scholarly journals Hyperpolarized [1-13C]lactate flux increased in the hippocampal region in diabetic mice

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Young-Suk Choi ◽  
Jae Eun Song ◽  
Jong Eun Lee ◽  
Eosu Kim ◽  
Chul Hoon Kim ◽  
...  
Keyword(s):  
Active Form ◽  
Lactate Production ◽  
Fold Increase ◽  
Serum Glucose ◽  
Control Group ◽  
Resonance Spectroscopy ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Hippocampal Region ◽  
Atp Citrate Lyase

Abstract Increasing evidence suggests there is a relationship between cognitive impairment and metabolic dysfunction. Diabetes is a chronic disease, and metabolic factors affecting brain metabolisms, such as serum glucose, insulin, and glucagon, are altered according to disease progression. In our previous study, we applied hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy in prediabetic mice after feeding them a 60% high-fat diet (HFD) for 6 months. Ultimately, we detected significantly increased [1-13C]lactate conversion in the whole brain and an almost five-fold increased [1-13C]lactate/pyruvate ratio in the hippocampal region. In the present study, we induced diabetes in mice by injecting streptozotocin and feeding them an HFD for 6 months. Unlike in prediabetic mice, [1-13C]lactate conversion in the diabetic mice did not differ from that in the control group, but [1-13C]lactate/total 13C ratio showed an almost 1.4-fold increase in the hippocampal region. We measured the amount of the lactate and mRNA levels of glucose transporters from isolated hippocampus and cortex samples. In the hippocampus, significantly decreased GLUT1 mRNA levels and increased lactate were detected, suggesting an inconsistency between glucose and pyruvate metabolism. Pyruvate can be produced from oxaloacetate as well as glucose. We investigated ATP citrate lyase (ACLY) because it cleaves citrate into oxaloacetate and acetyl CoA. Phosphorylated ACLY (Ser455), the active form, was increased in both hippocampus and cortex samples of mice injected with streptozotocin and fed an HFD. Also, phosphorylated ACLY/total ACLY showed a positive correlation with lactate amount in the hippocampus. Our results suggest that the brain has different responses to diabetic progression, but, in the hippocampus, maintains metabolic alteration toward increasing lactate production from the prediabetic to the diabetic stage. We suggest that ACLY-mediated pyruvate be used to support lactate levels in the hippocampus in cases of limited glucose availability.

scholarly journals Endometrial injury concurrent with hysteroscopy increases the expression of Leukaemia inhibitory factor: a preliminary study

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Suat Suphan Ersahin ◽  
Aynur Ersahin
Keyword(s):  
Mrna Expression ◽  
Fold Increase ◽  
Inhibitory Factor ◽  
Leukaemia Inhibitory Factor ◽  
Control Group ◽  
Mrna Levels ◽  
Promoting Effect ◽  
Chain Reactions ◽  
Endometrial Injury ◽  
Before And After

Abstract Objective It is not known by which mechanism endometrial injury increases pregnancy rates. Leukaemia inhibitory factor (LIF) is a cytokine involved in wound healing and implantation. The aim of this study was to determine the change in endometrial LIF mRNA expression before and after mechanical injury during hysteroscopy. Methods Forty patients with a history of two or more unsuccessful implantations who decided to undergo hysteroscopy in the proliferative phase were divided into two equal groups: one with endometrial injury (scratching group) and the other with noninjury (control group). Endometrial sampling was conducted before injury on the patients in the scratching group, and then injury was performed with monopolar needle forceps. Only diagnostic hysteroscopy was performed on the patients in the control group. Endometrial tissues were collected using a Pipelle catheter between Days 20 and 23 of the mid-luteal phase of the next cycles in both the scratching and control groups. Endometrial LIF mRNA expression was evaluated with the use of reverse-transcription polymerase chain reactions. Results Relative changes in mRNA expression levels of the LIF gene in endometrial samples taken before and after injury were calculated using the 2-ΔΔCt method, and the fold changes obtained were compared between and within the groups. Compared with preinjury values, an 11.1-fold increase was found in postinjury LIF mRNA expression in patients with monopolar forceps injury (p < 0.001). There was a 3.9-fold significant increase in postinjury LIF mRNA levels compared with those in the control group (p < 0.02). Conclusions The fertility-promoting effect of hysteroscopy-guided mechanical endometrial injury may be mediated by LIF mRNA.

