scholarly journals Experimental Stroke Induces Chronic Gut Dysbiosis and Neuroinflammation in Male Mice

2020 ◽  
Author(s):  
Allison L. Brichacek ◽  
Divine C. Nwafor ◽  
Stanley A. Benkovic ◽  
Sreeparna Chakraborty ◽  
Sophia M. Kenney ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Experimental Stroke ◽  
List Type ◽  
Study Objective ◽  
Post Stroke ◽  
Gut Dysbiosis ◽  
Intestinal Pathology ◽  
Chronic Intestinal Inflammation

AbstractRecent literature implicates gut epithelia mucosa and intestinal microbiota as important players in post-stroke morbidity and mortality. As most studies have focused on the acute effects of stroke on gut dysbiosis, our study objective was to measure chronic, longitudinal changes in the gut microbiota and intestinal pathology following ischemic stroke. We hypothesized that mice with experimental ischemic stroke would exhibit chronic gut dysbiosis and intestinal pathology up to 36 days post-stroke compared to sham controls. Male C57BL/6J mice were subjected to 60 minutes of transient middle cerebral artery occlusion (tMCAO) or sham surgery. To determine the long-term effects of tMCAO on gut dysbiosis, fecal boli were collected pre- and post-tMCAO on days 0, 3, 14, and 28. Bioinformatics analysis demonstrate significant differences in abundance among Firmicutes and Bacteroidetes taxa at the phylum, family, and species levels in tMCAO compared to sham mice that persisted up to one month post-stroke. The most persistent changes in post-stroke microbial abundance were a decrease in bacteria family S24-7 and significant increases in Ruminococcaceae. Overall, these changes resulted in a persistently increased Firmicutes:Bacteroidetes ratio in stroke animals. Intestinal histopathology showed evidence of chronic intestinal inflammation that included marked increases in immune cell infiltration with mild-moderate epithelial hyperplasia and villous blunting. Increased astrocyte and microglial activity were also detected one-month post-stroke. These results demonstrate that acute, post-stroke disruption of the gut-brain-microbiota axis progresses to chronic gut dysbiosis, intestinal inflammation, and chronic neuroinflammation.Clinical PerspectivesThe microbiota-gut-brain axis, recently implicated in several neurological disorders, remains largely unexplored at chronic time points post-tMCAO.Our results demonstrate chronic gut dysbiosis, prolonged behavioral deficits, and persistent cerebral and intestinal inflammation post-tMCAO in male C57BL/6J mice.These results suggest that manipulation of microbiota may help reduce poor outcomes after stroke and lead to improved post-stroke functional recovery.

scholarly journals Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade

2020 ◽  
Author(s):  
Katarzyna Winek ◽  
Sebastian Lobentanzer ◽  
Bettina Nadorp ◽  
Serafima Dubnov ◽  
Claudia Dames ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Immune Responses ◽  
Small Rna ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Transfer Rna ◽  
Raw 264.7 Cells ◽  
Post Stroke ◽  
Susceptibility To Infection ◽  
Rna Fragments

AbstractStroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced two days after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by RT-qPCR validated the top 6 upregulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+ monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+ monocytes upregulated the top 6 stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using an ssRNA mimic induced downregulation of immune regulator Z-DNA binding protein 1 (Zbp1). In summary, we identified a “changing of the guards” between RNA types that may systemically affect homeostasis in post-stroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein- and RNA-level.Significance StatementIschemic stroke triggers peripheral immunosuppression, increasing the susceptibility to post-stroke pneumonia that is linked with poor survival. The post-stroke brain initiates intensive communication with the immune system, and acetylcholine contributes to these messages; but the responsible molecules are yet unknown. We discovered a “changing of the guards,” where microRNA levels decreased but small transfer RNA fragments (tRFs) increased in post-stroke blood. This molecular switch may re-balance acetylcholine signaling in CD14+ monocytes by regulating their gene expression and modulating post-stroke immunity. Our observations point out to tRFs as molecular regulators of post-stroke immune responses that may be potential therapeutic targets.

scholarly journals Transcriptome Based Profiling of the Immune Cell Gene Signature in Rat Experimental Colitis and Human IBD Tissue Samples

