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121-534: Based on this reaction, mathematician Dorothy Wrinch hypothesized in a series of five papers in the late 1930s a structural model of globular proteins. She postulated that, under some conditions, amino acids will spontaneously make the maximum possible number of cyclol crosslinks, resulting in cyclol molecules and cyclol fabrics . She further proposed that globular proteins have a tertiary structure corresponding to Platonic solids and semiregular polyhedra formed of cyclol fabrics with no free edges. In contrast to

242-437: A myelin sheath, rich in cholesterol since it is derived from compacted layers of Schwann cell or oligodendrocyte membranes, provides insulation for more efficient conduction of impulses. Demyelination (loss of myelin) is believed to be part of the basis for multiple sclerosis . Cholesterol binds to and affects the gating of a number of ion channels such as the nicotinic acetylcholine receptor , GABA A receptor , and

363-509: A 1933 lecture by Astbury to the Oxford Junior Scientific Society, physicist Frederick Frank suggested that the fibrous protein α-keratin might be stabilized by an alternative mechanism, namely, covalent crosslinking of the peptide bonds by the cyclol reaction above. The cyclol crosslink draws the two peptide groups close together; the N and C atoms are separated by ~1.5  Å , whereas they are separated by ~3  Å in

484-428: A cell via endocytosis . These vesicles then fuse with a lysosome , where the lysosomal acid lipase enzyme hydrolyzes the cholesterol esters. The cholesterol can then be used for membrane biosynthesis or esterified and stored within the cell, so as to not interfere with the cell membranes. LDL receptors are used up during cholesterol absorption, and its synthesis is regulated by SREBP , the same protein that controls

605-412: A change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteasome . This enzyme's activity can also be reduced by phosphorylation by an AMP-activated protein kinase . Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low. As an isolated molecule, cholesterol

726-403: A cyclol fabric. An encyclopedic summary of the chemical and structural evidence against the cyclol model was given by Pauling and Niemann. Moreover, a supporting piece of evidence—the result that all proteins contain an integer multiple of 288 amino-acid residues—was likewise shown to be incorrect in 1939. Wrinch replied to the steric-clash, free-energy, chemical and residue-number criticisms of

847-429: A full complement of amide carbonyl groups; both observations contradict the cyclol hypothesis that such carbonyls are converted to hydroxyl groups in folded proteins. Finally, proteins were known to contain proline in significant quantities (typically 5%); since proline lacks the amide hydrogen and its nitrogen already forms three covalent bonds, proline seems incapable of the cyclol reaction and of being incorporated into

968-722: A great deal of a parent's time (away from their career). The book next offers a constructive solution to this problem. Wrinch proposed that there should be Child Rearing Services that assume from parents nearly every aspect of raising the child, except in four areas where a parent's involvement is absolutely crucial: "impregnation," "gestation," "childbirth," and "lactation." The Child Rearing Services (C.R.S.) would be divided into four bureaus, A, B, C, and D. The C.R.S.A. would deal with refitting homes so as to make them more comfortable and hospitable to child rearing, providing services like electrical work, plumbing services and repairs, insulation and soundproofing, and reliable hot water. The C.R.S.B.

1089-409: A hexagonal structure. Wrinch summarized her model and the supporting molecular-weight experimental data in three review articles. Having proposed a model of globular proteins, Wrinch investigated whether it was consistent with the available structural data. She hypothesized that bovine tuberculin protein (523) was a C 1 closed cyclol consisting of 72 residues and that the digestive enzyme pepsin

1210-445: A key prediction of the cyclol model, whereas Meyer and Hohenemser showed that cyclol condensations of amino acids did not exist even in minute quantities as a transition state . More general chemical arguments against the cyclol model were given by Bergmann and Niemann and by Neuberger . Infrared spectroscopic data showed that the number of carbonyl groups in a protein did not change upon hydrolysis, and that intact, folded proteins have

1331-462: A lower intake of food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP cleavage-activating protein) and INSIG-1 . When cholesterol levels fall, INSIG-1 dissociates from

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1452-495: A manual of child-care, propounding ideas of societal reorganisation to make child rearing more compatible with professional life. Nicholson's mental health deteriorated in the late 1920s, and in 1930 he was certified as mentally ill and confined in the Warneford Hospital until his death in 1955. In 1937 Wrinch was granted a divorce on grounds of her husband's insanity. From 1930 Wrinch was close emotionally and intellectually to

1573-456: A model of protein structure , which she called the " cyclol " structure. The model generated considerable controversy and was attacked by the chemist Linus Pauling . In these debates Wrinch's lack of training in chemistry was a great weakness. By 1939, evidence had accumulated that the model was wrong but Wrinch continued working on it. However, experimental work by Irving Langmuir done in collaboration with Wrinch to validate her ideas catalysed

1694-466: A paper with William Astbury , noting the possibility of a keto-enol isomerization of the >CH and an amide carbonyl group >C=O, producing a crosslink >C-C(OH)< and again converting the oxygen to a hydroxyl group. Such reactions could yield five-membered rings, whereas the classic cyclol hypothesis produces six-membered rings. This keto-enol crosslink hypothesis was not developed much further. In her fifth paper on cyclols (1937), Wrinch identified

1815-410: A part in the beginnings of much of present research in molecular biology." On a more personal level, Hodgkin wrote, "I like to think of her as she was when I first knew her, gay, enthusiastic and adventurous, courageous in face of much misfortune and very kind." Wrinch's book first summarizes the impact of having children on women’s careers, which often included termination for professional women, and

1936-412: A precursor for other compounds, such as phytosterols and steroidal glycoalkaloids , with cholesterol remaining in plant foods only in minor amounts or absent. Some plant foods, such as avocado , flax seeds and peanuts , contain phytosterols, which compete with cholesterol for absorption in the intestines and reduce the absorption of both dietary and bile cholesterol. A typical diet contributes on