scholarly journals D-limonene in diabetic rats

2021 ◽  
Vol 10 (3) ◽  
pp. e24-e24
Author(s):  
Shahrokh Bagheri ◽  
Mostafa Moradi Sarabi ◽  
Mohammadreza Gholami ◽  
Vahideh Assadollahi ◽  
Reza Mohammadrezaei Khorramabadi ◽  
...  
Keyword(s):  
Real Time ◽  
Kidney Tissue ◽  
Serum Levels ◽  
Diabetic Control ◽  
Serum Glucose ◽  
Diabetic Rats ◽  
Tissue Homogenate ◽  
Control Group ◽  
Mrna Levels ◽  
Male Wistar Rats

Introduction: Diabetes mellitus (DM) is a multi-factorial condition associated with oxidative stress. Limonene, as a plant-derived antioxidant, can be used for treating DM. Objectives: An investigation on antioxidant effects in diabetic rats exposed to D-limonene. Materials and Methods: Sixty male Wistar rats were categorized into six groups as follows: control (healthy rats), diabetic control (untreated diabetic rats), sham glibenclamide, diabetic glibenclamide, sham limonene, and finally diabetic limonene. Alloxan (100 mg/dL) was infused intraperitoneally to induce type 1 diabetes in rats. Rats in certain groups were given limonene (100 mg/dL) and glibenclamide (10 mg/dL) orally for 8 weeks. Subsequently, animals were killed, and their kidneys were removed. Serum levels of biochemical factors (including serum creatinine, urea, and glucose) were determined, and factors such as nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), and myeloperoxidase (MPO) were measured in kidney tissue homogenate. The gene expression and enzymatic activity of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) in the kidney were measured by real-time polymerase chain reaction (real-time PCR) and spectrophotometry, respectively. Results: Limonene treatment significantly decreased serum glucose, creatinine, and urea. Additionally, MDA, MPO, and NO significantly decreased while GSH increased after treatment with limonene. Real-time RT-PCR showed significant elevation (P<0.05) in mRNA levels of GPx, CAT, and SOD in the limonene-treated compared with the diabetic control group. Conclusion: Our results demonstrated that limonene as an herbal antioxidant had better effects on antioxidant markers compared to glibenclamide in rat models of diabetes.

scholarly journals Thyroid states regulate subcellular glucose phosphorylation activity in male mice

2017 ◽  
Vol 6 (5) ◽  
pp. 311-322 ◽  
Author(s):  
Flavia Letícia Martins Peçanha ◽  
Reinaldo Sousa dos Santos ◽  
Wagner Seixas da-Silva
Keyword(s):  
Gastrocnemius Muscle ◽  
Glucose Utilization ◽  
Fold Increase ◽  
Control Group ◽  
Mrna Levels ◽  
Mechanism Analysis ◽  
Mouse Tissues ◽  
Glucose Phosphorylation ◽  
Cellular Compartments ◽  
First Time

The thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), are very important in organism metabolism and regulate glucose utilization. Hexokinase (HK) is responsible for the first step of glycolysis, catalyzing the conversion of glucose to glucose 6-phosphate. HK has been found in different cellular compartments, and new functions have been attributed to this enzyme. The effects of hyperthyroidism on subcellular glucose phosphorylation in mouse tissues were examined. Tissues were removed, subcellular fractions were isolated from eu- and hyperthyroid (T3, 0.25 µg/g, i.p. during 21 days) mice and HK activity was assayed. Glucose phosphorylation was increased in the particulate fraction in soleus (312.4% ± 67.1, n = 10), gastrocnemius (369.2% ± 112.4, n = 10) and heart (142.2% ± 13.6, n = 10) muscle in the hyperthyroid group compared to the control group. Hexokinase activity was not affected in brain or liver. No relevant changes were observed in HK activity in the soluble fraction for all tissues investigated. Acute T3 administration (single dose of T3, 1.25 µg/g, i.p.) did not modulate HK activity. Interestingly, HK mRNA levels remained unchanged and HK bound to mitochondria was increased by T3 treatment, suggesting a posttranscriptional mechanism. Analysis of the AKT pathway showed a 2.5-fold increase in AKT and GSK3B phosphorylation in the gastrocnemius muscle in the hyperthyroid group compared to the euthyroid group. Taken together, we show for the first time that THs modulate HK activity specifically in particulate fractions and that this action seems to be under the control of the AKT and GSK3B pathways.

scholarly journals Antidiabetic and Antihyperlipidemic Effects of Sulphurenic Acid, a Triterpenoid Compound from Antrodia camphorata, in Streptozotocin-Induced Diabetic Mice

