المؤلفون: Chloé Rauzier, Benoît Lamarche, André J. Tremblay, Patrick Couture, Frédéric Picard

المصدر: Journal of Lipid Research, Vol 63, Iss 10, Pp 100269- (2022)

مصطلحات موضوعية: dyslipidemia, IGFBP-2, lipoproteins, biomarker, tracer, clearance, Biochemistry, QD415-436

الوصف: Low circulating concentrations of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with dyslipidemia, notably with high triglyceride (TG) levels. However, the determinants by which IGFBP-2 influences lipoprotein metabolism, especially that of TG-rich lipoproteins (TRLs), are poorly understood. Here, we aimed to assess the relationships between IGFBP-2 levels and lipoprotein production and catabolism in human subjects. Fasting IGFBP-2 concentrations were measured in the plasma of 219 men pooled from previous lipoprotein kinetics studies. We analyzed production rate and fractional catabolic rates of TRLapoB-48, and LDL-, IDL-, and VLDLapoB-100 by multicompartmental modeling of l-[5,5,5-D3] leucine enrichment data after a 12 h primed constant infusion in individuals kept in a constant nutritional steady state. Subjects had an average BMI of 30 kg/m2, plasma IGFBP-2 levels of 157 ng/ml, and TG of 2.2 mmol/l. After adjustments for age and BMI, IGFBP-2 levels were negatively associated with plasma TG (r = −0.29; P < 0.0001) and positively associated with HDL-cholesterol (r = 0.26; P < 0.0001). In addition, IGFBP-2 levels were positively associated with the fractional catabolic rate of VLDLapoB-100 (r = 0.20; P < 0.01) and IDLapoB-100 (r = 0.19; P < 0.05) and inversely with the production rate of TRLapoB-48 (r = −0.28; P < 0.001). These correlations remained statistically significant after adjustments for age, BMI, and the amount of fat given during the tracer infusion. These findings show that the association between low plasma IGFBP-2 and high TG concentrations could be due to both an impaired clearance of apoB-100-containing VLDL and IDL particles and an increased production of apoB-48-containing chylomicrons. Additional studies are necessary to investigate whether and how IGFBP-2 directly impacts the kinetics of TRL.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S002222752200102XTest; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/804beca5debc4829ac7466d82ff842adTest

المؤلفون: Jean-Philippe Drouin-Chartier, RD, PhD, André J. Tremblay, PhD, Dominic Godbout, MD, Alexandre Gagnon, MD, Marie-Annick Clavel, DVM, PhD, Marine Clisson, BSc, Benoit J. Arsenault, PhD, Philippe Pibarot, DVM, PhD, Éric Larose, MD, MSc, Patrick Couture, MD, PhD

المصدر: CJC Open, Vol 3, Iss 1, Pp 62-70 (2021)