2057-399: A purely conformational change that resulted in the exposure of amino-acid side chains to the solvent. Wu's hypothesis was also advanced independently in 1936 by Mirsky and Linus Pauling . Nevertheless, protein scientists could not exclude the possibility that denaturation corresponded to a chemical change in the protein structure, a hypothesis that was considered a (distant) possibility until

2178-487: A rat eats the lower the blood cholesterol. During the first seven hours after ingestion of cholesterol, as absorbed fats are being distributed around the body within extracellular water by the various lipoproteins (which transport all fats in the water outside cells), the concentrations increase. Plants make cholesterol in very small amounts. In larger quantities they produce phytosterols , chemically similar substances which can compete with cholesterol for reabsorption in

2299-417: A relationship between the two of them. Nicholson was a graduate of Owens College Manchester and also a Cambridge Wrangler. In 1921 he was elected into a Fellowship at Balliol College, Oxford . The couple had one child, Pamela, born in 1927. Wrinch's book on parenthood, Retreat from Parenthood (1930) published under the pseudonym Jean Ayling and dedicated to Russell, was a venture into public health rather than

2420-616: A romantic relationship with Russell. She was for some years a close intellectual companion of Harold Jeffreys, and some contemporary observers thought them engaged. It may have been the breaking of their engagement that encouraged Jeffreys to enter psychoanalysis, which was at the time fashionable in Cambridge. In 1922 Wrinch married her graduate supervisor at King's College London, the mathematical physicist John William Nicholson. The examination for her DSc in 1921 had, unusually, an additional referee, which may have been because of perceptions of

2541-471: A typical hydrogen bond . The idea intrigued J. D. Bernal , who suggested it to the mathematician Dorothy Wrinch as possibly useful in understanding protein structure. Wrinch developed this suggestion into a full-fledged model of protein structure . The basic cyclol model was laid out in her first paper (1936). She noted the possibility that polypeptides might cyclize to form closed rings ( true ) and that these rings might form internal crosslinks through

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2662-429: A typical protein is remarkably long—hundreds of amino-acid residues —and several distinguished scientists were unsure whether such long, linear macromolecules could be stable in solution. Further doubts about the polypeptide nature of proteins arose because some enzymes were observed to cleave proteins but not peptides, whereas other enzymes cleave peptides but not folded proteins. Attempts to synthesize proteins in

2783-639: A way as to bind large steroid substrates like cholesterol. Animal fats are complex mixtures of triglycerides , with lesser amounts of both the phospholipids and cholesterol molecules from which all animal (and human) cell membranes are constructed. Since all animal cells manufacture cholesterol, all animal-based foods contain cholesterol in varying amounts. Major dietary sources of cholesterol include red meat , egg yolks and whole eggs , liver , kidney , giblets , fish oil , shellfish, and butter . Human breast milk also contains significant quantities of cholesterol. Plant cells synthesize cholesterol as

2904-461: A well-defined testable model, to work out the consequences of its assumptions and to make predictions that could be tested experimentally. In these goals, she succeeded; however, within a few years, experiments and further modeling showed that the cyclol hypothesis was untenable as a model for globular proteins. In two tandem Letters to the Editor (1936), Wrinch and Frank addressed the question of whether

3025-440: Is esterified , which causes it to be poorly absorbed by the gut. The body also compensates for absorption of ingested cholesterol by reducing its own cholesterol synthesis. For these reasons, cholesterol in food, seven to ten hours after ingestion, has little, if any effect on concentrations of cholesterol in the blood. Surprisingly, in rats, blood cholesterol is inversely correlated with cholesterol consumption. The more cholesterol

3146-407: Is also implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane , which brings receptor proteins in close proximity with high concentrations of second messenger molecules. In multiple layers, cholesterol and phospholipids, both electrical insulators, can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers,

3267-466: Is associated with atheromatous disease progression in the arteries. Cholesterol is susceptible to oxidation and easily forms oxygenated derivatives called oxysterols . Three different mechanisms can form these: autoxidation, secondary oxidation to lipid peroxidation, and cholesterol-metabolizing enzyme oxidation. A great interest in oxysterols arose when they were shown to exert inhibitory actions on cholesterol biosynthesis. This finding became known as

3388-535: Is formed when an OH hydroxyl group is added to a peptidyl carbonyl group. Likewise, a thiacyclol is formed by adding an SH thiol moiety to a peptidyl carbonyl group. The oxacyclol alkaloid ergotamine from the fungus Claviceps purpurea was the first identified cyclol. The cyclic depsipeptide serratamolide is also formed by an oxacyclol reaction. Chemically analogous cyclic thiacyclols have also been obtained. Classic azacyclols have been observed in small molecules and tripeptides. Peptides are naturally produced from

3509-666: Is identical, although some is carried as its native "free" alcohol form (the cholesterol-OH group facing the water surrounding the particles), while others as fatty acyl esters, known also as cholesterol esters, within the particles. Lipoprotein particles are organized by complex apolipoproteins , typically 80–100 different proteins per particle, which can be recognized and bound by specific receptors on cell membranes, directing their lipid payload into specific cells and tissues currently ingesting these fat transport particles. These surface receptors serve as unique molecular signatures, which then help determine fat distribution delivery throughout

3630-437: Is of low abundance in lipid rafts. PC localizes to the disordered region of the cell along with the polyunsaturated lipid phosphatidylinositol 4,5-bisphosphate (PIP2). PLD2 has a PIP2 binding domain . When PIP2 concentration in the membrane increases, PLD2 leaves the cholesterol-dependent domains and binds to PIP2 where it then gains access to its substrate PC and commences catalysis based on substrate presentation. Cholesterol

