Why did the Canterville ghost give the jewel box to Virginia?

In Chapter Six of "The Canterville Ghost," Virginia returns to her family after a brief disappearance, holding a box of jewels. She then explains how she came to be in possession of the jewels:

I have been with the ghost...He had been very wicked, but he was really sorry for all that he had done, and he gave me this box of beautiful jewels before he died.

The jewels, therefore, are a gift from the ghost to express his gratitude to Virginia. In Chapter Five, Virginia agreed to accompany the ghost through the Tapestry door. Here, she fulfilled the prophecy that is written on the library window by shedding her tears so that God would forgive the ghost. In return, the ghost received redemption and a place in the Garden of Death.

On a deeper level, the jewels are more than just a symbol of gratitude. They also a function as a symbol of reconciliation. Thanks to Virginia, the conflict between the ghost and the Otis family is finally over. The ghost is now at peace in the Garden of Death and the Otis family are free to enjoy Canterville Chase, without any supernatural disturbance. 

Athena, disguised as Mentor, tells Telemachus, "Odysseus’ cunning has hardly given out in you" (2.312), but what are examples of Telemachus's...

During this same speech, Athena instructs Telemachus to go home "and mix with the suitors there. / But get [his] rations ready [...]." In other words, he is to return home and mingle with the suitors, never betraying the plan he and Athena have devised for him to escape Ithaca in secret and go in search of news of his lost father. He is to make preparations for a journey and keep those preparations clandestine: such dissembling is certainly evidence of his cunning.

Then, when Telemachus does return home, Antinous (the suitors' unofficial leader) tries to draw him in and compel him to eat and drink with them, promising the prince that they will provide him with a ship and crew to go in search of news of his father. However, Telemachus will not be drawn in, and he says only that he will go, but "only as a passenger, nothing more," and he "nonchalantly drew his hand from Antinous's hand" while the other suitors taunt and jeer at him. Telemachus will not allow them to get to him, though, and he maintains his calm in the face of their insults so that he can protect his plan; this shows his cunning as well. He understands that deceiving them is paramount, and he has a will strong enough not to give in to his pride when they abuse him.

Why does Sal seem to notice that there is something wrong with Mrs. Winterbottom, but Phoebe doesn't?

Since her mother left, Sal has become more sensitive to others, rather than just concerned about herself. She reflects back on the events that preceded her mother’s leaving. This makes her aware of some similar unhappiness and dissatisfaction in Mrs. Winterbottom. She sees how Phoebe, her sister, and her father almost ignore Mrs.Winterbottom, who is desperately trying to reach out for someone to notice her. She talks a great deal at the dinner table, even though no one answers her. Sal notices this, and perhaps she sees her mother’s reaching out before she left. Sal wonders if she was exactly like Phoebe, and if this was a reason that her mother left, through not feeling fulfilled within her family. Mrs. Hiddle has suffered loss, as revealed later in the story. In hindsight, Sal realizes that she should have seen how unhappy her mother was. She wants to warn Phoebe, but does not know how to break through Phoebe’s self-centeredness to do so.

What is the Alexander technique (AT)?

Overview

The Alexander technique (AT) is a system of body alignment, movement, and thought that was developed in the early twentieth century. The technique focuses on posture, poise, breathing, body awareness, efficiency of movement, and elegance of stride. AT is used extensively by singers, musicians, and actors.

The technique was developed Frederick Matthias Alexander, a Shakespearean actor
and orator whose chronic hoarseness had threatened to derail his career. Doctors
could do nothing to help him, but, determined not to give up, he tried to discover
the cause of his chronic voice problems by observing himself in a mirror as he
spoke in his stage voice. What he saw was poor body alignment: His head was pulled
back, his neck muscles were tensed, and his breathing was awkward and gasping. In
effect, his larynx had been compressed by the extreme tension in his
neck muscles.

Alexander knew that changing his posture would not be easy. Just thinking that he was about to speak would cause his neck muscles to tense. He ended up using a sort of reverse psychology to retrain his body. “Don’t speak,” he would tell himself, noticing a release of tension in his neck. His retraining would become the Alexander technique. AT, as it is still taught, is not only about posture and movement but also about mind and thought.

Mechanism of Action

Students of AT will typically meet individually with a teacher for 20 to 30 minutes, once each week. Lessons are hands-on, with the instructor gently guiding the student to lengthen and widen the body through gentle pressure. Particular attention is paid to the neck and head. The neck should be loose, with the head forward and raised. The shoulders should be lowered (“untensed”) and raised. Each session typically includes time to sit, to stand, and then to lie on a treatment table with one’s head resting lightly on a book; the knees are bent. A lesson will also include specific training for the particular body movement that brought the student to the class (breathing and vocalizing, for instance, for a student who is a singer). Lessons are usually repeated weekly for several months or several years.

Uses and Applications

Those seeking the technique may range from violinists experiencing intermittent
shoulder pain, to office workers who have upper back and neck problems from
extended computer use, to overweight persons who feel pain in their hips after
walking as little as one block. AT instructors are careful to refer to their
clients as “students,” not as “patients,” even though the majority of people who
seek out lessons are suffering either from specific aches or pains or from
generalized physical symptoms associated with stress and
could, thus, be considered medical “patients.”

AT is widely accepted in Europe, especially in England, where Alexander lived
and taught. In all countries, the technique is especially popular among
performers. Many music schools, including that at the prestigious Juilliard School in New York
City, have certified AT instructors as faculty. It is not
surprising that actors, such as Alexander himself, frequently practice AT. Famous
actors who are said to have studied the Alexander technique include
Paul
Newman, Kevin Kline, Mary Steenburgen, Ralph Fiennes, John
Cleese, and William Hurt. Another person who studied and practiced AT long-term
was American philosopher-educator John Dewey.

Scientific Evidence

No scientific studies of the Alexander technique have been conducted.

Safety Issues

No known safety concerns are associated with the Alexander technique.

Bibliography

American Society for the Alexander Technique. http://www.amsatonline.org.

Bloch, Michael. F. M: The Life of Frederick Matthias Alexander, Founder of the Alexander Technique. Boston: Little, Brown, 2004.

Vineyard, Missy. How You Stand, How You Move, How You Live: Learning the Alexander Technique to Explore Your Mind-Body Connection and Achieve Self-Mastery. New York: Marlowe, 2007.

What is typhus?

Causes and Symptoms

The causative agent of epidemic
typhus is the bacterium Rickettsia prowazeckii, an obligate intracellular parasite. These bacteria are transmitted to humans following the bite from an infected body louse,
Pediculus humanus corporis. The pathogen is excreted with the louse feces and invades the site of a louse bite when the bitten host scratches the bite. The onset of the disease is marked by a high and prolonged fever with accompanying headache and rash. The bacteria are spread throughout the body through the bloodstream and can cause secondary lesions in many tissues, including the kidneys, heart, and brain. Mortality can be as high as 40 to 60 percent in untreated cases.

Treatment and Therapy

Antibiotic treatment is essential for reducing the severity of the disease, and chloramphenicol, tetracycline, and doxycycline are the antibiotics of choice. Improved sanitation and living conditions since the 1920s have virtually eliminated this disease in countries such as the United States. The last US epidemic was in 1922. Since then, there have been sporadic reports of isolated cases involving transmission from flying squirrels, indicating a possible animal reservoir; however, there is no real evidence to support this. Epidemic typhus still persists in some regions of Africa, Central America, and South America. The best course of action for prevention is to practice good hygiene and sanitation, and to avoid areas where there might be rat fleas and lice.

Perspective and Prospects

Epidemic typhus, also known as jail fever, is primarily a disease of crowded, substandard living conditions and poor sanitation. Millions of cases occurred in the trenches of World War I and in the concentration camps of World War II. Anne Frank, the noted teenage diarist, died of typhus contracted while at a concentration camp. It has been said that Napoleon’s retreat from Russia was started by a louse, and that lice have defeated the most powerful armies of Europe and Asia.

The pioneering investigations of Howard Taylor Ricketts
and Stanislas von Prowazeck in the early twentieth century paved the way for the discovery of both the bacteria and the louse vector, although both men died from the disease that they studied. They were honored posthumously when the bacterium was named Rickettsia prowazeckii.

Bibliography

Dugdale, David C. III, Jatin M. Vyas, and David Zieve. "Typhus." MedlinePlus, Oct. 6, 2012.

Eremeeva, Marina E., and Gregory A. Dasch. "Rickettsial (Spotted and Typhus Fevers) and Related Infections (Analplasmosis and Ehrlichiosis." Centers for Disease Control and Prevention, July 1, 2011.

Lock, Stephen, John Last, and George M. Dunea, eds. The Oxford Companion to Medicine. 3d ed. New York: Oxford University Press, 2006.

Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. Medical Microbiology. 7th ed. Philadelphia: Mosby/Elsevier, 2013.

Tortora, Gerard J., Berdell R. Funke, and Christine L. Case. Microbiology: An Introduction. 11th ed. San Francisco: Pearson Benjamin Cummings, 2013.

"Typhus Fever (Endemic Louse-Borne Typhus)." World Health Organization, 2013.

Zinsser, Hans. Rats, Lice, and History. New York: Black Dog & Leventhal, 1996.

What is sociopathy?

Introduction

Sociopathy is a clinical condition marked by a pattern of disturbed interpersonal, emotional, and behavioral functioning. It is characterized by remorselessness, manipulativeness, lack of concern for the welfare of others, deceit, shallow emotional experience, and poor impulse control. Sociopaths tend to be superficially charming and often make a good first impression on others. Nevertheless, they are typically egocentric, dishonest, and irresponsible, often without apparent motivation. They tend to be callous, externalize blame, and fail to learn from negative consequences. Many authors use the term “sociopathy” interchangeably with psychopathy.

History

Georgia psychiatrist Hervey Cleckley’s classic book The Mask of Sanity (1941) was the first to delineate the core features of the syndrome. Cleckley described sociopathy as characterized by a mask of normalcy that conceals a pernicious mental disorder, and he listed sixteen criteria as essential features of this condition. Among these criteria are the presence of superficial charm, the absence of delusions and nervousness, a lack of remorse and shame, irresponsibility, and untruthfulness.

