Phosphatidylserine

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Phosphatidylserine
Phosphatidyl-Serine.svg
Components of phosphatidylserines:
Blue, green: variable fatty acid groups
Black: glycerol
Red: phosphate
Purple: serine
Identifiers
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. [1] It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apoptotic mimicry. [2] Its exposure on the outer surface of a membrane marks the cell for destruction via apoptosis. [3]

Contents

Structure

Phosphatidylserine is a phospholipid—more specifically a glycerophospholipid—which consists of two fatty acids attached in ester linkage to the first and second carbon of glycerol and serine attached through a phosphodiester linkage to the third carbon of the glycerol. [4]

Phosphatidylserine sourced from plants differs in fatty acid composition from that sourced from animals. [5] It is commonly found in the inner (cytoplasmic) leaflet of biological membranes. [6] It is almost entirely found in the inner monolayer of the membrane with only less than 10% of it in the outer monolayer.

Biosynthesis

Phosphatidylserine (PS) is the major acidic phospholipid class that accounts for 13–15% of the phospholipids in the human cerebral cortex. [7] In the plasma membrane, PS is localized exclusively in the cytoplasmic leaflet where it forms part of protein docking sites necessary for the activation of several key signaling pathways. These include the Akt, protein kinase C (PKC) and Raf-1 signaling that is known to stimulate neuronal survival, neurite growth, and synaptogenesis. [8] [9] [10] [11] [12] [13] Modulation of the PS level in the plasma membrane of neurons has a significant impact on these signaling processes.

Composition

Biosynthesis of phosphatidylserine Biosynthesis of phosphatidylglycerol, phosphatidylserine, and phosphatidylethanolamine.svg
Biosynthesis of phosphatidylserine

Phosphatidylserine is formed in bacteria (such as E. coli ) through a displacement of cytidine monophosphate (CMP) through a nucleophilic attack by the hydroxyl functional group of serine. CMP is formed from CDP-diacylglycerol by PS synthase. Phosphatidylserine can eventually become phosphatidylethanolamine by the enzyme PS decarboxylase (forming carbon dioxide as a byproduct). [6] Similar to bacteria, yeast can form phosphatidylserine in an identical pathway.

In mammals, phosphatidylserine is instead derived from phosphatidylethanolamine or phosphatidylcholine through one of two Ca2+-dependent head-group exchange reactions in the endoplasmic reticulum. Both reactions require a serine but product an ethanolamine or choline, respectively. These are promoted by phosphatidylserine synthase 1 (PSS1) or 2 (PSS2). [6] Conversely, phosphatidylserine can also give rise to phosphatidylethanolamine and phosphatidylcholine, although in animals the pathway to generate phosphatidylcholine from phosphatidylserine only operates in the liver. [14]

Role in Cognitive Function

PS is essential for maintaining cognitive function and has been studied for its potential in improving memory, learning, and concentration. Supplementation with PS has shown promise in enhancing cognitive performance in the elderly and individuals with cognitive decline. [15]

Role in Apoptosis

Phosphatidylserine plays a crucial role in the process of apoptosis, or programmed cell death. During apoptosis, PS translocates from the inner to the outer leaflet of the cell membrane, serving as a signal for phagocytic cells to engulf the dying cell. [16]

Dietary sources

The average daily phosphatidylserine intake in a Western diet is estimated to be 130 mg. [17] Phosphatidylserine may be found in meat and fish. Only small amounts are found in dairy products and vegetables, with the exception of white beans and soy lecithin. Phosphatidylserine is found in soy lecithin at about 3% of total phospholipids. [18]

Table 1. Phosphatidylserine content in different foods. [19]