3751-423: Is only minimally soluble in water , or hydrophilic . Because of this, it dissolves in blood at exceedingly small concentrations. To be transported effectively, cholesterol is instead packaged within lipoproteins , complex discoidal particles with exterior amphiphilic proteins and lipids, whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble. This allows it to travel through

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3872-446: Is oxidized by the liver into a variety of bile acids . These, in turn, are conjugated with glycine , taurine , glucuronic acid , or sulfate . A mixture of conjugated and nonconjugated bile acids, along with cholesterol itself, is excreted from the liver into the bile . Approximately 95% of the bile acids are reabsorbed from the intestines, and the remainder are lost in the feces. The excretion and reabsorption of bile acids forms

3993-411: Is present in varying degrees in all animal cell membranes , but is absent in prokaryotes. It is required to build and maintain membranes and modulates membrane fluidity over the range of physiological temperatures. The hydroxyl group of each cholesterol molecule interacts with water molecules surrounding the membrane, as do the polar heads of the membrane phospholipids and sphingolipids , while

4114-399: Is separate from peripheral cholesterol, i.e., the dietary and hepatic cholesterol do not cross the blood brain barrier. Rather, astrocytes produce and distribute cholesterol in the brain. De novo synthesis, both in astrocytes and hepatocytes, occurs by a complex 37-step process. This begins with the mevalonate or HMG-CoA reductase pathway , the target of statin drugs, which encompasses

4235-472: Is taken up from here to the bloodstream by the liver. VLDL particles are produced by the liver from triacylglycerol and cholesterol which was not used in the synthesis of bile acids. These particles contain apolipoprotein B100 and apolipoprotein E in their shells and can be degraded by lipoprotein lipase on the artery wall to IDL. This arterial wall cleavage allows absorption of triacylglycerol and increases

4356-494: Is then reduced to mevalonate by the enzyme HMG-CoA reductase . Production of mevalonate is the rate-limiting and irreversible step in cholesterol synthesis and is the site of action for statins (a class of cholesterol-lowering drugs). Mevalonate is finally converted to isopentenyl pyrophosphate (IPP) through two phosphorylation steps and one decarboxylation step that requires ATP . Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through

4477-533: The Aristotelian Society , including a debate between D'Arcy Thompson and John Scott Haldane on the nature of physics, biology and psychology, and she became a friend of Thompson. Wrinch spoke to the Society herself on the 'summation of pleasures', and through the Society she encountered Harold Jeffreys and Raphael Demos . In the autumn of 1918 Wrinch registered for graduate study on asymptotic expansions with

4598-526: The Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning some of the mechanisms and methods of regulation of cholesterol and fatty acid metabolism . Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake of food leads to a net decrease in endogenous production, whereas

4719-490: The calcium metabolism and all steroid hormones , including the adrenal gland hormones cortisol and aldosterone , as well as the sex hormones progesterone , estrogens , and testosterone , and their derivatives. The stratum corneum is the outermost layer of the epidermis. It is composed of terminally differentiated and enucleated corneocytes that reside within a lipid matrix, like "bricks and mortar." Together with ceramides and free fatty acids, cholesterol forms

4840-405: The chemical suffix -ol for an alcohol . Cholesterol is essential for all animal life. While most cells are capable of synthesizing it, the majority of cholesterol is ingested or synthesized by hepatocytes and transported in the blood to peripheral cells. The levels of cholesterol in peripheral tissues is dictated by a balance of uptake and export. Under normal conditions, brain cholesterol

4961-552: The gallbladder , which then excretes them in a non- esterified form (via bile) into the digestive tract. Typically, about 50% of the excreted cholesterol is reabsorbed by the small intestine back into the bloodstream. Almost all animal tissues synthesize cholesterol from acetyl-CoA . All animal cells (exceptions exist within the invertebrates) manufacture cholesterol, for both membrane structure and other uses, with relative production rates varying by cell type and organ function. About 80% of total daily cholesterol production occurs in

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5082-406: The inward-rectifier potassium channel . Cholesterol also activates the estrogen-related receptor alpha (ERRα), and may be the endogenous ligand for the receptor . The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body. Inhibition of ERRα signaling by reduction of cholesterol production has been identified as a key mediator of

5203-441: The liver and the intestines ; other sites of higher synthesis rates include the brain , the adrenal glands , and the reproductive organs . Synthesis within the body starts with the mevalonate pathway where two molecules of acetyl CoA condense to form acetoacetyl-CoA . This is followed by a second condensation between acetyl CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl CoA ( HMG-CoA ). This molecule

5324-423: The tetracyclic ring of cholesterol contributes to the fluidity of the cell membrane, as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar. In this structural role, cholesterol also reduces the permeability of the plasma membrane to neutral solutes, hydrogen ions, and sodium ions. Cholesterol regulates the biological process of substrate presentation and

5445-511: The "oxysterol hypothesis". Additional roles for oxysterols in human physiology include their participation in bile acid biosynthesis, function as transport forms of cholesterol, and regulation of gene transcription. In biochemical experiments, radiolabelled forms of cholesterol, such as tritiated-cholesterol, are used. These derivatives undergo degradation upon storage, and it is essential to purify cholesterol prior to use. Cholesterol can be purified using small Sephadex LH-20 columns. Cholesterol

5566-651: The 1.6–3.0 grams per day range (Health Canada, EFSA, ATP III, FDA). A meta-analysis demonstrated a 12% reduction in LDL-cholesterol at a mean dose of 2.1 grams per day. The benefits of a diet supplemented with phytosterols have also been questioned. According to the lipid hypothesis , elevated levels of cholesterol in the blood lead to atherosclerosis which may increase the risk of heart attack , stroke , and peripheral artery disease . Since higher blood LDL – especially higher LDL concentrations and smaller LDL particle size – contributes to this process more than