Cleckley depicted sociopaths as appearing to be relatively normal. They are not psychotic (out of touch with reality); rather, in the words of nineteenth century British physician James Cowles Prichard, they are “morally insane,” meaning they have a core deficit in conscience. Sociopaths’ personality characteristics, such as poor impulse control and callousness, render many of them prone to violence. Nevertheless, the view that all sociopaths engage in violent behavior—or that all violent people are sociopaths—is a misconception. As an attractive and intelligent young man, Theodore “Ted” Bundy, the prolific U.S. serial killer of the 1970s, fit the profile of a typical sociopath. However, the fact that Bundy was violent does not mean he was sociopathic. Instead, his charm, callousness, deceit, and lack of empathy and guilt are what mark him as a bona fide sociopath. Indeed, some authors have suggested that sociopathic characteristics may be expressed in a variety of ways, with a few individuals being extremely violent, others moderately violent, and still others even entirely nonviolent. Moreover, at least some sociopaths may be drawn to socially adaptive occupations, like politics, business, and contact sports, although systematic research on this conjecture is lacking.

Cleckley’s rich clinical descriptions catalyzed research on sociopathy. In 1957, University of Minnesota psychologist David Lykken demonstrated that sociopaths showed diminished responses to a buzzer that was paired repeatedly with an electric shock. Based on this finding, Lykken proposed that the core deficit of sociopaths is fearlessness. This lack of fear, he proposed, gives rise to the other features of the disorder, such as lack of guilt and poor impulse control, which depend on at least a modicum of fear for adequate socialization. As a consequence, psychopaths often display a failure of passive avoidance learning—learning to inhibit responses that lead to punishment. The finding that sociopaths are relatively fearless has since been replicated in a host of studies, although the hypothesis that fearlessness is the major cause of sociopathy remains controversial.

Prevalence of the Condition

Although sociopaths make up an estimated 1 percent of the general population, they are overrepresented in prisons, with around 25 percent of incarcerated men meeting research criteria for the condition. Most individuals who meet the criteria for sociopathy are men, although the causes of this gender difference remain unknown. Sociopathy appears to be a cross-cultural phenomenon. Research by Harvard University anthropologist Jane Murphy has shown that conditions similar or identical to sociopathy appear to be present in remote regions of Alaska and Nigeria that have had scant exposure to Western culture.

Relation to Antisocial Personality Disorder

The American Psychiatric Association’s
Diagnostic and Statistical Manual of Mental Disorders: DSM-5(2013) contains the diagnosis of antisocial personality disorder (ASPD), a condition that shares many characteristics with sociopathy. The two are not synonymous, however, as antisocial personality disorder designates a persistent pattern of antisocial and criminal infractions. Therefore, its diagnosis emphasizes behavioral indicators, whereas sociopathy emphasizes core personality traits. Some sociopaths are guiltless, dishonest, manipulative, and egocentric, but they display little or no history of criminal behavior.

Lykken posited that psychopathy and sociopathy are two distinct kinds of antisocial personality disorder, with the former primarily deriving from temperamental and biological differences and the latter primarily from negative sociological influences, such as poor parenting and exposure to delinquent peer groups. According to Lykken, both conditions predispose toward antisocial behavior and callous disregard of others, but stem from different causes. Nevertheless, many or most researchers use the terms psychopathy and sociopathy interchangeably.

Assessment of Sociopathy

The most widely used assessment tool for sociopathy is University of British Columbia psychologist Robert Hare’s Psychopathy Checklist-Revised (PCL-R). The PCL-R consists of twenty items derived in part from the Cleckley criteria. Each item is scored zero to two, based on a standardized clinical interview and criminal files. The PCL-R has been widely used in criminal populations, as scores above thirty are strong predictors of recidivism and violence.

The PCL-R, however, can be unwieldy to administer, requiring comprehensive interviews and file review. Further, the PCL-R may not be suited for detecting psychopathy among noninstitutional populations, in which some individuals may exhibit the key personality features of sociopathy while refraining from criminal behavior or avoiding detection by the legal system. Although the high levels of sociopathic traits in prison samples are expedient for research purposes, exclusive reliance on criminal samples may result in a failure to detect important characteristics that buffer some sociopaths against criminal behavior, such as adequate impulse control or intelligence. Promising attempts have been made to detect the core personality characteristics of sociopathy using self- or peer-rating scales. With the aim of constructing a measure of sociopathic personality traits in noninstitutional populations, Emory University psychologist Scott Lilienfeld developed the Psychopathic Personality Inventory (PPI). The PPI-R and several other self-report measures show promising but preliminary validity for the assessment of sociopathy.

Response to Treatment

Traditionally, sociopaths have been viewed as nonresponsive to treatment. Indeed, sociopaths are often viewed as incurable and therefore in need of control rather than treatment. Sociopaths’ emotional detachment and manipulativeness may often impede psychotherapy. However, this widespread clinical conviction may perpetuate the paucity of interventions aimed at curtailing sociopaths’ antisocial behavior. Jennifer Skeem of the University of California, Irvine, has found that sociopaths are as likely as nonsociopaths to respond to violence reduction interventions. More research directed toward understanding the development, nature, and causes of sociopathy, and the conditions under which sociopaths may respond to interventions, is essential before sociopathy can be effectively controlled in society.

Bibliography

Blair, R. J. R., Derek Mitchell, and Karina Blair. The Psychopath: Emotion and the Brain. Malden, Mass.: Blackwell, 2005. Print.

Cleckley, Hervey. The Mask of Sanity. 5th ed. Augusta, Ga.: Emily S. Cleckley, 1988. Print.

Derber, Charles. Sociopathic Society: A People's Sociology of the United States. Boulder: Paradigm, 2013. Print.

Edens, John F. "Examining the Prevalence, Role, and Impact of Evidence Regarding Antisocial Personality, Sociopathy, and Psychopathy in Capital Cases: A Survey of Defense Team Members." Behavioral Sciences and the Law 30.3 (May/June 2012): 239–55. Print.

Felthous, Alan R., and Henning Sass. The International Handbook of Psychopathic Disorders and the Law. Chichester: John Wiley, 2012. Print.

Hare, Robert D. Without Conscience: The Disturbing World of the Psychopaths Among Us. New York: Guilford Press, 1999. Print.

Lykken, David T. The Antisocial Personalities. Hillsdale, N.J.: Lawrence Erlbaum, 1995. Print.

Patrick, Christopher J., ed. Handbook of Psychopathy. New York: Guilford Press, 2006. Print.

What are some negative facts about Theodore Roosevelt?

Teddy Roosevelt was a larger-than-life character in the history of the United States. It can be said that Teddy liked being viewed in this manner. Teddy had a rather large ego and pretty much did what he wanted without regard to the consequences. He believed in American supremacy and was an advocate of American imperialism. A prime example of all of these qualities is his handling of the Panama Canal. When Colombia would not give the United States favorable terms to build a canal in their territory, Roosevelt instigated Panama do break free from Colombia. He did this without being honest to the American people about the situation.

He most likely acted in this way towards Colombia because he felt they were inferior to the Americans. Roosevelt had the attitude that white Europeans were a superior race to nonwhites. He demonstrated this feeling throughout his political career. He worked to exclude Chinese as immigrants and limit Japanese immigration. Roosevelt also railed against integration of other groups into American culture, especially Native Americans.

It can also be stated that Teddy Roosevelt was a war hawk. The Roosevelt Corollary to the Monroe Doctrine increased the likelihood of American intervention in conflicts in Latin America. He was also an agitator in American intervention in Cuba that led to two American wars: the Spanish-American War and the Philippine-American War. Roosevelt believed that America was so great that it deserved an empire. Involvement in these conflicts cost thousands of American lives.

What is fatal familial insomnia?

Definition

Fatal familial insomnia (FFI) is a rare, genetic prion disease transmitted as an autosomal dominant
trait. The responsible mutation causes prions (proteins found extensively in
the body) to assume abnormal shapes and thereby become pathogenic. A nongenetic
form of the disease, sporadic fatal insomnia, also exists.

Causes

The cause of FFI has been identified as a mutation at codon 178 of the prion-protein gene (PRNP) on chromosome 20. Disease characteristics, such as duration, are determined by a polymorphism at codon 129 of the PRNP gene.

Risk Factors

Each offspring of an affected parent has a 50 percent risk of inheriting the mutant gene, which is highly penetrant; as far as is known, those persons who inherit the gene will express the disease. Sporadic cases have no known risk factors.

Symptoms

Insomnia is the hallmark of this disease, although it is not
invariably present in the earliest stages. Symptoms are best understood in the
context of the histopathology of FFI, primarily involving degeneration and loss of
neurons in the thalamus. The thalamus has a crucial integrative function in the
brain, relaying all manner of sensory information to the cerebral cortex. A role
for the thalamus in regulating autonomic functions and key circadian
rhythms is consistent with prominent FFI symptoms.
Twenty-four-hour circadian patterns comprise not only the sleep-wake cycle but
also the normal ebb and flow of hormone secretions.

Other symptoms include severely impaired motor functions, uncoordinated and jerky muscle movements, and difficulty in speaking and swallowing. The autonomic dysregulation also manifests as fever and sweating. Affected persons are often described as inattentive, restless, and unable to concentrate. Cognition may also be affected.

Secretion of adrenocortical hormones is increased. These hormones are involved in the body’s stress reaction, and those affected experience chronic stress. The insomnia that characterizes this disease is progressive and untreatable, leading to the ultimate absence of any sleep patterns or responses.

The first reported case, in 1986, was that of a fifty-three-year-old man. The onset of FFI is most often in middle to late adulthood, although it has been reported in some patients in their early twenties. The duration of the disease, from less than one year to several years, largely depends on genetic factors.

Screening and Diagnosis

Neither careful clinical examination nor standard tests of sleep responses can
identify carriers of the FFI mutation before symptoms become
apparent. Findings of routine laboratory tests are generally normal.
Positron
emission tomography, however, which can measure the brain’s
consumption of glucose, has shown thalamic changes in an asymptomatic gene
carrier. Postmortem examination confirms the diagnosis.

Treatment and Therapy

Palliative
treatment has been the only reported treatment. Attempts to
alter the disease course with medications have been unsuccessful. Fatal familial
insomnia is considered untreatable.

Prevention and Outcomes

There is no known way to prevent the disease in a carrier. Prenatal diagnosis is theoretically possible.

