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143 Cards in this Set
- Front
- Back
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Eicosanoids are derivatives of _________ (20:4ω6), which is “stored” in membrane phospholipids. They include ________, _________ and ________.
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arachidonic acid; prostaglandins, thromboxanes, and leukotrienes
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arachidonic acid
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(20:4ω6)
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eicosanoids are produced in ___________
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nearly all tissues
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eicosanoids are biologically important because they contribute to the maintenance of _______ and mediate (4):
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healthy gastric tissue; platelet aggregation, inflammation, fever, and allergic response
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Analogs of eicosanoids synthesized from ω3-fatty acids – _______ and _______- acids - sometimes have different physiological effects than their arachidonate (ω6) cousins.
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eicosapentaenoic (EPA; 20:5ω3) and docosahexaenoic (DHA; 22:6ω3)
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Eicosanoids are derivatives of _________ (20:4ω6), which is “stored” in membrane phospholipids. They include ________, _________ and ________.
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arachidonic acid; prostaglandins, thromboxanes, and leukotrienes
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arachidonic acid
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(20:4ω6)
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eicosanoids are produced in ___________
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nearly all tissues
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eicosanoids are biologically important because they contribute to the maintenance of _______ and mediate (4):
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healthy gastric tissue; platelet aggregation, inflammation, fever, and allergic response
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Analogs of eicosanoids synthesized from ω3-fatty acids – _______ and _______- acids - sometimes have different physiological effects than their arachidonate (ω6) cousins.
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eicosapentaenoic (EPA; 20:5ω3) and docosahexaenoic (DHA; 22:6ω3)
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Isozymes of prostaglandin synthetase (_________; _______ and _________) have different localizations and are responsible for initiating synthesis of different (and often opposing) eicosanoid products.
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Cyclooxygenase 1 & 2; COX-1 & COX-2
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Differential inhibition of ________ and ______ by non-steroidal anti-inflammatory drugs (NSAIDS) like aspirin and by selective _____ inhibitors like Celebrex and Vioxx have important clinical implications such as (3):
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COX-1 and COX-2; COX-2; heart attacks, ulcers, arthritis relief
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eicosanoids, unlike paracrine hormones, act locally and are not stored prior to release (ie they are ___crine or ___crine); thus, they do not travel in the ______
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paracrine or autocrine; circulatory system
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physiological responses mediated by eicosanoids include (3):
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vasoconstriction/vasodilation; platelet aggregation (or lack thereof); smooth muscle contraction/relaxation
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physiological responses influenced by eicosanoids include (5):
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inflammation, fever, pain, ulcers/gastric integrity, blood clotting
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arachidonic acid (20:4ω6) must either be__________ or synthesized by chain-elongation and desaturation from the essential fatty acid, _____________
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obtained from the diet, linoleic acid (18:2ω6)
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physiologically important ω-3 analogs of eicosanoids can also be synthesized from _________ and _________, which in turn can either be ____________ (18:3ω3; flaxseed oil is a good source) or _________
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eicosapentaenoic acid (EPA; 20:5ω3), docosahexaenoic acid (DHA; 22:6ω3); synthesized from ω-linolenic acid, obtained in the diet.
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There is competition between _________ and __________ for enzymes involved in eicosanoid formation, and this can be physiologically relevant.
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arachidonic acid its ω-3 fatty acid analogs
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Arachidonic acid that is the precursor for eicosanoid synthesis is released from_________ (mostly ________ or _________) by _________ in response to a variety of signals (e.g., growth factors, hormones, cytokines).
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membrane-bound phospholipids; phosphatidlycholine or phosphatidylinositol); phospholipase A2
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The first step in prostaglandin/ thromboxane synthesis is the _________ of arachidonate by _________ to form the common precursor, _______.
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oxidative cyclization; cyclooxygenase; PGH2
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During prostaglandin/thromboxane synthesis, ________ is converted to various prostaglandins and thromboxanes by cell-specific _______, which determine the specificity (and this physiological effect) of the eicosanoids produced.
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PGH2; synthetases
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Most of the metabolic control for eicosanoid production is at the level of __________ activity – once arachidonate is liberated, the synthetic enzymes in the cell make the eicosanoid product(s) dictated by that cell’s enzymatic repertoire, with the amount of product produced depending on the amount of arachidonic acid liberated.