5687-530: The 1932 ICM in Zürich." The papers she wrote with Harold Jeffreys on scientific method formed the basis of his 1931 book Scientific Inference . In the Nature obituary Jeffreys wrote, "I should like to put on record my appreciation of the substantial contribution she made to [our joint] work, which is the basis of all my later work on scientific inference." From about 1932 Wrinch shifted towards theoretical biology. She

5808-444: The 1940s and allowed for the possibility of cyclols in interpreting her results. As the sequence of insulin began to be determined by Frederick Sanger , Anslow published a three-dimensional cyclol model with sidechains, based on the backbone of Wrinch's 1948 "minimal cyclol" model. The downfall of the overall cyclol model generally led to a rejection of its elements; one notable exception was J. D. Bernal 's short-lived acceptance of

5929-437: The 1950s. X-ray crystallography had just begun as a discipline in 1911, and had advanced relatively rapidly from simple salt crystals to crystals of complex molecules such as cholesterol . However, even the smallest proteins have over 1000 atoms, which makes determining their structure far more complex. In 1934, Dorothy Crowfoot Hodgkin had taken crystallographic data on the structure of the small protein, insulin , although

6050-538: The 2015 iteration of the Dietary Guidelines for Americans dropped the previously recommended limit of consumption of dietary cholesterol to 300 mg per day with a new recommendation to "eat as little dietary cholesterol as possible", thereby acknowledging an association between a diet low in cholesterol and reduced risk of cardiovascular disease. A 2013 report by the American Heart Association and

6171-670: The American College of Cardiology recommended focusing on healthy dietary patterns rather than specific cholesterol limits, as they are hard for clinicians and consumers to implement. They recommend the DASH and Mediterranean diet , which are low in cholesterol. A 2017 review by the American Heart Association recommends switching saturated fats for polyunsaturated fats to reduce cardiovascular disease risk. Some supplemental guidelines have recommended doses of phytosterols in

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6292-788: The Heretics Club run by Charles Kay Ogden , and it was through a 1914 lecture organised by Ogden that she first heard Bertrand Russell speak. She graduated in 1916 as a wrangler . For the academic year 1916–1917, Wrinch took the Cambridge Moral Sciences tripos and studied mathematical logic with Russell in London. In December she was invited to Garsington Manor , the home of Russell's then mistress Ottoline Morell , and there encountered Clive Bell and other Bloomsbury Group members, and in 1917 she introduced Russell to Dora Black who would later become his second wife. From 1917 Wrinch

6413-601: The Langmuir-Wrinch hypothesis that protein folding is driven by hydrophobic association. Nevertheless, cyclol bonds were identified in small, naturally occurring cyclic peptides in the 1950s. Clarification of the modern terminology is appropriate. The classic cyclol reaction is the addition of the NH amine of a peptide group to the C=O carbonyl group of another; the resulting compound is now called an azacyclol . By analogy, an oxacyclol

6534-498: The N-C and C-C bonds have the lengths 1.42 Å and 1.54 Å, respectively. These rings can be extended indefinitely to form a cyclol fabric (Figure 3). Such fabrics exhibit a long-range, quasi-crystalline order that Wrinch felt was likely in proteins, since they must pack hundreds of residues densely. Another interesting feature of such molecules and fabrics is that their amino-acid side chains point axially upwards from only one face;

6655-461: The Patterson diagrams of insulin taken by Dorothy Crowfoot Hodgkin showed that they were roughly consistent with the cyclol model; however, the agreement was not good enough to claim that the cyclol model was confirmed. The cyclol fabric was shown to be implausible for several reasons. Hans Neurath and Henry Bull showed that the dense packing of side chains in the cyclol fabric was inconsistent with

6776-493: The SREBP pathway regulates the expression of many genes that control lipid formation and metabolism and body fuel allocation. Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain. The membrane domain senses signals for its degradation. Increasing concentrations of cholesterol (and other sterols) cause

6897-535: The SREBP-SCAP complex, which allows the complex to migrate to the Golgi apparatus . Here SREBP is cleaved by S1P and S2P (site-1 protease and site-2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the sterol regulatory element (SRE), which stimulates the transcription of many genes. Among these are

7018-775: The action of geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum . Oxidosqualene cyclase then cyclizes squalene to form lanosterol . Finally, lanosterol is converted to cholesterol via either of two pathways, the Bloch pathway, or the Kandutsch-Russell pathway. The final 19 steps to cholesterol contain NADPH and oxygen to help oxidize methyl groups for removal of carbons, mutases to move alkene groups, and NADH to help reduce ketones . Konrad Bloch and Feodor Lynen shared

7139-471: The applied mathematician John Nicholson at King's College London, started to teach at University College, and continued to work with Jeffreys on the philosophy of scientific method. She moved into a flat in Mecklenburgh Square owned by Russell's then mistress Colette O'Neil. In 1920 Girton awarded Wrinch a four-year Yarrow Research Fellowship with the freedom to work on any area of her choice. In 1920 she

7260-572: The association more pronounced in younger subjects. Because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is larger in older people. Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates are high. A post hoc analysis of

7381-407: The association of so-called LDL cholesterol (actually a lipoprotein ) with "bad" cholesterol. HDL particles are thought to transport cholesterol back to the liver, either for excretion or for other tissues that synthesize hormones, in a process known as reverse cholesterol transport (RCT). Large numbers of HDL particles correlates with better health outcomes, whereas low numbers of HDL particles

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7502-428: The basis of the enterohepatic circulation , which is essential for the digestion and absorption of dietary fats. Under certain circumstances, when more concentrated, as in the gallbladder , cholesterol crystallises and is the major constituent of most gallstones ( lecithin and bilirubin gallstones also occur, but less frequently). Every day, up to 1 g of cholesterol enters the colon. This cholesterol originates from

