Fats (Lipids)

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Fats or, more technically, lipids, are nutrients. Fats, together with carbohydrates and proteins, are one of the three staples of the diet. As the seventeenth-century nursery rhyme relates, ‘Jack Sprat he ate no fat/His wife she ate no lean’. This does not mean, however, that Jack Sprat could not get fat, because excess carbohydrates and proteins can be broken down in the body and the fragments synthesized into fat. But had he eaten no fat whatsoever he would have been deprived of certain essential fatty acids, and of the fat-soluble vitamins. Fats serve many purposes: they not only provide thermal insulation and a source of energy, with stores in reserve, but also are involved in important functions, providing for example the materials for components of cell membranes, of the myelin sheaths that electrically insulate nerve fibres.

Fats, or lipids, are a group of chemical substances in food that are generally insoluble in water. There are several classes of fats. The triglycerides (triacylglycerols) are the predominant constituent of vegetable and animal fats and oils. They are composed of a 3-carbon glycerol backbone and three fatty acids of various types. The character of the fat is determined by these fatty acids.

Saturated fatty acids tend to make the fat "hard" or solid at room temperature and are associated with an increased risk of heart disease.

Monounsaturated fatty acids are prominent in olive and canola oils and do not increase the risk of heart disease. The third group of fatty acids, the polyunsaturated fatty acids, are important components of omega-3 fish and plant oils. They play a role in blood clotting and in inflammatory responses in the body.

Phospholipids are closely related to triacylglycerols, except that one of the carbons on the glycerol contains one of several phosphate groups; the other two carbons have fatty acids.

A third group, related to the first two, is the sphingomyelins and other complex brain lipids.

Cholesterol and its precursors are another group of fats that are essential for membranes; these are chemically composed of several 5-and 6-membered carbon rings. Steroids make up a fifth group of fats. Steroids are derived from cholesterol and include the androgens and estrogens, among others.

Classes of Fatty Acids

Fatty acids are a diverse family of structurally similar carbon chains that contain a single carboxylic acid group. Fatty acids differ from one another by their carbon chain length, which is usually an even number of carbons that can exceed twenty carbon atoms. Fatty acids are often categorized as short-chain, medium-chain, or long-chain fatty acids because each of these groups displays distinct physical properties. Short-chain fatty acids contain up to seven carbon molecules and are liquids even at cold temperatures. Medium-chain fatty acids, which contain between eight and twelve carbons, are liquids at room temperature but solidify when refrigerated. Long-chain fatty acids contain greater than twelve carbons and are solids at room temperature, but liquefy at elevated temperatures. Long-chain fatty acids are the most abundant fatty acids in plant and animal foods. Short-chain fatty acids are found in whole cow's milk, and medium-chain fatty acids are abundant in coconut milk.

Fatty acids also differ by the number and location of carbon–carbon double bonds, otherwise called the degree of saturation. Saturated fatty acids do not contain any carbon–carbon double bonds because all carbon molecules are "saturated" with hydrogen molecules. The most abundant saturated dietary fatty acids are palmitic and stearic acids, which are long-chain fatty acids found in foods derived from animals and are abundant in meat and dairy products (Table 1; see Figure 1). Monounsaturated fatty acids contain a single carbon–carbon double bond (see Figure 1). Oleic acid is a monounsaturated fatty acid and a common dietary component found in canola and olive oil. Polyunsaturated fatty acids contain up to six carbon–carbon double bonds that are always separated by a methylene group (wCH2w) (Figure 1). Polyunsaturated fatty acids that contain a series of double bonds that begins between the third and fourth carbon from the methyl or omega end of the molecule (see nomenclature system below) are referred to as omega-3 fatty acids. Linolenic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) are omega-3 fatty acids and flaxseed oil, walnut oil, and fatty fish are good sources of omega-3 fatty acids. Omega-6 fatty acids are another class of polyunsaturated fatty acids that includes linoleic acid and arachidonic acid. They contain a series of carbon–carbon double bonds that begin between the sixth and seventh carbon from the omega end of the fatty acid. Linoleic acid is the most common omega-6 fatty acid in Western-style diets and is found in corn, safflower, and soy oils.