FoodContent in mg/100 g
Soy lecithin1,650
Atlantic mackerel 480
Chicken heart414
Atlantic herring 360
Eel 335
Offal (average value)305
Pig's spleen 239
Pig's kidney 218
Tuna 194
Chicken leg, with skin, without bone134
Chicken liver123
White beans 107
Soft-shell clam 87
Chicken breast, with skin85
Mullet 76
Veal 72
Beef 69
Pork 57
Pig's liver 50
Turkey leg, without skin or bone50
Turkey breast without skin45
Crayfish 40
Cuttlefish 31
Atlantic cod 28
Anchovy 25
Whole grain barley 20
European hake 17
European pilchard (sardine) 16
Trout 14
Rice (unpolished)3
Carrot 2
Ewe's Milk 2
Cow's Milk (whole, 3.5% fat)1
Potato 1

Supplementation

Health claims

A panel of the European Food Safety Authority concluded that a cause and effect relationship cannot be established between the consumption of phosphatidylserine and "memory and cognitive functioning in the elderly", "mental health/cognitive function" and "stress reduction and enhanced memory function". [5] This conclusion follows because bovine brain cortex- and soy-based phosphatidylserine are different substances and might, therefore, have different biological activities. Therefore, the results of studies using phosphatidylserine from different sources cannot be generalized. [5]

Cognition

In May, 2003 the Food and Drug Administration gave "qualified health claim" status to phosphatidylserine thus allowing labels to state "consumption of phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly" along with the disclaimer "very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly." [20] [21] According to the FDA, there is a lack of scientific agreement amongst qualified experts that a relationship exists between phosphatidylserine and cognitive function. [20]

More recent reviews have suggested that the relationship may be more robust, [22] [23] though the mechanism remains unclear. [24] A 2020 review of three clinical trials found that phosphatidylserine is likely effective for enhancing cognitive function in older people with mild cognitive impairment. [25] Some studies have suggested that whether the phosphatidylserine is plant- or animal-derived may have significance, with the FDA's statement applying specifically to soy-derived products. [20] [26] [27] [28] [29]

Safety

Initially, phosphatidylserine supplements were derived from bovine cortex. However, due to the risk of potential transfer of infectious diseases such as bovine spongiform encephalopathy (or "mad cow disease"), soy-derived supplements became an alternative. [26] A 2002 safety report determined supplementation in elderly people at a dosage of 200 mg three times daily to be safe. [30] Some manufacturers of phosphatidylserine use sunflower lecithin instead of soy lecithin as a source of raw material production.

Related Research Articles

<span class="mw-page-title-main">Lipid</span> Substance of biological origin that is soluble in nonpolar solvents

Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

<span class="mw-page-title-main">Phospholipid</span> Class of lipids

Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline ( KOH-leen) is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin (vitamin B4). It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.

<span class="mw-page-title-main">Arachidonic acid</span> Fatty acid used metabolically in many organisms

Arachidonic acid is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). If its precursors or diet contains linoleic acid it is formed by biosynthesis and can be deposited in animal fats. It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.

<span class="mw-page-title-main">Lecithin</span> Generic term for amphiphilic substances of plant and animal origin

Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances, and are used for smoothing food textures, emulsifying, homogenizing liquid mixtures, and repelling sticking materials.

<span class="mw-page-title-main">Phosphatidylcholine</span> Class of phospholipids

Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybeans, from which they are mechanically or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. Dipalmitoylphosphatidylcholine (lecithin) is a major component of the pulmonary surfactant, and is often used in the lecithin–sphingomyelin ratio to calculate fetal lung maturity. While phosphatidylcholines are found in all plant and animal cells, they are absent in the membranes of most bacteria, including Escherichia coli. Purified phosphatidylcholine is produced commercially.

<span class="mw-page-title-main">Sphingomyelin</span> Class of chemical compounds

Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of plasma membrane lipids.

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(n−3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fatty fish, fish oil, or algae oil. The consumption of DHA (e.g., from fatty fish such as salmon, herring, mackerel and sardines) contributes to numerous physiological benefits, including cognition. As a component of neuronal membranes, the function of DHA is to support neuronal conduction and to allow the optimal functioning of neuronal membrane proteins (such as receptors and enzymes).

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.

<span class="mw-page-title-main">Inner mitochondrial membrane</span>

The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.