7623-546: The beginning, the cyclol reaction was considered as a covalent analog of the hydrogen bond . Therefore, it was natural to consider hybrid models with both types of bonds. This was the subject of Wrinch's fourth paper on the cyclol model (1936), written together with Dorothy Jordan Lloyd , who first proposed that globular proteins are stabilized by hydrogen bonds. A follow-up paper was written in 1937 that referenced other researchers on hydrogen bonding in proteins, such as Maurice Loyal Huggins and Linus Pauling . Wrinch also wrote

7744-701: The blood via emulsification . Unbound cholesterol, being amphipathic, is transported in the monolayer surface of the lipoprotein particle along with phospholipids and proteins. Cholesterol esters bound to fatty acid, on the other hand, are transported within the fatty hydrophobic core of the lipoprotein, along with triglyceride. There are several types of lipoproteins in the blood. In order of increasing density, they are chylomicrons , very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Lower protein/lipid ratios make for less dense lipoproteins. Cholesterol within different lipoproteins

7865-448: The blood, especially when bound to low-density lipoprotein (LDL, often referred to as "bad cholesterol"), may increase the risk of cardiovascular disease . François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. In 1815, chemist Michel Eugène Chevreul named the compound "cholesterine". The word cholesterol comes from Ancient Greek chole- ' bile ' and stereos 'solid', followed by

7986-469: The blood. These LDL particles are oxidized and taken up by macrophages , which become engorged and form foam cells. These foam cells often become trapped in the walls of blood vessels and contribute to atherosclerotic plaque formation. Differences in cholesterol homeostasis affect the development of early atherosclerosis (carotid intima-media thickness). These plaques are the main causes of heart attacks, strokes, and other serious medical problems, leading to

8107-464: The body. Chylomicrons, the least dense cholesterol transport particles, contain apolipoprotein B-48 , apolipoprotein C , and apolipoprotein E (the principal cholesterol carrier in the brain ) in their shells. Chylomicrons carry fats from the intestine to muscle and other tissues in need of fatty acids for energy or fat production. Unused cholesterol remains in more cholesterol-rich chylomicron remnants and

8228-542: The bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which both alters membrane fluidity and maintains membrane integrity so that animal cells do not need to build cell walls (like plants and most bacteria). The membrane remains stable and durable without being rigid, allowing animal cells to change shape and animals to move. The structure of

8349-570: The cholesterol content of the HDL particles, LDL particles are often termed "bad cholesterol". High concentrations of functional HDL, which can remove cholesterol from cells and atheromas, offer protection and are commonly referred to as "good cholesterol". These balances are mostly genetically determined, but can be changed by body composition, medications , diet, and other factors. A 2007 study demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with

8470-756: The concentration of circulating cholesterol. IDL particles are then consumed in two processes: half is metabolized by HTGL and taken up by the LDL receptor on the liver cell surfaces, while the other half continues to lose triacylglycerols in the bloodstream until they become cholesterol-laden LDL particles. LDL particles are the major blood cholesterol carriers. Each one contains approximately 1,500 molecules of cholesterol ester. LDL particle shells contain just one molecule of apolipoprotein B100 , recognized by LDL receptors in peripheral tissues. Upon binding of apolipoprotein B100 , many LDL receptors concentrate in clathrin -coated pits. Both LDL and its receptor form vesicles within

8591-403: The conditions under which two planar cyclol fabrics could be joined to make an angle between their planes while respecting the chemical bond angles. She identified a mathematical simplification, in which the non-planar six-membered rings of atoms can be represented by planar "median hexagon"s made from the midpoints of the chemical bonds. This "median hexagon" representation made it easy to see that

8712-407: The cyclol fabric planes can be joined correctly if the dihedral angle between the planes equals the tetrahedral bond angle δ = arccos(-1/3) ≈ 109.47°. A large variety of closed polyhedra meeting this criterion can be constructed, of which the simplest are the truncated tetrahedron , the truncated octahedron , and the octahedron , which are Platonic solids or semiregular polyhedra . Considering

8833-402: The cyclol form of the peptide group was indeed more stable than the amide form. A relatively simple calculation showed that the cyclol form is significantly less stable than the amide form. Therefore, the cyclol model would have to be abandoned unless a compensating source of energy could be identified. Initially, Frank proposed that the cyclol form might be stabilized by better interactions with

8954-412: The cyclol model and its relevance in biochemistry. She also published two books describing the cyclol theory and small peptides in general. Dorothy Maud Wrinch Dorothy Maud Wrinch (12 September 1894 – 11 February 1976; married names Nicholson , Glaser ) was a mathematician and biochemical theorist best known for her attempt to deduce protein structure using mathematical principles. She

9075-639: The cyclol model of globular proteins accounted for the early analytical ultracentrifugation results of Theodor Svedberg , which suggested that the molecular weights of proteins fell into a few classes related by integers. The cyclol model was consistent with the general properties then attributed to folded proteins. (1) Centrifugation studies had shown that folded proteins were significantly denser than water (~1.4  g / mL ) and, thus, tightly packed; Wrinch assumed that dense packing should imply regular packing. (2) Despite their large size, some proteins crystallize readily into symmetric crystals, consistent with

9196-503: The cyclol model, owing mainly to the influence of Linus Pauling , who favored the hypothesis that protein structure was stabilized by hydrogen bonds . Another twenty years had to pass before hydrophobic interactions were recognized as the chief driving force in protein folding. In her third paper on cyclols (1936), Wrinch noted that many "physiologically active" substances such as steroids are composed of fused hexagonal rings of carbon atoms and, thus, might be sterically complementary to