مصطلحات موضوعية: Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Background: Determinants of coronary artery calcification (CAC) prevalence and severity in heterozygous familial hypercholesterolemia (HeFH) remain understudied. The objective of this cross-sectional study was to investigate correlates of CAC in patients with HeFH. Methods: A CAC score was calculated by a noncontrast computed tomography scan in women (n = 68) and men (n = 78) with genetically defined HeFH. We classified CAC prevalence and severity using 3 categories: CAC score = 0 Agatston Unit (AU), CAC score = 1-100 AU, and CAC score > 100 AU. Information on potential correlates of CAC including familial and personal health history, cardiovascular risk factors, lipid-lowering medication, and lifestyle habits was collected. Results: A total of 95 patients had prevalent CAC. Independent correlates of CAC prevalence and severity included age (odds ratio [OR] per 10 years: 5.06, 95% confidence interval [CI]: 3.19, 7.93, P < 0.0001), family history of premature cardiovascular disease (OR: 3.88, 95% CI: 1.71, 8.81, P = 0.001), male sex (OR: 3.40, 95% CI: 1.49, 7.78, P = 0.004), statin use (OR: 15.5, 95% CI: 1.89, 126, P = 0.01), diet quality assessed with the Alternative Healthy Eating Index score (OR per 1 standard deviation: 0.59, 95% CI: 0.39, 0.90, P = 0.01), ever smoking (OR: 3.06, 95% CI: 1.20, 7.81, P = 0.02), receptor-negative genotype (OR: 3.17, 95% CI: 1.16, 8.66, P = 0.02), lipoprotein(a) year-score (OR per 1 standard deviation of log-transformed year-score: 1.53, 95% CI: 0.99, 2.36, P = 0.05). Conclusions: In individuals with HeFH, age, family history of premature cardiovascular disease, sex, statin use, diet quality, smoking status, the LDLR genotype, and lipoprotein(a) concentrations were independently associated with CAC prevalence and severity. Résumé: Contexte: Les déterminants de la prévalence et de la sévérité de la calcification des artères coronaires (CAC) dans l'hypercholestérolémie familiale hétérozygote (HFHe) demeurent peu étudiés. L’objectif de cette étude transversale était d'identifier les corrélats de la CAC chez des patients atteints d’HFHe. Méthodologie: Un score calcique coronarien (SCC) a été calculé par un examen de tomodensitométrie sans contraste chez des femmes (n = 68) et des hommes (n = 78) avec HFHe génétiquement définie. Nous avons classé la prévalence et la gravité de la CAC en trois catégories : SCC = 0 unité d’Agatston (UA), SCC = 1 à 100 UA et SCC > 100 UA. Des renseignements ont été recueillis sur des corrélats potentiels de la CAC, dont les antécédents médicaux familiaux et personnels, les facteurs de risque cardiovasculaire, les médicaments hypolipidémiants et les habitudes de vie. Résultats: Au total, 95 patients présentaient une CAC. Les corrélats indépendants de la prévalence et de la gravité de la CAC comprenaient l’âge (rapport de cotes [RC] par tranche de 10 ans : 5,06; intervalle de confiance [IC] à 95 % : 3,19 à 7,93; p < 0,0001), des antécédents familiaux de maladie cardiovasculaire précoce (RC : 3,88; IC à 95 % : 1,71 à 8,81; p = 0,001), le sexe masculin (RC : 3,40; IC à 95 % : 1,49 à 7,78; p = 0,004), l’emploi de statines (RC : 15,5; IC à 95 % : 1,89 à 126; p = 0,01), la qualité du régime alimentaire évaluée selon le score AHEI (Alternative Healthy Eating Index) (RC par écart-type : 0,59; IC à 95 % : 0,39 à 0,90; p = 0,01), le tabagisme (RC : 3,06; IC à 95 % : 1,20 à 7,81; p = 0,02), le génotype récepteur-négatif (RC : 3,17; IC à 95 % : 1,16 à 8,66; p = 0,02) et le score lipoprotéine(a)-année (RC par écart-type du score-année transformé en logarithme : 1,53; IC à 95 % : 0,99 à 2,36; p = 0,05). Conclusions: Chez les personnes atteintes d’HFHe, l’âge, les antécédents familiaux de maladie cardiovasculaire précoce, le sexe, l’emploi de statines, la qualité du régime alimentaire, le statut de tabagisme, le génotype du LDLR et les concentrations de lipoprotéine(a) ont été associés de façon indépendante à la prévalence et à la gravité de la CAC.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589790X2030144XTest; https://doaj.org/toc/2589-790XTest

الوصول الحر: https://doaj.org/article/3fd89e5fa28e46ee8e25988505c71742Test

المؤلفون: Jean-Philippe Drouin-Chartier, André J. Tremblay, Jean-Charles Hogue, Valéry Lemelin, Benoît Lamarche, Patrick Couture

المصدر: Journal of Lipid Research, Vol 59, Iss 8, Pp 1501-1509 (2018)

مصطلحات موضوعية: proprotein convertase subtilisin/kexin type 9, apolipoprotein B-48, cholesterol, Biochemistry, QD415-436

