المؤلفون: William Nolan, Clive Bate, Alun Williams

المصدر: Prion

مصطلحات موضوعية: 0301 basic medicine, Cell signaling, Glycosylphosphatidylinositols, animal diseases, Biology, medicine.disease_cause, Biochemistry, Prion Diseases, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Phospholipase A2, mental disorders, Protein targeting, medicine, Animals, Humans, PrPC Proteins, Lipid raft, health care economics and organizations, Extra Views, Cholesterol, Cell Biology, nervous system diseases, Sialic acid, Cell biology, carbohydrates (lipids), Phospholipases A2, 030104 developmental biology, Infectious Diseases, chemistry, Cell culture, Cytoplasm, biology.protein, lipids (amino acids, peptides, and proteins), human activities

الوصف: There is increasing interest in the role of the glycosylphosphatidylinositol (GPI) anchor attached to the cellular prion protein (PrP(C)). Since GPI anchors can alter protein targeting, trafficking and cell signaling, our recent study examined how the structure of the GPI anchor affected prion formation. PrP(C) containing a GPI anchor from which the sialic acid had been removed (desialylated PrP(C)) was not converted to PrP(Sc) in prion-infected neuronal cell lines and in scrapie-infected primary cortical neurons. In uninfected neurons desialylated PrP(C) was associated with greater concentrations of gangliosides and cholesterol than PrP(C). In addition, the targeting of desialylated PrP(C) to lipid rafts showed greater resistance to cholesterol depletion than PrP(C). The presence of desialylated PrP(C) caused the dissociation of cytoplasmic phospholipase A2 (cPLA2) from PrP-containing lipid rafts, reduced the activation of cPLA2 and inhibited PrP(Sc) production. We conclude that the sialic acid moiety of the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f4d4a106531e1f88c42ce47b5527f17fTest
https://doi.org/10.1080/19336896.2016.1148237Test

المؤلفون: Alun Williams, Clive Bate, William Nolan, Harriet McHale-Owen

المساهمون: Williams, Alun [0000-0003-0835-0200], Apollo - University of Cambridge Repository

المصدر: JOURNAL OF BIOLOGICAL CHEMISTRY

مصطلحات موضوعية: 0301 basic medicine, Glycan, Glycosylphosphatidylinositol, animal diseases, Synaptic Membranes, Oligosaccharides, Biology, Biochemistry, PRNP, Synapse, prion, 03 medical and health sciences, chemistry.chemical_compound, Mice, Neurobiology, synapse, mental disorders, Animals, PrPC Proteins, Prion protein, Molecular Biology, Cells, Cultured, Mice, Knockout, Neurons, cholesterol, Cell Biology, N-Acetylneuraminic Acid, Sialic acid, nervous system diseases, carbohydrates (lipids), 030104 developmental biology, chemistry, sialic acid, biology.protein, lipids (amino acids, peptides, and proteins), N-Acetylneuraminic acid, glycosylphosphatidylinositol (GPI anchor), Homing (hematopoietic)

الوصف: Although the cellular prion protein (PrP(C)) is concentrated at synapses, the factors that target PrP(C) to synapses are not understood. Here we demonstrate that exogenous PrP(C) was rapidly targeted to synapses in recipient neurons derived from Prnp knock-out((0/0)) mice. The targeting of PrP(C) to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or sialic acid from the GPI anchor reduced the targeting of PrP(C) to synapses. Isolated GPIs (derived from PrP(C)) were also targeted to synapses, as was IgG conjugated to these GPIs. The removal of sialic acid from GPIs prevented the targeting of either the isolated GPIs or the IgG-GPI conjugate to synapses. Competition studies showed that pretreatment with sialylated GPIs prevented the targeting of PrP(C) to synapses. These results are consistent with the hypothesis that the sialylated GPI anchor attached to PrP(C) acts as a synapse homing signal.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8ae09d15f45c8504c9fbc583b5916cedTest
https://researchonline.rvc.ac.uk/id/eprint/11377/1/11377.pdfTest

