Stream of consciousness

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Stream_of_consciousness

In literary criticism, stream of consciousness is a narrative mode or method that attempts "to depict the multitudinous thoughts and feelings which pass through the mind" of a narrator. The term was coined by Daniel Oliver in 1840 in First Lines of Physiology: Designed for the Use of Students of Medicine, when he wrote,

If we separate from this mingled and moving stream of consciousness, our sensations and volitions, which are constantly giving it a new direction, and suffer it to pursue its own spontaneous course, it will appear, upon examination, that this, instead of being wholly fortuitous and uncertain, is determined by certain fixed laws of thought, which are collectively termed the association of ideas.

Better known, perhaps, is the 1855 usage by Alexander Bain in the first edition of The Senses and the Intellect, when he wrote, "The concurrence of Sensations in one common stream of consciousness–on the same cerebral highway–enables those of different senses to be associated as readily as the sensations of the same sense". But it is commonly credited to William James who used it in 1890 in his The Principles of Psychology. In 1918, the novelist May Sinclair (1863–1946) first applied the term stream of consciousness, in a literary context, when discussing Dorothy Richardson's novels. Pointed Roofs (1915), the first work in Richardson's series of 13 semi-autobiographical novels titled Pilgrimage, is the first complete stream-of-consciousness novel published in English. However, in 1934, Richardson comments that "Proust, James Joyce, Virginia Woolf, and D.R. ... were all using 'the new method', though very differently, simultaneously". There were, however, many earlier precursors and the technique is still used by contemporary writers.

Definition

Stream of consciousness is a narrative device that attempts to give the written equivalent of the character's thought processes, either in a loose interior monologue (see below), or in connection to their actions. Stream-of-consciousness writing is usually regarded as a special form of interior monologue and is characterized by associative leaps in thought and lack of some or all punctuation. Stream of consciousness and interior monologue are distinguished from dramatic monologue and soliloquy, where the speaker is addressing an audience or a third person, which are chiefly used in poetry or drama. In stream-of-consciousness, the speaker's thought processes are more often depicted as overheard in the mind (or addressed to oneself); it is primarily a fictional device.

An early use of the term is found in philosopher and psychologist William James's The Principles of Psychology (1890): "consciousness, then, does not appear to itself as chopped up in bits ... it is nothing joined; it flows. A 'river' or a 'stream' are the metaphors by which it is most naturally described. In talking of it hereafter, let's call it the stream of thought, consciousness, or subjective life".

Cover of James Joyce's Ulysses (first edition, 1922), considered a prime example of stream of consciousness writing styles

In the following example of stream of consciousness from James Joyce's Ulysses, Molly seeks sleep:

a quarter after what an unearthly hour I suppose theyre just getting up in China now combing out their pigtails for the day well soon have the nuns ringing the angelus theyve nobody coming in to spoil their sleep except an odd priest or two for his night office the alarmclock next door at cockshout clattering the brains out of itself let me see if I can doze off 1 2 3 4 5 what kind of flowers are those they invented like the stars the wallpaper in Lombard street was much nicer the apron he gave me was like that something only I only wore it twice better lower this lamp and try again so that I can get up early.

Interior monologue

See also: Internal monologue

While many sources use the terms stream of consciousness and interior monologue as synonyms, the Oxford Dictionary of Literary Terms suggests that "they can also be distinguished psychologically and literarily. In a psychological sense, stream of consciousness is the subject matter, while interior monologue is the technique for presenting it". And for literature, "while an interior monologue always presents a character's thoughts 'directly', without the apparent intervention of a summarizing and selecting narrator, it does not necessarily mingle them with impressions and perceptions, nor does it necessarily violate the norms of grammar, or logic – but the stream‐of‐consciousness technique also does one or both of these things." Similarly, the Encyclopædia Britannica Online, while agreeing that these terms are "often used interchangeably", suggests that, "while an interior monologue may mirror all the half-thoughts, impressions, and associations that impinge upon the character's consciousness, it may also be restricted to an organized presentation of that character's rational thoughts".

Development

Beginnings to 1900

While the use of the narrative technique of stream of consciousness is usually associated with modernist novelists in the first part of the twentieth century, several precursors have been suggested, including Laurence Sterne's psychological novel Tristram Shandy (1757). John Neal in his novel Seventy-Six (1823) also used an early form of this writing style, characterized by long sentences with multiple qualifiers and expressions of anxiety from the narrator. Prior to the 19th century, associationist philosophers, like Thomas Hobbes and Bishop Berkeley, discussed the concept of the "train of thought".

It has also been suggested that Edgar Allan Poe's short story "The Tell-Tale Heart" (1843) foreshadows this literary technique in the nineteenth century. Poe's story is a first person narrative, told by an unnamed narrator who endeavours to convince the reader of his sanity while describing a murder he committed, and it is often read as a dramatic monologue. George R. Clay notes that Leo Tolstoy, "when the occasion requires it ... applies Modernist stream of consciousness technique" in both War and Peace (1869) and Anna Karenina (1878).

The short story, "An Occurrence at Owl Creek Bridge" (1890), by another American author, Ambrose Bierce, also abandons strict linear time to record the internal consciousness of the protagonist. Because of his renunciation of chronology in favor of free association, Édouard Dujardin's Les Lauriers sont coupés (1887) is also an important precursor. Indeed, James Joyce "picked up a copy of Dujardin's novel ... in Paris in 1903" and "acknowledged a certain borrowing from it".

Some point to Anton Chekhov's short stories and plays (1881–1904) and Knut Hamsun's Hunger (1890), and Mysteries (1892) as offering glimpses of the use of stream of consciousness as a narrative technique at the end of the nineteenth century. While Hunger is widely seen as a classic of world literature and a groundbreaking modernist novel, Mysteries is also considered a pioneer work. It has been claimed that Hamsun was way ahead of his time with the use of stream of consciousness in two chapters in particular of this novel. British author Robert Ferguson said: "There’s a lot of dreamlike aspects of Mysteries. In that book ... it is ... two chapters, where he invents stream of consciousness writing, in the early 1890s. This was long before Dorothy Richardson, Virginia Woolf and James Joyce". Henry James has also been suggested as a significant precursor, in a work as early as Portrait of a Lady (1881). It has been suggested that he influenced later stream-of-consciousness writers, including Virginia Woolf, who not only read some of his novels but also wrote essays about them.