9317-424: The cyclol model. On steric clashes, she noted that small deformations of the bond angles and bond lengths would allow these steric clashes to be relieved, or at least reduced to a reasonable level. She noted that distances between non-bonded groups within a single molecule can be shorter than expected from their van der Waals radii , e.g., the 2.93  Å distance between methyl groups in hexamethylbenzene. Regarding

9438-430: The cyclol reaction (also true, although rare). Assuming that the cyclol form of the peptide bond could be more stable than the amide form, Wrinch concluded that certain cyclic peptides would naturally make the maximal number of cyclol bonds (such as cyclol 6 , Figure 2). Such cyclol molecules would have hexagonal symmetry, if the chemical bonds were taken as having the same length, roughly 1.5  Å ; for comparison,

9559-419: The cyclol reaction itself, these hypothetical molecules, fabrics and polyhedra have not been observed experimentally. The model has several consequences that render it energetically implausible, such as steric clashes between the protein sidechains. In response to such criticisms J. D. Bernal proposed that hydrophobic interactions are chiefly responsible for protein folding , which was indeed borne out. By

9680-567: The diet, bile, and desquamated intestinal cells, and it can be metabolized by the colonic bacteria. Cholesterol is converted mainly into coprostanol , a nonabsorbable sterol that is excreted in the feces. Although cholesterol is a steroid generally associated with mammals, the human pathogen Mycobacterium tuberculosis is able to completely degrade this molecule and contains a large number of genes that are regulated by its presence. Many of these cholesterol-regulated genes are homologues of fatty acid β-oxidation genes, but have evolved in such

9801-445: The effects of statins and bisphosphonates on bone , muscle , and macrophages . On the basis of these findings, it has been suggested that the ERRα should be de-orphanized and classified as a receptor for cholesterol. Within cells, cholesterol is also a precursor molecule for several biochemical pathways . For example, it is the precursor molecule for the synthesis of vitamin D in

9922-405: The enzymes that use substrate presentation as a mechanism of their activation. Phospholipase D2 ( PLD2 ) is a well-defined example of an enzyme activated by substrate presentation. The enzyme is palmitoylated causing the enzyme to traffic to cholesterol dependent lipid domains sometimes called " lipid rafts ". The substrate of phospholipase D is phosphatidylcholine (PC) which is unsaturated and

10043-414: The epidermis. Steroid sulfate sulfatase then decreases its concentration in the stratum corneum, the outermost layer of the epidermis. The relative abundance of cholesterol sulfate in the epidermis varies across different body sites with the heel of the foot having the lowest concentration. Cholesterol is recycled in the body. The liver excretes cholesterol into biliary fluids, which are then stored in

10164-416: The experimental density observed in protein films. Maurice Huggins calculated that several non-bonded atoms of the cyclol fabric would approach more closely than allowed by their van der Waals radii ; for example, the inner H and C atoms of the lacunae would be separated by only 1.68  Å (Figure 5). Haurowitz showed chemically that the outside of proteins could not have a large number of hydroxyl groups,

10285-456: The face of cyclol molecules without the amino-acid side chains. Wrinch proposed that steric complementarity was one of chief factors in determining whether a small molecule would bind to a protein. Wrinch speculated that proteins are responsible for the synthesis of all biological molecules. Noting that cells digest their proteins only under extreme starvation conditions, Wrinch further speculated that life could not exist without proteins. From

10406-450: The feeling was not mutual and she had to ask her father to explain this to Watson; nevertheless Watson later recommended Wrinch as his replacement lecturer at University College London. Around the postwar time of her intellectual closeness to Russell, Wrinch may have had a romantic connection with his brother Frank and probably did have an unhappy attachment with another of his disciples, Raphael Demos. Sources differ on whether Wrinch wanted

10527-488: The first 18 steps. This is followed by 19 additional steps to convert the resulting lanosterol into cholesterol. A human male weighing 68 kg (150 lb) normally synthesizes about 1 gram (1,000 mg) of cholesterol per day, and his body contains about 35 g, mostly contained within the cell membranes. Typical daily cholesterol dietary intake for a man in the United States is 307 mg. Most ingested cholesterol

10648-542: The first series of "closed cyclols" (those modeled on the truncated tetrahedron), Wrinch showed that their number of amino acids increased quadratically as 72 n , where n is the index of the closed cyclol C n . Thus, the C 1 cyclol has 72 residues, the C 2 cyclol has 288 residues, etc. Preliminary experimental support for this prediction came from Max Bergmann and Carl Niemann , whose amino-acid analyses suggested that proteins were composed of integer multiples of 288 amino-acid residues ( n =2). More generally,

10769-611: The first woman to receive an Oxford DSc . Wrinch's first paper was a 1917 defence of Russell's philosophy, and between 1918 and 1932 she published 20 papers on pure and applied mathematics and 16 on scientific methodology and on the philosophy of science . At the 1928 International Congress of Mathematics in Bologna she delivered the paper "On a method for constructing harmonics for surfaces of revolution." She also presented on "Harmonics Associated with Certain Inverted Spheroids" at

10890-410: The free-energy penalty for the cyclol reaction, Wrinch disagreed with Pauling's calculations and stated that too little was known of intramolecular energies to rule out the cyclol model on that basis alone. In reply to the chemical criticisms, Wrinch suggested that the model compounds and simple bimolecular reactions studied need not pertain to the cyclol model, and that steric hindrance may have prevented

11011-411: The greatest amounts. In the brain, astrocytes produce cholesterol and transport it to neurons . It is absent among prokaryotes ( bacteria and archaea ), although there are some exceptions, such as Mycoplasma , which require cholesterol for growth. Cholesterol also serves as a precursor for the biosynthesis of steroid hormones , bile acid and vitamin D . Elevated levels of cholesterol in