المؤلفون: William Nolan, Alun Williams, Clive Bate

المصدر: Communicative & Integrative Biology
Communicative & Integrative Biology, Vol 9, Iss 2 (2016)

مصطلحات موضوعية: 0301 basic medicine, Gene isoform, animal diseases, Cell, Biology, Cell membrane, 03 medical and health sciences, chemistry.chemical_compound, Phospholipase A2, mental disorders, medicine, lcsh:QH301-705.5, chemistry.chemical_classification, cholesterol, glycosylphosphatidylinositols, Sialic acid, nervous system diseases, Article Addendum, 030104 developmental biology, Enzyme, medicine.anatomical_structure, chemistry, Biochemistry, lcsh:Biology (General), Cytoplasm, sialic acid, biology.protein, phospholipase A2, General Agricultural and Biological Sciences, Intracellular

الوصف: There is increasing interest in the role of glycosylphosphatidylinositol (GPI) anchors that attach some proteins to cell membranes. Far from being biologically inert, GPIs influence the targeting, intracellular trafficking and function of the attached protein. Our recent paper demonstrated the role of sialic acid on the GPI of the cellular prion protein (PrP(C)). The "prion diseases" arise following the conversion of PrP(C) to a disease-associated isoform called PrP(Sc) or "prion". Our paper showed that desialylated PrP(C) inhibited PrP(Sc) formation. Aggregated PrP(Sc) creates a signaling platform in the cell membrane incorporating and activating cytoplasmic phospholipase A2 (cPLA2), an enzyme that regulates PrP(C) trafficking and hence PrP(Sc) formation. The presence of desialylated PrP(C) caused the dissociation of cPLA2 from PrP-containing platforms, reduced the activation of cPLA2 and inhibited PrP(Sc) production. We concluded that sialic acid contained within the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::83ff25ba141c2b3f89d1571830a1a6efTest
https://pubmed.ncbi.nlm.nih.gov/27195066Test

المؤلفون: Alun Williams, Clive Bate, William Nolan

المساهمون: Williams, Alun [0000-0003-0835-0200], Apollo - University of Cambridge Repository

مصطلحات موضوعية: 0301 basic medicine, Cell signaling, Glycosylation, PrPSc Proteins, Glycosylphosphatidylinositols, Prions, animal diseases, Neuraminidase, Biochemistry, Models, Biological, Cell Line, prion, 03 medical and health sciences, chemistry.chemical_compound, Mice, Phospholipase A2, Membrane Microdomains, Neurobiology, Polysaccharides, mental disorders, Animals, Molecular Biology, phospholipase A, Phospholipase A, biology, Protein Stability, Group IV Phospholipases A2, cholesterol, Cell Biology, N-Acetylneuraminic Acid, Sialic acid, Cell biology, nervous system diseases, 030104 developmental biology, Cross-Linking Reagents, chemistry, Cytoplasm, sialic acid, biology.protein, lipids (amino acids, peptides, and proteins), N-Acetylneuraminic acid, glycosylphosphatidylinositol (GPI anchor), Signal Transduction

الوصف: The prion diseases occur following the conversion of the cellular prion protein (PrP(C)) into disease-related isoforms (PrP(Sc)). In this study, the role of the glycosylphosphatidylinositol (GPI) anchor attached to PrP(C) in prion formation was examined using a cell painting technique. PrP(Sc) formation in two prion-infected neuronal cell lines (ScGT1 and ScN2a cells) and in scrapie-infected primary cortical neurons was increased following the introduction of PrP(C). In contrast, PrP(C) containing a GPI anchor from which the sialic acid had been removed (desialylated PrP(C)) was not converted to PrP(Sc). Furthermore, the presence of desialylated PrP(C) inhibited the production of PrP(Sc) within prion-infected cortical neurons and ScGT1 and ScN2a cells. The membrane rafts surrounding desialylated PrP(C) contained greater amounts of sialylated gangliosides and cholesterol than membrane rafts surrounding PrP(C). Desialylated PrP(C) was less sensitive to cholesterol depletion than PrP(C) and was not released from cells by treatment with glimepiride. The presence of desialylated PrP(C) in neurons caused the dissociation of cytoplasmic phospholipase A2 from PrP-containing membrane rafts and reduced the activation of cytoplasmic phospholipase A2. These findings show that the sialic acid moiety of the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation. These results suggest that pharmacological modification of GPI glycosylation might constitute a novel therapeutic approach to prion diseases.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::88563cf2e67ecdb5b9138cb1331e5fc9Test
https://www.repository.cam.ac.uk/handle/1810/253081Test