<span class="mw-page-title-main">Phospholipid scramblase</span> Protein

Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases, flippases, and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet, facing the inside of the cell, contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme, present in the cell membrane, that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet, and vice versa.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Phosphatidylethanolamine</span> Group of chemical compounds

Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine can subsequently methylate the amine of phosphatidylethanolamines to yield phosphatidylcholines.

<span class="mw-page-title-main">Annexin A5</span> Protein-coding gene in the species Homo sapiens

Annexin A5 is a cellular protein in the annexin group. In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of phospholipase A1. These properties have been found by in vitro experiments.

Phospholipase A<sub>1</sub> Mammalian protein found in Homo Sapiens

Phospholipase A1 (EC 3.1.1.32; systematic name: phosphatidylcholine 1-acylhydrolase) encoded by the PLA1A gene is a phospholipase enzyme which removes the 1-acyl group:

<span class="mw-page-title-main">Citicoline</span> Chemical compound

Citicoline (INN), also known as cytidine diphosphate-choline (CDP-choline) or cytidine 5'-diphosphocholine is an intermediate in the generation of phosphatidylcholine from choline, a common biochemical process in cell membranes. Citicoline is naturally occurring in the cells of human and animal tissue, in particular the organs.

<span class="mw-page-title-main">Lysophosphatidylcholine</span> Class of compounds

Lysophosphatidylcholines, also called lysolecithins, are a class of chemical compounds which are derived from phosphatidylcholines.

<span class="mw-page-title-main">1-Lysophosphatidylcholine</span>

1-Lysophosphatidylcholines are a class of phospholipids that are intermediates in the metabolism of lipids. They result from the hydrolysis of an acyl group from the sn-1 position of phosphatidylcholine. They are also called 2-acyl-sn-glycero-3-phosphocholines. The synthesis of phosphatidylcholines with specific fatty acids occurs through the synthesis of 1-lysoPC. The formation of various other lipids generates 1-lysoPC as a by-product.

<span class="mw-page-title-main">Mitochondria associated membranes</span> Cellular structure

Mitochondria-associated membranes (MAMs) represent regions of the endoplasmic reticulum (ER) which are reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.

<span class="mw-page-title-main">Milk fat globule membrane</span>

Milk fat globule membrane (MFGM) is a complex and unique structure composed primarily of lipids and proteins that surrounds milk fat globule secreted from the milk producing cells of humans and other mammals. It is a source of multiple bioactive compounds, including phospholipids, glycolipids, glycoproteins, and carbohydrates that have important functional roles within the brain and gut.

