document_title: Blood sugar level

question_text: what is the normal range for plasma glucose concentration

text: Blood sugar level

text: Units[edit]

text: The international standard way of measuring blood glucose levels is in terms of a molar concentration, measured in mmol/L (millimoles per litre; or millimolar, abbreviated mM). In the United States, West-Germany and other countries mass concentration is measured in mg/dL (milligrams per decilitre).[4]

text: Since the molecular weight of glucose C6H12O6 is 180, the difference between the two units is a factor of 18, so that 1 mmol/L of glucose is equivalent to 18 mg/dL.[5]

text: Normal values in humans[edit]

text: Normal value ranges may vary slightly among different laboratories. Many factors affect a person's blood sugar level. The body's homeostatic mechanism of blood sugar regulation (known as glucose homeostasis), when operating normally, restores the blood sugar level to a narrow range of about 4.4 to 6.1 mmol/L (79.2 to 110 mg/dL) (as measured by a fasting blood glucose test).[6]

text: The normal blood glucose level (tested while fasting) for non-diabetics, should be between 3.9 and 5.5 mmol/L (70 to 100 mg/dL). The mean normal blood glucose level in humans is about 5.5 mmol/L (100 mg/dL);[5] however, this level fluctuates throughout the day. Blood sugar levels for those without diabetes and who are not fasting should be below 6.9 mmol/L (125 mg/dL).[7] The blood glucose target range for diabetics, according to the American Diabetes Association, should be 5.0–7.2 mmol/l (90–130 mg/dL) before meals, and less than 10 mmol/L (180 mg/dL) after meals (as measured by a blood glucose monitor).[8]

text: Despite widely variable intervals between meals or the occasional consumption of meals with a substantial carbohydrate load, human blood glucose levels tend to remain within the normal range. However, shortly after eating, the blood glucose level may rise, in non-diabetics, temporarily up to 7.8 mmol/L (140 mg/dL) or slightly more. For people with diabetes maintaining 'tight diabetes control', the American Diabetes Association recommends a post-meal glucose level of less than 10 mmol/L (180 mg/dL) and a fasting plasma glucose of 3.9 to 7.2 mmol/L (70–130 mg/dL).[9]

text: The actual amount of glucose in the blood and body fluids is very small. In a healthy adult male of 75 kg with a blood volume of 5 liters, a blood glucose level of 5.5 mmol/L (100 mg/dL) amounts to 5g, equivalent to about a teaspoonful of sugar.[10] Part of the reason why this amount is so small is that, to maintain an influx of glucose into cells, enzymes modify glucose by adding phosphate or other groups to it.

text: Animals[edit]

text: In general, ranges of blood sugar in common domestic ruminants are lower than in many monogastric mammals.[11] However this generalization does not extend to wild ruminants or camelids. For serum glucose in mg/dL, reference ranges of 42 to 75 for cows, 44 to 81 for sheep, and 48 to 76 for goats, but 61 to 124 for cats; 62 to 108 for dogs, 62 to 114 for horses, 66 to 116 for pigs, 75 to 155 for rabbits, and 90 to 140 for llamas have been reported.[12] A 90 percent reference interval for serum glucose of 26 to 181 mg/dL has been reported for captured mountain goats (Oreamnos americanus), where no effects of the pursuit and capture on measured levels were evident.[13] For beluga whales, the 25–75 percent range for serum glucose has been estimated to be 94 to 115 mg/dL.[14] For the white rhinoceros, one study has indicated that the 95 percent range is 28 to 140 mg/dL.[15] For harp seals, a serum glucose range of 4.9 to 12.1 mmol/L [i.e. 88 to 218 mg/dL] has been reported; for hooded seals, a range of 7.5 to 15.7 mmol/L [i.e. about 135 to 283 mg/dL] has been reported.[16]

text: Regulation[edit]

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text: The body's homeostatic mechanism keeps blood glucose levels within a narrow range. It is composed of several interacting systems, of which hormone regulation is the most important.

text: There are two types of mutually antagonistic metabolic hormones affecting blood glucose levels:

text:
catabolic hormones (such as glucagon, cortisol and catecholamines) which increase blood glucose;[17]
and one anabolic hormone (insulin), which decreases blood glucose.