However, it has also been argued that Arthur Schnitzler (1862–1931), in his short story '"Leutnant Gustl" ("None but the Brave", 1900), was the first to make full use of the stream of consciousness technique.

Early twentieth century

It was not until the twentieth century that this technique was fully developed by modernists. Marcel Proust is often presented as an early example of a writer using the stream of consciousness technique in his novel sequence À la recherche du temps perdu (1913–1927) (In Search of Lost Time), but Robert Humphrey comments that Proust "is concerned only with the reminiscent aspect of consciousness" and that he "was deliberately recapturing the past to communicate; hence he did not write a stream-of-consciousness novel". Novelist John Cowper Powys also argues that Proust did not use stream of consciousness: "while we are told what the hero thinks or what Swann thinks we are told this rather by the author than either by the 'I' of the story or by Charles Swann."

Let us go then, you and I,
When the evening is spread out against the sky
Like a patient etherized upon a table;
Let us go, through certain half-deserted streets,
The muttering retreats
Of restless nights in one-night cheap hotels
And sawdust restaurants with oyster-shells:
Streets that follow like a tedious argument
Of insidious intent
To lead you to an overwhelming question ...
Oh, do not ask, "What is it?"
Let us go and make our visit.

In the room, the women come and go
Talking of Michelangelo.

T. S. Eliot, "The Love Song of J. Alfred Prufrock"
1915

The term was first applied in a literary context in The Egoist, April 1918, by May Sinclair, in relation to the early volumes of Dorothy Richardson's novel sequence Pilgrimage. Richardson, however, describes the term as a "lamentably ill-chosen metaphor".

James Joyce was a major pioneer in the use of stream of consciousness. Some hints of this technique are already present in A Portrait of the Artist as a Young Man (1916), along with interior monologue, and references to a character's psychic reality rather than to his external surroundings. Joyce began writing A Portrait in 1907 and it was first serialised in the English literary magazine The Egoist in 1914 and 1915. Earlier in 1906, Joyce, when working on Dubliners, considered adding another story featuring a Jewish advertising canvasser called Leopold Bloom under the title Ulysses. Although he did not pursue the idea further at the time, he eventually commenced work on a novel using both the title and basic premise in 1914. The writing was completed in October 1921. Serial publication of Ulysses in the magazine The Little Review began in March 1918. Ulysses was finally published in 1922. While Ulysses represents a major example of the use of stream of consciousness, Joyce also uses "authorial description" and Free Indirect Style to register Bloom's inner thoughts. Furthermore, the novel does not focus solely on interior experiences: "Bloom is constantly shown from all round; from inside as well as out; from a variety of points of view which range from the objective to the subjective". In his final work Finnegans Wake (1939), Joyce's method of stream of consciousness, literary allusions and free dream associations was pushed to the limit, abandoning all conventions of plot and character construction, and the book is written in a peculiar and obscure English, based mainly on complex multi-level puns.

Another early example is the use of interior monologue by T. S. Eliot in his poem "The Love Song of J. Alfred Prufrock" (1915), "a dramatic monologue of an urban man, stricken with feelings of isolation and an incapability for decisive action," a work probably influenced by the narrative poetry of Robert Browning, including "Soliloquy of the Spanish Cloister".

1923 to 2000

Prominent uses in the years that followed the publication of James Joyce's Ulysses include Italo Svevo, La coscienza di Zeno (1923),^[33] Virginia Woolf in Mrs Dalloway (1925) and To the Lighthouse (1927), and William Faulkner in The Sound and the Fury (1929). However, Randell Stevenson suggests that "interior monologue, rather than stream of consciousness, is the appropriate term for the style in which [subjective experience] is recorded, both in The Waves and in Woolf's writing generally." Throughout Mrs Dalloway, Woolf blurs the distinction between direct and indirect speech, freely alternating her mode of narration between omniscient description, indirect interior monologue, and soliloquy. Malcolm Lowry's novel Under the Volcano (1947) resembles Ulysses, "both in its concentration almost entirely within a single day of [its protagonist] Firmin's life ... and in the range of interior monologues and stream of consciousness employed to represent the minds of [the] characters".

Samuel Beckett, a friend of James Joyce, uses interior monologue in novels like Molloy (1951), Malone meurt (1951; Malone Dies) and L'innommable (1953: The Unnamable). and the short story "From an Abandoned Work" (1957). French writer Jean-Paul Sartre employed the technique in his Roads to Freedom trilogy of novels, most prominently in the second book The Reprieve (1945).

The technique continued to be used into the 1970s in a novel such as Robert Anton Wilson/Robert Shea collaborative Illuminatus! (1975), concerning which The Fortean Times warns readers to "[b]e prepared for streams of consciousness in which not only identity but time and space no longer confine the narrative".

Although loosely structured as a sketch show, Monty Python produced an innovative stream-of-consciousness for their TV show Monty Python's Flying Circus, with the BBC stating, "[Terry] Gilliam's unique animation style became crucial, segueing seamlessly between any two completely unrelated ideas and making the stream-of-consciousness work".

Scottish writer James Kelman's novels are known for mixing stream of consciousness narrative with Glaswegian vernacular. Examples include The Busconductor Hines (1984), A Disaffection (1989), How Late It Was, How Late (1994) and many of his short stories. With regard to Salman Rushdie, one critic comments that "[a]ll Rushdie's novels follow an Indian/Islamic storytelling style, a stream-of-consciousness narrative told by a loquacious young Indian man". Other writers who use this narrative device include Sylvia Plath in The Bell Jar (1963) and Irvine Welsh in Trainspotting (1993).

Stream of consciousness continues to appear in contemporary literature. Dave Eggers, author of A Heartbreaking Work of Staggering Genius (2000), according to one reviewer, "talks much as he writes – a forceful stream of consciousness, thoughts sprouting in all directions". Novelist John Banville describes Roberto Bolaño's novel Amulet (1999), as written in "a fevered stream of consciousness".

Twenty-first century

The twenty-first century brought further exploration, including Jonathan Safran Foer's Everything is Illuminated (2002) and many of the short stories of American author Brendan Connell.

Song lyrics

Stream of consciousness technique is also used in song lyrics. Songwriters such as Sun Kil Moon and Courtney Barnett use it in their songs. An early example is Outkast's song "A Life in the Day of Benjamin André (Incomplete)" off their 2003 album Speakerboxxx/The Love Below.