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phospholipase A2
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______ is constitutive in most tissues; in the stomach, its products help maintain the integrity of the stomach lining in its acidic environment. ______ is also present in platelets, where its products promote platelet aggregation and cause vasoconstriction.
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COX-1, COX-1
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_____ is inducible in a limited number of tissues (including macrophages) active in the inflammatory and immune responses. Inducible ____ is thus responsible for production of most pro-inflammatory eicosanoids; these lead to the pain, heat, redness, and swelling of inflammation, and the fever of infection. _____ is also present in endothelial cells where its products inhibit ____ and promote _____.
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COX-2, COX-2, COX-2; platelet aggregation, vasodilation
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Leukotrienes are also produced from released arachidonic acid by the enzyme _____ (and subsequent cell-specific leukotriene synthetases). They are _____ derivatives of arachidonic acid (unlike prostaglandins and leukotrienes, which are cyclized derivatives).
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lipoxygenase, linear hydroperoxy
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Leukotrienes are mediators of _____, and are also involved in _______. Lipoxygenase and ________ often compete for substrates within the same cell.
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the allergic response, inflammation; cyclooxygenase
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Following their synthesis, eicosanoids are rapidly transported outside the cell by means of a __________.
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prostaglandin transporter protein
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There are _____ different receptors for many different eicosanoids. Most all of the intracellular signaling pathways activated by eicosanoid-receptor binding involve ____ activation or inhibition of second messenger systems such as _______ and ______.
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many; G-protein; cAMP and Ca++/IP3
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Cortisol and related steroidal anti-inflammatory drugs (SAIDS) inhibit _______, and thus prevent the release of arachidonic acid required for _________, _________ and _______synthesis.
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phospholipase A2; prostaglandin, thromboxane, and leukotriene
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NSAIDs inhibit ________
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cyclooygenase
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NSAIDs include (4):
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aspirin (acetlysalicylic acid), acetaminophen, ibuprofen (Advil, Motrin), naproxen (Aleve)
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COX-2 specific (or selective) inhibitors include (3):
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Celebrex, Vioxx, and Bextra
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Inhibitors of the lipoxygenase pathway, which are useful in the treatment of asthma, include ________ and ________.
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Accolate (zafirlukast) and Zyflo (zileuton)
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travoprost, a prostaglandin FP receptor agonist, is the current drug of choice for treatment of _______, a major risk factor for development of glaucoma.
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elevated intraocular pressure
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Plavix (clopidogrel) irreversibly blocks _________
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ADP receptors on platelets
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A myocardial infraction (heart attack) can begin when ____________; this inflammation is often secondary to the presence of _______________.
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torn and damaged blood vessels become inflamed; unsthable atherosclerotic plaques
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Among the compounds released during MI are: ________ (a vasoconstrictor that helps close off the damaged vessels), __________ and _____________
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Serotonin, adenosine diphosphate (ADP) and platelet aggregating factor (PAF)
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_______ are responsible for “non-specific” degradation, while the ________ system takes care of “targeted” protein degradation
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lysosomes, ubiquitin-proteasome
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There is always some amino acid catabolism – quite a bit during prolonged fasting (mostly from muscle protein) to support _________ in liver.
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gluconeogenesis
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Waste NH3 is eliminated mostly as _____ (liver).
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urea
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_________ trade NH3 among amino acids/α-keto acids, and importantly, funnel waste NH3 to _______. ________ releases this waste NH3, which is used to synthesize urea (aspartate supplies the 2nd NH3 group of urea). Urea then travels in blood to the _______ for excretion.
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Transaminases (aminotransferases), glutamate; glutamate dehydrogenase; kidneys
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C-skeletons of amino acids (α-keto acidss) can be (3):
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oxidized for energy, serve as gluconeogenic substrates in liver during fasting, or be stored as triglycerides for later energy use
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________ supply the nitrogen required for the nucleotide building blocks (e.g., ATP, GTP) for RNA and DNA.
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amino acids
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The metabolic energy requirements for synthesis of proteins to replace those turning over (about 400 g/day) and those excreted as digestive enzymes or lost from cells lining the small intestine (about 20 g/day) is considerable, as much as ________ of the total daily energy requirement.