المؤلفون: Clive Bate, Alun Williams, Mourad Tayebi

المصدر: Journal of Biological Chemistry. 285:22017-22026

مصطلحات موضوعية: PrPSc Proteins, Glycosylphosphatidylinositols, animal diseases, Scrapie, Biology, Biochemistry, Cell Line, Cell membrane, Mice, chemistry.chemical_compound, Neurobiology, Extracellular, medicine, Animals, PrPC Proteins, Inositol, Platelet Activating Factor, Molecular Biology, Lipid raft, Glucosamine, Cell Membrane, Cell Biology, nervous system diseases, Cell biology, Phospholipases A2, Cholesterol, medicine.anatomical_structure, chemistry, Cytoplasm, Cell culture, lipids (amino acids, peptides, and proteins), Signal transduction, Extracellular Space

الوصف: A hallmark of prion diseases is the conversion of the host-encoded prion protein (PrP(C) where C is cellular) into an alternatively folded, disease-related isoform (PrP(Sc), where Sc is scrapie), the accumulation of which is associated with synapse degeneration and ultimately neuronal death. The formation of PrP(Sc) is dependent upon the presence of PrP(C) in specific, cholesterol-sensitive membrane microdomains, commonly called lipid rafts. PrP(C) is targeted to these lipid rafts because it is attached to membranes via a glycosylphosphatidylinositol anchor. Here, we show that treatment of prion-infected neuronal cell lines (ScN2a, ScGT1, or SMB cells) with synthetic glycosylphosphatidylinositol analogues, glucosamine-phosphatidylinositol (glucosamine-PI) or glucosamine 2-O-methyl inositol octadecyl phosphate, reduced the PrP(Sc) content of these cells in a dose-dependent manner. In addition, ScGT1 cells treated with glucosamine-PI did not transmit infection following intracerebral injection to mice. Treatment with glucosamine-PI increased the cholesterol content of ScGT1 cell membranes and reduced activation of cytoplasmic phospholipase A(2) (PLA(2)), consistent with the hypothesis that the composition of cell membranes affects key PLA(2)-dependent signaling pathways involved in PrP(Sc) formation. The effect of glucosamine-PI on PrP(Sc) formation was also reversed by the addition of platelet-activating factor. Glucosamine-PI caused the displacement of PrP(C) from lipid rafts and reduced expression of PrP(C) at the cell surface, putative sites for PrP(Sc) formation. We propose that treatment with glucosamine-PI modifies local micro-environments that control PrP(C) expression and activation of PLA(2) and subsequently inhibits PrP(Sc) formation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b19762abf87691e81b3f470491efba05Test
https://doi.org/10.1074/jbc.m110.108548Test

المؤلفون: Mourad Tayebi, Alun Williams, Luisa Diomede, Clive Bate, Mario Salmona

المصدر: Neurotoxicity Research. 17:203-214

مصطلحات موضوعية: Simvastatin, Docosahexaenoic Acids, Prions, animal diseases, Synaptophysin, Enzyme-Linked Immunosorbent Assay, In Vitro Techniques, Hippocampal formation, Neurotransmission, Toxicology, Hippocampus, Synapse, Mice, Animals, Humans, Neurotoxin, Drug Interactions, Cells, Cultured, Cerebral Cortex, Mice, Knockout, Neurons, chemistry.chemical_classification, Dose-Response Relationship, Drug, biology, Caspase 3, General Neuroscience, Embryo, Mammalian, Eicosapentaenoic acid, Peptide Fragments, nervous system diseases, Cell biology, Neuroprotective Agents, Eicosapentaenoic Acid, Gene Expression Regulation, nervous system, chemistry, Biochemistry, Docosahexaenoic acid, Fatty Acids, Unsaturated, biology.protein, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, Synaptosomes, Polyunsaturated fatty acid