The fatty acid composition of triglycerols found in mammals is usually complex and is influenced by the fatty acid consumed in the diet and by the tissue where it resides. The most common fatty acids in humans are 16, 18, and 20 carbons in length, but longer-chain fatty acids are found in the central nervous system. Most diets contain mixtures of all types of fatty acids, but saturated and monounsaturated fatty acids constitute the vast majority of fatty acids that are consumed in a typical Western diet. A single triacylglycerol molecule rarely contains three identical fatty acids.

Table 1

Classes of fatty acids
Trivial name Systematic name Numerical symbol
Saturated fatty acids
Lauric acid Dodecanoic 12:0
Myristic acid Tetradecanoic 14:0
Palmitic acid Hexadecanoic 16:0
Stearic acid Octadecanoic 18:0
Monounsaturated fatty acids
Palmitoleic acid cis-9-hexadecenoic 16:1(9)
Oleic acid cis-9-octadecenoic 18:1(9)
Polyunsaturated fatty acids (omega-6)
Linoleic acid cis, cis-9, 12-octadecadienoic 18:2 (9,12)
Arachidonic acid All cis-5,8,11, 14-eicosatetraenoic 20:4 (5,8,11,14)
Polyunsaturated fatty acids (omega-3)
Linolenic acid All cis-9-12-15-octadecatrienoic 18:3 (9,12,15)
EPA All cis-5,8,11,14, 17-Eicosapentaenoic 20:5 (5,8,11,14,17)
DHA All cis-4,7,10,13,16, 19-Docosahexaenoic 22:6 (4,7,10,13,16,19)

Essential Fatty Acids

Rodents placed on a fat-restricted diet are growth impaired, infertile, and develop lesions in the skin and kidney. These pathologies are not observed if the diet is supplemented with linolenic (omega-3) and linoleic acid (omega-6). The results of these studies indicated that mammals cannot synthesize these fatty acids and therefore that these fatty acids are essential components of a healthy diet. Human deficiencies of these essential fatty acids are rare but can occur in infants and children or as a result of intestinal absorption disorders. Human essential fatty acid deficiency compromises liver function, results in unhealthy skin, and impairs growth and development in infants including impaired cognitive function, visual acuity, and hearing.

Essential fatty acids are necessary to maintain the architecture of cell membranes and the integrity of the skin. They are also precursors for the synthesis of eicosanoids ("eicosa" meaning twenty carbons in length), which are bioactive, hormone-like compounds derived from linoleic and linolenic acid. The eicosanoids include prostaglandins, which elicit numerous and varied biological responses including induction of labor, regulation of the female reproductive cycle, and modification of pituitary function. Thromboxane is an eicosanoid that functions in platelet aggregation and blood clotting; leukotrienes function in the inflammation and allergic responses. The omega-3 fatty acid alpha-linolenic acid is also a precursor for eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA) synthesis. Both DHA and arachidonic acid are important for nervous system and retina development. DHA may be an essential dietary fatty acid for preterm infants because studies indicate that it is not synthesized in sufficient quantities to meet the infant's needs.

There is no Recommended Dietary Allowance (RDA) for essential fatty acids. The minimal adequate adult intake of omega-6 fatty acids is estimated to be 2 to 4 g/day of linoleic acid. Americans normally consume about 10 to 15 g/day. The minimal adequate adult intake of omega-3 fatty acids is estimated to be 0.2 to 0.4 g/day, but intakes as high as 3 g/day may have added benefit. Omega-3 fatty acid intakes should be increased during pregnancy and lactation. The World Health Organization recommends an omega-6/omega-3 ratio of 4:1 to 10:1.

Fatty Acids Derived from Food Processing

Synthetic or unnatural types of fatty acids are also common components of Western diets and result from food processing. Fats are processed to increase their shelf life and to alter their physical properties. Monounsaturated and unsaturated fatty acids are chemically inert, whereas polyunsaturated fats are susceptible to oxidation. Polyunsaturated fatty acids degrade by oxidation and become rancid, thereby spoiling foods that contain these compounds. Therefore, products containing polyunsaturated fatty acids tend to have a reduced shelf life, but can be stabilized by converting the polyunsaturated fatty acids contained within these products to more stable monounsaturated and saturated fatty acids through the process of chemical hydrogenation. This processes converts carbon–carbon double bonds to single bonds (Reaction 1):