Bibliography

Bosque, Patrick J., and Kenneth L. Tyler. “Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases).” In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Gerald L. Mandell, John F. Bennett, and Raphael Dolin. 7th ed. New York: Churchill Livingstone/Elsevier, 2010.

Brown, David R., ed. Neurodegeneration and Prion Disease. New York: Springer, 2005.

Max, Daniel T. The Family That Couldn’t Sleep: A Medical Mystery. New York: Random House, 2007.

_______. “The Secrets of Sleep.” National Geographic, May, 2010, pp. 74-93.

Prusiner, Stanley B. “The Prion Diseases.” Scientific American 272, no. 1 (January, 1995): 48-57.

_______, ed. Prion Biology and Diseases. 2d ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2004.

Rowland, Lewis P., and Timothy A. Pedley, eds. Merritt’s Textbook of Neurology. 12th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

What is Mr. Collins's view on his position in society in Pride and Prejudice?

Mr. Collins seems to believe that, with Lady Catherine de Bourgh as his patroness, his position in society is somewhat higher than it actually is.  Though he has some education, he is a silly man whose ridiculousness is readily apparent to almost everyone with whom he comes in contact.  The narrator says, "the respect which he felt for [Lady Catherine's] high rank, and his veneration for her as his patroness, mingling with a very good opinion of himself, of his authority as a clergyman, and his right as a rector, made him altogether a mixture of pride and obsequiousness, self-importance and humility."  He feels quite elevated in society by his association with Lady Catherine as well as his own occupational authority and position within her estate, and so while he is humble -- at least in regard to her eminence -- Mr. Collins is also quite proud. 

His opinion of his position in society is perhaps best demonstrated by his impromptu (and socially inappropriate) conversation with Mr. Darcy at the Netherfield ball; without having been introduced, he simply approaches Lady Catherine's nephew because he feels that his position exempts him from the social rules that govern such interactions.  He addresses a man who is his social superior as though he were an equal, and this gives us a good clue that Mr. Collins's perspective on himself and his relative social position differs from others.

What is conception?

Process and Effects

The process of conception begins with the act of intercourse. When the male’s penis is inserted into the female’s vagina, the stimulation of the penis by movement within the vagina triggers a reflex resulting in the ejaculation of sperm. During ejaculation, involuntary muscles in many of the male reproductive organs contract, causing semen, a mixture of sperm and fluid, to move from its sites of storage out through the urethra within the penis.

The average volume of semen in a typical human ejaculation is only 3.5 milliliters, but this small volume normally contains two hundred million to four hundred million sperm. Other constituents of semen include prostaglandins, which cause contractions of involuntary muscles in both the male and the female; the sugar fructose, which provides energy to the sperm; chemicals that adjust the activity of the semen; and a number of enzymes and other chemicals.

In a typical act of intercourse, the semen is deposited high up in the woman’s vagina. Within a minute after ejaculation, the semen begins to coagulate, or form a clot, because of the activation of chemicals within the semen. Sperm are not able to leave the vagina until the semen becomes liquid again, which occurs spontaneously fifteen to twenty minutes after ejaculation.

Once the semen liquefies, sperm begin moving through the female system. The path to the ovum (if one is present) lies through the cervix, then through the hollow cavity of the uterus, and up through the oviduct, where fertilization normally occurs. The sperm are propelled through the fluid within these organs by the swimming movements of their tails called flagella, as well as by female organ contractions that are stimulated by the act of intercourse and by prostaglandins contained in the semen. The contractions allow sperm to reach the oviduct within five minutes after leaving the vagina, a rate of movement that far exceeds their own swimming abilities.

Although some sperm can reach the oviduct quite rapidly, others never enter the oviduct at all. Of the two hundred million to four hundred million sperm deposited in the vagina, it is estimated that only one hundred to one thousand enter the oviducts. Some of the other millions of sperm may be defective, lacking the proper swimming ability. Other apparently normal sperm may become lost within the female’s organs, possibly trapped in clefts between cells in the organ linings. The damaged and lost sperm will eventually be destroyed by white blood cells produced by the female.

Sperm movement through the female system is enhanced around the time of ovulation. For example, at the time of ovulation, the hormones associated with ovulation cause changes in the cervical mucus that aid sperm transport. The mucus at that time is extremely liquid and contains fibers that align themselves into channels, which are thought to be used by the sperm to ease their passage through the cervix. The hormones present at the time of ovulation also increase the contractions produced by the uterus and oviduct, and thus sperm transport through the structures is enhanced as well.

During transport through the female system, sperm undergo a number of important chemical changes, collectively called capacitation, that enable them to fertilize the ovum successfully. Freshly ejaculated sperm are not capable of penetrating the layers surrounding the ovum, a fact that was uncovered when scientists first began to experiment with in vitro fertilization (the joining of sperm and ovum outside the body). Capacitation apparently occurs during transport of the sperm through the uterus and possibly the oviduct, and it is presumably triggered by some secretion of the female reproductive system. With in vitro fertilization, capacitation is achieved by adding female blood serum to the dish that contains the sperm and ovum. Capacitation is not instantaneous; it has been estimated that this process requires an hour or more in humans. Even though the first sperm may arrive in the vicinity of the ovum within twenty minutes after ejaculation, fertilization cannot take place
until capacitation is completed. In 2003, scientists discovered that sperm has a type of chemical sensor that causes the sperm to swim vigorously toward concentrations of a chemical attractant. While researchers long have known that chemical signals are an important component of conception, the 2003 findings were the first to demonstrate that sperm will respond in a predictable and controllable way, a fact promising for future contraception and fertility research.

The site where ovum and sperm typically come together is within the oviduct. At the time of ovulation, an ovum is released from the surface of the ovary and drawn into the upper end of the oviduct. Once within the oviduct, the ovum is propelled by contractions of the oviduct and possibly by wavelike motions of cilia, hairlike projections that line the inner surface of the oviduct. It takes about three days for the ovum to travel the entire length of the oviduct to the uterus, and since the ovum only remains fertilizable for twelve to twenty-four hours, successful fertilization must occur in the oviduct.

Upon reaching the ovum, the sperm must first penetrate two layers surrounding it. The outermost layer, called the corona radiata, consists of cells that break away from the ovary with the ovum during ovulation; the innermost layer, the zona pellucida, is a clear, jellylike substance that lies just outside the ovum cell membrane. Penetration of these two layers is accomplished by the release of enzymes carried by the sperm. Once through the zona pellucida, the sperm are ready to fertilize the ovum.

Fertilization occurs when a sperm fuses its membrane with the membrane of the ovum. This act triggers a protective change in the zona pellucida that prevents any additional sperm from reaching the ovum and providing it with extra chromosomes. Following fusion of the fertilizing sperm and ovum, the chromosomes of each become mingled and pair up; the resulting one-celled zygote contains a complete set of chromosomes, half contributed by the mother and half by the father.

It is at the moment of fertilization that the sex of the new child is decided. Genetic sex is determined by a pair of chromosomes denoted X and Y. Female body cells contain two Xs, and each ovum produced contains only one X. Male body cells contain an X and a Y chromosome, but each sperm contains either an X or a Y chromosome. Men usually produce equal numbers of X- and Y-type sperm. The sex of the new individual is determined by which type of sperm fertilizes the ovum: If it is a Y-bearing sperm, the new individual will be male, and if it is an X-bearing sperm, the new individual will be female. Since entry of more than one sperm is prohibited, the first sperm to reach the ovum is the one that will fertilize it.

Following fertilization, the zygote or early embryo begins a series of cell divisions while it travels down the oviduct. When it arrives at the uterus about three days after ovulation, the zygote will be in the form of a hollow ball of cells called a blastocyte. Initially, this ball of cells floats in the fluid-filled cavity of the uterus, but two or three days after its arrival in the uterus (five to six days after ovulation), it will attach to the uterine lining. In 2003, researchers made an exciting discovery when they identified how embryos stop and burrow into the lining of a woman’s uterus. A protein, called L-selectin, on the surface of the embryo acts like a puzzle piece when it touches and quickly locks into carbohydrate molecules found on the uterine surface. This implantation process must occur in exact synchrony during a very short time in a woman’s cycle. (If it occurs outside the uterus, usually in one of the Fallopian tubes, then the result is an ectopic pregnancy, which is often a medical emergency.) In the weeks following conception, the cells of the zygote will form the fetus and the placenta, which surrounds and provides nutrients to the fetus. Over the next nine months, the fetus will increasingly take on a human form, developing muscle tissue, bone, organs, and skin. Pregnancy typically lasts for forty weeks from conception until childbirth. .

Complications and Disorders

Three factors limit the time frame in which conception is possible: the fertilizable lifetime of the ovulated ovum, estimated to be between twelve and twenty-four hours; the fertilizable lifetime of ejaculated sperm in the female tract, usually assumed to be about forty-eight hours; and the time required for sperm capacitation, which is one hour or more. The combination of these factors determines the length of the fertile period, the time during which intercourse must occur if conception is to be achieved. Taking the three factors into account, the fertile period is said to extend from forty-eight hours prior to ovulation until perhaps twenty-four hours after ovulation. For example, if intercourse occurs forty-eight hours before ovulation, the sperm will be capacitated in the first few hours and will still be within their fertilizable lifetime when ovulation occurs. On the other hand, if intercourse occurs twenty-four hours after ovulation, the sperm will still require time for capacitation, but the ovum will be near the end of its viable period. Thus the later limit of the fertile period is equal to the fertilizable lifetime of the ovum, minus the time required for capacitation.

Obviously, a critical factor in conception is the timing of ovulation. In a typical twenty-eight-day menstrual cycle, ovulation occurs about halfway through the cycle, or fourteen days after the first day of menstrual bleeding. In actuality, cycle length varies widely from month to month. It appears that generally the first half of the cycle is more variable in length, with the second half more stable. Thus, no matter how long the entire menstrual cycle is, ovulation usually occurs fourteen days prior to the first day of the next episode of menstrual bleeding. Therefore, it is relatively easy to determine when ovulation occurred by counting backward, but difficult to predict the time of ovulation in advance.