11132-473: The idea of symmetric faces that match up upon association. (3) Proteins bind metal ions; since metal-binding sites must have specific bond geometries (e.g., octahedral), it was plausible to assume that the entire protein also had similarly crystalline geometry. (4) As described above, the cyclol model provided a simple chemical explanation of denaturation and the difficulty of cleaving folded proteins with proteases. (5) Proteins were assumed to be responsible for

11253-581: The intestinal tract, thus potentially reducing cholesterol reabsorption. When intestinal lining cells absorb phytosterols, in place of cholesterol, they usually excrete the phytosterol molecules back into the GI tract , an important protective mechanism. The intake of naturally occurring phytosterols, which encompass plant sterols and stanols , ranges between ≈200–300 mg/day depending on eating habits. Specially designed vegetarian experimental diets have been produced yielding upwards of 700 mg/day. Cholesterol

11374-436: The labor of child rearing like changing diapers, preparing meals, laundry, cleaning dishes, and so on. The C.R.S.C. would deal with food safety, inspection, diet, and delivery, with a focus on ensuring that each child was well-nourished and given the best possible diet. The C.R.S.D. would deal with all medical, nursing, psychological, and other services necessary for the health and well-being of parents and child, from pregnancy to

11495-407: The lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides (≈50% by weight), cholesterol (≈25% by weight), and free fatty acids (≈15% by weight), with smaller quantities of other lipids also being present. Cholesterol sulfate reaches its highest concentration in the granular layer of

11616-461: The low-density lipoprotein ( LDL ) receptor and HMG-CoA reductase . The LDL receptor scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase in endogenous production of cholesterol. A large part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in the 1970s. In 1985, they received the Nobel Prize in Physiology or Medicine for their work. Their subsequent work shows how

11737-438: The mathematician Eric Neville in a friendship which lasted until 1961. In 1939 Wrinch and her daughter moved to the United States, partly because the chancellor of Oxford University and Foreign Secretary Lord Halifax advised her she would be most useful to the war effort by research and lecturing there. In 1941 she married Otto Charles Glaser , chairman of the biology department and vice-president of Amherst College , and it

11858-407: The mid-1930s, analytical ultracentrifugation studies by Theodor Svedberg had shown that proteins had a well-defined chemical structure, and were not aggregations of small molecules. The same studies appeared to show that the molecular weight of proteins fell into a few well-defined classes related by integers, such as M w = 23  Da , where p and q are nonnegative integers. However, it

11979-443: The opposite face has no side chains. Thus, one face is completely independent of the primary sequence of the peptide, which Wrinch conjectured might account for sequence-independent properties of proteins. In her initial article, Wrinch stated clearly that the cyclol model was merely a working hypothesis , a potentially valid model of proteins that would have to be checked. Her goals in this article and its successors were to propose

12100-461: The order of 0.2 gram of phytosterols, which is not enough to have a significant impact on blocking cholesterol absorption. Phytosterols intake can be supplemented through the use of phytosterol-containing functional foods or dietary supplements that are recognized as having potential to reduce levels of LDL -cholesterol. In 2015, the scientific advisory panel of U.S. Department of Health and Human Services and U.S. Department of Agriculture for

12221-630: The principle of the Hydrophobic effect being the driving force for protein folding . In 1936 Ida Busbridge secured a position as assistant to Wrinch from whom she took over mathematics tutorials for all five women’s colleges. In 1939 Wrinch moved to the United States. She had a variety of teaching positions at three small Massachusetts colleges, Amherst College , Smith College , and Mount Holyoke College . From 1942 until she retired in 1971 Wrinch held research positions at Smith. Prior to 1918 Wrinch's Cambridge tutor GN Watson had proposed to her but

12342-467: The psychological and physical impact on parents and children caused by leaving to most parents practically all functions necessary to raise a child. Of special concern to her was the fact that parents generally lack the necessary expertise in practical matters like the suitable diet and social environment best-suited for a child's development, since their professional expertise is often in other areas, and that scientifically understanding these matters requires

12463-405: The reversion of azacylols, a key prediction of the cyclol model. Hundreds of cyclol molecules have now been identified, despite Linus Pauling 's calculation that such molecules should not exist because of their unfavorably high energy . After a long hiatus during which she worked mainly on the mathematics of X-ray crystallography , Wrinch responded to these discoveries with renewed enthusiasm for

12584-410: The school door. Cholesterol Cholesterol is the principal sterol of all higher animals , distributed in body tissues , especially the brain and spinal cord , and in animal fats and oils . Cholesterol is biosynthesized by all animal cells and is an essential structural and signaling component of animal cell membranes . In vertebrates , hepatic cells typically produce

12705-410: The structure and allows those bonds to be attacked by proteases , consistent with experiment. Early studies showed that proteins denatured by pressure are often in a different state than the same proteins denatured by high temperature , which was interpreted as possibly supporting the cyclol model of denaturation. The Langmuir-Wrinch hypothesis of hydrophobic stabilization shared in the downfall of

12826-625: The structure of folded proteins; thus, denaturation could involve a chemical change that converted folded proteins into polypeptides. The process of protein denaturation (as distinguished from coagulation ) had been discovered in 1910 by Harriette Chick and Charles Martin , but its nature was still mysterious. Tim Anson and Alfred Mirsky had shown that denaturation was a reversible, two-state process that results in many chemical groups becoming available for chemical reactions, including cleavage by enzymes. In 1929, Hsien Wu hypothesized correctly that denaturation corresponded to protein unfolding,

12947-408: The structure of that and other proteins were not solved until the late 1960s. However, pioneering X-ray fiber diffraction data had been collected in the early 1930s for many natural fibrous proteins such as wool and hair by William Astbury , who suggested that "globular proteins in general might be folded from elements essentially like the elements of fibrous proteins." Since protein structure