(Reaction 1; Chemical Hydrogenation)

This process not only stabilizes food, but also changes its physical properties. For example, margarine is produced by the chemical hydrogenation of vegetable oils. This process produces a product that is more stable and solid than vegetable oil and mimics the consistency of natural butter. However, chemical hydrogenation of polyunsaturated fatty acids also results in the formation of "unnatural" trans-fatty acids, which are normally found only in trace quantities in foods from natural sources. Trans-fatty acids do not differ from natural fatty acids in their carbon chain length or degree of saturation, but differ in the orientation or stereochemistry of the carbon–carbon double bonds. Carbon–carbon double bonds can exist in both a cis (the hydrogen atoms that are attached to the carbon atoms that flank the double bond reside on a common plane) or trans (hydrogen atoms reside on different planes) conformation; this is a fundamental principle of organic stereochemistry. The double bonds present in fatty acids from natural, unprocessed food sources usually exist in the cis conformation (see Figure 1). Trans-fatty acids are abundant in foods that undergo chemical hydrogenation and their consumption may increase risk for disease.

Nomenclature of Fatty Acids

All fatty acids can be identified by their "trivial" names, such as oleic or linoleic acid, but these names do not contain information that is necessary to infer their structure or physical properties, that is, the length of their carbon chains or the number and location of carbon–carbon double bonds. Therefore, a nomenclature system has been devised that describes the precise chemical structure of the molecule (see Table 1). The carbon atom that constitutes the carboxylic acid of the fatty acid is referred to as the alpha carbon and is designated as carbon number one; the methyl carbon that constitutes the other end of the molecule is referred to as the omega carbon. Fatty acids are named by the number of carbons in the chain and the number and location of carbon–carbon double bonds. For example, oleic acid is referred to as cis-9-octadecenoic acid, or 18:1(9); the 18 refers to the number of carbons in the fatty acid carbon chain, the 1 refers to the number of carbon–carbon double bonds, and the 9 in parentheses refers to the position of the double bond counting from the carboxylate carbon that is in the cis conformation.

Fatty acids as membrane components and emulsifiers. Fatty acids and triglycerols are lipid soluble and therefore are hydrophobic molecules that do not dissolve readily in water (as evidenced by the appearance of distinct oil and water layers in many oil-based salad dressings). In aqueous environments, fatty acids aggregate and form ordered structures. All life forms have taken advantage of the hydrophobic properties of fatty acids to make cell membranes, which are semipermeable barriers that separate cells from their environment. Membranes delineate the boundaries of the cell, enable cells to retain water, and form specialized internal structures called subcellular organelles that include mitochondria, Golgi apparatus, and lysosomes. Cell membranes are lipid bilayers that are primarily composed of lipid and membrane-bound proteins. Fatty acids present in cell membranes are components of phospholipids, and phosphoglycerides are the most abundant phospholipids in membranes. Phosphoglycerides are similar in structure to triglycerols. They contain two fatty acid molecules and one phosphate molecule esterified to a glycerol molecule. The phosphate molecule has a hydrophilic amino acid or sugar molecule attached to it. Phospholipids are amphipathic molecules because one end of the molecule contains a water-soluble phosphate molecule, and the other end contains a lipid-soluble carbon chain of the fatty acids. Therefore, phospholipids are ideal components of cell membranes because the phosphate end can dissolve in water while the fatty acid end interacts with other lipid molecules to form a barrier that restricts the efflux of water.

The amphipathic properties of phospholipids make them effective emulsifiers, which are chemicals that interact with both water and oils and prevent them from separating and forming two layers. Lecithin is a phospholipid that is synthesized by mammals and is found in high concentrations in eggs. It is also an effective emulsifier and a common food additive in margarine, salad dressings, chocolate, and a variety of baked items. Fatty acids are components of many household products including lubricants, cooking oils, soaps, and detergents.