الوصف: Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important in the pathogenesis of atherosclerosis in insulin resistance (IR). We investigated the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations with apoB-48-containing TRL metabolism in 148 men displaying various degrees of IR by measuring in vivo kinetics of TRL apoB-48 during a constant-fed state after a primed-constant infusion of L-[5,5,5-D3]leucine. Plasma PCSK9 concentrations positively correlated with TRL apoB-48 pool size (r = 0.31, P = 0.0002) and production rate (r = 0.24, P = 0.008) but not the fractional catabolic rate (r = −0.04, P = 0.6). Backward stepwise multiple linear regression analysis identified PCSK9 concentrations as a positive predictor of TRL apoB-48 production rate (standard β = +0.20, P = 0.007) independent of BMI, age, T2D/metformin use, dietary fat intake during the kinetic study, and fasting concentrations of TGs, insulin, glucose, LDL cholesterol, or C-reactive protein. We also assessed intestinal expression of key genes involved in chylomicron processing from duodenal samples of 71 men. Expression of PCSK9 and HMG-CoAR genes was positively associated (r = 0.43, P = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520330595Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/dae75d428cce42258318ecaedab03da1Test

المؤلفون: Patrick Couture, André J. Tremblay, Isabelle Kelly, Valéry Lemelin, Arnaud Droit, Benoît Lamarche

المصدر: Journal of Lipid Research, Vol 55, Iss 1, Pp 128-137 (2014)

مصطلحات موضوعية: apolipoprotein B-48, apolipoprotein B-100, cholesterol, fatty acids, kinetic, intestine, Biochemistry, QD415-436

الوصف: Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin. However, the mechanisms underlying the overaccumulation of apolipoprotein (apo)B-48-containing TRLs in individuals with IR are not yet fully understood. This study examined the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. The in vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h with the participants in a constantly fed state. The expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism was assessed by performing real-time PCR quantification and LC-MS/MS on duodenal biopsy specimens. The TRL apoB-48 pool size and production rate were 102% (P < 0.0001) and 87% (P = 0.01) greater, respectively, in the men with IR versus the IS men. On the other hand, intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4α, and microsomal triglyceride transfer protein were significantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and significant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S002222752031748XTest; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/e3af7f41526b43e6981074e37c9d8a6eTest

المؤلفون: André J. Tremblay, Benoît Lamarche, Valéry Lemelin, Lizbeth Hoos, Suzanne Benjannet, Nabil G. Seidah, Jr. Harry R. Davis, Patrick Couture

المصدر: Journal of Lipid Research, Vol 52, Iss 3, Pp 558-565 (2011)

مصطلحات موضوعية: Niemann-Pick C1-like 1, cholesterol metabolism, 3-hydroxy-3-methylglutaryl CoA reductase, intestine, low density lipoprotein receptor, Biochemistry, QD415-436

الوصف: Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520409368Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/e0fff4ce37b64fb288719a8b97956b60Test

المؤلفون: Jean-Charles Hogue, Benoît Lamarche, André J. Tremblay, Jean Bergeron, Claude Gagné, Patrick Couture

المصدر: Journal of Lipid Research, Vol 48, Iss 6, Pp 1336-1342 (2007)

مصطلحات موضوعية: kinetic study, stable isotope, hypertriglyceridemia, Biochemistry, QD415-436

الوصف: Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n = 11) and nondiabetic controls (n = 13) using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these subfractions.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520425611Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/59ffcd88385e446395122181e5624f64Test

المؤلفون: Jean-Charles Hogue, Benoît Lamarche, Daniel Gaudet, Mathieu Larivière, André J. Tremblay, Jean Bergeron, Isabelle Lemieux, Jean-Pierre Després, Claude Gagné, Patrick Couture

المصدر: Journal of Lipid Research, Vol 45, Iss 6, Pp 1077-1083 (2004)

مصطلحات موضوعية: atherosclerosis, enzyme-linked immunosorbent assay, low density lipoprotein size, Biochemistry, QD415-436