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 974
Author(s):  
Éva Boros ◽  
Bence Prontvai ◽  
Zoltán Kellermayer ◽  
Péter Balogh ◽  
Patrícia Sarlós ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Gene Signature ◽  
Immune Gene ◽  
Colon Tissue ◽  
Tissue Samples ◽  
Chronic Intestinal Inflammation ◽  
Whole Transcriptome

Chronic intestinal inflammation is characteristic of Inflammatory Bowel Disease (IBD) that is associated with the exaggerated infiltration of immune cells. A complex interplay of inflammatory mediators and different cell types in the colon are responsible for the maintenance of tissue homeostasis and affect pathological conditions. Gene expression alteration of colon biopsies from IBD patients and an in vivo rat model of colitis were examined by RNA-Seq and QPCR, while we used in silico methods, such as Ingenuity Pathway Analysis (IPA) application and the Immune Gene Signature (ImSig) package of R, to interpret whole transcriptome data and estimate immune cell composition of colon tissues. Transcriptome profiling of in vivo colitis model revealed the most significant activation of signaling pathways responsible for leukocyte recruitment and diapedesis. We observed significant alteration of genes related to glycosylation or sensing of danger signals and pro- and anti-inflammatory cytokines and chemokines, as well as adhesion molecules. We observed the elevated expression of genes that implies the accumulation of monocytes, macrophages, neutrophils and B cells in the inflamed colon tissue. In contrast, the rate of T-cells slightly decreased in the inflamed regions. Interestingly, natural killer and plasma cells do not show enrichment upon colon inflammation. In general, whole transcriptome analysis of the in vivo experimental model of colitis with subsequent bioinformatics analysis provided a better understanding of the dynamic changes in the colon tissue of IBD patients.

Abstract TP282: Eotaxin Shows a Sex-specific Association With Positive Ischemic Stroke Outcomes and Post-stroke Peripheral Leukocyte Activation

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Meaghan Roy-O'Reilly ◽  
Sarah Conway ◽  
Ilene Staff ◽  
Gilbert Fortunado ◽  
Madeline Levy ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
T Cell Activation ◽  
Whole Blood ◽  
Experimental Stroke ◽  
Stroke Severity ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Age Related ◽  
Specific Association ◽  
Peripheral Leukocytes

Background and Purpose: Eotaxin, a TH2 chemokine, has been shown to increase in mouse brain and plasma following experimental stroke. While eotaxin has been associated with age-related deficits in neurogenesis, little is known about its role in ischemic injury. Hypothesis: We tested the hypothesis that serum eotaxin levels are associated with long-term stroke outcome, with follow up mechanistic studies in a mouse model of ischemic stroke. Methods: Serum was taken from patients (n=158) 24 hours after ischemic stroke onset. Levels of serum eotaxin were quantified by ELISA, then analyzed for outcome association. For murine studies, animals (n=14) underwent 90-minute middle cerebral artery occlusion and were sacrificed at 24 hours, with sham surgery mice serving as controls. Blood was incubated with or without eotaxin (100 ng/ml) and stained for leukocyte markers and CD62L (L-selectin). Results: Although eotaxin protein levels were not significantly different between sexes, a multivariate analysis controlling for age, stroke severity and cardiovascular risk factors revealed a male-specific association between higher eotaxin levels at 24 hours post-stroke and a positive functional outcome at three months (p=.010). Analysis of peripheral leukocytes isolated from both sham and stroke mice revealed that addition of eotaxin to whole blood significantly increased the activation of myeloid cells in both in male (p=.0031) and female (p=.0048) animals, as measured by shedding of L-selectin. Further experiments demonstrated that shedding of L-selectin on CD8+ T-cells after treatment of whole blood with eotaxin was significant only in female animals (p=.0008). Conclusion: In conclusion, the results of this study suggest that eotaxin has a sex-specific association with improved stroke outcomes. Murine studies demonstrate that eotaxin causes activation of peripheral leukocytes (as measured by loss of L-selectin), with a sexually dimorphic effect on CD8+ T-cell activation that may alter the character of the post-stroke immune response and support a pro-recovery inflammatory phenotype in males. This research underscores the importance of studying both sexes in future ischemic inflammatory research.