Assessment of ovulation time in women is notoriously difficult. There is no easily observable outward sign of ovulation. Some women do detect slight abdominal pain about the time of ovulation; this is referred to as Mittelschmerz, which means, literally, pain in the middle of the cycle. This slight pain may be localized on either side of the abdomen and is thought to be caused by irritation of the abdominal organs by fluid released from the ovary during ovulation. Other signs of ovulation are an increased volume of the cervical mucus and flexibility of the cervix and a characteristic fernlike pattern of the mucus when it is dried on a glass slide. There is also a slight rise in body temperature after ovulation, which again makes it easier to determine the time of ovulation after the fact rather than in advance. It is also possible to measure the amount of luteinizing hormone (LH) in urine or blood; this hormone shows a marked increase about sixteen hours prior to ovulation. Home test kits to detect LH levels are available for urine samples. There are additional signs of the time of ovulation, such as a slight opening of the cervix and a change in the cells lining the vagina, that can be used by physicians to determine the timing and occurrence of ovulation.

Since ovulation time is so difficult to detect in most women on an ongoing basis, most physicians would counsel that, to achieve a pregnancy, couples should plan on having
intercourse every two days. This frequency will ensure that sperm capable of fertilization are always present, so that the exact time of ovulation becomes unimportant. A greater frequency of intercourse is not advised, since sperm numbers are reduced when ejaculation occurs often. Approximately 85 to 90 percent of couples will achieve pregnancy within a year when intercourse occurs about three times a week.

Couples often wonder if it is possible to predetermine the sex of their child by some action taken in conjunction with intercourse. Scientists have found no consistent effect of diet, position assumed during intercourse, timing of intercourse within the menstrual cycle, or liquids that are introduced into the vagina to kill one type of sperm selectively. In the laboratory, it is possible to achieve partial separation of sperm in a semen sample by subjecting the semen to an electric current or other procedure due to the physical difference of X- and Y-containing sperm. The separated sperm can then be used for artificial insemination (the introduction of semen through a tube into the uterus). This method is not 100 percent successful in producing offspring of the desired sex and so is available only on an experimental basis.

Some couples have difficulty in conceiving a child, in a few cases as a result of some problem associated with intercourse. For example, the male may have difficulty in achieving erection or ejaculation. The vast majority of these cases are caused by psychological factors such as stress and tension rather than any physiological problem. Fortunately, therapists can teach couples how to overcome these psychological problems.

About 10 to 15 percent of couples suffer from some type of biological infertility—that is, infertility that persists for more than one year when intercourse occurs successfully. In about 10 to 20 percent of the cases of infertility, doctors are unable to establish a cause. About one-third of infertility cases are caused by the female partner's problems, while another one-third of infertility cases are caused by the male partner's problems. The remaining cases of infertility are caused by both male and female problems or are unexplained..

In men, the most commonly diagnosed cause of infertility is low sperm count. Sometimes low sperm count is caused by a treatable imbalance of hormones. If not treatable, this problem can sometimes be circumvented by the use of pooled semen samples in artificial insemination or through in vitro fertilization. In vitro fertilization may also be a solution for men who produce normal numbers of sperm but whose sperm lack swimming ability. Another cause of male infertility is blockage of the tubes that carry the semen from the body, which may be caused by a previous infection. Surgery is sometimes successful in removing such a blockage. Another problem, called varicocele, occurs when the veins on the testicle are too large or do not properly circulate blood. This causes the testicles to overheat, which may affect the number or the viability of the sperm. Varicocelectomy, the surgical correction of this problem, may be performed on an outpatient basis.

In women, a common cause of infertility is a hormonal problem that interferes with ovulation. Polycystic ovarian syndrome (PCOS) is a hormone imbalance that affects normal ovulation and is the most common cause of female infertility. Women with PCOS typically have high levels of androgens and many ovarian cysts. Treatment with one of a number of so-called fertility drugs may be successful in promoting ovulation. Clomiphene, a selective estrogen receptor modulator (SERM), is the most commonly prescribed fertility medication. Fertility drugs, however, have some disadvantages: They have a tendency to cause ovulation of more than one ovum, thus raising the possibility of multiple pregnancy, which is considered risky; and they may alter the environment of the uterus, making implantation of a resulting embryo less likely. Therefore, other causes of infertility, both male and female, should be ruled out before fertility drugs are used.

Another common cause of female infertility is blockage of the oviducts or the fallopian tubes resulting from scar tissue formation in the aftermath of some type of infection or prior surgery. Because surgery is not always successful, this condition may require the use of in vitro fertilization or the new technique of surgically introducing ova and sperm directly into the oviduct at a point below the blockage. Another cause of female infertility is an abnormally shaped uterus, which may interfere with the fertilized egg's ability to attach to the uterine wall. Uterine fibroids, noncancerous growths in the uterus, are very common among women and most often cause no symptoms; however, in certain cases, uterine fibroids can make it difficult for the fertilized egg to attach to the uterine wall. Surgery may be performed to shrink or remove the fibroids.

Finally, some cases of infertility result from biological incompatibility between the man and the woman. It may be that the sperm are unable to penetrate the cervical mucus, or perhaps that the woman’s immune system treats the sperm cells as foreign, destroying them before they can reach the ovum. Techniques such as artificial insemination and in vitro fertilization offer hope for couples experiencing these problems.

Perspective and Prospects

For most of history, the events surrounding conception were poorly understood. For example, microscopic identification of sperm did not occur until 1677, and the ovum was not identified until 1827 (although the follicle in which the ovum develops was recognized in the seventeenth century). Prior to these discoveries, people held the belief espoused by early writers such as Aristotle and Galen that conception resulted from the mixing of male and female fluids during intercourse.

There was also confusion about the timing of the fertile period. Some early doctors thought that menstrual blood was involved in conception and therefore believed that the fertile period coincided with menstruation. Others recognized that menstrual bleeding was a sign that pregnancy had not occurred; they assumed that the most likely time for conception to result was immediately after the menstrual flow ceased. It was not until the 1930s that the first scientific studies on the timing of ovulation were completed.

Since there was little scientific understanding of the processes involved in conception, medical practice for most of human history was little different from magic, revolving around the use of rituals and herbal treatments to aid or prevent conception. Gradually, people rejected these practices, often because of religious teachings. By the twentieth century, conception had been established as an area of intense privacy, thought by physicians and the general public to be unsuitable for medical intervention.

In the early part of the twentieth century, the role of physicians in aiding conception was mostly limited to educating and advising couples finding difficulty in conceiving. There were few techniques, other than artificial insemination and fertility drug treatment, available to assist in conception at that time.

The situation changed with the first successful in vitro fertilization in 1978. This event ushered in an era of intense medical and public interest in assisting conception. Other methods to aid conception were soon introduced, including embryo transfer, frozen storage of embryos, and surgical placement of ova and sperm directly into the oviduct.

Paralleling the development of these techniques has been demand on the part of society for medicine to apply them. In most developed countries, infertility rates have been gradually increasing. One reason for increased infertility has been the increasing age at which couples decide to start a family, since the fertility of women appears to undergo a decline past the age of thirty-five. Another factor affecting fertility rates of both men and women has been an increased incidence of various sexually transmitted diseases, which can result in chronic inflammation of the reproductive organs and infertility caused by scar tissue formation.

People’s attitudes toward medical intervention in conception have also changed. The earlier taboos against interference in conception have been somewhat relaxed, although some individuals still do not approve of certain methods of fertility management. Although there remain ethical issues to be resolved, the general public seems to have accepted the idea that medicine should provide assistance to those who wish to, but cannot, conceive children.

Bibliography

Doherty, C. Maud, and Melanie M. Clark. Fertility Handbook: A Guide to Getting Pregnant. Omaha, Nebr.: Addicus Books, 2002.

Harkness, Carla. The Infertility Book: A Comprehensive Medical and Emotional Guide. Rev 2d ed. Berkeley, Calif.: Celestial Arts, 1992.

"Infertility." Medline Plus, February 26, 2012.

"Infertility Fact Sheet." US Department of Health and Human Services—Office on Women's Health, July 16, 2012.

"In Vitro Fertilization (IVF)." Medline Plus, February 26, 2012.

Jones, Richard E., and Kristin H. Lopez. Human Reproductive Biology. 4th ed. Burlington, Mass.: Academic Press/Elsevier, 2013.

Kearney, Brian. High-Tech Conception: A Comprehensive Handbook for Consumers. New York: Bantam Books, 1998.

"Pregnancy: Condition Information." Eunice Kennedy Shriver National Institute of Child Health and Human Development, April 3, 2013.

Weschler, Toni. Taking Charge of Your Fertility. Rev. ed. New York: Collins, 2006.

Wisot, Arthur L., and David R. Meldrum. Conceptions and Misconceptions: The Informed Consumer’s Guide Through the Maze of In Vitro Fertilization and Other Assisted Reproduction Techniques. 2d ed. Point Roberts, Wash.: Hartley & Marks, 2004.

What are some different character perspectives from Great Expectations, and how would this change the novel?

In the character perspective of Joe Gargery, the story would be of the loss of a beloved family member through poor judgment and wrong choices. Joe sees Pip go down a path that can lead only to heartache, trying to live a lifestyle where he will never fit in. In that society, a gentleman is born, not made. Pip, no matter how much money he has, will always be shut out of the society of such people as Estella and Miss Havisham.

In the perspective of Abel Magwitch, the story would be a parallel of Pip and Magwitch each recreating themselves, Pip in London and Magwitch in New South Wales. Magwitch’s transformation would unfold more than it does in the present story, where we could see how much of his moral character changes. He would see himself through Pip with distant eyes, receiving only infrequent reports of his success in aiding the child who did not turn in him to the law.

From Estella’s perspective, the story would follow a young girl being trained to be a “man-killer” and the successes she gains through her treatment of Pip. It would also follow her downfall, as she marries an abusive husband. Her regret would be an integral part of the end of the story, as she and Pip meet again.

Why is Dave running late returning home from school?

While he was at school on a field trip, Dave and five of his friends chased a lizard up a cherry tree. Under the strain of their collective weight, the cherry tree split and was ruined. The tree belonged to a Mr. Crabtree and he had been plowing at the time and caught them in the act of destroying the tree. Mr. Crabtree decided to make each boy pay one dollar to cover the cost of the tree. Dave doesn't have a dollar, so Professor Herbert says he must stay after school two hours on two consecutive days. At twenty-five cents an hour, he will then be paid up. Dave has farm work to do at home. He knows his father will be mad with him for being late. He even fears that he will be whipped for being late. He explains to Professor Herbert that his father is a bit old fashioned in this way: 

"You don't know my father," I says to Professor Herbert. "He might be called a little old-fashioned. He makes us mind him until we're twenty-one years old. He believes: 'If you spare the rod you spoil the child.' I'll never be able to make him understand about the cherry tree. I'm the first of my people to go to high school." 

