emotional and social behaviors. Tianeptine Sulfate. Serum proteomic profiling of major depressive disorder. The present study was conducted on the animals that underwent behavior assessment and were classified according to behavior parameters resembling depressive- and anxiety-like behaviors and antidepressant efficacy14. This work was supported by the Grant of Ministry of Education, Science and Technological Development of the Republic of Serbia (451-03-9/2021-14/ 200017) to I.P and D.F, Grant from the Deutsche Forschungsgemeinschaft (GA 427/12-1) to P.G and by grants from the Deutsche Forschungsgemeinschaft (DFG) IN 68/3-1, the Ingeborg Stnder Foundation, the ERA-NET NEURON program, the Bundesministerium fr Bildung und Forschung (BMBF) under the frame of Neuron Cofund (ERA-NET NEURONNMDAR-PSY) and the Swiss National Foundation (SNF) 186346 to D.I. The majority of up-regulated proteins were enzymes involved in glucose metabolism (Aldoa, Aldoart2, Aldoc, Eno3, Gpi, Pdhb, Pgam1, Pgk1, Pkm) and tricarboxylic acid (TCA) (MDH2). Steward, O. For more of my own personal experiences, thoughts, and comparisons please see the written and video reviews in the sidebar. Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity. Psychiatry Clin. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. J. PubMed Hence, Tian-induced up-regulation of Glud1 may target TCA cycle in the hippocampus of CSIS rats, having a beneficial impact on the glutamate metabolism in the brain. Curr. Collins, B. M., McCoy, A. J., Kent, H. M., Evans, P. R. & Owen, D. J. Molecular architecture and functional model of the endocytic AP2 complex. Luine, V., Villegas, M., Martinez, C. & McEwen, B. S. Repeated stress causes reversible impairments of spatial memory performance. Tianeptine modulates synaptic vesicle dynamics and favors - Nature The neurobiological properties of Tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation HHS Public Access. Briefly, sections (Bregma -3.12 to -3.60mm, according to Paxinos and Watson45) were rinsed three times in PBS containing 0.05% Triton and subsequently incubated with 0.6% hydrogen-peroxide in PBS with Triton for 30min. Article There is some discrepancy by comparing the Tian-induced sub-proteome changes in the CSIS rats with those observed in Controls (Table 2). Pegasus Nootropic Supplement Capsules - Tianeptine Plus Nootropics and Botanicals 700mg BLEND PER CAPSULE CONTAINS TIANEPTINE , SAKAE NAA AKA COMBRETUM QUADRANGULARE & KAVA 15 CT JAR SAKAE NAA is considered similar in effects to green or white strain kratom and more known for its uplifting energizing effects. In spite of the efforts, the involvement of hippocampal synapses with the underlying pathophysiology of MDD, as well as the treatment remain elusive. Eur. Upon sacrification, whole brains were immediately isolated and kept in 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS) at 4C during the night. 11, 114 (2017). Everything is theraputic & helpful especially /w Social Anxiety. Tianeptine Sulfate Capsules - Nootropic Source | Best Nootropics Neuroimage 142, 544552 (2016). Tonix Pharmaceuticals Announces Presentation of Data Supporting 4b). volume11, Articlenumber:17747 (2021) Tian up-regulated the proteins with known neuroprotective roles, Prdx5, Sod_Cu domain-containing protein and Gsto1. In addition, Tian-induced antidepressant effects are associated with increased phosphorylation level of AMPA receptor subunit GluA1, on both Camk2 and PKA site60. https://doi.org/10.1007/s12035-016-9807-4 (2016). This enzyme converts L-glutamate into alpha-ketoglutarate, a TCA cycle intermediate75. Cruceanu, C. et al. Where To Buy Nootropics Online - Top 16 Best Suppliers (2022) Peri, I., Costina, V., Djordjevi, S. et al. Neurosci. Quantity b. 26, 15691583 (2012). Chem. Tianeptine Sodium: A Nootropic With Potentially Lethal Consequences Prim Care Companion CNS Disord. Neuron 44, 749757 (2004). CaMKII phosphorylates collapsin response mediator protein 2 and modulates axonal damage during glutamate excitotoxicity. Ishida, A., Noda, Y. The expression of proteins involved in regulation of signal transduction (Camk2d, Gdi1, Gnai2, Gnai2, Mapk1, Pebp1, Ppp3ca, Prkcg, Rab2a, Rab3a, Rhob), synaptic transmission (Snap25, Stx1b, Stxbp1, Syn1, Syn2, Syt1, Syt2) and vesicle-mediated transport in synapse (Dnm1, Dpysl2, Rab3a) was up-regulated. On the other hand, Tian seams to stimulate TCA cycle reactions and oxidative phosphorylation, at least judged by the expression of those components involved in generation of the electrochemical gradient. The final number of animals per group was n=6. Psychiatry 4, e411 (2014). Thus, increasing the expression of the Ap2a2 part of AP-2 complex, CSIS probably supports the interneuron exchange. If tianeptine really does act in the way that the author of this article has abstracted from the available literature, it could be one of the most effective antidepressants ever and have minimal risk of tolerance/addiction. The activated pathway by KEGG was oxidative phosphorylation (Fig. Nat. Similar pattern of expression changes was revealed in the dDG hippocampal subregion. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). We conducted a proteomic study on the hippocampal synaptosomal fractions of adult male Wistar rats exposed to chronic social isolation (CSIS, 6weeks), an animal model of depression and after chronic Tian treatment in controls (nootropic effect) and CSIS-exposed rats (lasting 3weeks of 6-week CSIS) (therapeutic effect). What are Nootropics? - Top Tianeptine | Nootropics Nucleic Acids Res. Brain Res. Rev. Nausea and vomiting . The increased energy demands, observed by up-regulation of TCA cycle and oxidative-phosphorylation proteins, are in compliance with an increased expression of transport-involved protein Vdac1, possibly suggesting the reinforcement of mitochondrial transport. An official website of the United States government. Kuipers, S. D., Trentani, A., van der Zee, E. A. Peri, I., Costina, V., Stanisavljevi, A., Findeisen, P. & Filipovi, D. Proteomic characterization of hippocampus of chronically socially isolated rats treated with fluoxetine: Depression-like behaviour and fluoxetine mechanism of action. Epub 2013 Nov 25. Our result corroborates a recent study demonstrating an increased level of Glud1 in the prefrontal cortex of prenatally stressed rats chronically treated with tianeptine38. Only proteins showing protein fold changes higher than 1.2 and lower than 0.8 have been considered for further analysis. Proteomic data are presented according to software pre-set p<0.01 for peptides and p<0.05 for proteins. Care Companion J Clin Psychiatry 3, 2227 (2001). Many molecular alterations associated with the pathophysiology and severity of MDD as well as the effects of the fast acting antidepressants reside within the synapse47,48. Like in Controls, Tian up-regulated the proteins involved in vesicle-mediated transport (Rab2a, Rab3a, Rab33b, Rab7a, Rala, Ywhaz, Vesicle-associated membrane protein 2).
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