Dialogue in films

Some filmmakers use the narrative technique. For example, the documentary Anonymous Club about songwriter Courtney Barnett is narrated using stream-of-consciousness. Terrence Malick's films use it as well. The 2022 film You Won't Be Alone also uses it.

Personality

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Personality

Personality is a structure gathering interrelated behavioral, cognitive and emotional patterns that biological and environmental factors influence; these interrelated patterns are relatively stable over time periods, but they change over the entire lifetime. While there is no generally agreed-upon definition of personality, most theories focus on motivation and psychological interactions with the environment one is surrounded by. Trait-based personality theories, such as those defined by Raymond Cattell, define personality as traits that predict an individual's behavior. On the other hand, more behaviorally-based approaches define personality through learning and habits. Nevertheless, most theories view personality as relatively stable.

The study of the psychology of personality, called personality psychology, attempts to explain the tendencies that underlie differences in behavior. Psychologists have taken many different approaches to the study of personality, including biological, cognitive, learning, and trait-based theories, as well as psychodynamic, and humanistic approaches. The various approaches used to study personality today reflect the influence of the first theorists in the field, a group that includes Sigmund Freud, Alfred Adler, Gordon Allport, Hans Eysenck, Abraham Maslow, and Carl Rogers.

Measuring

Personality can be determined through a variety of tests. Due to the fact that personality is a complex idea, the dimensions of personality and scales of such tests vary and often are poorly defined. Two main tools to measure personality are objective tests and projective measures. Examples of such tests are the: Big Five Inventory (BFI), Minnesota Multiphasic Personality Inventory (MMPI-2), Rorschach Inkblot test, Neurotic Personality Questionnaire KON-2006, or Eysenck's Personality Questionnaire (EPQ-R). All of these tests are beneficial because they have both reliability and validity, two factors that make a test accurate. "Each item should be influenced to a degree by the underlying trait construct, giving rise to a pattern of positive intercorrelations so long as all items are oriented (worded) in the same direction." A recent, but not well-known, measuring tool that psychologists use is the 16PF. It measures personality based on Cattell's 16-factor theory of personality. Psychologists also use it as a clinical measuring tool to diagnose psychiatric disorders and help with prognosis and therapy planning.

Personality is frequently broken into factors or dimensions, statistically extracted from large questionnaires through factor analysis. When brought back to two dimensions, often the dimensions of introvert-extrovert and neuroticism (emotionally unstable-stable) are used as first proposed by Eysenck in the 1960s.

Five-factor inventory

The Big Five personality traits

Many factor analyses found what is called the Big Five, which are openness to experience, conscientiousness, extraversion, agreeableness, and neuroticism (or emotional stability), known as "OCEAN". These components are generally stable over time, and about half of the variance appears to be attributable to a person's genetics rather than the effects of one's environment.

Some research has investigated whether the relationship between happiness and extraversion seen in adults also can be seen in children. The implications of these findings can help identify children who are more likely to experience episodes of depression and develop types of treatment that such children are likely to respond to. In both children and adults, research shows that genetics, as opposed to environmental factors, exert a greater influence on happiness levels. Personality is not stable over the course of a lifetime, but it changes much more quickly during childhood, so personality constructs in children are referred to as temperament. Temperament is regarded as the precursor to personality.

Another interesting finding has been the link found between acting extraverted and positive affect. Extraverted behaviors include acting talkative, assertive, adventurous, and outgoing. For the purposes of this study, positive affect is defined as experiences of happy and enjoyable emotions. This study investigated the effects of acting in a way that is counter to a person's dispositional nature. In other words, the study focused on the benefits and drawbacks of introverts (people who are shy, socially inhibited, and non-aggressive) acting extraverted, and of extraverts acting introverted. After acting extraverted, introverts' experience of positive affect increased whereas extraverts seemed to experience lower levels of positive affect and suffered from the phenomenon of ego depletion. Ego depletion, or cognitive fatigue, is the use of one's energy to overtly act in a way that is contrary to one's inner disposition. When people act in a contrary fashion, they divert most, if not all, (cognitive) energy toward regulating this foreign style of behavior and attitudes. Because all available energy is being used to maintain this contrary behavior, the result is an inability to use any energy to make important or difficult decisions, plan for the future, control or regulate emotions, or perform effectively on other cognitive tasks.

One question that has been posed is why extroverts tend to be happier than introverts. The two types of explanations that attempt to account for this difference are instrumental theories and temperamental theories. The instrumental theory suggests that extraverts end up making choices that place them in more positive situations and they also react more strongly than introverts to positive situations. The temperamental theory suggests that extroverts have a disposition that generally leads them to experience a higher degree of positive affect. In their study of extraversion, Lucas and Baird found no statistically significant support for the instrumental theory but did, however, find that extraverts generally experience a higher level of positive affect.

Research has been done to uncover some of the mediators that are responsible for the correlation between extraversion and happiness. Self-esteem and self-efficacy are two such mediators.

Self-efficacy is one's belief about abilities to perform up to personal standards, the ability to produce desired results, and the feeling of having some ability to make important life decisions. Self-efficacy has been found to be related to the personality traits of extraversion and subjective well-being.

Self-efficacy, however, only partially mediates the relationship between extraversion (and neuroticism) and subjective happiness. This implies that there are most likely other factors that mediate the relationship between subjective happiness and personality traits. Self-esteem maybe another similar factor. Individuals with a greater degree of confidence about themselves and their abilities seem to have both higher degrees of subjective well-being and higher levels of extraversion.

Other research has examined the phenomenon of mood maintenance as another possible mediator. Mood maintenance is the ability to maintain one's average level of happiness in the face of an ambiguous situation – meaning a situation that has the potential to engender either positive or negative emotions in different individuals. It has been found to be a stronger force in extroverts. This means that the happiness levels of extraverted individuals are less susceptible to the influence of external events. This finding implies that extraverts' positive moods last longer than those of introverts.

Developmental biological model

Modern conceptions of personality, such as the Temperament and Character Inventory have suggested four basic temperaments that are thought to reflect basic and automatic responses to danger and reward that rely on associative learning. The four temperaments, harm avoidance, reward dependence, novelty-seeking and persistence, are somewhat analogous to ancient conceptions of melancholic, sanguine, choleric, phlegmatic personality types, although the temperaments reflect dimensions rather than distance categories.