So, Dave hurries home because the later he is, the angrier his father will be. Having stayed two hours after school, he is late and his father is angry. This instigates the confrontation between his father and Professor Herbert the following day. 

What is in the briefcase that the man gives to Winston, and why is this item of special importance?

In Part Two, Chapter Eight, O'Brien arranges to give Winston a briefcase:

At some time during the day, in the street, a man will touch you on the arm and say “I think you have dropped your brief-case.” The one he gives you will contain a copy of Goldstein’s book. You will return it within fourteen days.

As arranged, Winston receives the briefcase the day before Hate Week begins but is so busy that he is unable to open it immediately and look at its contents.

The significance of this briefcase cannot be overstated. Inside, it contains a copy of "the book," penned by Goldstein, an enemy of the party. This book contains the truth about the party's hold on the people of Oceania and explains how they use war as a means of manipulating and controlling the people. 

Receiving the briefcase, then, is symbolic of Winston's open state of rebellion. He has outed himself to O'Brien and voiced his anti-party sentiments. Receiving the briefcase is representative of his commitment to the resistance movement and his desire to overthrow Big Brother and create a new society.

In an ironic twist, however, it is later revealed that this was all a ruse. O'Brien is, in fact, a senior member of the Thought Police who has used the briefcase to detect Winston's thoughtcrime. So, while the briefcase came to symbolise Winston's freedom from the party's control, it now becomes the symbol of his downfall. In Part Two, Chapter Ten, the briefcase and the book lead directly to his arrest and his torture at the hands of O'Brien. 

What is bonding?

Physical and Psychological Factors

Bonding is usually associated with neonates (newborns), but it is an ongoing relationship that occurs between infants, toddlers, or children and their caretakers.

After the initial cry, the neonate calms down and uses its first touch with the mother to relax. This experience may occur in a brightly lit hospital room with medical attendants or in a semidark birthing room at home with nurses or midwives attending. Usually, the infant is placed on the mother’s abdomen for contact to begin. The initial moments of connection may include the parents touching, rubbing, and stroking the baby’s cheeks, fingers, toes, abdomen, and back. Research reports that even in these early moments, an infant may engage in limited imitations of the parents by moving the head, opening and closing the mouth, and responding to their facial gestures.

These first touches begin the relationship that may initiate a successful bonding attachment with the primary caregivers and the extended family. Some circumstances, however, may start a process that does not lead to successful attachment. The process of bonding between a newborn and caregivers is an essential part of normal development. The care that the infant receives at this point, as well as through the subsequent early stages of life, is vital to his or her healthy development. Some infants, however, may need ancillary medical care that removes the child from the mother’s touch and postpones connecting immediately after birth.

As the infant begins to grow, the early stages of development should be supported, sharpened, and enhanced during the continuing developmental and bonding process. Babies actively seek stimulation, and the first week of life involves hearing, seeing, smelling, and touching. Distinguishing sounds is a learning process. Soft noises, lullabies, and soft music are soothing. Basic visual powers exist that are important for communication and learning. Infants are sensitive to the intensity of light. They can discriminate shapes and patterns. Feeding involves smelling food, distinguishing tastes, and becoming aware of the presence of the mother or primary caregiver. The infant can feel changes in temperature and respond to skin contact and touch.

While bonding tends to be associated with the mother-infant relationship, the attachment and bonding process also includes the relationship with the other parent, siblings, and other relatives who come into frequent contact with the developing baby. The interaction within this social network creates a variety of relationships and opportunities for positive and responsive stimulation, support, and encouragement. Connections with grandparents, aunts, uncles, and cousins can provide strong supportive bonds that help infants thrive. The strength of these relationships can make up for limitations with the primary caregivers.

Disorders and Effects

The relationship between some caregivers and infants may encounter serious problems as they try to establish attachment. Bonding disorders such as failure to thrive
can occur with infants who are abused or neglected. One of the major reasons that babies in institutions do not do well is the infrequent handling and touching that they receive.

Infants exhibiting failure to thrive show a variety of symptoms. They are usually quite small. They appear ill, listless, and immobile and may be unable to digest food. Other symptoms of failure to thrive include low birth weight, eye contact avoidance, and evidence of delayed development. Improvements can occur with appropriate feeding and care. Failure to thrive may also occur due to purely physical causes, such as congenital genetic disorders. Such disorders are generally not reversible, unless the specific defect can be corrected medically.

If a mother had early developmental experiences of abuse and neglect, these experiences may appear as obstacles to the development of her own infant. The mother of a failure-to-thrive infant may be using drugs or alcohol. She may be depressed, physically or mentally ill, or unable to cope well enough to provide a positive bonding experience for her child. She may have recently been involved in a significant crisis that was emotionally draining.

Significant variables may precede the attachment phase, or environmental forces may impede the infant’s maternal attachment as the bonding process proceeds. If the infant does not have a positive experience with the mother during the first months of life, developmental problems may begin. When the mother or infant must remain in a hospital for a prolonged period of time, the mother may be unavailable; nurturing can be delayed or occur only for short periods. A mother may be psychologically unable to be close to her infant because of other young children or her own psychological problems or disorders. Some mothers experience postpartum depression as a result of hormonal imbalances and overwhelming demands. Economic and social circumstances may also impede the bonding process.

Establishing warm, comforting relationships through interactions between babies, parents, caregivers, and other family members in the earliest weeks is critical to forming secure attachments and developing successful bonding.

Bibliography

A.D.A.M. Medical Encyclopedia. "Infant—Newborn Development." MedlinePlus, January 17, 2011.

Caplan, Theresa. The First Twelve Months of Life: Your Baby’s Growth Month by Month. New York: Bantam, 1995.

Cohen, Lawrence. Playful Parenting. New York: Random House, 2002.

Craig, Grace J., Marguerite D. Kermis, and Nancy Digdon. Children Today. 2d ed. Toronto, Ont.: Prentice Hall, 2002.

Kids Health. "Bonding with Your Baby." Nemours Foundation, January 2012.

Leach, Penelope. Your Baby and Child: From Birth to Age Five. London: Dorling Kindersley, 2003.

MedlinePlus. "Infant and Newborn Care." MedlinePlus, June 17, 2013.

Mercer, Jean. Understanding Attachment: Parenting, Child Care, and Emotional Development. Westport, Conn.: Praeger, 2006.

Parker, DeAnsin Goodson, and Karen W. Bressler. Yoga Baby: Exercises to Help You Bond with Your Baby, Physically, Emotionally, and Spiritually. New York: Broadway Books, 2000.

Sears, William, and Martha Sears. The Attachment Parenting Book: A Commonsense Guide to Understanding and Nurturing Your Baby. New York: Little, Brown, 2001.

What is cancer biology?

Characteristics of human cancers: Mutations that are present in the germ cells (egg and sperm) can be passed to the next generation. Mutations that occur in any other cells of the body, called somatic mutations, may affect the cell or tissue in which they occur, but they will not be passed to the next generation. Both germ-line and somatic mutations can cause cancer; it is estimated that approximately 10 percent of cancers are caused by germ-line, or inherited, mutations.

Tumors can be either benign (those that remain localized and noninvasive), malignant (those that invade the basement membrane and underlying tissue), or metastatic (those that shed cells that seed tumors in other locations of the body). Progressive degrees of abnormality are observed in benign, malignant, and metastatic tumors, suggesting that cancer develops in a stepwise process.

Cancers can arise in almost all tissue types in the body, although approximately 80 to 85 percent of human cancers arise from epithelial cells those cells that cover internal and external surfaces of the body, including the linings of internal organs and glands.

The incidence of many types of cancer varies worldwide, and epidemiologic studies show that environment is the largest factor in variations in cancer incidence from country to country. Indeed, a number of environment and lifestyle elements, tobacco smoking being the most obvious, are known to be strongly correlated with the incidence of certain types of cancer. In 1975, it was shown that many chemicals that are capable of causing mutations in deoxyribonucleic acid (DNA) are also capable of causing cancer in laboratory animals. Later research showed, however, that not all chemicals that cause cancer also cause mutations. Therefore, other mechanisms besides DNA mutation must be involved in at least some cancers.

Gene expression and signaling pathways: For the cells of an organism’s various tissues (lung and bone, for example) to display complex, tissue-specific characteristics, large groups of genes must be coordinately expressed while other genes must be repressed. Specialized proteins known as transcription factors are responsible for achieving this coordinated expression. Transcription factors bind to specific DNA sequences in the control region of each gene. The transcription of most genes is controlled by the binding of several distinct transcription factors in the gene’s control region. A single transcription factor can affect the expression of multiple genes that contain its binding sequence in their control regions. In cancer cells, a defective transcription factor may affect the expression of multiple genes, the end result of which is to create a cancer cell from a normal cell.

Normal cells within tissues and within an organism communicate with each other in a regulated fashion through a multitude of chemical signals and pathways. Disruption of these normal signaling pathways is an important component of the formation of cancer. In normal cells, signals are transmitted through the various pathways in a number of ways: by a change in the level of activity of signaling molecules by noncovalent modifications, changes in the concentration of a signaling molecule inside a cell, or the direction of signaling molecules to particular locations within the cell.

Oncogenes: Normal cells contain a class of genes involved in the regulation of growth and division called proto-oncogenes. A proto-oncogene can mutate into a version that is permanently activated and causes uncontrolled cell division, one of the hallmarks of a cancer cell. The transformation of a proto-oncogene into an oncogene may involve a change to the structure of the protein itself or an increase in its expression. A change involving the structure of the protein itself may require only very small changes; in some cases a single base pair mutation is sufficient. A change involving an increase in expression often occurs through increasing the number of copies of the gene in the DNA. There are several ways that amplification of a gene can occur: by enhanced replication of a chromosome segment that carries its DNA or by the breaking away of such a chromosome segment to form a small chromosome-like particle that is capable of replicating independently.

Scientists have identified more than one hundred oncogenes. They include growth factors, proteins that signal a cell to divide; growth factor receptors, proteins on the cell surface to which growth factors bind; signal transducers, proteins that make up the signaling pathways between the growth factor receptor and the cell nucleus; and transcription factors.