الوصف: A loss of synapses is characteristic of the early stages of the prion diseases. Here we modelled the synapse damage that occurs in prion diseases by measuring the amount of synaptophysin, a pre-synaptic membrane protein essential for neurotransmission, in cortical or hippocampal neurones incubated with the disease associated isoform of the prion protein (PrP(Sc)), or with the prion-derived peptide PrP82-146. The addition of PrP(Sc) or PrP82-146 caused a dose-dependent reduction in the synaptophysin content of PrP wildtype neurones indicative of synapse damage. They did not affect the synaptophysin content of PrP null neurones. The loss of synaptophysin in PrP wildtype neurones was preceded by the accumulation of PrP82-146 within synapses. Since supplements containing polyunsaturated fatty acids (PUFA) are frequently taken for their perceived health benefits including reported amelioration of neurodegenerative conditions, the effects of some common PUFA on prion-mediated synapse damage were examined. Pre-treatment of cortical or hippocampal neurones with docosahexaenoic (DHA) or eicosapentaenoic acids (EPA) protected neurones against the loss of synaptophysin induced by PrP82-146 or PrP(Sc). This effect of DHA and EPA was selective as they did not alter the loss of synaptophysin induced by a snakevenom neurotoxin. The effects of DHA and EPA were associated with a significant reduction in the amount of FITC-PrP82-146 that accumulated within synapses. Such observations raise the possibility that supplements containing PUFA may protect against the synapse damage and cognitive loss seen during the early stages of prion diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5351409a315ff0f09ced6daba2de3c03Test
https://doi.org/10.1007/s12640-009-9093-2Test

المؤلفون: Alun Williams, Clive Bate

المصدر: Future Neurology. 3:367-370

مصطلحات موضوعية: chemistry.chemical_classification, Gene isoform, Chemistry, Cholesterol, animal diseases, Endoplasmic reticulum, Neurodegeneration, Sterol O-acyltransferase, Cell, Stimulation, medicine.disease, nervous system diseases, Cell biology, chemistry.chemical_compound, Enzyme, medicine.anatomical_structure, Neurology, medicine, lipids (amino acids, peptides, and proteins), Neurology (clinical)

الوصف: The transmissible spongiform encephalopathies (TSEs) are associated with the conversion of a host-encoded cellular protein (PrPC) to alternatively folded, disease-associated isoforms (PrPSc) [1]. These diseases are unique in that the only identified component of the infectious agent is a self-replicating protein (PrPSc); which explains why such diseases are commonly called prion diseases (protein-only infectious agent). The accumulation of PrPSc is closely associated with the main pathological features of prion diseases; loss of synapses, activation of glial cells, neuronal loss and the spongiform degeneration of the brain [2]. However, the cellular and molecular mechanisms leading to neurodegeneration in these diseases are imperfectly understood. In this review, we outline developments implicating prion-induced changes in the levels of membrane cholesterol as a trigger of abnormal cell signaling, which leads to neurodegeneration. Recent studies have demonstrated that prion infection has a significant impact on the biochemistry of neuronal cell membranes; it significantly increased the amounts of free cholesterol, but reduced the amounts of esterified cholesterol [3]. In addition, a highly significant correlation between the amounts of PrPSc and the concentration of free cholesterol in cell membranes was observed. Crucially, the effects of prion infection were not replicated by stimulating cholesterol biosynthesis. Stimulation of cholesterol production in uninfected neurons had the opposite effect to prion infection; it increased cholesterol ester formation without altering the amounts of free cholesterol. Such observations indicate that prion infection increased the capacity of cell membranes to solubilize free cholesterol. Cellular cholesterol is found as either free cholesterol in membranes, or as cholesterol esters that are stored in cytoplasmic droplets. A dynamic equilibrium between the pools of free cholesterol and cholesterol esters is tightly controlled by acyl-coenzyme A:cholesterol acyltransferase (ACAT), an endoplasmic reticulum (ER)-resident enzyme that esterifies free cholesterol with long-chain fatty acids [4]. Therefore, the combination of increased free cholesterol and reduced cholesterol esters observed in prion-infected cells may result from inhibition of ACAT, or from the sequestration of free cholesterol in microenvironments that avoid ACAT.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::86092e83a37f0a3920d75ae7341b2a41Test
https://doi.org/10.2217/14796708.3.4.367Test