The harm avoidance trait has been associated with increased reactivity in insular and amygdala salience networks, as well as reduced 5-HT2 receptor binding peripherally, and reduced GABA concentrations. Novelty seeking has been associated with reduced activity in insular salience networks increased striatal connectivity. Novelty seeking correlates with dopamine synthesis capacity in the striatum and reduced auto receptor availability in the midbrain. Reward dependence has been linked with the oxytocin system, with increased concentration of plasma oxytocin being observed, as well as increased volume in oxytocin-related regions of the hypothalamus. Persistence has been associated with increased striatal-mPFC connectivity, increased activation of ventral striatal-orbitofrontal-anterior cingulate circuits, as well as increased salivary amylase levels indicative of increased noradrenergic tone.

Environmental influences

It has been shown that personality traits are more malleable by environmental influences than researchers originally believed. Personality differences predict the occurrence of life experiences.

One study has shown how the home environment, specifically the types of parents a person has, can affect and shape their personality. Mary Ainsworth's strange situation experiment showcased how babies reacted to having their mother leave them alone in a room with a stranger. The different styles of attachment, labeled by Ainsworth, were Secure, Ambivalent, avoidant, and disorganized. Children who were securely attached tend to be more trusting, sociable, and are confident in their day-to-day life. Children who were disorganized were reported to have higher levels of anxiety, anger, and risk-taking behavior.

Judith Rich Harris's group socialization theory postulates that an individual's peer groups, rather than parental figures, are the primary influence of personality and behavior in adulthood. Intra- and intergroup processes, not dyadic relationships such as parent-child relationships, are responsible for the transmission of culture and for environmental modification of children's personality characteristics. Thus, this theory points at the peer group representing the environmental influence on a child's personality rather than the parental style or home environment.

Tessuya Kawamoto's Personality Change from Life Experiences: Moderation Effect of Attachment Security talked about some significant laboratory tests. The study mainly focused on the effects of life experiences on change in personality and life experiences. The assessments suggested that "the accumulation of small daily experiences may work for the personality development of university students and that environmental influences may vary by individual susceptibility to experiences, like attachment security".

Some studies suggest that a shared family environment between siblings has less influence on personality than individual experiences of each child. Identical twins have similar personalities largely because they share the same genetic makeup rather than their shared environment.

Cross-cultural studies

There has been some recent debate over the subject of studying personality in a different culture. Some people think that personality comes entirely from culture and therefore there can be no meaningful study in cross-culture study. On the other hand, many believe that some elements are shared by all cultures and an effort is being made to demonstrate the cross-cultural applicability of "the Big Five".

Cross-cultural assessment depends on the universality of personality traits, which is whether there are common traits among humans regardless of culture or other factors. If there is a common foundation of personality, then it can be studied on the basis of human traits rather than within certain cultures. This can be measured by comparing whether assessment tools are measuring similar constructs across countries or cultures. Two approaches to researching personality are looking at emic and etic traits. Emic traits are constructs unique to each culture, which are determined by local customs, thoughts, beliefs, and characteristics. Etic traits are considered universal constructs, which establish traits that are evident across cultures that represent a biological basis of human personality. If personality traits are unique to the individual culture, then different traits should be apparent in different cultures. However, the idea that personality traits are universal across cultures is supported by establishing the Five-Factor Model of personality across multiple translations of the NEO-PI-R, which is one of the most widely used personality measures. When administering the NEO-PI-R to 7,134 people across six languages, the results show a similar pattern of the same five underlying constructs that are found in the American factor structure.

Similar results were found using the Big Five Inventory (BFI), as it was administered in 56 nations across 28 languages. The five factors continued to be supported both conceptually and statistically across major regions of the world, suggesting that these underlying factors are common across cultures. There are some differences across culture, but they may be a consequence of using a lexical approach to study personality structures, as language has limitations in translation and different cultures have unique words to describe emotion or situations. Differences across cultures could be due to real cultural differences, but they could also be consequences of poor translations, biased sampling, or differences in response styles across cultures. Examining personality questionnaires developed within a culture can also be useful evidence for the universality of traits across cultures, as the same underlying factors can still be found. Results from several European and Asian studies have found overlapping dimensions with the Five-Factor Model as well as additional culture-unique dimensions. Finding similar factors across cultures provides support for the universality of personality trait structure, but more research is necessary to gain stronger support.

Historical development of concept

The modern sense of individual personality is a result of the shifts in culture originating in the Renaissance, an essential element in modernity. In contrast, the Medieval European's sense of self was linked to a network of social roles: "the household, the Kinship network, the guild, the corporation – these were the building blocks of personhood". Stephen Greenblatt observes, in recounting the recovery (1417) and career of Lucretius' poem De rerum natura: "at the core of the poem lay key principles of a modern understanding of the world." "Dependent on the family, the individual alone was nothing," Jacques Gélis observes. "The characteristic mark of the modern man has two parts: one internal, the other external; one dealing with his environment, the other with his attitudes, values, and feelings." Rather than being linked to a network of social roles, the modern man is largely influenced by the environmental factors such as: "urbanization, education, mass communication, industrialization, and politicization." In 2006, for example, scientists reported a relationship between personality and political views as follows: "Preschool children who 20 years later were relatively liberal were characterized as: developing close relationships, self-reliant, energetic, somewhat dominating, relatively under-controlled, and resilient. Preschool children subsequently relatively conservative at age 23 were described as: feeling easily victimized, easily offended, indecisive, fearful, rigid, inhibited, and relatively over-controlled and vulnerable."

Temperament and philosophy

William James (1842–1910)

William James (1842–1910) argued that temperament explains a great deal of the controversies in the history of philosophy by arguing that it is a very influential premise in the arguments of philosophers. Despite seeking only impersonal reasons for their conclusions, James argued, the temperament of philosophers influenced their philosophy. Temperament thus conceived is tantamount to a bias. Such bias, James explained, was a consequence of the trust philosophers place in their own temperament. James thought the significance of his observation lay on the premise that in philosophy an objective measure of success is whether philosophy is peculiar to its philosopher or not, and whether a philosopher is dissatisfied with any other way of seeing things or not.