Tumor-suppressor genes: The class of tumor-suppressor genes includes a large number of genes whose protein products are involved in a multitude of normal cellular functions that in some way regulate a cell’s division and reduce the chance that the cell will become cancerous. Tumor-suppressor genes in cancer cells are often inactivated through mutation or other mechanisms. An inherited increased risk of developing a specific type of cancer in some families is often the result of the presence of a defective tumor-suppressor gene. It is the loss of function of tumor-suppressor genes that can lead to cancer, in contrast to oncogenes, which have gained functions or lost the ability to be controlled in their mutant form.

The protein product of a particularly important tumor-suppressor gene, called TP53, causes cessation of cell division and even programmed cell death (apoptosis) in normal cells if the process of cell division malfunctions. In this way the cell’s well-being is monitored, protecting the organism from the effects of runaway division of wayward cells by activating the apoptotic pathway in such cells. Apoptosis is an orderly process in which the DNA of a cell is degraded and the cell itself fragmented into smaller pieces that are taken up by nearby white blood cells whose job is to clean up such debris. Loss of the ability to undergo apoptosis allows cancer cells to survive a variety of environmental stresses and signaling imbalances. The TP53 gene in the DNA of cancer cells often carries mutations that cause it to malfunction; more than 90 percent of small-cell lung cancers and more than 50 percent of breast and colon cancers have been shown to be associated with mutant forms of TP53.

Normal cells throughout the body grow and divide to generate two daughter cells in a highly organized and controlled series of events called the cell cycle. A subclass of tumor-suppressor genes controls cell-cycle events in normal cells. Control mechanisms at various steps of the cell cycle function to ensure that a preceding step is completed before the next step can begin. These control mechanisms are inactivated in many types of cancer cells, allowing them to divide in an unregulated fashion. A particularly important tumor-suppressor gene in this class is the retinoblastoma (RB1) gene. The protein product for which the RB1 gene codes, pRb, is affected in most if not all types of human cancer cells. Loss of normal regulation of the signaling pathway of which pRb is a component leads to unrestrained cell proliferation.

Cell immortalization: The ability of a cell to divide indefinitely, called cell immortalization, appears to be a characteristic of all cancer cells. This ability has been shown to be related to the structures of the ends of chromosomes, called telomeres, which are composed of several thousand repeats of a six-base-pair sequence element. Every time a cell duplicates its DNA, the telomeres are shortened by fifty to one hundred base pairs, with the result that normal cellular DNA has the capacity for a finite number of replications. The ability to indefinitely maintain telomere length has been observed in virtually all types of cancer cells, the majority of which accomplish this by increasing the expression of the enzyme, telomerase, which is responsible for synthesizing telomeres.

Angiogenesis: All cells depend on the availability of oxygen and nutrients for their growth and survival. Virtually all cells in a tissue must be located close to a capillary blood vessel that can deliver nutrients and take away metabolic waste products. For a cancer cell to progress to a macroscopic tumor, it must acquire the ability to induce the formation of new blood vessels, a process called angiogenesis. In normal cells, various negative and positive signaling pathways control the angiogenic process. Cancer cells appear to induce angiogenesis in a number of steps that change the balance of angiogenesis inducers and inhibitors during tumor development.

Metastasis: Most types of human cancer will at some point undergo metastasis, the process whereby new tumors are seeded at distant sites from the primary tumor. Metastases are responsible for approximately 90 percent of all cancer deaths. Metastasis involves tumor cells leaving the primary tumor, invading adjacent tissues, and from there traveling to sites where they are able to settle and start the growth of new tumors. The primary route of metastasis is through the circulatory system, although metastatic cancer cells may also spread through lymph ducts to lymph nodes. Sometimes cancer cells traveling through the circulation form small obstructions that lodge in the arterioles and capillaries of various tissues. Complex interactions between the metastasizing cell and the microenvironment of the host tissue in which it lands govern the process of invasion into the tissue and colonization to form a metastasis in a process that is not well understood.

Cancer cells that metastasize do not appear to have undergone major changes in their DNA compared with other cells in the original tumor. However, cancer cells that possess metastatic potential have alterations in several classes of proteins involved in the attachment of cells to their surroundings in a tissue, which render them less able to form such attachments. Cancer cells with metastatic potential may also have an increased ability to degrade proteins in their immediate environment. Metastasizing cells from various types of cancers tend to spread preferentially to some organs; for instance, prostate and breast cancers have a strong tendency to metastasize to the bone marrow, and colon cancer has a strong tendency to metastasize to the liver. The reason for this phenomenon is not well understood.

Genomic instability: It has been estimated that multiple genetic changes, perhaps five to seven, are needed for the development of a full-fledged human cancer. A normal cell has numerous control and repair mechanisms that ensure the fidelity of DNA replication and, therefore, that the occurrence of mutations is rare. Malfunctioning of components of these control and repair mechanisms, such as TP53, leads to the observed chromosomal instability and variability of cancer cells. Genetic instability is pervasive in human cancer cells, which commonly exhibit various types of aberrantly structured chromosomes: the loss of entire chromosomes, the presence of extra copies of chromosomes, or the fusion of part of one chromosome with part of another. These chromosomal abnormalities disrupt normal DNA sequence and arrangement and probably help explain how precancerous cells acquire the necessary mutations to render them cancerous.

Hanahan, D., and R. A. Weinberg. “The Hallmarks of Cancer.” Cell 100 (2000): 57–70. Print.

Karp, Gerald. Cell and Molecular Biology. 7th ed. New York: Wiley, 2013. Print.

Pecorino, Lauren. Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics. 3rd ed. New York: Oxford UP, 2012.

Pelengaris, Stella, and Michael Khan. The Molecular Biology of Cancer: A Bridge from Bench to Bedside. 2nd ed. Chichester: Wiley, 2013. Digital file.

Saxe, Charles. “Unlocking the Mysteries of Metastasis.” American Cancer Society. American Cancer Society, 23 Jan. 2013. Web. 2 Oct. 2014.

Weinberg, Robert A. The Biology of Cancer. 2nd ed. New York: Garland Science, 2014. Print.

What did Mildred tell Montag when he asked if she had seen Clarisse?

In "Part 1: The Hearth and the Salamander," Montag is lying in bed next to his wife, and he tells Mildred that he hasn't seen their neighbor, Clarisse, in four days. Montag asks Mildred if she's seen Clarisse and Mildred tells him that she has not. Mildred mentions that she forgot to tell Montag something. Mildred then tells Montag that she thinks Clarisse's family is gone because Clarisse is dead. Montag is shocked and says that they couldn't possibly be talking about the same Clarisse. Mildred tells him Clarisse McClellan was ran over by a car four days ago, and she thinks Clarisse is dead. Mildred says she's pretty sure Clarisse died, but forgot to mention it to Montag. After telling her husband the startling news, Mildred casually puts her Seashell radio back into her ear and dozes off. Mildred's attitude towards Clarisse's death is apathetic and insentient.

In The Odd Couple, what is the set?

The Odd Couple takes place in three acts, all in the New York City apartment of Oscar Madison.  The play was written in the 1960's, but the message is somewhat universal, so that it could be (and often is) performed in a modern setting as well. 

In the opening scene, Oscar and some friends are in the apartment playing poker.  Oscar's apartment is terrifically messy, which is a running gag through the play (and even more so in the television series that followed).  It is a hot summer evening, which leads to the general crankiness by the men in the scene.  As the play begins, we learn that their friend Felix Unger has been missing since breaking up with his wife earlier that evening.  Felix eventually comes to the apartment and they talk about his broken relationship.  The poker game dissolves, and Oscar invites Felix to stay with him in the apartment.

In the next scene, some time has passed, and it is another poker game night in the same apartment.  However, this time the apartment is spotlessly clean, and we see the effect that Felix has had by staying in Oscar's apartment.  As the dialogue goes on, we also learn that, along with cleaning, Felix has been getting on Oscar's nerves and the friendship is becoming tense.

The final act of the play is, again, in the same apartment.  The tension between Oscar and Felix reaches its peak as Felix is continuously cleaning and driving Oscar mad.  We see ways that this has interfered with Oscar's dating life.  Eventually, the two agree that they cannot continue living together, and Felix leaves, but there is an indication that the friendship will continue.

The setting, though simple in the single apartment, contributes to the advancement of the story as we see changes in the cleanliness of the apartment, and we learn of the impact of Felix's cleaning, both on his marriage and on his friendship with Oscar.

In To Kill a Mockingbird, what does Jem do that shocks Dill and Scout in Chapter 14?

Scout stepped on something in the dark in her bedroom.  Thinking it was a snake, she went to Jem's room to get him.  Upon further inspection, they discovered that it was Dill, who had run away from home.  Scout, Jem, and Dill trusted one another.  Dill expressed his desire for them not to reveal his presence in the Finch house.  Jem, however, made a decision that shocked Scout and Dill.  He told Dill that they should let his mother know.  Then Jem decided to tell Atticus:

"Dill's eyes flickered at Jem, and Jem looked at the floor.  Then he rose and broke the remaining code of our childhood" (To Kill a Mockingbird, Chapter 14).

When Jem called for Atticus, he broke the trust that he had previously had with Dill and Scout.  They felt betrayed by him.  Atticus came into the room.  He made Dill feel welcomed, but did decide to tell his aunt.  After Atticus left, "Jem was standing in a corner of the room, looking like the traitor he was."

What is the y-intercept of `f(x)=4^x` ?

Hello!

By definition, the y-intercept of a function (or its graph) is the ordinate (y-coordinate) of a point where the graph intersects the y-axis.

For one-valued function g it is g(0), if g is defined at x=0. Our function f is one-valued and defined at 0, and `f(0)=4^0=1,` because anything except 0 at the degree 0 is 1.

Thus the answer is: the y-intercept of f(x) is 1.

That said, f has no x-intercepts because `4^x` always greater than zero.

What similarities can be found in the characters of Margaret Atwood's short story "Happy Endings" and O. Henry's short story "The Gift of the Magi"?

One similarity between the characters in Margaret Atwood's short story "Happy Endings" and the characters in O. Henry's short story "The Gift of the Magi" concerns the fact that they all value material possessions.