A low-cost mouse cage warming system provides improved intra-ischemic and post-ischemic body temperature control – application for reducing variability in experimental stroke studies

2021 ◽  
Author(s):  
Sung-Ha Hong ◽  
Jeong-Ho Hong ◽  
Matthew T. Lahey ◽  
Liang Zhu ◽  
Jessica M. Stephenson ◽  
...  
Keyword(s):  
Body Temperature ◽  
Temperature Control ◽  
Support System ◽  
Low Cost ◽  
Ambient Air ◽  
Experimental Stroke ◽  
List Type ◽  
Precise Control ◽  
Post Stroke ◽  
Ischemic Period

AbstractExperimental guidelines have been proposed to improve the rigor and reproducibility of experimental stroke studies in rodents. As brain temperature is a strong determinant of ischemic injury, tight management of brain or body temperature (Tcore) during the experimental protocol is highly recommended. However, little guidance is provided regarding how or for how long temperature support should be provided. We compared a commonly used heat support method (cage on heating pad) with a low-cost custom built warm ambient air cage (WAAC) system. Both heat support systems were evaluated for the middle cerebral artery occlusion (MCAo) model in mice. The WAAC system provided improved temperature control (more normothermic Tcore and less Tcore variation) during the intra-ischemic period (60 min) and post-ischemic period (3 hrs). Neurologic deficit score showed significantly less variance at post-stroke day 1 (PSD1) in WAAC system mice. Mean infarct volume was not statistically different by heat support system, however, standard deviation was 54% lower in the WAAC system group. In summary, we provide a simple low-cost heat support system that provides superior Tcore management in mice during the intra-ischemic and post-ischemic periods, which results in reduced variability of experimental outcomes.HighlightsWe describe the fabrication of a low-cost mouse cage warming system (warmed ambient air cage; WAAC system) that can be assembled and applied in any stroke laboratory.The WAAC system provides more precise control of post-stroke mouse body temperature compared with traditional heating pad warming system.The more precise control of post-stroke core temperature reduces variability in some experimental measures in more severely injured mice.

scholarly journals The Asparaginyl Endopeptidase Legumain after Experimental Stroke

2010 ◽  
Vol 30 (10) ◽  
pp. 1756-1766 ◽  
Author(s):  
Taku Ishizaki ◽  
Agnes Erickson ◽  
Enida Kuric ◽  
Mehrdad Shamloo ◽  
Ikuko Hara-Nishimura ◽  
...  
Keyword(s):  
Immune Cell ◽  
Infarct Volume ◽  
Recovery Period ◽  
Gene Array ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Asparaginyl Endopeptidase ◽  
Infarct Area ◽  
Deficient Mice

Various proteases in the brain contribute to ischemic brain injury. We investigated the involvement of the asparaginyl endopeptidase legumain after experimental stroke. On the basis of gene array studies and in situ hybridizations, we observed an increase of legumain expression in the peri-infarct area of rats after transient occlusion of the middle cerebral artery (MCAO) for 120 mins with a maximum expression at 24 and 48 h. Immunohistochemical analyses revealed the expression of legumain in Iba1+ microglial cells and glial fibrillary acidic protein-positive astrocytes of the peri-infarct area in mice after MCAO. Post-stroke recovery was also studied in aged legumain-deficient mice (45 to 58 weeks old). Legumain-deficient mice did not show any differences in physiologic parameters compared with respective littermates before, during MCAO (45 mins), and the subsequent recovery period of 8 days. Moreover, legumain deficiency had no effect on mortality, infarct volume, and the neurologic deficit determined by the rotating pole test, a standardized grip strength test, and the pole test. However, a reduced number of invading CD74+ cells in the ischemic hemisphere indicates an involvement in post-stroke inflammation. We conclude that legumain is not essential for the functional deficit after MCAO but may be involved in mechanisms of immune cell invasion.

Coming to the Rescue: Regulatory T Cells for Promoting Recovery After Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (12) ◽  
Author(s):  
Yueman Zhang ◽  
Arthur Liesz ◽  
Peiying Li
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Inflammatory Lesion ◽  
Experimental Stroke ◽  
Immune Cell Population ◽  
Neuroinflammatory Response ◽  
Mediated Effects ◽  
Injured Brain