Mental make-up

James argued that temperament may be the basis of several divisions in academia, but focused on philosophy in his 1907 lectures on Pragmatism. In fact, James' lecture of 1907 fashioned a sort of trait theory of the empiricist and rationalist camps of philosophy. As in most modern trait theories, the traits of each camp are described by James as distinct and opposite, and maybe possessed in different proportions on a continuum, and thus characterize the personality of philosophers of each camp. The "mental make-up" (i.e. personality) of rationalist philosophers is described as "tender-minded" and "going by "principles", and that of empiricist philosophers is described as "tough-minded" and "going by "facts." James distinguishes each not only in terms of the philosophical claims they made in 1907, but by arguing that such claims are made primarily on the basis of temperament. Furthermore, such categorization was only incidental to James' purpose of explaining his pragmatist philosophy and is not exhaustive.

Empiricists and rationalists

John Locke (1632–1704)

According to James, the temperament of rationalist philosophers differed fundamentally from the temperament of empiricist philosophers of his day. The tendency of rationalist philosophers toward refinement and superficiality never satisfied an empiricist temper of mind. Rationalism leads to the creation of closed systems, and such optimism is considered shallow by the fact-loving mind, for whom perfection is far off. Rationalism is regarded as pretension, and a temperament most inclined to abstraction.

Empiricists, on the other hand, stick with the external senses rather than logic. British empiricist John Locke's (1632–1704) explanation of personal identity provides an example of what James referred to. Locke explains the identity of a person, i.e. personality, on the basis of a precise definition of identity, by which the meaning of identity differs according to what it is being applied to. The identity of a person is quite distinct from the identity of a man, woman, or substance according to Locke. Locke concludes that consciousness is personality because it "always accompanies thinking, it is that which makes everyone to be what he calls self," and remains constant in different places at different times.

Benedictus Spinoza (1632–1677)

Rationalists conceived of the identity of persons differently than empiricists such as Locke who distinguished identity of substance, person, and life. According to Locke, Rene Descartes (1596–1650) agreed only insofar as he did not argue that one immaterial spirit is the basis of the person "for fear of making brutes thinking things too." According to James, Locke tolerated arguments that a soul was behind the consciousness of any person. However, Locke's successor David Hume (1711–1776), and empirical psychologists after him denied the soul except for being a term to describe the cohesion of inner lives. However, some research suggests Hume excluded personal identity from his opus An Inquiry Concerning Human Understanding because he thought his argument was sufficient but not compelling. Descartes himself distinguished active and passive faculties of mind, each contributing to thinking and consciousness in different ways. The passive faculty, Descartes argued, simply receives, whereas the active faculty produces and forms ideas, but does not presuppose thought, and thus cannot be within the thinking thing. The active faculty mustn't be within self because ideas are produced without any awareness of them, and are sometimes produced against one's will.

Rationalist philosopher Benedictus Spinoza (1632–1677) argued that ideas are the first element constituting the human mind, but existed only for actually existing things. In other words, ideas of non-existent things are without meaning for Spinoza, because an idea of a non-existent thing cannot exist. Further, Spinoza's rationalism argued that the mind does not know itself, except insofar as it perceives the "ideas of the modifications of body", in describing its external perceptions, or perceptions from without. On the contrary, from within, Spinoza argued, perceptions connect various ideas clearly and distinctly. The mind is not the free cause of its actions for Spinoza. Spinoza equates the will with the understanding and explains the common distinction of these things as being two different things as an error which results from the individual's misunderstanding of the nature of thinking.

Biology

The biological basis of personality is the theory that anatomical structures located in the brain contribute to personality traits. This stems from neuropsychology, which studies how the structure of the brain relates to various psychological processes and behaviors. For instance, in human beings, the frontal lobes are responsible for foresight and anticipation, and the occipital lobes are responsible for processing visual information. In addition, certain physiological functions such as hormone secretion also affect personality. For example, the hormone testosterone is important for sociability, affectivity, aggressiveness, and sexuality. Additionally, studies show that the expression of a personality trait depends on the volume of the brain cortex it is associated with.

Personology

Personology confers a multidimensional, complex, and comprehensive approach to personality. According to Henry A. Murray, personology is:

The branch of psychology which concerns itself with the study of human lives and the factors that influence their course which investigates individual differences and types of personality ... the science of men, taken as gross units ... encompassing "psychoanalysis" (Freud), "analytical psychology" (Jung), "individual psychology" (Adler) and other terms that stand for methods of inquiry or doctrines rather than realms of knowledge.

From a holistic perspective, personology studies personality as a whole, as a system, but at the same time through all its components, levels, and spheres.

Growth hormone

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Growth_hormone

 

Growth hormone 1 (pituitary)
Growth hormone

Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of IGF-1 and increases the concentration of glucose and free fatty acids. It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.

A recombinant form of HGH called somatropin (INN) is used as a prescription drug to treat children's growth disorders and adult growth hormone deficiency. In the United States, it is only available legally from pharmacies by prescription from a licensed health care provider. In recent years in the United States, some health care providers are prescribing growth hormone in the elderly to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. Many of the functions of HGH remain unknown.

In its role as an anabolic agent, HGH has been used by competitors in sports since at least 1982, and has been banned by the IOC and NCAA. Traditional urine analysis does not detect doping with HGH, so the ban was not enforced until the early 2000s, when blood tests that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by WADA at the 2004 Olympic Games in Athens, Greece, targeted primarily HGH. Use of the drug for performance enhancement is not currently approved by the FDA.

GH has been studied for use in raising livestock more efficiently in industrial agriculture and several efforts have been made to obtain governmental approval to use GH in livestock production. These uses have been controversial. In the United States, the only FDA-approved use of GH for livestock is the use of a cow-specific form of GH called bovine somatotropin for increasing milk production in dairy cows. Retailers are permitted to label containers of milk as produced with or without bovine somatotropin.

Nomenclature

The names somatotropin (STH) or somatotropic hormone refer to the growth hormone produced naturally in animals and extracted from carcasses. Hormone extracted from human cadavers is abbreviated hGH. The main growth hormone produced by recombinant DNA technology has the approved generic name (INN) somatropin and the brand name Humatrope, and is properly abbreviated rhGH in the scientific literature. Since its introduction in 1992 Humatrope has been a banned sports doping agent, and in this context is referred to as HGH.

The term growth hormone has been incorrectly applied to refer to anabolic sex hormones in the European beef hormone controversy, which initially restricts the use of estradiol, progesterone, testosterone, zeranol, melengestrol acetate and trenbolone acetate.

Biology

Gene

Main articles: Growth hormone 1 and Growth hormone 2

Genes for human growth hormone, known as growth hormone 1 (somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.

Structure

The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22,124 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. It appears that, in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and Old World monkey growth hormones have significant effects on the human growth hormone receptor.