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20%
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Chronic inflammatory diseases such as rheumatoid arthritis involve extracellular release of ________, which attack surrounding tissues.
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lysosomal enzymes
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_________ is a central molecule in amino acid and N metabolism. _______ funnel waste NH3 to α-ketoglutarate to form _______.
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glutamate; transaminases, glutamate
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Glutamate can be oxidatively deaminated to release
______, which enters the urea cycle (liver). |
free ammonia
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Aspartate, formed by transamination of _________, provides the other NH3 group for urea; the C-skeleton of what used to be _______ is eventually recycled to oxaloacetate, then _______ to regenerate aspartate.
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oxaloacetate; aspartate, transaminated
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transamination reactions serve two purposes: 1) help maintain adequate levels of _______________ required for protein synthesis 2) funnel amino groups from catabolized amino acids to ________ and ________ for eventual excretion as urea
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non-essential amino acids; glutamate, aspartate
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transaminases (generally) require α-ketoglutarate as a NH3 acceptor, producing ______ and _________; they all require __________ (comes from vitamin B6)
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glutamate and an α-keto acid; pyridoxal phosphate
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in contrast to transaminase reactions, oxidative deamination yields an ______ with release of the amino group as free ammonia; _______ in liver is the most important enzyme involved.
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α-keto acid; glutamate dehydrogenase
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________ is the only amino acid that is rapidly deaminated
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glutamate
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two major sources of waste ammonia (other than deamination rxns) are amines in the diet and “monoamines” (hormones and neurotransmitters like dopamine, serotonin, epinephrine and norepinephrine); _______ catalyze the oxidative deamination of these molecules
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monoamine oxidases
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two major mechanisms to transport ammonia to liver for its conversion to urea and ultimate excretion in the urine: 1) ________ puts free ammonia on glutamate to form glutamine, an energy-requiring process and 2) the _______ cycle
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glutamine synthetase; the glucose-alanine cycle
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_______ ιs a non-toxic transport form of ammonia (it is actually α-ketoglutarate carrying 2 NH3 groups)
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glutamine
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glutamine, a non-toxic transport form of ammonia, travels in the blood to the liver, where _______ releases free ammonia which can enter the urea cycle, and regenerates _______
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glutaminase, glutamate
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the kidneys can also form ammonia from glutamine by action of _____
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renal glutaminase
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in the glucose-alanine cycle, amino acids derived from skeletal muscle protein breakdown are converted to _____, which is transported to liver where it is deaminated to form ____; waste NH3 groups then enter the urea cycle, while pyruvate is used for _______
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alanine, pyruvate, gluconeogenesis
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the rxn that is a prelude to the urea cycle is catalyzed by ________ ("activated ammonia"), the major control point in urea synthesis.
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carbamoyl phosphate synthetase
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overall, _____ (equivalent to 4 ATP) are required to form urea, which gets rid of 2 amino groups
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4 ~P
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in the ______, ammonia, produced by oxidative deamination of glutamate (which collects amino groups from other amino acids) and the amine group from aspartate combine with carbon dioxide (actually a HCO3- ion) to form urea. The urea is carried through the blood to the ____, which sequesters it for excretion in the urine.
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liver, kidney
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major classes of animal tissue (4):
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connective, epithelial, nerve, muscle
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characteristics of connective tissue:
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extracellular matrix (ECM) plentiful, cells sparse, most of the mechanical load is borne by ECM
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characteristics of epithelial tissue:
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cells are tightly bonded in sheets, ECM sparse and most volume occupied by cells; stresses borne by the contiguous cell layer that rests on a layer of ECM, the basement membrane
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characteristics of nerve tissue:
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nerve cells are surrounded by basement membranes
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characteristics of muscle tissue
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skeletal muscle is surrounded by basement membrane
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Typically, the surfaces of epithelial cells are divided into two distinct regions, the _______and the _____surfaces, and these two regions are separated by ________.
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apical and basolateral; tight junctions
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_______ is a carbohydrate-rich coating of the exposed surfaces of cells, derived mainly from the glycosyl moieties of PM glycoproteins and glycolipids
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glycocalyx
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The glycocalyx is prominent in ________ cells where it may have a protective function. In some cells, the glycocalyx may be involved in _________, i.e. transmitting mechanical forces into intracellular signals. This may occur in _____ cells which line blood vessels and which are exposed to shear forces from blood flow.