In version A of Atwood's short story, Mary and John are described as being in love, living in a "charming house," having "live-in help," going on "fun vacations," and having hobbies. Clearly, all of this happiness is a direct result of being able to afford the material possessions that can make them comfortable. Their continuing love for each other is directly proportional to their material possessions, since their comfort allows them to keep thinking well of each other and therefore keep loving each other.

Similarly, in O. Henry's short story, we see how much Della and Jim value material possessions. Unlike Mary and John, Della and Jim are currently a bit unhappy because times are financially hard; Jim's salary has just dropped from $30 a week to $20 a week, and since there are so many necessary expenses, they are unable to save any money for extra pleasures. Despite not having as much money as Mary and John in Atwood's story, it's clear just how much Della and Jim equate happiness and feeling love with material possessions. This is clear due to the fact that Della cries when she realizes she has only been able to save as much as a $1.87 to buy Jim's Christmas present. It's further clear due to the fact that both sell their only material possessions of value in order to get more material possessions to express their love for one another; Della sells her beautiful hair that Jim prizes, and Jim sells the gold watch he inherited from his grandfather that Della prizes in order to buy her combs for her hair.

However, Della and Jim are happy by the end of the story, despite being without the material possessions they once had. Their continued happiness is a direct result of their genuine love for each other and of their hope for a better future to come. Their hope in the future is expressed when Jim smiles and says, "Dell ... let's put our Christmas presents away and keep 'em a while. They're too nice to use just at present." Their happiness stands in stark contrast against the story of Mary and John, who most likely would not have remained happy without their material possessions.

In The Great Gatsby, chapter 9, what shocking piece of information does Nick Carraway receive during his chance meeting with Tom Buchanan? What is...

Nick had a chance meeting with Tom Buchanan in New York, on Fifth Avenue. Tom was the one who noticed him and came to shake Nick's hand but Nick refused the gesture. When Tom asked him if he was refusing to shake hands with him, Nick bluntly replied, "Yes. You know what I think of you." It is either that Tom was too idiotic to realize why Nick despised him or that he could not believe that someone could actually dislike him, for he could not understand, as he called it, 'what was wrong with' Nick.

At that point, Nick pertinently asked him what he had told Mr. Wilson the afternoon after Myrtle's accidental death when she was knocked down by Daisy whilst she was driving Jay Gatsby's car. Tom was dumbstruck and Nick knew he had guessed correctly - that Tom had informed Wilson that it was Jay who had knocked down his wife, killing her. As Nick walked away, Tom grabbed his arm and confessed to what Nick suspected:

“I told him the truth,” he said. “He came to the door while we were getting ready to leave, and when I sent down word that we weren’t in he tried to force his way up-stairs. He was crazy enough to kill me if I hadn’t told him who owned the car. His hand was on a revolver in his pocket every minute he was in the house ——”

What makes this revelation shocking is not only the fact that Tom acknowledged that he was indirectly responsible for Jay's death by implicating him, but also that firstly, Daisy seemed to have lied to him about who had been driving the car at the time and, secondly, that he assumed an attitude of righteous indignation for Nick's resentment, for he says:

“What if I did tell him? That fellow had it coming to him. He threw dust into your eyes just like he did in Daisy’s, but he was a tough one. He ran over Myrtle like you’d run over a dog and never even stopped his car.”

Nick then told him the truth. Tom further displays his lack of remorse and self-absorption by trying to glean some sympathy from Nick. He tells him:

 “And if you think I didn’t have my share of suffering — look here, when I went to give up that flat and saw that damn box of dog biscuits sitting there on the sideboard, I sat down and cried like a baby. By God it was awful ——”

Nick was unforgiving and felt that Tom believed that his actions were justified. He concluded that Tom and Daisy were careless people who made a mess and expected others to clean up after them so that they could return to the comfort of their wealth and their careless lives. Nick felt as if he was talking to a child, alluding to Tom's utter inability to even realize the wrongfulness of his actions. 

Nick's sentiments in this instance echo what he had previously told Jay about the Buchanan's and their sort:

“They’re a rotten crowd,” I shouted across the lawn. “You’re worth the whole damn bunch put together.”

It is a pity that our hopeful idealist never saw it that way and paid for his folly with his life.

How did Nelson Mandela overcome racism and rise to become an outstanding leader as described in Long Walk to Freedom?

Long Walk to Freedom is an autobiography of Nelson Mandela, the first black president of South Africa. It begins by describing his early life, in which as well as learning the traditional skills of a Xhosa warrior and cattle-herder, unusually for someone of his background, he went to school, and because he displayed talent for schoolwork, his uncle paid to send him to continue his education at boarding schools. His educational background enabled him to mediate between traditional South African black communities and white ones, as he was educated in both traditions. 

Mandela was gradually radicalized as a member of ANC’s Youth League and became involved in civil disobedience as the laws of apartheid became increasingly more restrictive and codified in 1948, and access to education for black people was restricted. Mandela participated in the Defiance Campaign in 1951, in which black people disobeyed apartheid laws by sitting in areas in public transportation reserved for whites, travelling without a permit, and walking in white-only areas.

After being acquitted on charges of treason for his protest activities, Mandela continued to be active in the protest movements. A defining moment for him was March 21, 1960. When the police killed nonviolent protesters in the Sharpeville township, Mandela realized that nonviolent protest was not succeeding. He became part of Umkhonto we Sizwe (Spear of the Nation), a group aimed at overthrowing the government of South Africa using such tactics as sabotage of infrastructure.

In 1961 Mandela was sent to Robben Island prison, where he continued to work against apartheid and began writing his autobiography. His steadfastness and eventual willingness to negotiate with Botha led to his becoming a hero to the South African people. 

What are the common properties in the Alkaline Earth Metals (group 2)?

Alkaline earth metals are located in group 2 of the periodic table of elements. The alkali earth metals include beryllium, magnesium, calcium, strontium, barium and radium. There are certain common properties in these elements. These are listed here:

• All the alkaline earth metals are metals.


• These elements have a fully filled s-shell. 


• These elements readily lose the 2 outermost electrons and form cations.


• The oxidation number of the cations formed by these elements is +2.


• These metals readily react with halogens (group 17 elements) to form halides, such as calcium chloride and magnesium chloride.


• All these elements are silver-white and are soft.


• All the alkaline earth metals occur naturally.


• They have relatively low boiling and melting points.


• All these elements have low electronegativities.


• All the alkaline earth metals have low affinity for electrons.

Hope this helps. 

Why does the clock have such a dramatic effect on the dancers in "The Masque of the Red Death"?

Time is an important theme in this story. The seven rooms symbolize the seven stages of life. Therefore, this one evening is construed in terms of a life span. As the guests move from room to room, and as the clock signals the passing hours, they move closer and closer to death.

The fact that the clock is "gigantic" illustrates how powerful and unstoppable time is. They cannot stop time and, therefore, they cannot prevent their own deaths. The clock is in the western room. Note the symbolism of the succession of rooms, from east to west, and the path of the sun rising in the east and setting in the west. This all emphasizes the passage of time. This allegorically parallels the life span and the notions of morning/birth and night/death.

When the clock signals the hour, the sound is: 

 . . . so peculiar a note and emphasis that, at each lapse of an hour, the musicians of the orchestra were constrained to pause, momentarily, in their performance, to harken to the sound; and thus the waltzers perforce ceased their evolutions; and there was a brief disconcert of the whole gay company . . . 

Each chiming of the hour interrupts the guests' good feelings. Each chime reminds them of time itself and that each hour, regardless of whether or not the plague might get to them, signals they are one step closer to their own deaths.

At midnight, the clock sounds twelve times. Once again, the music and the dancing stops while the clock sounds the hour. This gives the guests more time (twelve tones) to reflect upon the passage of time. This is the point. Each hour, there is one additional tone. So, each time the hour strikes and the music stops, the guests have increasingly more time to stop and ponder time, life, and death. Symbolically, it is at the twelfth hour that they have the time to notice the masked figure.

What were some of the subjects of F. Scott Fitzgerald's stories?

F. Scott Fitzgerald's works are often semi-autobiographical; he used his writing to express his own thoughts and feelings and to provide a commentary on the social life he had come to know. Fitzgerald was born to an upper-middle class family and had all the trappings of a well-to-do young man. He attended Catholic preparatory school and then Princeton University. Throughout his young life he was no stranger to the social atmosphere of high society, and his most famous novel, The Great Gatsby, deals with the decadence he perceived in the American almost-aristocracy.

Though his books have the grand themes of love and longing, youth and old age, he also included a number of subjects which would have been quite touchy at the time. Gatsby has details of prostitution, extramarital affairs, and racism. The Beautiful and Damned is an example of one of Fitzgerald's rather thinly-veiled and fictionalized accounts of his marriage and deals with the theme of addiction to alcohol. Tender is the Night, another semi-autobiographical account, tells of a psychoanalyst who falls in love with one of his patients. This story deals with both the hush-hush subject of mental illness and the ethics of loving someone who lives in an institution. 

Fitzgerald did not shy from difficult subject matter, and it made his characters and stories all the more real because they addressed issues society might have preferred not to discuss. 

What is synaptic transmission?

Introduction

Transmission refers to the transferring of signals from a source to a receiving end through or across a medium. Synaptic transmission specifically refers to the transferring of a signal from a neuron
(a nerve cell) across a space called the synaptic cleft to a target cell. The nerve impulse is generated in the cell body of the neuron and is related to the movement of sodium ions across the cell membrane of the axon (the axon is an extension of the neuron cell body). This impulse is known as an action potential. When the impulse reaches the axon terminal, this presynaptic signal either remains as an electrical signal or is converted to a chemical signal; either way, it is then transmitted through this space and exerts an influence on the target cell. The synapse contains three areas: the presynaptic terminal, the synaptic cleft, and the postsynaptic membrane.

Physical activity and behavior involve neuronal activities and the resulting contractions and relaxations of many muscles. The winking of an eye, for example, involves the control of contraction and relaxation of eyelid muscles. The axon terminals of the motor neurons must synapse with the eyelid muscles. A synapse between neuron and muscle cells is called a neuromuscular junction. The axon terminal releases a neurochemical that acts on the receptors embedded in the cell membrane of the postsynaptic muscle cells, resulting in muscle contraction. The synaptic area is a key to the control of neural effects; most chemicals that affect the nervous system vary physiological and behavioral responses at this site.