المؤلفون: Alun Williams, Clive Bate

المصدر: Journal of General Virology. 85:3797-3804

مصطلحات موضوعية: Glycosylphosphatidylinositols, Prions, animal diseases, Apoptosis, Dinoprostone, Phospholipases A, Mice, chemistry.chemical_compound, Phospholipase A2, Cell Line, Tumor, Virology, medicine, Animals, Phosphatidylinositol, Prostaglandin E2, Neurons, Microglia, biology, Caspase 3, Neurodegeneration, Neurotoxicity, medicine.disease, Caspase Inhibitors, nervous system diseases, Sialic acid, Enzyme Activation, Phospholipases A2, medicine.anatomical_structure, Biochemistry, chemistry, Nerve Degeneration, biology.protein, Arachidonic acid, medicine.drug

الوصف: Prion-induced neuronal injury in vivo is associated with prostaglandin E(2) production, a process that can be reproduced in tissue-culture models of prion disease. In the present study, neuronal phospholipase A(2) was activated by glycosylphosphatidylinositols (GPIs) isolated from the cellular prion protein (PrP(c)) or from disease-associated isoforms (PrP(Sc)), resulting in prostaglandin E(2) production, but not by GPIs isolated from Thy-1. The ability of GPIs to activate neuronal phospholipase A(2) was lost following the removal of acyl chains or cleavage of the phosphatidylinositol-glycan linkage, and was inhibited by a mAb that recognized phosphatidylinositol. In competition assays, pretreatment of neurons with partial GPIs, inositol monophosphate or sialic acid reduced the production of prostaglandin E(2) in response to a synthetic miniprion (sPrP106), a synthetic correlate of a PrP(Sc) species found in Gerstmann-Straussler-Scheinker disease (HuPrP82-146), prion preparations or high concentrations of PrP-GPIs. In addition, neurons treated with inositol monophosphate or sialic acid were resistant to the otherwise toxic effects of sPrP106, HuPrP82-146 or prion preparations. This protective effect was selective, as inositol monophosphate- or sialic acid-treated neurons remained susceptible to the toxicity of arachidonic acid or platelet-activating factor. Addition of PrP-GPIs to cortical neuronal cultures increased caspase-3 activity, a marker of apoptosis that is elevated in prion diseases. In contrast, treatment of such cultures with inositol monophosphate or sialic acid greatly reduced sPrP106-induced caspase-3 activity and, in co-cultures, reduced the killing of sPrP106-treated neurons by microglia. These results implicate phospholipase A(2) activation by PrP-GPIs as an early event in prion-induced neurodegeneration.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9776e3b7d0a445671d69419fe426aae2Test
https://doi.org/10.1099/vir.0.80366-0Test

المؤلفون: Alun Williams, Clive Bate, Stuart Reid

المصدر: Journal of Biological Chemistry. 279:36405-36411

مصطلحات موضوعية: Gene isoform, Time Factors, PrPSc Proteins, Prions, Phospholipase A2 inhibitor, animal diseases, Enzyme-Linked Immunosorbent Assay, Pharmacology, Biochemistry, Dexamethasone, Dinoprostone, Phospholipases A, Cell Line, chemistry.chemical_compound, Phospholipase A2, Cell Line, Tumor, medicine, Humans, Enzyme Inhibitors, Platelet Activating Factor, Glucocorticoids, Molecular Biology, Phospholipids, Infectivity, Dose-Response Relationship, Drug, biology, Platelet-activating factor, Neurodegeneration, Cell Biology, medicine.disease, nervous system diseases, Phospholipases A2, Metabolic pathway, chemistry, Cell culture, biology.protein, lipids (amino acids, peptides, and proteins), Signal Transduction