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intestinal epithelial cells; mechanotransduction; endothelial cells
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types of cell-cell junctions (3):
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occluding/tight, anchoring, communicating
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_________ form an “O-ring seal” between adjacent cells preventing diffusion of molecules through the cell layers at the interface between cells; also serve to separate the apical from basolateral surfaces of epithelial cells, preventing diffusion of plasma membrane proteins from one domain to the other
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Tight junctions (zonula occludens)
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Key proteins in tight junctions are ____ and members of the ____ family.
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occludin, claudin
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classes of anchoring junctions (4):
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zonula adherens (adherens junctions), desmosomes (macula adherens), hemidesmosomes, focal adhesions
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_________ are continuous junctions around epithelial cells, providing strong adhesion between epithelial cells and attachment for actin microfilaments
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zonula adherens (adherens junctions)
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key transmembrane proteins are _______
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cadherins
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________ provide strong intercellular adhesions in localized spots; keratins/tonofilaments, a class of intermediate filament, insert into these junctions
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desmosomes (macula adherens)
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key transmembrane proteins for demosomes are _______
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cadherins
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_______ provide spot adhesions to basement membrane instead of to other cells and also attach intermediate filaments
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hemidesmosomes
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key transmembrane proteins for hemidesmosomes are _______
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integrins (α6β4)
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________ provide strong adhesion to extracellular matrix and attachment for actin microfilaments
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focal adhesions
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key transmembrane proteins for focal adhesions are _________
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integrins
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Tight junctions, adherens junctions and desmosomes collectively exist as the __________; however, ________ also exist elsewhere.
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junctional complex; desmosomes
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_______ allow communication between adjacent cells by passing molecules <1500Da through an array of tube-like channels termed connexons.
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gap junctions
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The protein making up connexons is known as ________. Gap junction permeability is regulated by ______ and ______. As intracellular calcium concentrations rise (for example, as cells die), gap junctions ______ preventing cytoplasmic communication between adjacent cells.
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connexin; intracellular [Ca++] and pH; close
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arrays of gap junctions are often visualized by _____________
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freeze fracture electron microscopy
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four classes of cell adhesions molecules (CAMs):
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cadherins, members of the Ig superfamily, selectins, integrins
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Cell adhesion is mediated by CAMs acting in both _____ and ________ adhesion mechanisms. The latter reactions provide cell to cell specificity enabling cells to ________ before full-blown junctions are formed.
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junctional and nonjunctional; organize into tissues
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cadherins
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Ca++-dependent
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members of the Ig superfamily
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Ca++-independent
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selectins
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recognize carbohydrate moiety - Ca++-dependent
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integrins
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require divalent cations, but not necessarily Ca++
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CAMs (a, b, c) are primarily involved in cell to cell adhesion whereas the ______, while often involved in cell-extracellular matrix adhesion, can be involved in cell-cell adhesion.
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integrins
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cadherins are transmembrane glycoproteins which bind adjacent cells in a Ca++-dependent, ______ fashion. E-cadherin is the major adhesion molecule in _______ junctions.
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homophilic, adherens
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How cadherins link to the actin cytoskeleton is controversial; most textbooks indicate that this is via _______ which binds to the cadherin cytoplasmic domain and alpha-catenin, which binds to ______.
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beta-catenin, actin
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hemidesmosomes do not contain cadherins but a specific ________ that binds to extracellular matrix on the outside and intermediate filaments on the inside
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integrin
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These molecules, part of the immunoglobulin (Ig) superfamily, appear on the surfaces of neural cells, lymphoid cells, and endothelial cells among others. They do not require Ca2+ for function and may exhibit homo- or hetero- philic binding.
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members of the Ig superfamily
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N-CAMs, a member of the ______, function in a Ca++ independent manner, binding to each other in a homophilic fashion
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the Ig superfamily
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three major forms of Ig superfamily molecules: 1) ___ (membrane-spanning) 2) _____ (membrane-spanning) 3) _________ (GPI-linked) . These three forms a produced via _______.
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N-CAM180, N-CAM140 and N-CAM120; alternative splicing
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In addition to playing a role in intercellular adhesion, _____ have a signaling function.