Dietary and Biosynthetic Sources of Fat

Fatty acids found in mammals are derived from both dietary sources and intracellular biosynthesis. Humans can synthesize all of the necessary fatty acids with the exception of the essential fatty acids. Fatty acids are synthesized in most cells from excess dietary carbohydrate, amino acids, and from other fatty acids. Palmitic acid (16:0) is synthesized by mammals and is a precursor for the synthesis of all other nonessential fatty acids. The carbon chain of palmitic acid is extended by the sequential addition of two carbons to the carboxy terminal end of the molecule. This is an enzyme catalyzed reaction that uses acetyl coenzyme A (CoA) as a source of the two carbon atoms. Mono-and polyunsaturated fatty acids are synthesized by the desaturation of saturated fatty acids. The first double bond is formed between the C–9 and C–10 of palmitate or stearate to form palmitoleic or oleic acid. This is the first step in the synthesis of polyunsatirated fatty acids. This reaction is inhibited by dietary polyunsaturated fatty acids but activated by insulin and thyroid hormone.

Triglycerols are synthesized by most tissues from glycerol 3-phosphate, an intermediate in carbohydrate metabolism, and chemically activated fatty acids known as fatty acyl CoAs. This reaction occurs most frequently in the liver and white adipose tissue. In the liver, triacylglycerol synthesis is necessary for the assembly of lipoproteins, whereas triacylglycerol synthesis in adipose tissue functions to create long-term energy stores for mammals. Although a storage form of energy, fat is a dynamic tissue. Triacylglycerols constantly undergo hydrolysis and resynthesis in adipocytes. Newly synthesized triacylglycerol molecules remain intact for only a few days.

Digestion and Transport

About 90 percent of dietary lipid is in the form of triacylglycerols, and typical adults consume about 60 to 150 g/day. During digestion, dietary lipids aggregate and form water-insoluble particles in the gut that must be disrupted before absorption. Specific enzymes in the stomach, called gastric lipases, and in the intestine, called pancreatic lipases, bind to the lipid droplets and catalyze the hydrolysis or removal of fatty acids from triacylglycerols resulting in the liberation of free fatty acids, diacylglycerols, and monoacylglycerols. Fatty acids are also liberated from phospholipids by pancreatic phospholipases. The products of triglycerol hydrolysis are made soluble by bile acids, which are negatively charged detergents that are synthesized from cholesterol in the liver and secreted into the duodenum. Bile acids form micelles, which are disc-shaped particles with a negatively charged exterior that is water soluble and a hydrophobic center that sequesters fatty acids. During digestion, liberated fatty acids are continuously transferred from lipid droplets to micelles. Virtually all free fatty acids are transported from the micelles into intestinal epithelial cells by passive diffusion. Lipids that cannot be made soluble are not absorbed and are excreted.

Once absorbed into the intestinal cells, short-and medium-chain fatty acids are released directly into blood and taken up by the liver. Long-chain fatty acids are resynthesized into triacylglycerols and complex with apolipoproteins to form lipid globules known as chylomicrons. Chylomicrons travel through the lymphatic system and then through the venous plasma. Most triacylglycerol in chylomicrons is metabolized by lipoprotein lipase that is bound to the surface of adipose and muscle cells.

Metabolism of Fat

Most fat cells are derived in infancy and adolescence except in instances of severe childhood obesity. As fat stores accumulate, adipocytes increase in size but generally not in number. Normal fat stores provide sufficient energy to sustain humans for several weeks during total starvation. During fasting, fatty acids are catabolized or broken down to acetyl-CoA, which is an intermediate in the citric acid cycle. This reaction requires carnitine, a derivative of the amino acid lysine. The oxidative breakdown of fatty acids occurs in mitochondria through a series of reactions known as beta-oxidation. Fatty acids are rich sources of energy; 44 moles of ATP are generated by the complete oxidation of 1 mole of a six-carbon fatty acid, whereas only 38 moles of ATP are generated from 1 mole of glucose, a six-carbon sugar. During starvation, acetyl-CoA can be converted to ketone bodies, which include acetone, acetoacetate and alpha-hydroxybutyrate. These compounds are produced exclusively in the liver but readily enter the circulatory system by passive diffusion. The odor associated with the generation of these ketones becomes apparent in the breath and urine of individuals. Ketone bodies are an alternative energy source for glucose during starvation, and are utilized by the brain and other tissues. Normally, ketones are rapidly metabolized by the peripheral tissues and do not accumulate in blood. However, if the citric acid cycle is depressed by low glucose due to starvation, diabetes mellitus, or a high-fat, low-carbohydrate diet, ketones accumulate in serum and a state of ketosis can result. High concentrations of ketones in blood can lower its pH and result in metabolic acidosis, which can be fatal during diabetic ketosis.