13068-431: The surface hydroxyl groups from reacting. On the residue-number criticism, Wrinch extended her model to allow for other numbers of residues. In particular, she produced a "minimal" closed cyclol of only 48 residues, and, on that (incorrect) basis, may have been the first to suggest that the insulin monomer had a molecular weight of roughly 6000  Da . Therefore, she maintained that the cyclol model of globular proteins

13189-434: The surrounding solvent; later, Wrinch and Irving Langmuir hypothesized that hydrophobic association of nonpolar sidechains provides stabilizing energy to overcome the energetic cost of the cyclol reactions. The lability of the cyclol bond was seen as an advantage of the model, since it provided a natural explanation for the properties of denaturation ; reversion of cyclol bonds to their more stable amide form would open up

13310-483: The synthesis of all biological molecules, including other proteins. Wrinch noted that a fixed, uniform structure would be useful for proteins in templating their own synthesis, analogous to the Watson - Francis Crick concept of DNA templating its own replication. Given that many biological molecules such as sugars and sterols have a hexagonal structure, it was plausible to assume that their synthesizing proteins likewise had

13431-404: The synthesis of cholesterol de novo , according to its presence inside the cell. A cell with abundant cholesterol will have its LDL receptor synthesis blocked, to prevent new cholesterol in LDL particles from being taken up. Conversely, LDL receptor synthesis proceeds when a cell is deficient in cholesterol. When this process becomes unregulated, LDL particles without receptors begin to appear in

13552-563: The test tube were unsuccessful, mainly due to the chirality of amino acids; naturally occurring proteins are composed of only left-handed amino acids. Hence, alternative chemical models of proteins were considered, such as the diketopiperazine hypothesis of Emil Abderhalden . However, no alternative model had yet explained why proteins yield only amino acids and peptides upon hydrolysis and proteolysis. As clarified by Linderstrøm-Lang , these proteolysis data showed that denatured proteins were polypeptides, but no data had yet been obtained about

13673-558: Was a C 2 closed cyclol of 288 residues. These residue-number predictions were difficult to verify, since the methods then available to measure the mass of proteins were inaccurate, such as analytical ultracentrifugation and chemical methods. Wrinch also predicted that insulin was a C 2 closed cyclol consisting of 288 residues. Limited X-ray crystallographic data were available for insulin which Wrinch interpreted as "confirming" her model. However, this interpretation drew rather severe criticism for being premature. Careful studies of

13794-526: Was a champion of the controversial ' cyclol ' hypothesis for the structure of proteins. Dorothy Wrinch was born in Rosario, Argentina , the daughter of Hugh Edward Hart Wrinch, an engineer, and Ada Souter. The family returned to England and Dorothy grew up in Surbiton , near London. She attended Surbiton High School and in 1913 entered Girton College , Cambridge to read mathematics. Wrinch often attended meetings of

13915-556: Was awarded an MSc and in 1921 a DSc by the University of London. Wrinch moved to Oxford in 1922 upon her marriage, where she held a succession of research fellowships and lectureships or tutorships at the Oxford women's colleges for the next 16 years. She was Lady Carlisle Research Fellow at Somerville College, Oxford and first female Lecturer in Mathematics at the University. In 1929 she was

14036-519: Was difficult to determine the exact molecular weight and number of amino acids in a protein. Svedberg had also shown that a change in solution conditions could cause a protein to disassemble into small subunits, now known as a change in quaternary structure . The chemical structure of proteins was still under debate at that time. The most accepted (and ultimately correct) hypothesis was that proteins are linear polypeptides , i.e., unbranched polymers of amino acids linked by peptide bonds . However,

14157-511: Was funded by Girton College as a research student, officially supervised by G.H. Hardy in Cambridge but in practice by Russell in London. When, in May 1918, Russell was imprisoned for his anti-war activities, Wrinch assisted with his writing projects by bringing him books and articles. Wrinch also secured the first publication of Ludwig Wittgenstein 's (not yet so named) Tractatus in a German philosophical journal in 1921. In London Wrinch attended

14278-513: Was in part through him that she was able to obtain teaching positions. In 1944 Glaser was forced to resign as chairman because he had allowed his research assistant to spend time working for Wrinch. Glaser retired in 1948 and died in 1951. Wrinch died in Falmouth, Massachusetts on 11 February 1976. Dorothy Hodgkin wrote in Wrinch's obituary that she was "a brilliant and controversial figure who played

14399-487: Was one of founders of the Biotheoretical Gathering (aka the 'Theoretical Biology Club'), an inter-disciplinary group that sought to explain life by discovering how proteins work. Also involved were Joseph Henry Woodger , Joseph and Dorothy Needham , C. H. Waddington , J. D. Bernal , Karl Popper and Dorothy Crowfoot Hodgkin . From then on Wrinch could be described as a theoretical biologist. She developed

14520-426: Was so poorly understood in the 1930s, the physical interactions responsible for stabilizing that structure were likewise unknown. Astbury hypothesized that the structure of fibrous proteins was stabilized by hydrogen bonds in β-sheets. The idea that globular proteins are also stabilized by hydrogen bonds was proposed by Dorothy Jordan Lloyd in 1932, and championed later by Alfred Mirsky and Linus Pauling . At

14641-505: Was still potentially viable and even proposed the cyclol fabric as a component of the cytoskeleton . However, most protein scientists ceased to believe in it and Wrinch turned her scientific attention to mathematical problems in X-ray crystallography , to which she contributed significantly. One exception was physicist Gladys Anslow , Wrinch's colleague at Smith College , who studied the ultraviolet absorption spectra of proteins and peptides in

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