Publications by authors named "Teresa Tropea"

11 Publications

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Caloric restriction enhances vascular tone of cerebral and mesenteric resistance arteries in aged rats.

Mech Ageing Dev 2021 Jul 12;197:111520. Epub 2021 Jun 12.

Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036, Rende, Italy; Department of Obstetrics, Gynecology and Reproductive Science, University of Vermont, Burlington, VT, 05405, USA. Electronic address:

Vascular changes of tone and biomechanical properties induced by ageing increase the risk for cardiovascular diseases. Caloric restriction (CR) has been shown to protect against cardiovascular diseases and improve endothelial dysfunction in cerebral resistance arteries. We hypothesise that CR will enhance vascular tone and structural properties of cerebral resistance arteries and exert comparable beneficial effects on the systemic vasculature of aged rat model. Eighteen-month-old male Sprague-Dawley rats were feed either ad libitum or restricted to 60 % of calorie consumption up to 24 months of age, when body weight (BW) measurements were taken and functional and structural properties of resistance arteries were assessed using a pressure myograph. In cerebral arteries, CR increased myogenic tone (p < 0.001) and distensibility (p < 0.01) in response to intraluminal pressure and concentration-dependent constriction to KCl (p < 0.001). In mesenteric arteries constriction in response to KCl was increased (p < 0.0001) and wall thickness reduced (p < 0.01) in CR rats. BW was reduced (p < 0.0001) in FR rats. Our findings demonstrate that CR improves vascular tone of resistance arteries regardless the type of stimulus and independently of the vascular bed. CR may be a beneficial dietary approach to prevent age-related vascular diseases.
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http://dx.doi.org/10.1016/j.mad.2021.111520DOI Listing
July 2021

Enhanced Nitrite-Mediated Relaxation of Placental Blood Vessels Exposed to Hypoxia Is Preserved in Pregnancies Complicated by Fetal Growth Restriction.

Int J Mol Sci 2021 Apr 26;22(9). Epub 2021 Apr 26.

Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK.

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow-low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs ( < 0.001), and in both normal ( < 0.001) and FGR ( < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal ( < 0.0001) and FGR ( < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP ( < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.
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http://dx.doi.org/10.3390/ijms22094500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123398PMC
April 2021

Extra Virgin Olive Oil Phenols Vasodilate Rat MesentericResistance Artery via Phospholipase C (PLC)-CalciumMicrodomains-Potassium Channels (BK) Signals.

Biomolecules 2021 01 21;11(2). Epub 2021 Jan 21.

Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy.

Recent evidence suggests that the reason Extra Virgin Olive Oil (EVOO) lowers blood pressure and reduces the risk of developing hypertension is partly due to minor components of EVOO, such as phenols. However, little is still known about the mechanism(s) through which EVOO phenols mediate anti-hypertensive effects. The aim of the present study was to investigate the mechanisms of action of EVOO phenols on mesenteric resistance arteries. A pressure myograph was used to test the effect of EVOO phenols on isolated mesenteric arteries in the presence of specific inhibitors of: 1) BKca channels (Paxillin, 10 M); 2) L-type calcium channels (Verapamil, 10 M); 3) Ryanodine receptor, RyR (Ryanodine, 10 M); 4) inositol 1,4,5-triphosphate receptor, IP3R, (2-Aminoethyl diphenylborinate, 2-APB, 3 × 10 M); 5) phospholipase C, PLC, (U73122, 10 M), and 6) GPCR-G signaling, (Pertussis Toxin, 10 M). EVOO phenols induced vasodilation of mesenteric arteries in a dose-dependent manner, and this effect was reduced by pre-incubation with Paxillin, Verapamil, Ryanodine, 2-APB, U73122, and Pertussis Toxin. Our data suggest that EVOO phenol-mediated vasodilation requires activation of BKca channels potentially through a local increase of subcellular calcium microdomains, a pivotal mechanism on the base of artery vasodilation. These findings provide novel mechanistic insights for understanding the vasodilatory properties of EVOO phenols on resistance arteries.
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http://dx.doi.org/10.3390/biom11020137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912046PMC
January 2021

Grape Seed Extract Polyphenols Improve Resistance Artery Function in Pregnant eNOS Mice.

Front Physiol 2020 6;11:588000. Epub 2020 Nov 6.

Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom.