2019 ◽  
Vol 20 (19) ◽  
pp. 4897 ◽  
Author(s):  
Cheng-Hsiu Lin ◽  
Li-Wei Hsiao ◽  
Yueh-Hsiung Kuo ◽  
Chun-Ching Shih
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Protective Effect ◽  
Fatty Acid Synthase ◽  
Control Group ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Antrodia Camphorata ◽  
Expression Levels ◽  
Lower Blood

The present study was designed to evaluate the protective effect of sulphurenic acid (SA), a pure compound from Antrodia camphorata, on diabetes and hyperlipidemia in an animal model study and to clarify the underlying molecular mechanism. Diabetes was induced by daily 55 mg/kg intraperitoneal injections of streptozotocin (STZ) solution over five days. Diabetic mice were randomly divided into six groups and orally gavaged with SA (at three dosages) or glibenclamide (Glib), fenofibrate (Feno) or vehicle for 3 weeks. Our findings showed that STZ-induced diabetic mice had significantly increased fasting blood glucose, glycated hemoglobin (HbA1C), plasma triglyceride (TG), and total cholesterol (TC) levels (p < 0.001, p < 0.001, p < 0.001, and p < 0.05, respectively) but decreased blood insulin, adiponectin, and leptin levels compared to those of the control group (p < 0.001, p < 0.001, and p < 0.001, respectively). Administration of SA to STZ-induced diabetic mice may lower blood glucose but it increased the insulin levels with restoration of the size of the islets of Langerhans cells, implying that SA protected against STZ-induced diabetic states within the pancreas. At the molecular level, SA treatment exerts an increase in skeletal muscle expression levels of membrane glucose transporter 4 (GLUT4) and phospho-Akt to increase the membrane glucose uptake, but the mRNA levels of PEPCK and G6Pase are decreased to inhibit hepatic glucose production, thus leading to its hypoglycemic effect. Moreover, SA may cause hypolipidemic effects not only by enhancing hepatic expression levels of peroxisome proliferator-activated receptor α (PPARα) with increased fatty acid oxidation but also by reducing lipogenic fatty acid synthase (FAS) as well as reducing mRNA levels of sterol regulatory element binding protein (SREBP)1C and SREBP2 to lower blood TG and TC levels. Our findings demonstrated that SA displayed a protective effect against type 1 diabetes and a hyperlipidemic state in STZ-induced diabetic mice.

scholarly journals Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1772
Author(s):  
Hugo Ramos ◽  
Patricia Bogdanov ◽  
David Sabater ◽  
Jordi Huerta ◽  
Marta Valeri ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Neuroprotective Effect ◽  
Topical Administration ◽  
Control Group ◽  
Eye Drops ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Neuroprotective Effects ◽  
Dipeptidyl Peptidase 4 ◽  
Presynaptic Proteins

Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role.

Plasma Levels of Lipoprotein(a) Are Elevated in Patients with the Antiphospholipid Antibody Syndrome

1994 ◽  
Vol 71 (04) ◽  
pp. 424-427 ◽  
Author(s):  
Masahide Yamazaki ◽  
Hidesaku Asakura ◽  
Hiroshi Jokaji ◽  
Masanori Saito ◽  
Chika Uotani ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Active Form ◽  
Plasminogen Activator Inhibitor ◽  
Arterial System ◽  
Control Group ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Lipoprotein A ◽  
Soluble Thrombomodulin ◽  
Relationship Of

SummaryThe mechanisms underlying clinical abnormalities associated with the antiphospholipid antibody syndrome (APAS) have not been elucidated. We measured plasma levels of lipoprotein(a) [Lp(a)], the active form of plasminogen activator inhibitor (active PAI), thrombin-antithrombin III complex (TAT) and soluble thrombomodulin (TM), to investigate the relationship of these factors to thrombotic events in APAS. Mean plasma levels of Lp(a), TAT, active PAI and TM were all significantly higher in patients with aPL than in a control group of subjects. Plasma levels of Lp(a) and active PAI were significantly higher in patients with aPL and arterial thromboses than in patients with aPL but only venous thromboses. There was a significant correlation between plasma levels of Lp(a) and active PAI in patients with aPL. These findings suggest that patients with aPL are in hypercoagulable state. High levels of Lp(a) in plasma may impair the fibrinolytic system resulting in thromboses, especially in the arterial system.