Several molecular isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio, while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions. This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosylated variant of 23 kDa identified in the pituitary gland. Furthermore, these variants circulate partially bound to a protein (growth hormone-binding protein, GHBP), which is the truncated part of the growth hormone receptor, and an acid-labile subunit (ALS).

Regulation

See also: Hypothalamic–pituitary–somatotropic axis

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides growth hormone-releasing hormone (GHRH or somatocrinin) and growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL. Maximal secretion of GH may occur within minutes of the onset of slow-wave (SW) sleep (stage III or IV). Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages. Surges of secretion during the day occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night. Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks were situated around 10-20 ng/mL.

A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones. Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day. Sleep deprivation generally suppresses GH release, particularly after early adulthood.

Stimulators of growth hormone (GH) secretion include:

• Peptide hormones
  • GHRH (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR)
  • Ghrelin through binding to growth hormone secretagogue receptors (GHSR)
• Sex hormones
  • Increased androgen secretion during puberty (in males from testes and in females from adrenal cortex)
  • Testosterone and DHEA
  • Estrogen
• Clonidine and L-DOPA by stimulating GHRH release
• α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine
• Hypoglycemia, arginine and propranolol by inhibiting somatostatin release
• Deep sleep
• Glucagon
• Niacin as nicotinic acid (vitamin B₃)
• Fasting
• Vigorous exercise

Inhibitors of GH secretion include:

• GHIH (somatostatin) from the periventricular nucleus 
• circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)
• Hyperglycemia
• Glucocorticoids
• Dihydrotestosterone
• Insulin
• Phenothiazines

In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptors) are known to influence GH secretion and function.

Function

Main pathways in endocrine regulation of growth

Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other peptide hormones, GH acts by interacting with a specific receptor on the surface of cells.

Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:

1. Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.
2. GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:

• Increases calcium retention, and strengthens and increases the mineralization of bone
• Increases muscle mass through sarcomere hypertrophy
• Promotes lipolysis
• Increases protein synthesis
• Stimulates the growth of all internal organs excluding the brain
• Plays a role in homeostasis
• Reduces liver uptake of glucose
• Promotes gluconeogenesis in the liver
• Contributes to the maintenance and function of pancreatic islets
• Stimulates the immune system
• Increases deiodination of T4 to T3

Biochemistry

GH has a short biological half-life of about 10 to 20 minutes.

Clinical significance

Excess

The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually, the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.

Prolonged GH excess thickens the bones of the jaw, fingers and toes, resulting in heaviness of the jaw and increased size of digits, referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves (e.g. carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.

GH-secreting tumors are typically recognized in the fifth decade of life. It is extremely rare for such a tumor to occur in childhood, but, when it does, the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.

Surgical removal is the usual treatment for GH-producing tumors. In some circumstances, focused radiation or a GH antagonist such as pegvisomant may be employed to shrink the tumor or block function. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary.

Deficiency

Main article: Growth hormone deficiency

The effects of growth hormone (GH) deficiency vary depending on the age at which they occur. Alterations in somatomedin can result in growth hormone deficiency with two known mechanisms; failure of tissues to respond to somatomedin, or failure of the liver to produce somatomedin. Major manifestations of GH deficiency in children are growth failure, the development of a short stature, and delayed sexual maturity. In adults, somatomedin alteration contributes to increased osteoclast activity, resulting in weaker bones that are more prone to pathologic fracture and osteoporosis. However, deficiency is rare in adults, with the most common cause being a pituitary adenoma. Other adult causes include a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.

Adults with GHD "tend to have a relative increase in fat mass and a relative decrease in muscle mass and, in many instances, decreased energy and quality of life".

Diagnosis of GH deficiency involves a multiple-step diagnostic process, usually culminating in GH stimulation tests to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli.

Psychological effects

Quality of life

Several studies, primarily involving patients with GH deficiency, have suggested a crucial role of GH in both mental and emotional well-being and maintaining a high energy level. Adults with GH deficiency often have higher rates of depression than those without. While GH replacement therapy has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown.

Cognitive function

GH has also been studied in the context of cognitive function, including learning and memory. GH in humans appears to improve cognitive function and may be useful in the treatment of patients with cognitive impairment that is a result of GH deficiency.

Medical uses

Main article: Growth hormone therapy

Replacement therapy

GH is used as replacement therapy in adults with GH deficiency of either childhood-onset or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being. Long acting growth hormone (LAGH) analogues are now available for treating growth hormone deficiency both in children and adults. These are once weekly injections as compared to conventional growth hormone which has to be taken as daily injections. LAGH injection 4 times a month has been found to be as safe and effective as daily growth hormone injections.

Other approved uses

GH can be used to treat conditions that produce short stature but are not related to deficiencies in GH. However, results are not as dramatic when compared to short stature that is solely attributable to deficiency of GH. Examples of other causes of shortness often treated with GH are Turner syndrome, Growth failure secondary to chronic kidney disease in children, Prader–Willi syndrome, intrauterine growth restriction, and severe idiopathic short stature. Higher ("pharmacologic") doses are required to produce significant acceleration of growth in these conditions, producing blood levels well above normal ("physiologic").

One version of rHGH has also been FDA approved for maintaining muscle mass in wasting due to AIDS.

Off-label use

Main article: HGH controversies

Off-label prescription of HGH is controversial and may be illegal.

Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study wherein GH was used to treat 12 men over 60. At the conclusion of the study, all the men showed statistically significant increases in lean body mass and bone mineral density, while the control group did not. The authors of the study noted that these improvements were the opposite of the changes that would normally occur over a 10- to 20-year aging period. Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were misinterpreted as indicating that GH is an effective anti-aging agent. This has led to organizations such as the controversial American Academy of Anti-Aging Medicine promoting the use of this hormone as an "anti-aging agent".

A Stanford University School of Medicine meta-analysis of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by about 2 kg and decreased body fat by the same amount. However, these were the only positive effects from taking GH. No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. Researchers also did not discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass.

GH has also been used experimentally to treat multiple sclerosis, to enhance weight loss in obesity, as well as in fibromyalgia, heart failure, Crohn's disease and ulcerative colitis, and burns. GH has also been used experimentally in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.

In 1990, the US Congress passed an omnibus crime bill, the Crime Control Act of 1990, that amended the Federal Food, Drug, and Cosmetic Act, that classified anabolic steroids as controlled substances and added a new section that stated that a person who "knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services" has committed a felony.