Electrical and Chemical Modes

Two distinct modes of synaptic transmission have been delineated, one electrical and the other chemical. At an electrical synapse, the presynaptic current spreads across the intercellular gap to the target cell. For this spreading to occur, a low-resistance pathway is required; this is achieved by a close apposition of cells with a gap of about 2 nanometers (1 nanometer is one-billionth of a meter). This type of coupling is called a gap junction. In electrical transmission, unlike chemical transmission, an impulse in the presynaptic terminal is transmitted to the postsynaptic terminal with little attenuation (lessening) and with no time delay. Electrical synapses are very common in the nervous systems of invertebrates, lower vertebrates, and embryonic animals.

At a chemical synapse, the gap is about 20 to 30 nanometers. The high resistance does not allow the presynaptic current to spread to the postsynaptic current. On arrival of impulses, a presynaptic terminal releases chemicals termed neurotransmitters. These molecules then diffuse through the cleft and interact with receptors, complex protein molecules embedded in the postsynaptic membrane. The neurotransmitter molecules are stored in vesicles. The wall of the vesicle becomes fused to the presynaptic membrane because of the influx of calcium ions on arrival of the impulse; this results in release of the molecules. The interaction between neurotransmitter and receptor results in certain electrical and chemical events in the target cell. In chemical transmission, the signals are attenuated, and the process takes more time than electrical transmission—about 0.3 millisecond, which is termed the synaptic delay. Neurotransmitters secreted by the presynaptic terminals include acetylcholine, dopamine, epinephrine, norepinephrine, serotonin, certain amino acids (gamma-aminobutyric acid, glutamate, glycine, aspartate), and many peptides.

Neurons come in various shapes and possess varying numbers of branches. Basically, however, each consists of the dendrites, the soma (cell body), and the axon. Synapses are classified in terms of the nature of the presynaptic terminal and the postsynaptic end. The presynaptic terminal is usually an axon; however, it has been found that dendrites may communicate with other dendrites directly at a synapse termed a dendrodendritic synapse. Three types of synapses between neurons are axodendritic, axosomatic, and axoaxonic. An axodendritic synapse couples an axon terminal to a dendrite of another neuron and usually produces a depolarization or excitatory postsynaptic potential. An axosomatic synapse couples an axon terminal to the soma of another neuron, and it may produce a hyperpolarization or inhibitory postsynaptic potential as well as an excitatory postsynaptic potential. An axoaxonic synapse couples an axon terminal to another axon terminal, which results in reduction of excitatory postsynaptic potential in the target neuron of the second neuron, so the net effect is inhibitory. When an axon terminal is coupled to a muscle cell or a glandular cell, the synapse is called a neuromuscular junction or a neuroeffector junction. The excitatory postsynaptic potential occurring in the muscle is called end-plate potential. When the sum of those potential changes reaches the threshold of firing, an action potential is generated, resulting in a propagating impulse or muscular contraction.

Studying the Nervous System

The release of a neurotransmitter substance, the binding of neurotransmitter molecules to receptors, and the termination of neurotransmitter activities are among the key considerations in understanding the regulation of the effects of the nervous system. The synthesis and storage (in vesicles) of these substances are also important. The magnitude and duration of many physiological and behavioral responses are jointly determined by various neuronal effects. Neuroactive drugs are crucial tools, and various ones manipulate different phases of transmission, synthesis, storage, release, binding, and termination of neurotransmitters. These drugs may be used to study the functions of various neurochemicals as well as to control synaptic transmission for therapeutic purposes.

Neuroactive drugs and chemicals are classified in terms of their facilitating or inhibitory effects. Agonists are those that enhance the effects of a neurotransmitter; antagonists inhibit the effects. For example, curare, a compound extracted from a vine by South American Indians for use as an arrow posion to paralyze animals, is an antagonist of the neurotransmitter acetylcholine at the neuromuscular junction. Curare interferes with synaptic transmission at this junction, resulting in muscle paralysis.

A lock-and-key analogy is often employed to explain how synaptic transmission works. The neurotransmitter molecule represents the key, and the receptor molecule represents the lock. Just as the correct key is needed to open the lock on a door, the appropriate chemical “key” is needed to start the effect. The molecular lock has the recognition site and the active site as well as the support structure, just as the door has the keyhole with specific notch configurations, as well as other parts. A neurotransmitter may be able to open several different locks, termed receptor subtypes, which are named for the chemical compounds specific to each subtype. (In this sense, a neurotransmitter is like a submaster key that will fit several doors, while a subtype-specific compound is the key for only one door.) The neurotransmitter acetylcholine, for example, acts on two receptor subtypes—nicotinic and muscarinic. The nicotinic receptor is so named because it reacts specifically to nicotine, a substance found in tobacco. This receptor subtype is found in the smooth and cardiac muscles; the muscarinic subtype, on the other hand, is abundant in the brain.

Nicotine and muscarine, in other words, each affect only one subtype, but acetylcholine affects both; thus, acetylcholine and nicotine are both nicotinic receptor agonists, and acetylcholine and muscarine are both muscarinic receptor agonists. To return to the example of curare, it is a subtype-specific blocker that acts on the nicotinic receptor to block the effect of acetylcholine, causing paralysis of the skeletal muscles. Chemical variants of curare are used clinically to cause muscle relaxation before surgery.

Atropine is a muscarinic receptor blocker, so the cholinergic effects that are mediated by this subtype are antagonized. This drug is used to reduce motion sickness, to induce pupillary dilation for retinal examination, and to fight the sickening effects of certain gases used in chemical warfare. It is because those gases often involve cholinergic agonists that atropine is an appropriate antidote. There are many other compounds that can affect cholinergic effects through interfering with the release, receptor binding, and termination mechanisms. For example, the venom of the black widow spider facilitates the release of acetylcholine, whereas botulinum food poison inhibits its release. Physostigmine, a compound obtained from the Calabar bean in West Africa, enhances acetylcholine effects. Physostigmine is used to treat glaucoma and to help control the forgetfulness of Alzheimer’s disease patients.

Synthetic Neurotransmitters

The potency and efficacy of a drug are presumably related to the degree of fit between the drug molecule and the receptor molecule; a potent drug is one with a good fit to a receptor or subtype. The pharmaceutical industry is constantly working to synthesize variants of neurotransmitters and neuroactive compounds to make the effects of the drug both potent and specific, thus reducing undesirable side effects.

Because acetylcholine in the brain is known to be related to learning and memory, and since Alzheimer’s disease
involves memory loss, it is theorized that the disease may involve cholinergic subfunctioning. Indeed, cholinergic neurons have been found to be lacking in Alzheimer’s patients’ brains. Thus, drugs that could alleviate the symptoms are cholinergic agonists of various kinds, such as physostigmine, and various cholinomimetics, drugs that mimic acetylcholine. Many cholinomimetics are so-called nootropic drugs, compounds that may be able to improve learning, memory, and cognitive functions. Dopamine, another neurotransmitter in the brain, has been found to be involved with the hallucinations and delusions of schizophrenics, and dopamine antagonists are used as
antipsychotic drugs. Amphetamine is known to induce those psychotic symptoms; this type of drug promotes the release of dopamine.

Furthermore, a lack of dopamine activity has been linked to the symptoms of Parkinson’s disease, so anti-Parkinson’s drugs tend to be dopamine agonists. Depression has been found to be related to reduced activity of norepinephrine in the brain, so some antidepressants are norepinephrine agonists. Morphine is a well-known pain reducer; in the body, there are chemically similar compounds known as endorphins (from “endogenous morphine”). They are released by neurons within the spinal cord, resulting in a reduction of the release of the neurotransmitter (called substance P) related to pain signaling, thus suppressing pain. Arousal is known to be related to acetylcholine and norepinephrine in the brain; dreaming has also been related to norepinephrine. The action of the tranquilizer diazepam (Valium), the most commonly prescribed drug in the United States, is related to the activity of an inhibitory neurotransmitter, gamma-aminobutyric acid. Neuropsychopharmacology is the area of study that explores the relationships among neurophysiology, neuroanatomy, and pharmacology. Neurotransmission is an important key to discovering these relationships. Beyond the importance of such research efforts, however, it must also be remembered that behavior, both normal and abnormal, is inextricably related to the effects of synaptic transmission.

Discovering New Neurotransmitters

In the earliest years of the twentieth century, neurotransmission was thought to be solely electrical. The discovery of the synaptic cleft, however, made neuroscientists wonder whether an electrical current could jump a gap of this magnitude. The chemical hypothesis of neurotransmission was then proposed, although it was not until 1921 that convincing evidence of chemical transmission was obtained. Otto Loewi, a German physiologist, electrically stimulated the parasympathetic vagus nerve of a frog and recorded the effect on the frog’s heart. He then transferred the liquid from the stimulated heart to an unstimulated frog heart and observed that the recipient heart reacted as if it were stimulated. The effect of the vagal stimulation—decreasing the heart rate—was transferred to the unstimulated heart via the liquid from the stimulated heart. This transferral could only occur if the electrical stimulation of the vagus had resulted in the release of a chemical into the heart and this chemical was transferred to the new heart, thus inducing the same effect. Loewi called this substance Vagusstoff, since it was released from the vagus nerve. Later chemical analysis revealed the substance to be acetylcholine, the first neurotransmitter to be identified.

No fewer than fifty neurotransmitter substances have been identified, and researchers are still discovering new ones. To classify a substance as a neurotransmitter, a scientist needs to show that it fulfills a number of conditions. The substance (referred to as a putative neurotransmitter) should be found in the presynaptic terminals. Exogenous applications of the substance should mimic the effect of endogenously released substance when the presynaptic neurons are electrically stimulated. The drug effect should be the same as the effect of the exogenously applied substance and the same as the effect of the endogenously released transmitter substance. A mechanism must exist for the synthesis of the substance in the presynaptic neuron. A mechanism must also exist for the termination of the transmitter activity of the substance. As can be seen, it is not easy to identify and define a new neurotransmitter substance.

The United States Public Health Service proclaimed the 1990’s to be the decade of the brain. The synthesis of drugs that may be related to brain functions is still an area of intense research activity. Neuropsychopharmacological studies test the effects of various compounds; the new compounds are also used to test for specific neuronal bases of brain functions. New drugs not only increase the possibilities for controlling neuronal function but also reduce the undesirable side effects of drug therapy by making the effects specific to receptor subtypes. Better, more effective drugs will undoubtedly continue to be produced.

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