Immune cell infiltration to the injured brain is a key component of the neuroinflammatory response after ischemic stroke. In contrast to the large amount of proinflammatory immune cells, regulatory T cells, are an important subgroup of T cells that are involved in maintaining immune homeostasis and suppress an overshooting immune reaction after stroke. Numerous previous reports have consistently demonstrated the beneficial role of this immunosuppressive immune cell population during the acute phase after experimental stroke by limiting inflammatory lesion progression. Two recent studies expanded now this concept and demonstrate that regulatory T cells-mediated effects also promote chronic recovery after stroke by promoting a proregenerative tissue environment. These recent findings suggest that boosting regulatory T cells could be beneficial beyond modulating the immediate neuroinflammatory response and improve chronic functional recovery.

scholarly journals IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells

2012 ◽  
Vol 209 (9) ◽  
pp. 1595-1609 ◽  
Author(s):  
Margherita Coccia ◽  
Oliver J. Harrison ◽  
Chris Schiering ◽  
Mark J. Asquith ◽  
Burkhard Becher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Pathology ◽  
Bowel Diseases ◽  
Chronic Intestinal Inflammation

Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus–triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell–specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4+ T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4+ T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.

Abstract 43: Neuroprotective Effects of Inhibition of α5β1 Integrin Following Experimental Stroke: A Dual Center Pre-Clinical Study

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Danielle Edwards ◽  
Biav Reber Kittani ◽  
Gillian Grohs ◽  
Mhairi Macrae ◽  
Justin F Fraser ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Infarct Volume ◽  
Experimental Stroke ◽  
Β1 Integrin ◽  
Integrin Receptor ◽  
Post Stroke ◽  
Enhanced Mri ◽  
Bbb Permeability ◽  
Α5β1 Integrin

Blood-brain barrier (BBB) dysfunction after ischemic stroke exacerbates brain damage by contributing to edema and inflammation. The β1 integrin receptor family may contribute to this dysfunction via alteration of BBB-forming tight junction proteins. We hypothesize that inhibition of the β1 integrin receptor subtype α5β1, which is acutely expressed in infarct and peri-infarct vasculature after experimental stroke, reduces BBB permeability, reduces infarct volume, and improves functional recovery. A randomized and blinded trial was conducted using transient middle cerebral artery occlusion (MCAO) in mice (60 min; n=8) and rats (90 min; n=15) in two independent laboratories. ATN-161 (α5β1 inhibitor; 1 mg/kg) was administered IV immediately upon reperfusion and on post-stroke day 1 and 2. Infarct volume was determined by cresyl violet (mice) and T 2 weighted MRI (rat) at day 3 post MCAO. Steady state contrast enhanced MRI was used to assess BBB breakdown in rats at day 3. ATN-161 resulted in a significant reduction in infarct volume in both mice and rats when measured at post-stroke day 3 (p<0.001). BBB permeability was decreased upon ATN-161 treatment in vivo as determined by reduced IgG and claudin-5 immunostaining in mice and reduced extent of Gadolinium enhanced MRI signal change in rats. Behavioral tests (open field, rotorod, sticky label and 28 point neuroscore), demonstrated significantly improved functional recovery in both mice and rats following treatment with ATN-161. Finally, in vitro studies where stroke was simulated using oxygen and glucose deprivation or TNF-α, ATN-161 (10 μM) treatment demonstrated decreased barrier permeability as measured by trans-endothelial cell electrical resistance, FITC-dextran permeability, and claudin-5 immunocytochemistry. Collectively, our results demonstrate that post-stroke inhibition of α5β1 integrin with the small peptide ATN-161 profoundly reduces infarct volume, improves functional outcome and decreases BBB permeability in both mice and rats using two different ischemic stroke models. Therefore, inhibition of α5β1 by ATN-161 could represent a novel stroke therapeutic target worthy of further investigation.

scholarly journals Differential Transcriptomic Profiles in Canine Intestinal Organoids Following Lipopolysaccharide Stimulation

2022 ◽  
Author(s):  
Dipak K. Sahoo ◽  
Dana C. Borcherding ◽  
Lawrance Chandra ◽  
Albert E. Jergens ◽  
Todd Atherly ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cancer Progression ◽  
Intestinal Inflammation ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Signal Transduction Pathway ◽  
Glutathione Metabolism ◽  
Study Objective ◽  
Altered Expression ◽  
Chronic Intestinal Inflammation