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N-CAMs
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_____ appear to provide the most strength for intercellular adhesion, while _______ may provide fine tuning and regulation to cell-cell adhesion.
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cadherins, members of the immunoglobulin superfamily
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ICAM-1 (Intercellular adhesion molecule-1) is an Ig family member that is expressed on the surface of ________ in response to ________. ICAM-1 is bound by specific ______ on the surface of circulating ________ and is one of the key cell adhesion molecules that recruits leukocytes from the circulation in response to inflammation.
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endothelial cells, inflammatory signals; integrins, leukocytes
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Selectins are proteins found on _____ and _________; they mediate interactions between blood cells and the endothelial lining. Such interactions are crucial to _____ and the inflammatory response.
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leukocytes, endothelial cells; lymphocyte homing
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selectins recognize specific sugar residues on the opposing cell in a manner that depends on the presence of _____
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Ca++
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three known types of selections: 1) __ (stored in vesicles in platelets and endothelial cells) 2) on the endothelial cell surface in response to inflammatory signals 3) ____
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1) P-selectin 2) E-selectin 3) L-selectin
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_____ mediates the first interaction of endothelial cells with polymorphonuclear leukocytes (PMNs, also known as neutrophils). This is the first step in recruiting PMNs to sites of _______-.
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P-selectin, inflammation
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Linkage of the ______ to the cytoskeleton is generally required for cell-cell adhesions to be strong.
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CAM
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Interactions between ____ on neighboring cells will transmit signals from one cell to another.
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CAMs
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pemphigus is an autoimmune condition in which individuals develop antibodies against _____ (desmogleins). This leads to _________, which can result in major infections.
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desmosomal cadherins, blistering of the skin
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Pemphigoid is a condition in which antibodies are developed against ______ proteins, again resulting in severe blistering.
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hemidesmosomal
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protein-protein interactions mediated by receptor tyrosine kinases result in the activation of intercellular relays involving: 1) _____ (eg RAS) 2) ______ (eg RAF --> MAPKK --> MAPK), 3) ________ (eg PI-3-K)
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1) monomeric G-proteins (eg RAS), 2) Protein kinase cascades (e.g. Raf-->MAPKK-->MAPK), 3) messenger producing enzymes (e.g. PI-3-K)
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Inappropriate activation of receptor tyrosine kinase pathways causes uncontrolled cell proliferation and is associated with ______ and _______.
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transformation and cancer
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4 elements of RTK domain organization:
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extracellular hormone binding domain, transmembrane-spanning domain, juxtamembrane regulatory domain, cytoplasmic protein tyrosine kinase domain
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Class 1 RTKs are characterized by a _______ ligand free receptor and _____ ligand, and have their critical phosphorylation sites _________.
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monomeric receptor, monomeric ligand, on the cytoplasmic domain
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Class II RTKs are characterized by a _______ ligand free receptor and _____ ligand, and have their critical phosphorylation sites _________.
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disulfide-crosslinked dimer receptor, monomeric ligand, on the Insulin Receptor Substrate
(protein associated with receptor cytoplasmic domain) |
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Class III RTKs are characterized by a _______ ligand free receptor and _____ ligand, and have their critical phosphorylation sites _________.
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monomeric receptor, dimeric ligand, on the cytoplasmic domain
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steps of class I RTK action:
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1) ligand binding induces monomer dimerization 2) autophosphorylation of cytoplasmic domain
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steps of class II RTK action:
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1) ligand binding induces active conformation of dimer (was already dimerized, but inactive) 2) autophosphorylation of cytoplasmic domain and IRS (insulin receptor substrate)
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steps of class III RTK action:
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1) dimer ligand cross-links monomers 2) autophosphorylation of cytoplasmic domain
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the important distinction between class I&III RTKs and class II RTKs is that, while classes I&III phosphorylate __________, class II phosphorylate associated proteins called _________
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on their own cytoplasmic domains, Insulin Receptor Substrates (IRS)
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activation of different signaling pathways is coordinated via ___________
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simultaneous binding to multiple signaling proteins serves
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Intracellular signaling molecules are typically modular proteins with “function” domain(s) and one or more “conserved” domain(s) that are found in many signal proteins; ________ the building blocks of signaling complexes
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conserved domains
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conserved ________ domains bind to short peptide motifs of proteins containing phospho-tyrosine
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SH2
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conserved ________ domains bind to short peptide motifs of proteins containing either phospho-tyrosine or tyrosine
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PTB
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conserved __________ domains bind to proline-rich motifs
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SH3
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conserved _______ domains promote associations with phospholipids of membranes and possibly to integral membrane proteins
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PH
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RAS is a membrane-associated monomeric ___________ that is postranslationally modified by covalent attachment of a lipophilic farnesyl group to its _______; • Lipid modification promotes _________(i.e. signal independent) membrane association of Ras.