References

  1. ↑ Kannan, Muthukumar; Riekhof, Wayne R.; Voelker, Dennis R. (2015). "Transport of Phosphatidylserine from the Endoplasmic Reticulum to the Site of Phosphatidylserine Decarboxylase2 in Yeast". Traffic. 16 (2): 123–134. doi: 10.1111/tra.12236 . ISSN   1600-0854. PMID   25355612.
  2. ↑ Meertens L, Carnec X, Lecoin MP, Ramdasi R, Guivel-Benhassine F, Lew E, Lemke G, Schwartz O, Amara A (October 2012). "The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry". Cell Host & Microbe. 12 (4): 544–57. doi:10.1016/j.chom.2012.08.009. PMC   3572209 . PMID   23084921.
  3. ↑ Glade, Michael J.; Smith, Kyl (June 2015). "Phosphatidylserine and the human brain". Nutrition. 31 (6): 781–786. doi:10.1016/j.nut.2014.10.014. ISSN   0899-9007.
  4. ↑ Nelson D, Cox M (2008). Lehninger Principles of biochemistry (5 ed.). W.H Freeman and company. pp.  350. ISBN   9781429208925.
  5. 1 2 3 EFSA Panel on Dietetic Products, Nutrition and Allergies (2010-10-01). "Scientific Opinion on the substantiation of health claims related to phosphatidyl serine (ID 552, 711, 734, 1632, 1927) pursuant to Article 13(1) of Regulation (EC) No 1924/2006". EFSA Journal. 8 (10): 1749. doi: 10.2903/j.efsa.2010.1749 . ISSN   1831-4732.
  6. 1 2 3 Nelson, David L.; Cox, Michael M.; Hoskins, Aaron; Lehninger, Albert L. (16 March 2021). Lehninger Principles of Biochemistry (8th ed.). New York: Macmillan International, Higher Education. ISBN   978-1-319-38149-3. OCLC   1249676451.
  7. ↑ Svennerholm, Lars (September 1968). "Distribution and fatty acid composition of phosphoglycerides in normal human brain" (PDF). Journal of Lipid Research . 9 (5): 570–579. doi: 10.1016/S0022-2275(20)42702-6 . PMID   4302302 . Retrieved 2021-06-14.
  8. ↑ Akbar, Mohammed; Calderon, Frances; Wen, Zhiming; Kim, Hee-Yong (2005-08-02). "Docosahexaenoic acid: a positive modulator of Akt signaling in neuronal survival". Proceedings of the National Academy of Sciences of the United States of America . 102 (31): 10858–10863. Bibcode:2005PNAS..10210858A. doi: 10.1073/pnas.0502903102 . PMC   1182431 . PMID   16040805.
  9. ↑ Huang, Bill X.; Akbar, Mohammed; Kevala, Karl; Kim, Hee-Yong (2011-03-21). "Phosphatidylserine is a critical modulator for Akt activation". Journal of Cell Biology . 192 (6): 979–992. doi:10.1083/jcb.201005100. PMC   3063130 . PMID   21402788 . Retrieved 2021-06-13.
  10. ↑ Kim, Hee-Yong; Akbar, Mohammed; Lau, Audrey; Edsall, Lisa (2000-11-10). "Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3): Role of phosphatidylserine in antiapoptotic effect". Journal of Biological Chemistry . 275 (45): 35215–35223. doi: 10.1074/jbc.M004446200 . PMID   10903316 . Retrieved 2021-06-14.
  11. ↑ Kim, Hee-Yong (2007-06-29). "Novel metabolism of docosahexaenoic acid in neural cells". Journal of Biological Chemistry . 282 (26): 18661–18665. doi: 10.1074/jbc.R700015200 . PMID   17488715 . Retrieved 2021-06-14.
  12. ↑ Kim, Hee-Yong; Akbar, Mohammed; Kim, Yang-Suk (2010). "Phosphatidylserine-dependent neuroprotective signaling promoted by docosahexaenoic acid" . Prostaglandins, Leukotrienes and Essential Fatty Acids . 82 (4–6): 165–172. doi:10.1016/j.plefa.2010.02.025. PMC   3383770 . PMID   20207120 . Retrieved 2021-06-14.
  13. ↑ Newton, Alexandra C.; Keranen, Lisa M. (1994-05-31). "Phosphatidyl-L-serine is necessary for protein kinase C's high-affinity interaction with diacylglycerol-containing membranes" . Biochemistry . 33 (21): 6651–6658. doi:10.1021/bi00187a035. PMID   8204602 . Retrieved 2021-06-14.
  14. ↑ Christie WW (12 June 2014). "Phosphatidylcholine and Related Lipids: Structure, Occurrence, Biochemistry and Analysis" (PDF). The American Oil Chemists’ Society Lipid Library. Retrieved 20 April 2017.