Fatty Acid Regulation of Gene Expression

Polyunsaturated fatty acids and eicosanoids are informational or signaling molecules that can influence the expression of certain genes involved in lipid synthesis, breakdown, and transport. Omega-3 and omega-6 polyunsaturated fatty acids lower the accumulation of triacylglycerol in muscle by inhibiting triacylglycerol synthesis in the liver and accelerating the breakdown of fatty acids in the liver and skeletal muscle. Linoleic and linolenic acid, as well as certain pharmaceuticals, bind to and activate the transcriptional activity of a family of related nuclear receptors known as the peroxisome proliferator–activator receptors (PPARs). These receptors are transcription factors that can directly bind DNA and elevate the transcription of genes. The target genes are involved in the metabolism, storage, and transport of lipids, triacylglycerol, and fatty acids. These receptors also regulate the differentiation of immature adipocytes into mature fat cells.

Individual members of the PPAR family have different functions. In the fasting liver, PPAR-alpha activates genes that encode enzymes that metabolize lipids to ketone bodies and decreases expression of genes involved in fatty acid synthesis. As fatty acids are hydrolyzed from triacyglyceride, PPAR-alpha is further activated. PPAR-alpha activates the expression of genes in fat cells that are necessary for fatty acid uptake, triacylglycerol synthesis, and fat storage.

Determinants of Total Body Fat

Fat is a storage form of energy, and as such only accumulates when energy intake exceeds energy output. Total body fat accumulation is determined by complex interactions among genes, environment, and behavior. The human body can adjust to a wide range of fat intake, but both deficiency and excess are associated with disease. In a normal, healthy individual, fat stores constitute 12 to 18 percent of total body weight in males and 18 to 24 percent in females. Excessive consumption of high-calorie foods and/or a lack of exercise elevate fat stores. In some cases, the genetic background alone can determine total body fat in the absence of strict dietary control. Children with obese parents are at higher risk of becoming obese, and studies of identical twins also indicate that risk for obesity has a strong hereditary component. Furthermore, more than 75 percent of the Pima Indians are obese, again indicating a strong influence of genetics on fat accumulation. Many genes have been identified that control weight gain. The products of these genes regulate energy balance and expenditure and are signaling hormones that regulate appetite and fat metabolism. Some studies indicate that genetic factors, and the metabolic signals they generate, balance energy expenditure and appetite to form an individual's "set point" that specifies body weight. These signals include the satiety hormones such as serotonin and leptin. The neurotransmitter serotonin is responsible for "cravings" that can increase consumption of particular food types. Leptin is a peptide hormone that is secreted by fat cells and signals the hypothalamus. Leptin secretion is proportional to fat cell size, and increased leptin concentrations in blood signal the brain to increase energy expenditure and decrease food intake. Mice lacking the leptin gene or the leptin receptor become obese. Human mutations in the leptin gene are rare but result in obesity.

Dietary Fat and Disease Risk

Lipids constitute about 33 percent of total energy intake in the typical North American diet, whereas Japanese diets have a lower fat intake (11 percent of energy from fat). Western-style diets are deficient in omega-3 fatty acids and contain excess omega-6 fatty acids. Some evidence indicates that prehistoric diets that were consumed through much of human evolution contained an omega-6/omega-3 fatty acid ratio that was near 1.0, whereas this ratio is about 20 in the typical Western diet. Vegetarian diets also tend to contain excess omega-6 fatty acids. Diets deficient in omega-3 fatty acids or diets that contain an elevated omega-6/omega-3 ratio may increase risk for cardiovascular disease and cancer.