Effect of Chelated Mineral Mixture on Blood Biochemistry, Hormone and Mineral Status in Repeat Breeder Buffaloes in Tribal Areas of Dahod District in Gujarat, India

2019 ◽  
Vol 15 (01) ◽  
pp. 40-44 ◽  
Author(s):  
P M Joshi ◽  
D Patel ◽  
P D Patel
Keyword(s):  
Treatment Group ◽  
Experimental Period ◽  
Serum Glucose ◽  
Blood Biochemistry ◽  
Control Group ◽  
Blood Collection ◽  
Mineral Status ◽  
Blood Biochemical ◽  
Mineral Mixture ◽  
Repeat Breeder

An on-farm trial for 90 days was conducted at four tribal villages to assess the effect of chelated mineral mixture (CMM) supplementation on blood biochemistry as well as hormonal and mineral status, nutrient intake and reproductive performance of the repeat breeder buffaloes (n = 24). The animals selected were randomly divided into two groups of 12 animals each. The group T1 was control group (farmer’s feeding schedule), and T2 treatment group (T1 + CMM @ 50 g/animal/day). Blood collection was done at 0, 45 and 90 days of the experiment from both the groups for assessment of blood biochemical, hormonal and mineral status of the animals. Average DM, DCP and TDN intake in repeat breeder buffaloes calculated as per information collected from farmers were statistically similar among both the groups and were as per ICAR requirements of animals. Results revealed significant (p less than 0.05) improvement in hemoglobin, serum glucose, total protein, total cholesterol, progesterone, and macro (Ca, P)–micro (Zn, Fe, Cu, Co, Mn) mineral status of chelated mineral supplemented group as compared to control animals. The number of days taken for a successful conception in repeat breeder buffaloes as well as the cost of feeding was also reduced upon supplementation of CMM in T2 as compared to T1 group. The control group recorded a 22.12% higher cost of rearing than the treatment group during the experimental period. The findings revealed the beneficial role of cheated minerals supplementation in improving health, nutritional and reproductive status of repeat breeding buffaloes.

scholarly journals Arginase Isoform Expression in Chronic Rhinosinusitis

2019 ◽  
Vol 8 (11) ◽  
pp. 1809 ◽  
Author(s):  
Diana Vlad ◽  
Silviu Albu
Keyword(s):  
Nitric Oxide ◽  
Chronic Rhinosinusitis ◽  
Defense Mechanisms ◽  
Upper Airway ◽  
Control Group ◽  
Mrna Levels ◽  
Tissue Samples ◽  
Endoscopic View ◽  
Important Regulator ◽  
Arginase I

Nitric oxide (NO) has emerged as an important regulator of upper airway inflammation, mainly as part of the local naso-sinusal defense mechanisms. Increased arginase activity can reduce NO levels by decreasing the availability of its precursor, L-arginine. Chronic rhinosinusitis (CRS) has been associated with low levels of nasal nitric oxide (nNO). Thus, the present study investigates the activity of arginase I (ARG1) and II (ARG2) in CRS and its possible involvement in the pathogenesis of this disease. Under endoscopic view, tissue samples of pathologic (n = 36) and normal (n = 29) rhinosinusal mucosa were collected. Arginase I and II mRNA levels were measured using real-time PCR. Our results showed low arginase I activity in all samples. The levels of ARG2 were significantly higher in patients with chronic rhinosinusitis compared to the control group (fold regulation (FR) 2.22 ± 0.42 vs. 1.31 ± 0.21, p = 0.016). Increased ARG2 expression was found in patients with CRS without nasal polyposis (FR 3.14 ± 1.16 vs. 1.31 ± 0.21, p = 0.0175), in non-allergic CRS (FR 2.55 ± 0.52 vs. 1.31 ± 0.21, p = 0.005), and non-asthmatic CRS (FR 2.42 ± 0.57 vs. 1.31 ± 0.21, p = 0.028). These findings suggest that the upregulation of ARG2 may play a role in the pathology of a distinctive phenotype of CRS.

scholarly journals PDIA6 contributes to aerobic glycolysis and cancer progression in oral squamous cell carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ling Mao ◽  
Xiaoweng Wu ◽  
Zhengpeng Gong ◽  
Ming Yu ◽  
Zhi Huang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Growth ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Expression Pattern ◽  
Cancer Progression ◽  
Squamous Cell ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Control Group