text: These hormones are secreted from pancreatic islets which are bundles of endocrine tissues. There are four types of pancreatic islets, alpha (A) cells, beta (B) cells, Delta (D) cells and F cells. Glucagon is secreted from alpha cells, while insulin is secreted by beta cells. Together they regulate the blood-glucose levels through negative feedback, a process where the end product of one reaction stimulates the beginning of another reaction. In blood-glucose levels, insulin lowers the concentration of glucose in the blood. The lower blood-glucose level (a product of the insulin secretion) triggers glucagon to be secreted, and repeats the cycle. [18]

text: In order for blood glucose to be kept stable, modifications to insulin, glucagon, epinephrine and cortisol are made. Each of these hormones have a different responsibility to keep blood glucose regulated; when blood sugar is too high, insulin tells muscles to take up excess glucose for storage. Glucagon responds to too low of blood glucose level, it informs the tissue to produce more glucose. Epinephrine prepares the muscles and respiratory system for activity in the case of a "fight and flight" response. Lastly, cortisol supplies the body with fuel in times of heavy stress.[19]

text: Abnormality in blood sugar levels[edit]

text: High blood sugar[edit]

text: If blood sugar levels remain too high the body suppresses appetite over the short term. Long-term hyperglycemia causes many of the long-term health problems including heart disease, eye, kidney, and nerve damage.

text: The most common cause of hyperglycemia is diabetes. When diabetes is the cause, physicians typically recommend an anti-diabetic medication as treatment. From the perspective the majority of patients, treatment with an old, well-understood diabetes drug such as metformin will be the safest, most effective, least expensive, most comfortable route to managing the condition.[20] Diet changes and exercise implementation may also be part of a treatment plan for diabetes.

text: Fasting blood glucose levels may be higher than the post meal blood glucose in many of the healthy subjects. Such individuals may be said to have physiological insulin resistance and may develop diabetes mellitus as long term complication. In clinical and laboratory practices, many of the time a healthy normal subject will present a fasting blood glucose value higher than the post meal blood glucose value. This creates confusion since there is a common perception that in blood, postprandial (PP) glucose level should be higher than fasting (F) glucose level. The repeated investigation subsequently yields somewhat similar type of result.[21]

text: Low blood sugar[edit]

text: If blood sugar levels drop too low, a potentially fatal condition called hypoglycemia develops. Symptoms may include lethargy, impaired mental functioning; irritability; shaking, twitching, weakness in arm and leg muscles; pale complexion; sweating; loss of consciousness.

text: Mechanisms that restore satisfactory blood glucose levels after extreme hypoglycemia (below 40 mg/dl) must be quick and effective to prevent extremely serious consequences of insufficient glucose: confusion or unsteadiness and, in the extreme (below 15 mg/dl) loss of consciousness and seizures. Without discounting the potentially quite serious conditions and risks due to or oftentimes accompanying hyperglycemia, especially in the long-term (diabetes or pre-diabetes, obesity or overweight, hyperlipidemia, hypertension, etc.), it is still generally more dangerous to have too little glucose- especially if levels are very low- in the blood than too much, at least temporarily, because glucose is so important for metabolism and nutrition and the proper functioning of the body's organs. This is especially the case for those organs that are metabolically active or that require a constant, regulated supply of blood sugar (the liver and brain are examples). In healthy individuals, blood glucose-regulating mechanisms are generally quite effective, and symptomatic hypoglycemia is generally found only in diabetics using insulin or other pharmacological treatment, and in starvation or severe malnutrition or malabsorption (of various causes), and conditions such as anorexia[dubious – discuss]. Hypoglycemic episodes can vary greatly between persons and from time to time, both in severity and swiftness of onset. For severe cases, prompt medical assistance is essential, as damage to brain and other tissues and even death will result from sufficiently low blood-glucose levels.

text: Glucose measurement[edit]

text: Sample source[edit]

text: Glucose testing in a fasting individual, show comparable levels of glucose in arterial, venous, and capillary blood. But following meals, capillary and arterial blood glucose levels can be significantly higher than venous levels. This is because tissue cells consume some of the glucose in the blood as it passes from arteries through the capillary bed and into the veins.[22] Although these differences vary widely, one study found that following the consumption of 50 grams of glucose, "the mean capillary blood glucose concentration is higher than the mean venous blood glucose concentration by 35%."[22][23][24]

text: Sample type[edit]

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text: Glucose is measured in whole blood, plasma or serum. Historically, blood glucose values were given in terms of whole blood, but most laboratories now measure and report plasma or serum glucose levels. Because red blood cells (erythrocytes) have a higher concentration of protein (e.g., hemoglobin) than serum, serum has a higher water content and consequently more dissolved glucose than does whole blood. To convert from whole-blood glucose, multiplication by 1.14[25] has been shown to generally give the serum/plasma level.