Abstract Lipopolysaccharide (LPS) is associated with chronic intestinal inflammation and promotes intestinal cancer progression in the gut. While the interplay between LPS and intestinal immune cells has been well characterized, little is known about LPS and intestinal epithelium interactions. In this study, we explored the differential effect of LPS on proliferation and the transcriptome in 3D enteroids/colonoids obtained from dogs with naturally occurring gastrointestinal (GI) diseases, such as Inflammatory Bowel Disease (IBD) and GI mast cell tumor. The study objective was to analyze LPS-induced modulation of signaling pathways involving the intestinal epithelia and critical to colorectal cancer development in the context of IBD or a tumor microenvironment. While LPS incubation resulted in a pro-cancer gene expression pattern and stimulated proliferation of IBD enteroids and colonoids, down-regulation of several cancer-associated genes like CRYZL1, Gpatch4, SLC7A1, ATP13A2, and ZNF358 was also observed in tumor enteroids. Genes participating in porphyrin metabolism (CP), thiamine and purine metabolism (TAP2, EEF1A1), arachidonic acid, and glutathione metabolism (GPX1) exhibited a similar pattern of altered expression between IBD enteroids and IBD colonoids following LPS stimulation. In contrast, genes involved in anion transport, transcription and translation, apoptotic processes, and regulation of adaptive immune responses showed opposite expression patterns between IBD enteroids and colonoids following LPS treatment. In brief, the cross-talk between LPS/TLR4 signal transduction pathway and several metabolic pathways, such as fatty acid degradation and biosynthesis, and purine, thiamine, arachidonic acid, and glutathione metabolism, may be important in driving chronic intestinal inflammation and intestinal carcinogenesis.

Abstract W P98: Monocyte Chemotactic Protein-3 Elevated in Stoke and Aging

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Courtney A Townshend ◽  
Edward C Koellhoffer ◽  
Jeremy Grenier ◽  
Anjali Chauhan ◽  
Sharon DiMauro ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Tissue ◽  
Immune Cell ◽  
The Body ◽  
Cell Trafficking ◽  
Serum Samples ◽  
Post Stroke ◽  
Monocyte Chemotactic Protein ◽  
Aged Brain ◽  
Chemotactic Protein

Background: It is now recognized that stroke is a systemic stressor that triggers profound changes throughout the body, leading to alterations in the immune system and response. In the CNS, cell death from ischemic stroke activates glial cells, leading to trafficking of leukocytes into the brain and subsequent inflammation. Chemokines play an active role in modulating this recruitment process. Monocyte chemotactic protein-3 (MCP-3), also known as CCL7, is a chemokine that attracts a broad spectrum of immune cells. Although secreted at lower levels than the better-understood monocyte chemotactic protein-1, MCP-3 is released after injury and regulates migration of leukocytes, thus facilitating inflammation. As neuroinflammation is a well-documented complication after ischemic stroke, we hypothesized that MCP-3 levels would be elevated after stroke. In light of the fact that age is the principle risk factor for stroke, and that a chronic pro-inflammatory milieu is associated with aging, we also hypothesized that MCP-3 would increase with age. Methods: Young (10 weeks) and aged (18 months) male C57B16 mice were subjected to transient (60 minute) middle cerebral artery occlusion (MCAO) or a sham surgery. MCP-3 protein levels in brain tissue and serum samples from these stroked mice, as well as from cohorts of young and aged naïve mice, were analyzed with an ELISA. Results: The comparisons of naïve aged (n=4, mean=0.042±0.005 pg/μg) to naïve young (n=4, mean=0.017±0.009 pg/μg) mice showed a significant increase (p<.01) in MCP-3 in aged brain tissue. Additionally, when comparing aged MCAO to young MCAO (n=3, mean=0.01±0.007 pg/μg), MCP-3 was significantly elevated (p<.01) in the aged group. In comparing aged MCAO (n=6, mean=0.31±0.11 pg/ug ) to aged sham (n=6, mean=0.03±0.006 pg/μg), MCP-3 was significantly elevated (p<.05). No significant differences in MCP-3 levels in serum or between young stroke and young sham brain were seen. Conclusions: We demonstrated that levels of MCP-3 are increased post-stroke in aged mice, but not in young mice. Given what is known about the role of MCP-3 in immune cell trafficking, our data imply that MCP-3 plays a role in inflammation post-stroke, and that it also primes the aged brain for a greater inflammatory response post-stroke.

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