Research over the past few decades has indicated that excess consumption of saturated fat increases risk for disease including heart disease (arteriosclerosis), obesity, diabetes, and certain cancers (see "Fat and Heart Disease"). Obesity is a clinical condition defined as having a body weight that is greater than 20 percent above a desirable body weight standard or a body mass index that exceeds 30 kg/m2. Obesity occurs in epidemic proportions in the United States and other Western societies, especially in individuals from lower socioeconomic level. Its prevalence is rapidly increasing in developing societies that are adapting Western lifestyles. The combination of increased fat intake and sedentary lifestyle (otherwise referred to as excess energy intake) increases risk for overweight and obesity. Increased body fat, in turn, is an independent risk for heart disease, diabetes, and high blood pressure. Elevated fat intake can also increase risk for cancers of the colon, prostate, and breast. The incidence of cancers of the breast is high in populations with high intakes of either natural saturated fat or trans-fatty acids, but not diets rich in olive oil, which contains high levels of monounsaturated fatty acids. High polyunsaturated fat intake in the form of linoleic acid (omega-6) increases risk for breast cancer incidence in mice, compared to diets high in omega-3 fatty acids.

Cultures in which traditional foods have high concentrations of monounsaturated fats, products that include olive oil and fish, have lower incidence of heart disease compared to the United States. The prevalence of heart disease in Mediterranean countries is only 50 percent of that found in the United States, even when fat represents almost 40 percent of total energy intake. However, the decreased rates of heart diseases in these countries also reflects other dietary patterns including a high consumption of fresh fruits and vegetables and other lifestyle differences.

Fat and Heart Disease

Risk for heart disease results from excess fat consumption and the type of fat that is present in the diet. Diets high in saturated fatty acids, especially those found in animal fat, increase the concentration of lowdensity lipoprotein (LDL) cholesterol or "bad" cholesterol. Elevations in serum LDL concentrations increase risk for arteriosclerosis. Consumption of trans-fatty acids, although only representing between 2 and 4 percent of calories in Western diets, also increases risk for heart disease, but the pathogenic mechanisms are not certain. Trans-fatty acids may be as efficient as natural saturated fat in increasing serum LDL concentrations, and their consumption replaces foods that contain beneficial unsaturated fatty acids. Consumption of omega-3 and omega-6 fatty acids, especially when they replace consumption of saturated fat, decreases risk for heart disease, in part by lowering LDL cholesterol levels. Omega-3 fatty acids are more protective than omega-6 fatty acids. Omega-6 fatty acids may lower serum HDL cholesterol, which is harmful because HDL protects the heart from disease. Omega-3 fatty acids may prevent heart disease by improving immune function, lowering blood pressure, and inhibiting the growth of plaques on blood vessel walls. Omega-3 fatty acids obtained from whole food sources such as fatty fish seems to be more beneficial than dietary supplements.

Pharmaceuticals That Target F>at Metabolism

Many of the most prevalent diseases in Western cultures are related to excessive caloric intake and sedentary lifestyles, diseases that include obesity, hyperlipidemia, diabetes, and arteriosclerosis. These states often occur in combination, and are diagnosed as syndrome x. Pharmaceutical have been developed to manage these disorders. These agents either inhibit intestinal fat absorption or affect fat metabolism by manipulating the activity of PPARs.

Fibrates (gemfibrozil, bezafibrate, fenofibrate) are pharmaceuticals that target and inhibit the function of PPAR-alpha. Thiazolidinediones target PPAR-alpha. Fibrates are effective in the treatment of cardiovascular disease. They function to elevate HDL levels by increasing the expression of proteins necessary for its structure, and decreasing plasma triglyceride by accelerating fatty acid oxidation in the liver. TZDs are effective in the treatment of Type 2 diabetes because they have a hypolipidemic and hypoglycemic effect.

Nondigestible commercial lipids have also been developed to limit total fat intake. One product, Olestra, contains fatty acids linked to the sugar sucrose. These products replace natural fat in foods, and were designed to taste like natural fat. However, they cannot be hydrolyzed in the gut and therefore are not absorbed. Other pharmaceuticals target and inhibit pancreatic lipase, such that natural dietary lipids are not broken down to fatty acids and therefore are not absorbed.

Bibliography

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Devlin, Thomas M. Biochemistry, 5th ed. New York: Wiley-Liss, 2002.

Kersten, Sander, Beatrice Desvergne, and Walter Wahli. "Roles of PPARs in Health and Disease." Nature 405 (2000): 421–424.

Simopoulos, Artemis P. "The Mediterranean Diets: What Is So Special About the Diet of Greece?" Journal of Nutrition 131 (2001): 3065S–3073S.

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—Patrick J. Stover

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