Abstract Background/objective Accumulated evidence has demonstrated that aerobic glycolysis serves as a regulator of tumor cell growth, invasion, and angiogenesis. Herein, we explored the role of protein disulfide isomerase family 6 (PDIA6) in the aerobic glycolysis and the progression of oral squamous cell carcinoma (OSCC). Methods The expression pattern of PDIA6 in OSCC tissues was determined by qPCR and western blotting. Lentivirus and small interfering RNAs (siRNAs) were introduced into cells to upregulate and downregulate PDIA6 expression. CCK-8, flow cytometry, transwell, and xenotransplantation models were applied to detect cell proliferation, apoptosis, migration, invasion, and tumorigenesis, respectively. Results A high expression pattern of PDIA6 was observed in OSCC tissues, which was closely associated with lower overall survival and malignant clinical features in OSCC. Compared with the control group, overexpression of PDIA6 induced significant enhancements in cell growth, migration, invasiveness, and tumorigenesis and decreased cell apoptosis, while knockdown of PDIA6 caused opposite results. In addition, overexpression of PDIA6 increased glucose consumption, lactate production, and ATP level in OSCC cells. Conclusion This study demonstrated that PDIA6 expression was elevated in OSCC tissues, and overexpression of it promoted aerobic glycolysis and OSCC progression.

scholarly journals MicroRNA-513b-5p targets COL1A1 and COL1A2 associated with the formation and rupture of intracranial aneurysm

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zheng Zheng ◽  
Yan Chen ◽  
Yinzhou Wang ◽  
Yongkun Li ◽  
Qiong Cheng
Keyword(s):  
Cell Death ◽  
Intracranial Aneurysm ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Control Group ◽  
Type I ◽  
Mrna Levels ◽  
Reporter Assay ◽  
Over Expression ◽  
Tnf Α

AbstractCollagen-type I alpha 1 chain (COL1A1) and COL1A2 are abnormally expressed in intracranial aneurysm (IA), but their mechanism of action remains unclear. This study was performed to investigate the mechanism of COL1A1 and COL1A2 affecting the occurrence and rupture of IA. Quantitative real-time polymerase chain reaction was used to measure the expression of hsa-miR-513b-5p, COL1A1, COL1A2, TNF-α, IL-6, MMP2, MMP3, MMP9 and TIMP4 in patients with ruptured IA (RA) (n = 100), patients with un-ruptured IA (UA) (n = 100), and controls (n = 100). Then, human vascular smooth muscle cells (HASMCs) were cultured, and dual luciferase reporter assay was performed to analyse the targeting relationship between miR-513b-5p and COL1A1 or COL1A2. The effects of the miR-513b-5p mimic and inhibitor on the proliferation, apoptosis, and death of HASMC and the RIP1-RIP3-MLKL and matrix metalloproteinase pathways were also explored. The effect of silencing and over-expression of COL1A1 and COL1A2 on the role of miR-513b-5p were also evaluated. Finally, the effects of TNF-α on miR-513b-5p targeting COL1A1 and COL1A2 were tested. Compared with those in the control group, the serum mRNA levels of miR-513b-5p, IL-6 and TIMP4 were significantly decreased in the RA and UA groups, but COL1A1, COL1A2, TNF-α, IL-1β, MMP2, MMP3 and MMP9 were significantly increased (p < 0.05). Compared with those in the UA group, the expression of COL1A1, COL1A2, TNF-α, IL-1β and MMP9 was significantly up-regulated in the RA group (p < 0.05). Results from the luciferase reporter assay showed that COL1A1 and COL1A were the direct targets of miR-513b-5p. Further studies demonstrated that miR-513b-5p targeted COL1A1/2 to regulate the RIP1-RIP3-MLKL and MMP pathways, thereby enhancing cell death and apoptosis. Over-expression of COL1A1 or COL1A2, rather than silencing COL1A1/2, could improve the inhibitory effect of miR-513b-5p on cell activity by regulating the RIP1-RIP3-MLKL and MMP pathways. Furthermore, over-expression of miR-513b-5p and/or silencing COL1A1/2 inhibited the TNF-α-induced cell proliferation and enhanced the TNF-α-induced cell death and apoptosis. The mechanism may be related to the inhibition of collagen I and TIMP4 expression and promotion of the expression of RIP1, p-RIP1, p-RIP3, p-MLKL, MMP2 and MMP9. MiR-513b-5p targeted the inhibition of COL1A1/2 expression and affected HASMC viability and extracellular mechanism remodelling by regulating the RIP1-RIP3-MLKL and MMP pathways. This process might be involved in the formation and rupture of IA.

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