  15. ↑ Jorissen, B.L.; Brouns, F.; Van Boxtel, M.P.J.; Ponds, R.W.H.M.; Verhey, F.R.J.; Jolles, J.; Riedel, W.J. (January 2001). "The Influence of Soy-derived Phosphatidylserine on Cognition in Age-Associated Memory Impairment". Nutritional Neuroscience. 4 (2): 121–134. doi:10.1080/1028415x.2001.11747356. ISSN   1028-415X.
  16. ↑ Fadok, V A; Voelker, D R; Campbell, P A; Cohen, J J; Bratton, D L; Henson, P M (1992-04-01). "Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages". The Journal of Immunology. 148 (7): 2207–2216. doi:10.4049/jimmunol.148.7.2207. ISSN   0022-1767.
  17. ↑ Souci SW, Fachmann E, Kraut H: Food Composition and Nutrition Tables. Stuttgart. 2000, Medpharm Scientific Publishers
  18. ↑ Miranda, Dalva T. S. Z.; Batista, Vanessa G.; Grando, Fernanda C. C.; Paula, Fernanda M.; Felício, Caroline A.; Rubbo, Gabriella F. S.; Fernandes, Luiz C.; Curi, Rui; Nishiyama, Anita (Dec 2008). "Soy lecithin supplementation alters macrophage phagocytosis and lymphocyte response to concanavalin A: a study in alloxan-induced diabetic rats". Cell Biochemistry and Function. 26 (8): 859–865. doi:10.1002/cbf.1517. ISSN   1099-0844. PMID   18846580. S2CID   9083077.
  19. ↑ Souci SW, Fachmann E, Kraut H (2008). Food Composition and Nutrition Tables. Medpharm Scientific Publishers Stuttgart.
  20. 1 2 3 Taylor CL (May 13, 2003). "Phosphatidylserine and Cognitive Dysfunction and Dementia (Qualified Health Claim: Final Decision Letter)". Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration. Retrieved 23 August 2014.
  21. ↑ "Summary of Qualified Health Claims Subject to Enforcement Discretion - Qualified Claims About Cognitive Function". Food and Drug Administration .
  22. ↑ Glade MJ, Smith K (June 2015). "Phosphatidylserine and the human brain". Nutrition. 31 (6): 781–6. doi:10.1016/j.nut.2014.10.014. PMID   25933483.
  23. ↑ Poddar, Jit; Pradhan, Munmun; Ganguly, Gargi; Chakrabarti, Sasanka (2019). "Biochemical deficits and cognitive decline in brain aging: Intervention by dietary supplements". Journal of Chemical Neuroanatomy. 95: 70–80. doi:10.1016/j.jchemneu.2018.04.002. ISSN   0891-0618. PMID   29678666. S2CID   5014367.
  24. ↑ Kim HY, Huang BX, Spector AA (October 2014). "Phosphatidylserine in the brain: metabolism and function". Progress in Lipid Research. 56: 1–18. doi:10.1016/j.plipres.2014.06.002. PMC   4258547 . PMID   24992464.
  25. ↑ Tardner, P. (2020-08-28). "The effects of phosphatidylserine supplementation on memory function in older people: A review of clinical literature • International Journal of Environmental Science & Technology". International Journal of Environmental Science & Technology. Retrieved 2020-09-01.
  26. 1 2 Smith, Glenn (2 June 2014). "Can phosphatidylserine improve memory and cognitive function in people with Alzheimer's disease?". Mayo Clinic. Retrieved 23 August 2014.
  27. ↑ Crook TH, Klatz RM, eds. (1998). Treatment of Age-Related Cognitive Decline: Effects of Phosphatidylserine in Anti-Aging Medical Therapeutics. Vol. 2. Chicago: Health Quest Publications. pp. 20–29.
  28. ↑ Jorissen BL, Brouns F, Van Boxtel MP, Ponds RW, Verhey FR, Jolles J, Riedel WJ (2001). "The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment". Nutritional Neuroscience. 4 (2): 121–34. doi:10.1080/1028415X.2001.11747356. PMID   11842880. S2CID   9426593. Archived from the original on 2014-08-26. Retrieved 2014-08-23.
  29. ↑ Kato-Kataoka A, Sakai M, Ebina R, Nonaka C, Asano T, Miyamori T (November 2010). "Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints". Journal of Clinical Biochemistry and Nutrition. 47 (3): 246–55. doi:10.3164/jcbn.10-62. PMC   2966935 . PMID   21103034.
  30. ↑ Jorissen BL, Brouns F, Van Boxtel MP, Riedel WJ (October 2002). "Safety of soy-derived phosphatidylserine in elderly people". Nutritional Neuroscience. 5 (5): 337–43. doi:10.1080/1028415021000033802. PMID   12385596. S2CID   5688203.
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