الوصف: A key feature of prion diseases is the conversion of the cellular prion protein (PrP(C)) into disease-related isoforms (PrP(Sc)), the deposition of which is thought to lead to neurodegeneration. In this study a pharmacological approach was used to determine the metabolic pathways involved in the formation of protease-resistant PrP (PrP(res)) in three prion-infected cell lines (ScN2a, SMB, and ScGT1 cells). Daily treatment of these cells with phospholipase A(2) (PLA(2)) inhibitors for 7 days prevented the accumulation of PrP(res). Glucocorticoids with anti-PLA(2) activity also prevented the formation of PrP(res) and reduced the infectivity of SMB cells. Treatment with platelet-activating factor (PAF) antagonists also reduced the PrP(res) content of cells, while the addition of PAF reversed the inhibitory effect of PLA(2) inhibitors on PrP(res) formation. ScGT1 cells treated with PLA(2) inhibitors or PAF antagonists for 7 days remained clear of detectable (PrPres) when grown in control medium for a further 12 weeks. Treatment of non-infected cells with PLA(2) inhibitors or PAF antagonists reduced PrP(C) levels suggesting that limiting cellular PrP(C) may restrict prion formation in infected cells. These data indicate a pivotal role for PLA(2) and PAF in controlling PrP(res) formation and identify them as potential therapeutic agents.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3e87d2efe54a1fcb3c2e47ac2540f44cTest
https://doi.org/10.1074/jbc.m404086200Test

المؤلفون: Paul Brennan, Jeanne E. Bell, Ioan Davies, Diane Ritchie, Neil McLennan, Mark Head, Alun Williams, Andrew P. Fotheringham, Alisdair McNeill, James W. Ironside, Francis Brannan, Kathleen A. Rennison

المصدر: The American Journal of Pathology. 165:227-235

مصطلحات موضوعية: Adult, Male, Heterozygote, Pathology, medicine.medical_specialty, animal diseases, Central nervous system, Ischemia, In situ hybridization, Biology, medicine.disease_cause, Neuroprotection, Pathology and Forensic Medicine, Mice, mental disorders, medicine, Animals, Humans, PrPC Proteins, Hypoxia, Brain, Crosses, Genetic, In Situ Hybridization, Aged, Aged, 80 and over, Mice, Knockout, Penumbra, Infant, Newborn, Wild type, Infant, Middle Aged, Hypoxia (medical), medicine.disease, Immunohistochemistry, nervous system diseases, Cell biology, Neuroprotective Agents, medicine.anatomical_structure, Female, medicine.symptom, Oxidative stress, Regular Articles

الوصف: The function of the normal conformational isoform of prion protein, PrP(C), remains unclear although lines of research have suggested a role in the cellular response to oxidative stress. Here we investigate the expression of PrP(C) in hypoxic brain tissues to examine whether PrP(C) is in part regulated by neuronal stress. Cases of adult cerebral ischemia and perinatal hypoxic-ischemic injury in humans were compared with control tissues. PrP(C) immunoreactivity accumulates within neuronal processes in the penumbra of hypoxic damage in adult brain, and within neuronal soma in cases of perinatal hypoxic-ischemic injury, and in situ hybridization analysis suggests an up-regulation of PrP mRNA during hypoxia. Rodents also showed an accumulation of PrP(C) in neuronal soma within the penumbra of ischemic lesions. Furthermore, the infarct size in PrP-null mice was significantly greater than in the wild type, supporting the proposed role for PrP(C) in the neuroprotective adaptive cellular response to hypoxic injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bb8690fd4e398dc8a7d33b4acc08aee6Test
https://doi.org/10.1016/s0002-9440Test(10)63291-9