الوصف: Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 ± 4.8 vs. 259.2 ± 4.1 Å; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = −0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations.These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520318058Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/a58a572867f24bbfabf2d2386126dfd9Test

المؤلفون: André J. Tremblay, Benoît Lamarche, Isabelle L. Ruel, Jean-Charles Hogue, Jean Bergeron, Claude Gagné, Patrick Couture

المصدر: Journal of Lipid Research, Vol 45, Iss 5, Pp 866-872 (2004)

مصطلحات موضوعية: apolipoprotein B-100, gas chromatography/mass spectrometry, kinetic, Biochemistry, QD415-436

الوصف: Early radiokinetic studies revealed that the classical metabolic defect in patients with familial hypercholesterolemia (FH) is hypocatabolism of LDL due to decreased LDL receptor activity. However, recent studies have suggested that hepatic oversecretion of apolipoprotein B-100 (apoB-100)-containing lipoproteins could also contribute to the markedly elevated plasma concentrations of LDL-cholesterol found in FH. The aim of this study was to examine the kinetics of apoB-100 labeled with a stable isotope (l-[5,5,5-D3] leucine) in five normolipidemic controls and in seven well-characterized FH subjects that included six FH heterozygotes and one FH homozygote carrying the same null LDL receptor gene mutation. As compared with controls, the VLDL apoB-100 production rate was increased by 50% in the FH heterozygotes and by 109% in the FH homozygote. Furthermore, FH subjects had significantly higher LDL apoB-100 pool size and lower LDL apoB-100 fractional catabolic rate than controls.These results indicate that the elevation of plasma LDL-cholesterol found in FH is attributable to both decreased clearance of LDL and increased hepatic production of apoB-100-containing lipoproteins.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520318265Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/49789aff7ec44dd597998e061c4ce3daTest

المؤلفون: André J Tremblay, Benoît Lamarche, Jean-Charles Hogue, Patrick Couture

المصدر: Journal of Lipid Research, Vol 50, Iss 7, Pp 1463-1471 (2009)

مصطلحات موضوعية: Apolipoprotein B-48, apolipoprotein B-100, cholesterol absorption and synthesis, gas chromatography/mass spectrometry, intestine, kinetic, Biochemistry, QD415-436

الوصف: Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (−43.0%), LDL-C (−53.6%), and triglycerides (−44.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (−48.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (−38.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r = 0.85; P < 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520307938Test; https://doaj.org/toc/0022-2275Test; https://doaj.org/article/ffd28ce249ef434fb58ec3dd9a4f4558Test

الإتاحة: https://doi.org/10.1194/jlr.P800061-JLR200Test
https://doaj.org/article/ffd28ce249ef434fb58ec3dd9a4f4558Test

المؤلفون: Patrick Couture, Lizbeth Hoos, Valéry Lemelin, Benoît Lamarche, Jr. Harry R. Davis, Nabil G. Seidah, André J. Tremblay, Suzanne Benjannet

المصدر: Journal of Lipid Research, Vol 52, Iss 3, Pp 558-565 (2011)

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Duodenum, Atorvastatin, Hyperlipidemias, Lathosterol, ABCG8, QD415-436, Biology, Biochemistry, Drug Administration Schedule, chemistry.chemical_compound, Endocrinology, Internal medicine, Hyperlipidemia, medicine, Humans, Pyrroles, RNA, Messenger, Intestinal Mucosa, 3-hydroxy-3-methylglutaryl CoA reductase, intestine, Niemann-Pick C1-like 1, Cholesterol, PCSK9, Membrane Proteins, Membrane Transport Proteins, nutritional and metabolic diseases, Cell Biology, medicine.disease, low density lipoprotein receptor, Intestines, Gene Expression Regulation, chemistry, Heptanoic Acids, LDL receptor, Commentary, Intestinal cholesterol absorption, cholesterol metabolism, lipids (amino acids, peptides, and proteins), medicine.drug

الوصف: Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::93533223ad8f12e6e60a9e300fd96b66Test
http://www.sciencedirect.com/science/article/pii/S0022227520409368Test