text: Collection of blood in clot tubes for serum chemistry analysis permits the metabolism of glucose in the sample by blood cells until separated by centrifugation.[26] Red blood cells, for instance, do not require insulin to intake glucose from the blood. Higher than normal amounts of white or red blood cell counts can lead to excessive glycolysis in the sample, with substantial reduction of glucose level if the sample is not processed quickly. Ambient temperature at which the blood sample is kept prior to centrifuging and separation of plasma/serum also affects glucose levels. At refrigerator temperatures, glucose remains relatively stable for several hours in a blood sample. Loss of glucose can be prevented by using Fluoride tubes (i.e., gray-top) since fluoride inhibits glycolysis. However, these should only be used when blood will be transported from one hospital laboratory to another for glucose measurement. Red-top serum separator tubes also preserve glucose in samples after being centrifuged isolating the serum from cells.

text: To prevent contamination of the sample with intravenous fluids, particular care should be given to drawing blood samples from the arm opposite the one in which an intravenous line is inserted. Alternatively, blood can be drawn from the same arm with an IV line after the IV has been turned off for at least 5 minutes, and the arm has been elevated to drain infused fluids away from the vein. Inattention can lead to large errors, since as little as 10% contamination with a 5% glucose solution (D5W) will elevate glucose in a sample by 500 mg/dL or more. Remember that the actual concentration of glucose in blood is very low, even in the hyperglycemic.

text: Measurement techniques[edit]

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text: Two major methods have been used to measure glucose. The first, still in use in some places, is a chemical method exploiting the nonspecific reducing property of glucose in a reaction with an indicator substance that changes color when reduced. Since other blood compounds also have reducing properties (e.g., urea, which can be abnormally high in uremic patients), this technique can produce erroneous readings in some situations (5–15 mg/dL has been reported). The more recent technique, using enzymes specific to glucose, is less susceptible to this kind of error. The two most common employed enzymes are glucose oxidase and hexokinase.[27] Average blood glucose concentrations can also be measured. This method measures the level of glycated hemoglobin, which is representative of the average blood glucose levels over the last, approximately, 120 days.[27]

text: In either case, the chemical system is commonly contained on a test strip which is inserted into a meter, and then has a blood sample applied. Test-strip shapes and their exact chemical composition vary between meter systems and cannot be interchanged. Formerly, some test strips were read (after timing and wiping away the blood sample) by visual comparison against a color chart printed on the vial label. Strips of this type are still used for urine glucose readings, but for blood glucose levels they are obsolete. Their error rates were, in any case, much higher. Errors when using test strips were often caused by the age of the strip or exposure to high temperatures or humidity.[28] More precise blood glucose measurements are performed in a medical laboratory, using hexokinase, glucose oxidase, or glucose dehydrogenase enzymes.

text: Urine glucose readings, however taken, are much less useful. In properly functioning kidneys, glucose does not appear in urine until the renal threshold for glucose has been exceeded. This is substantially above any normal glucose level, and is evidence of an existing severe hyperglycemic condition. However, as urine is stored in the bladder, any glucose in it might have been produced at any time since the last time the bladder was emptied. Since metabolic conditions change rapidly, as a result of any of several factors, this is delayed news and gives no warning of a developing condition. Blood glucose monitoring is far preferable, both clinically and for home monitoring by patients. Healthy urine glucose levels were first standardized and published in 1965[29] by Hans Renschler.

text:
I. CHEMICAL METHODS

A. Oxidation-reduction reaction

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{\displaystyle \mathrm {Glucose} +\mathrm {Alkaline\ copper\ tartarate} {\xrightarrow {\mathrm {Reduction} }}\mathrm {Cuprous\ oxide} }

1. Alkaline copper reduction

Folin-Wu method

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{\displaystyle \mathrm {Cu} ^{++}+\mathrm {Phosphomolybdic\ acid} {\xrightarrow {\mathrm {Oxidation} }}\mathrm {Phosphomolybdenum\ oxide} }

Blue end-product

Benedict's method

Modification of Folin–Wu method for qualitative urine glucose

Nelson–Somogyi method

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{\displaystyle \mathrm {Cu} ^{++}+\mathrm {Arsenomolybdic\ acid} {\xrightarrow {\mathrm {Oxidation} }}\mathrm {Arsenomolybdenum\ oxide} }

Blue end-product

Neocuproine method

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{\displaystyle \mathrm {Cu} ^{++}+\mathrm {Neocuproine} {\xrightarrow {\mathrm {Oxidation} }}\mathrm {Cu} ^{++}\mathrm {neocuproine\ complex} }

*
Yellow-orange color neocuproine[30]

Shaeffer–Hartmann–Somogyi

Uses the principle of iodine reaction with cuprous byproduct.
Excess I2 is then titrated with thiosulfate.