The Drug Enforcement Administration of the US Department of Justice considers off-label prescribing of HGH to be illegal, and to be a key path for illicit distribution of HGH. This section has also been interpreted by some doctors, most notably the authors of a commentary article published in the Journal of the American Medical Association in 2005, as meaning that prescribing HGH off-label may be considered illegal. And some articles in the popular press, such as those criticizing the pharmaceutical industry for marketing drugs for off-label use (with concern of ethics violations) have made strong statements about whether doctors can prescribe HGH off-label: "Unlike other prescription drugs, HGH may be prescribed only for specific uses. U.S. sales are limited by law to treat a rare growth defect in children and a handful of uncommon conditions like short bowel syndrome or Prader-Willi syndrome, a congenital disease that causes reduced muscle tone and a lack of hormones in sex glands." At the same time, anti-aging clinics where doctors prescribe, administer, and sell HGH to people are big business. In a 2012 article in Vanity Fair, when asked how HGH prescriptions far exceed the number of adult patients estimated to have HGH-deficiency, Dragos Roman, who leads a team at the FDA that reviews drugs in endocrinology, said "The F.D.A. doesn't regulate off-label uses of H.G.H. Sometimes it's used appropriately. Sometimes it's not."

Side effects

Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes. In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin's lymphoma.

One survey of adults that had been treated with replacement cadaver GH (which has not been used anywhere in the world since 1985) during childhood showed a mildly increased incidence of colon cancer and prostate cancer, but linkage with the GH treatment was not established.

Performance enhancement

Main article: Growth hormone in sports

The first description of the use of GH as a doping agent was Dan Duchaine's "Underground Steroid handbook" which emerged from California in 1982; it is not known where and when GH was first used this way.

Athletes in many sports have used human growth hormone in order to attempt to enhance their athletic performance. Some recent studies have not been able to support claims that human growth hormone can improve the athletic performance of professional male athletes. Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. However, because GH is a potent endogenous protein, it is very difficult to detect GH doping. In the United States, GH is legally available only by prescription from a medical doctor.

Dietary supplements

To capitalize on the idea that GH might be useful to combat aging, companies selling dietary supplements have websites selling products linked to GH in the advertising text, with medical-sounding names described as "HGH Releasers". Typical ingredients include amino acids, minerals, vitamins, and/or herbal extracts, the combination of which are described as causing the body to make more GH with corresponding beneficial effects. In the United States, because these products are marketed as dietary supplements, it is illegal for them to contain GH, which is a drug. Also, under United States law, products sold as dietary supplements cannot have claims that the supplement treats or prevents any disease or condition, and the advertising material must contain a statement that the health claims are not approved by the FDA. The FTC and the FDA do enforce the law when they become aware of violations.

Agricultural use

In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, and is legal to use GH in raising cows for beef; see article on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy.

The use of GH in poultry farming is illegal in the United States. Similarly, no chicken meat for sale in Australia is administered hormones.

Several companies have attempted to have a version of GH for use in pigs (porcine somatotropin) approved by the FDA but all applications have been withdrawn.

Drug development history

Main article: Growth hormone treatment § History

Genentech pioneered the use of recombinant human growth hormone for human therapy, which was approved by the FDA in 1985.

Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers. Attempts to create a wholly synthetic HGH failed. Limited supplies of HGH resulted in the restriction of HGH therapy to the treatment of idiopathic short stature. Very limited clinical studies of growth hormone derived from an Old World monkey, the rhesus macaque, were conducted by John C. Beck and colleagues in Montreal, in the late 1950s. The study published in 1957, which was conducted on "a 13-year-old male with well-documented hypopituitarism secondary to a crainiophyaryngioma," found that: "Human and monkey growth hormone resulted in a significant enhancement of nitrogen storage ... (and) there was a retention of potassium, phosphorus, calcium, and sodium. ... There was a gain in body weight during both periods. ... There was a significant increase in urinary excretion of aldosterone during both periods of administration of growth hormone. This was most marked with the human growth hormone. ... Impairment of the glucose tolerance curve was evident after 10 days of administration of the human growth hormone. No change in glucose tolerance was demonstrable on the fifth day of administration of monkey growth hormone." The other study, published in 1958, was conducted on six people: the same subject as the Science paper; an 18-year-old male with statural and sexual retardation and a skeletal age of between 13 and 14 years; a 15-year-old female with well-documented hypopituitarism secondary to a craniopharyngioma; a 53-year-old female with carcinoma of the breast and widespread skeletal metastases; a 68-year-old female with advanced postmenopausal osteoporosis; and a healthy 24-year-old medical student without any clinical or laboratory evidence of systemic disease.

In 1985, unusual cases of Creutzfeldt–Jakob disease were found in individuals that had received cadaver-derived HGH ten to fifteen years previously. Based on the assumption that infectious prions causing the disease were transferred along with the cadaver-derived HGH, cadaver-derived HGH was removed from the market.

In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere.

As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). In 2006, the U.S. Food and Drug Administration (FDA) approved a version of rHGH called Omnitrope (Sandoz). A sustained-release form of growth hormone, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); however, the product was discontinued by Genentech/Alkermes in 2004 for financial reasons (Nutropin Depot required significantly more resources to produce than the rest of the Nutropin line).

Polyketide synthase

From Wikipedia, the free encyclopedia

Polyketide synthases (PKSs) are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share striking similarities with fatty acid biosynthesis.

The PKS genes for a certain polyketide are usually organized in one operon or in gene clusters. Type I and type II PKSs form either large modular protein complexes or dissociable molecular assemblies; type III PKSs exist as smaller homodimeric proteins.

Classification

Reaction mechanisms of type I, II and III PKSs. Decarboxylation of malonyl unit followed by thio-Claisen condensation. a) (cis-AT) type I PKS with acyl carrier protein (ACP), keto synthase (KS) and acyl transferase (AT) domains covalently bound to another . b) Type II PKS with KSα-KSβ heterodimer and ACP as separate proteins. c) ACP-independent Type III PKS.