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G-protein; C-terminus; constitutive
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regulation of RAS activity occurs via ___________; The relative rates of GTP hydrolysis (_______) and GDP dissociation (_______) determine the fraction of the protein in the active GTP-bound or inactive GDP-bound states; activated receptor recruits a ______ to the membrane, resulting in its _______; this _________
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the basic GTPase cycle ; (kcat-GTP); (Kd-GDP); (GEF), co-localization with Ras, stimulates the inactive Ras to exchange its GDP for GTP and thus increases amount of active Ras.
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active RAS stimulates _________, which is made up of three sequentially acting ______; Ras activates __ (a serine/threonine kinase), Raf activates __; ___ activates ____; MAPK ____
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a MAPK activation cascade, protein kinases; Raf, MAPKK; MAPKK activates MAPK; MAPK phosphorylates target proteins
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PI-3K is an effector enzyme that generates the 2nd messenger ___; PI-3K has a regulatory subunit with two _____ domains that mediate its binding to an activated receptor and a catalytic subunit that _____
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PIP3; SH2; phosphorylates membrane phosphatidylinositols (PIs) at the 3- position
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after PI-K3 produces __, which creates a binding site for ___ on the plasma membrane, where it is accessible to the integral membrane kinase ____, which phosphorylates and activates it
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PIP3, PKB, PDK
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Co-ordinate regulation of the _____ pathway (MAPKs Erk1 and Erk2) and the _____ pathway (PKB) by RTKs controls cell proliferation and survival; inappropriate/constitutive activation of these pathways leads to uncontrolled cell proliferation and cancer.
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Ras, PI-3-K
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Saturated fatty acids contain _________ bonds in their structures and end in "___"
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no carbon-to-carbon double bonds; "anoic"
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Lauric (x:0) and myristic (x:0) acids are medium-chain fatty acids found in palm and coconut oil. They are frequently included in commercial baked goods because of their stability and texture. While usually listed as vegetable oils on the label, they raise serum cholesterol levels.
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12, 14
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Palmitic acid (X:0) is the most abundant saturated fatty acid and it raises cholesterol levels.
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16
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Stearic acid (X:0) is also a saturated fatty acid, but it has a neutral or cholesterol lowering effect.
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18
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Oleic acid (X:X) is the most abundant dietary monounsaturated fatty acid. It is relatively abundant in olive oil and is a key component of the "Mediteranean Diet". It appears to lower cholesterol levels without also lowering HDL levels.
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18:1
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Linoleic acid (X:X) is an essential polyunsaturated fatty acid of the ω6 series. It is found in vegetable oils and lowers serum cholesterol.
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18:2
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Linolenic acid (X:X) is an essential polyunsaturated fatty acid of the ω3 series. It is also found in vegetable oils and lowers serum cholesterol.
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18:3
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Arachidonic acid (X:X) is a polyunsaturated fatty acid made from linoleic acid and is a precursor for synthesis of the ω6 eicosanoids.
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20:4
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Eicosapentaenoic (X:X) and docosahexaenoic (X:X) acids are polyunsaturated fatty acids made from linolenic acid and are precursors for synthesis of the ω3 eicosanoids.). Recent studies have also suggested that decosahexaenoic acid may be essential for early neural and visual development.
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20:5, 22:6
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Recent research has shown that ___ fatty acids raise serum cholesterol as much as saturated fatty acids.
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trans
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phospholipids are composed of______, ________, ______, and in most cases, _________
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fatty acids, glycerol, phosphoric acid, a nitrogenous base
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_____ are insoluble, so they are broken down by mechanical action in the stomach; the necessary detergent effect is supplied by ____ and _____
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triglycerides; bile salts and partially digested fatty acids
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