Hypertension during pregnancy is a leading cause of maternal and fetal morbidity and mortality worldwide, increasing the risk of complications including preeclampsia, intracerebral hemorrhage and fetal growth restriction. Increased oxidative stress is known to contribute to poor vascular function; however, trials of antioxidant supplementation have raised concerns about fetal outcomes, including risk of low birthweight. Grape seed extract polyphenols (GSEP) have been suggested to promote cardiovascular protection, at least in part through antioxidant actions. We tested the hypothesis that administration of GSEP during pregnancy would reduce oxidative stress and improve resistance artery function with no detrimental effects on fetal growth, in an established model of maternal hypertension associated with vascular dysfunction, the endothelial NO synthase knockout (eNOS) mouse. Pregnant C57BL/6J (WT) and eNOS mice received either GSEP (200 mg/kg/day) or drinking water, between gestational (GD) day 10.5 and GD18.5. At GD17.5, maternal systolic blood pressure (SBP) was measured; at GD18.5, maternal malondialdehyde (MDA) concentrations, vascular function of aortic, mesenteric, uterine and posterior cerebral arteries was assessed, and fetal outcome evaluated. GSEP reduced maternal SBP ( < 0.01) and plasma MDA concentrations ( < 0.01) in eNOS mice. Whilst there was no effect of GSEP on vascular reactivity of aortas, GSEP improved endothelial-dependent relaxation in mesenteric and uterine arteries of eNOS mice ( < 0.05 and < 0.001, respectively) and normalized lumen diameters of pressurized posterior cerebral arteries in eNOS mice ( < 0.001). Supplementation with GSEP had no effect in WT mice and did not affect fetal outcomes in either genotype. Our data suggest that GSEP improve resistance artery function, potentially through antioxidant actions, and provide a basis to further investigate these beneficial effects including in the prevention of intracerebral hemorrhage. Maternal supplementation with GSEP may be a safe intervention to improve outcomes in pregnancies associated with hypertension and vascular dysfunction.
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http://dx.doi.org/10.3389/fphys.2020.588000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677241PMC
November 2020

Beetroot juice lowers blood pressure and improves endothelial function in pregnant eNOS mice: importance of nitrate-independent effects.

J Physiol 2020 09 27;598(18):4079-4092. Epub 2020 May 27.

Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Key Points: Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, the effects of nitrate-containing BRJ were compared with both 'placebo' (nitrate-depleted) BRJ as well as water to control for potential nitrate-independent effects. Our data show novel, nitrate-independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS ) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasize the importance of accounting for nitrate-independent effects of BRJ in study design and interpretation.

Abstract: Maternal hypertension is associated with adverse pregnancy outcomes, including fetal growth restriction (FGR), due in part to reductions in nitric oxide (NO) bioavailability. We hypothesized that maternal dietary nitrate administration would increase NO bioavailability to reduce systolic blood pressure (SBP), improve vascular function and increase fetal growth in pregnant endothelial NO synthase knockout (eNOS ) mice, which exhibit hypertension, endothelial dysfunction and FGR. Pregnant wildtype (WT) and eNOS mice were supplemented with nitrate-containing beetroot juice (BRJ+) from gestational day (GD) 12.5. Control mice received an equivalent dose of nitrate-depleted BRJ (BRJ-) or normal drinking water. At GD17.5, maternal SBP was measured; at GD18.5, maternal nitrate/nitrite concentrations, uterine artery (UtA) blood flow and endothelial function were assessed, and pregnancy outcomes were determined. Plasma nitrate concentrations were increased in both WT and eNOS mice supplemented with BRJ+ (P < 0.001), whereas nitrite concentrations were increased only in eNOS mice (P < 0.001). BRJ- did not alter nitrate/nitrite concentrations. SBP was lowered and UtA endothelial function was enhanced in eNOS mice supplemented with either BRJ+ or BRJ-, indicating nitrate-independent effects of BRJ. Improvements in endothelial function in eNOS mice were abrogated in the presence of 25 mm KCl, implicating enhanced EDH signalling in BRJ- treated animals. At GD18.5, eNOS fetuses were significantly smaller than WT animals (P < 0.001), but BRJ supplementation did not affect fetal weight. BRJ may be a beneficial intervention in pregnancies associated with hypertension, endothelial dysfunction and reduced NO bioavailability. Our data showing biological effects of non-nitrate components of BRJ have implications for both interpretation of previous findings and in the design of future clinical trials.
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http://dx.doi.org/10.1113/JP279655DOI Listing
September 2020

Aspirin causes endothelium-dependent vasodilation of resistance arteries from non-gravid and gravid rats.

Pregnancy Hypertens 2019 Jan 10;15:141-145. Epub 2019 Jan 10.

Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende (CS), Italy. Electronic address:

Objective: The objective of this study was to understand the effect of acetylsalicylic acid (aspirin) on resistance arteries from mesentery and uterus. During pregnancy, the uterine vasculature undergoes consistent growth to provide sufficient uteroplacental blood flow, a process whose failure is associated with pregnancy complications characterized by high uterine vascular resistance.

Methods: Uterine arcuate (UA) and mesenteric arteries (MA; diameter <300 µm) isolated from non-gravid, mid-gravid (day 14), and late-gravid rats (day 20) were exposed to aspirin (10 to 10 M). Further, in UA from late-gravid rats, aspirin was evaluated in presence of inhibitors of nitric oxide synthases, cyclooxygenase, cyclic nucleotides (cAMP, cGMP) and BK channels, and also on endothelium-denuded vessels.

Results: Aspirin dilated both UA and MA in a dose dependent manner. Pregnancy increased aspirin vasodilation in MA and UA from mid-gravid rats, an effect that was reduced in vessels from late gravid animals at concentrations >10 M. Further, uterine vasodilation was significantly reduced when the endothelium was removed (p < 0.001), and by inhibitors of nitric oxide synthase (p < 0.001), cyclooxygenase synthase (p < 0.05), cyclic nucleotides cGMP/cAMP and BK channels.

Conclusion: This is the first study to show a direct vasodilatory effect of aspirin on rat uterine artery that is mediated by a combination of cellular - primarily endothelial - mechanisms. Our results in UA suggest that the use of aspirin may be effective in enhancing uteroplacental blood flow, while its vasodilation effect on MA may lower peripheral resistance.
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http://dx.doi.org/10.1016/j.preghy.2019.01.001DOI Listing
January 2019

Nitrite mediated vasorelaxation in human chorionic plate vessels is enhanced by hypoxia and dependent on the NO-sGC-cGMP pathway.

Nitric Oxide 2018 11 1;80:82-88. Epub 2018 Sep 1.

Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, Maternal & Fetal Health Research Centre, University of Manchester, United Kingdom.

Adequate perfusion of the placental vasculature is essential to meet the metabolic demands of fetal growth and development. Lacking neural control, local tissue metabolites, circulating and physical factors contribute significantly to blood flow regulation. Nitric oxide (NO) is a key regulator of fetoplacental vascular tone. Nitrite, previously considered an inert end-product of NO oxidation, has been shown to provide an important source of NO. Reduction of nitrite to NO may be particularly relevant in tissue when the oxygen-dependent NO synthase (NOS) activity is compromised, e.g. in hypoxia. The contribution of this pathway in the placenta is currently unknown. We hypothesised that nitrite vasodilates human placental blood vessels, with enhanced efficacy under hypoxia. Placentas were collected from uncomplicated pregnancies and the vasorelaxant effect of nitrite (10-5x10 M) was assessed using wire myography on isolated pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) under normoxic (pO ∼5%) and hypoxic (pO ∼1%) conditions. The dependency on the NO-sGC-cGMP pathway and known nitrite reductase (NiR) activities was also investigated. Nitrite caused concentration-dependent vasorelaxation in both arteries and veins, and this effect was enhanced by hypoxia, significantly in CPVs (P < 0.01) and with a trend in CPAs (P = 0.054). Pre-incubation with NO scavengers (cPTIO and oxyhemoglobin) attenuated (P < 0.01 and P < 0.0001, respectively), and the sGC inhibitor ODQ completely abolished nitrite-mediated vasorelaxation, confirming the involvement of NO and sGC. Inhibition of potential NiR enzymes xanthine oxidoreductase, mitochondrial aldehyde dehydrogenase and mitochondrial bc complex did not attenuate vasorelaxation. This data suggests that nitrite may provide an important reservoir of NO bioactivity within the placenta to enhance blood flow when fetoplacental oxygenation is impaired, as occurring in pregnancy diseases such as pre-eclampsia and fetal growth restriction.
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http://dx.doi.org/10.1016/j.niox.2018.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199414PMC
November 2018

Melatonin Increases Fetal Weight in Wild-Type Mice but Not in Mouse Models of Fetal Growth Restriction.

Front Physiol 2018 15;9:1141. Epub 2018 Aug 15.

Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

Fetal growth restriction (FGR) presents with an increased risk of stillbirth and childhood and adulthood morbidity. Melatonin, a neurohormone and antioxidant, has been suggested as having therapeutic benefit in FGR. We tested the hypothesis that melatonin would increase fetal growth in two mouse models of FGR which together represent a spectrum of the placental phenotypes in this complication: namely the endothelial nitric oxide synthase knockout mouse (eNOS) which presents with abnormal uteroplacental blood flow, and the placental specific knockout mouse (P0) which demonstrates aberrant placental morphology akin to human FGR. Melatonin (5 μg/ml) was administered via drinking water from embryonic day (E)12.5 in C57Bl/6J wild-type (WT), eNOS, and P0 mice. Melatonin supplementation significantly increased fetal weight in WT, but not eNOS or P0 mice at E18.5. Melatonin did, however, significantly increase abdominal circumference in P0 mice. Melatonin had no effect on placental weight in any group. Uterine arteries from eNOS mice demonstrated aberrant function compared with WT but melatonin treatment did not affect uterine artery vascular reactivity in either of these genotypes. Umbilical arteries from melatonin treated P0 mice demonstrated increased relaxation in response to the nitric oxide donor SNP compared with control. The increased fetal weight in WT mice and abdominal circumference in P0, together with the lack of any effect in eNOS, suggest that the presence of eNOS is required for the growth promoting effects of melatonin. This study supports further work on the possibility of melatonin as a treatment for FGR.
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http://dx.doi.org/10.3389/fphys.2018.01141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104307PMC
August 2018

Effects of dietary nitrate supplementation, from beetroot juice, on blood pressure in hypertensive pregnant women: A randomised, double-blind, placebo-controlled feasibility trial.

Nitric Oxide 2018 11 9;80:37-44. Epub 2018 Aug 9.

Maternal & Fetal Health Research Centre, Division of Developmental Biology & Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; St Mary's Hospital, Manchester University Hospital NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, United Kingdom. Electronic address:

Chronic hypertension in pregnancy is associated with significant adverse pregnancy outcomes, increasing the risk of pre-eclampsia, fetal growth restriction and preterm birth. Dietary nitrate, abundant in green leafy vegetables and beetroot, is reduced in vivo to nitrite and subsequently nitric oxide, and has been demonstrated to lower blood pressure, improve vascular compliance and enhance blood flow in non-pregnant humans and animals. The primary aims of this study were to determine the acceptability and efficacy of dietary nitrate supplementation, in the form of beetroot juice, to lower blood pressure in hypertensive pregnant women. In this double-blind, placebo-controlled feasibility trial, 40 pregnant women received either daily nitrate supplementation (70 mL beetroot juice, n = 20) or placebo (70 mL nitrate-depleted beetroot juice, n = 20) for 8 days. Blood pressure, cardiovascular function and uteroplacental blood flow was assessed at baseline and following acute (3 h) and prolonged (8 days) supplementation. Plasma and salivary samples were collected for analysis of nitrate and nitrite concentrations and acceptability of this dietary intervention was assessed based on questionnaire feedback. Dietary nitrate significantly increased plasma and salivary nitrate/nitrite concentrations compared with placebo juice (p < 0.001), with marked variation between women. Compared with placebo, there was no overall reduction in blood pressure in the nitrate-treated group; however there was a highly significant correlation between changes in plasma nitrite concentrations and changes in diastolic blood pressure in the nitrate-treated arm only (r = -0.6481; p = 0.0042). Beetroot juice supplementation was an acceptable dietary intervention to 97% of women. This trial confirms acceptability and potential efficacy of dietary nitrate supplementation in pregnant women. Conversion of nitrate to nitrite critically involves oral bacterial nitrate reductase activities. We speculate that differences in efficacy of nitrate supplementation relate to differences in the oral microbiome, which will be investigated in future studies.
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http://dx.doi.org/10.1016/j.niox.2018.08.004DOI Listing
November 2018

Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy.

J Physiol 2017 08 27;595(15):5095-5102. Epub 2017 Feb 27.

School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, M13 9WL, UK.

Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth.
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http://dx.doi.org/10.1113/JP273331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538211PMC
August 2017

Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway.

PLoS One 2015 4;10(11):e0141997. Epub 2015 Nov 4.

Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy.

Background: The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature.

Aim: The aim of this study was to determine the function of GPER in uterine arteries mainly during pregnancy. Uterine arteries were isolated from nonpregnant and pregnant rats.

Methods: Vessels were contracted with phenylephrine and then incubated with incremental doses (10-12-10-5 M) of the selective GPER agonist G1.

Results: G1 induced a dose-dependent vasodilation which was: 1) significantly increased in pregnancy, 2) endothelium-dependent, 3) primarily mediated by NO/cGMP pathway and 4) unaffected by BKca channel inhibition.

Conclusion: This is the first study to show the potential importance of GPER signaling in reducing uterine vascular tone during pregnancy. GPER may therefore play a previously unrecognized role in the regulation of uteroplacental blood flow and normal fetus growth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633123PMC
June 2016
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