PKSs can be classified into three types:

• Type I PKSs are large, complex protein structures with multiple modules which in turn consist of several domains that are usually covalently connected to each other and fulfill different catalytic steps. The minimal composition of a type I PKS module consists of an acyltransferase (AT) domain, which is responsible for choosing the building block to be used, a keto synthase (KS) domain, which catalyzes the C-C bond formation and an acyl carrier protein (ACP) domain, also known as thiolation domain. The latter contains a conserved Ser residue, post-translationally modified with a phosphopantetheine at the end of which the polyketide chain is covalently bound during biosynthesis as a thioester. Moreover, multiple other optional domains can also exist within a module like ketoreductase or dehydratase domains which alter the default 1,3-dicarbonyl functionality of the installed ketide by sequential reduction to an alcohol and double bond, respectively. These domains work together like an assembly line. This type of type I PKSs is also referred to as cis-acyltransferase polyketide synthases (cis-AT PKSs). In contrast to that, so called trans-AT PKSs evolved independently and lack AT domains in their modules. This activity is provided by free-standing AT domains instead. Moreover, they often contain uncommon domains with unique catalytic activities.
• Type II PKSs behave very similarly to type I PKS but with one key difference: Instead of one large megaenzyme, type II PKSs are separate, monofunctional enzymes. The smallest possible type II PKS consists of an ACP, as well as two heterodimeric KS units (KSα, which catalyzes the C-C bond formation and KSβ, also known as 'chain length factor' — CLF, since it can determine the carbon chain length), which fulfill a similar function as the AT, KS and ACP domains in type I PKSs, even though type II PKSs are lacking a separate AT domain. Additionally, type II PKSs often work iteratively where multiple chain elongation steps are carried out by the same enzyme, similar to type III PKSs.
• Type III PKSs are small homodimers of 40 kDa proteins that combine all the activities from the essential type I and II PKS domains. However, in contrast to type I and II PKSs they do not require an ACP-bound substrate. Instead, they can use a free acyl-CoA substrate for chain elongation. Moreover, type III PKSs contain a Cys-His-Asn catalytic triad in their active center, with the cysteine residue acting as the attacking nucleophile, whereas type I and II PKSs are characterized by a Cys-His-His catalytic triad. Typical products of type III PKSs include phenolic lipids like alkylresorcinols

• In addition to these three types of PKSs, they can be further classified as iterative or noniterative. Iterative Type I PKSs reuse domains in a cyclic fashion. Other classifications include the degree of reduction performed during the synthesis of the growing polyketide chain.
  • NR-PKSs — non-reducing PKSs, the products of which are true polyketides
  • PR-PKSs — partially reducing PKSs
  • FR-PKSs — fully reducing PKSs, the products of which are fatty acid derivatives

Modules and domains

Biosynthesis of the doxorubicin precursor, є-rhodomycinone. The polyketide synthase reactions are shown on top.

Each type I polyketide-synthase module consists of several domains with defined functions, separated by short spacer regions. The order of modules and domains of a complete polyketide-synthase is as follows (in the order N-terminus to C-terminus):

• Starting or loading module: AT-ACP-
• Elongation or extending modules: -KS-AT-[DH-ER-KR]-ACP-
• Termination or releasing domain: -TE

Domains:

• AT: Acyltransferase
• ACP: Acyl carrier protein with an SH group on the cofactor, a serine-attached 4'-phosphopantetheine
• KS: Keto-synthase with an SH group on a cysteine side-chain
• KR: Ketoreductase
• DH: Dehydratase
• ER: Enoylreductase
• MT: Methyltransferase O- or C- (α or β)
• SH: PLP-dependent cysteine lyase
• TE: Thioesterase

The polyketide chain and the starter groups are bound with their carboxy functional group to the SH groups of the ACP and the KS domain through a thioester linkage: R-C(=O)OH + HS-protein <=> R-C(=O)S-protein + H₂O.

The ACP carrier domains are similar to the PCP carrier domains of nonribosomal peptide synthetases, and some proteins combine both types of modules.

Stages

The growing chain is handed over from one thiol group to the next by trans-acylations and is released at the end by hydrolysis or by cyclization (alcoholysis or aminolysis).

Starting stage:

• The starter group, usually acetyl-CoA or its analogues, is loaded onto the ACP domain of the starter module catalyzed by the starter module's AT domain.

Elongation stages:

• The polyketide chain is handed over from the ACP domain of the previous module to the KS domain of the current module, catalyzed by the KS domain.
• The elongation group, usually malonyl-CoA or methylmalonyl-CoA, is loaded onto the current ACP domain catalyzed by the current AT domain.
• The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain under CO₂ evolution, leaving a free KS domain and an ACP-bound elongated polyketide chain. The reaction takes place at the KS_n-bound end of the chain, so that the chain moves out one position and the elongation group becomes the new bound group.
• Optionally, the fragment of the polyketide chain can be altered stepwise by additional domains. The KR (keto-reductase) domain reduces the β-keto group to a β-hydroxy group, the DH (dehydratase) domain splits off H₂O, resulting in the α-β-unsaturated alkene, and the ER (enoyl-reductase) domain reduces the α-β-double-bond to a single-bond. It is important to note that these modification domains actually affect the previous addition to the chain (i.e. the group added in the previous module), not the component recruited to the ACP domain of the module containing the modification domain.
• This cycle is repeated for each elongation module.

Termination stage:

• The TE domain hydrolyzes the completed polyketide chain from the ACP-domain of the previous module.

Pharmacological relevance

Polyketide synthases are an important source of naturally occurring small molecules used for chemotherapy. For example, many of the commonly used antibiotics, such as tetracycline and macrolides, are produced by polyketide synthases. Other industrially important polyketides are sirolimus (immunosuppressant), erythromycin (antibiotic), lovastatin (anticholesterol drug), and epothilone B (anticancer drug).

Polyketides are a large family of natural products widely used as drugs, pesticides, herbicides, and biological probes.

There are antifungal and antibacterial polyketide compounds, namely ophiocordin and ophiosetin.

And are researched for the synthesis of biofuels and industrial chemicals.

Ecological significance

Only about 1% of all known molecules are natural products, yet it has been recognized that almost two thirds of all drugs currently in use are at least in part derived from a natural source. This bias is commonly explained with the argument that natural products have co-evolved in the environment for long time periods and have therefore been pre-selected for active structures. Polyketide synthase products include lipids with antibiotic, antifungal, antitumor, and predator-defense properties; however, many of the polyketide synthase pathways that bacteria, fungi and plants commonly use have not yet been characterized. Methods for the detection of novel polyketide synthase pathways in the environment have therefore been developed. Molecular evidence supports the notion that many novel polyketides remain to be discovered from bacterial sources.