2. Alkaline Ferricyanide Reduction

Hagedorn–Jensen

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{\displaystyle \mathrm {Glucose} +\mathrm {Alkaline\ ferricyanide} \longrightarrow \mathrm {Ferrocyanide} }

Colorless end product; other reducing substances interfere with reaction

B. Condensation

Ortho-toluidine method

Uses aromatic amines and hot acetic acid
Forms Glycosylamine and Schiff's base which is emerald green in color
This is the most specific method, but the reagent used is toxic

Anthrone (phenols) method

Forms hydroxymethyl furfural in hot acetic acid

II. ENZYMATIC METHODS

A. Glucose oxidase

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{\displaystyle \mathrm {Glucose} +\mathrm {O} _{2}{\xrightarrow[{\mathrm {Oxidation} }]{\mathrm {glucose\ oxidase} }}{\textrm {D-glucono-1,5-lactone}}+\mathrm {H_{2}O_{2}} }

Saifer–Gerstenfeld method

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{\displaystyle \mathrm {H_{2}O_{2}} +{\textit {O}}{\text{-dianisidine}}{\xrightarrow[{\mathrm {Oxidation} }]{\mathrm {peroxidase} }}\mathrm {H_{2}O} +\mathrm {oxidized\ chromogen} }

Inhibited by reducing substances like BUA, bilirubin, glutathione, ascorbic acid

Trinder method

uses 4-aminophenazone oxidatively coupled with phenol
Subject to less interference by increases serum levels of creatinine, uric acid or hemoglobin
Inhibited by catalase

Kodak Ektachem

A dry chemistry method
Uses spectrophotometry to measure the intensity of color through a lower transparent film

Glucometer

Home monitoring blood glucose assay method
Uses a strip impregnated with a glucose oxidase reagent

B. Hexokinase

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{\displaystyle {\begin{alignedat}{2}&\mathrm {Glucose} +\mathrm {ATP} {\xrightarrow[{\mathrm {Phosphorylation} }]{\mathrm {Hexokinase} +\mathrm {Mg} ^{++}}}{\textrm {G-6PO}}_{4}+\mathrm {ADP} \\&{\textrm {G-6PO}}_{4}+\mathrm {NADP} {\xrightarrow[{\mathrm {Oxidation} }]{\textrm {G-6PD}}}{\textrm {6-Phosphogluconate}}+\mathrm {NADPH} +\mathrm {H} ^{+}\\\end{alignedat}}}

NADP as cofactor
NADPH (reduced product) is measured in 340 nm
More specific than glucose oxidase method due to G-6PO4, which inhibits interfering substances except when sample is hemolyzed

text: Clinical correlation[edit]

text: The fasting blood glucose level, which is measured after a fast of 8 hours, is the most commonly used indication of overall glucose homeostasis, largely because disturbing events such as food intake are avoided. Conditions affecting glucose levels are shown in the table below. Abnormalities in these test results are due to problems in the multiple control mechanism of glucose regulation.

text: The metabolic response to a carbohydrate challenge is conveniently assessed by a postprandial glucose level drawn 2 hours after a meal or a glucose load. In addition, the glucose tolerance test, consisting of several timed measurements after a standardized amount of oral glucose intake, is used to aid in the diagnosis of diabetes.

text: Error rates for blood glucose measurements systems vary, depending on laboratories, and on the methods used. Colorimetry techniques can be biased by color changes in test strips (from airborne or finger borne contamination, perhaps) or interference (e.g., tinting contaminants) with light source or the light sensor. Electrical techniques are less susceptible to these errors, though not to others. In home use, the most important issue is not accuracy, but trend. Thus if a meter / test strip system is consistently wrong by 10%, there will be little consequence, as long as changes (e.g., due to exercise or medication adjustments) are properly tracked. In the US, home use blood test meters must be approved by the federal Food and Drug Administration before they can be sold.

text: Finally, there are several influences on blood glucose level aside from food intake. Infection, for instance, tends to change blood glucose levels, as does stress either physical or psychological. Exercise, especially if prolonged or long after the most recent meal, will have an effect as well. In the typical person, maintenance of blood glucose at near constant levels will nevertheless be quite effective. [clarification needed]

text:
Causes of abnormal glucose levels

Persistent hyperglycemia
Transient hyperglycemia
Persistent hypoglycemia
Transient hypoglycemia

Reference range, FBG: 70–110 mg/dL

Diabetes mellitus
Pheochromocytoma
Insulinoma
Acute alcohol ingestion

Adrenal cortical hyperactivity Cushing's syndrome
Severe liver disease
Adrenal cortical insufficiency Addison's disease
Drugs: salicylates, antituberculosis agents

Hyperthyroidism
Acute stress reaction
Hypopituitarism
Severe liver disease

Acromegaly
Shock
Galactosemia
Several glycogen storage diseases

Obesity
Convulsions
Ectopic insulin production from tumors
Hereditary fructose intolerance

text: Etymology and use of term[edit]

text: This section has no medical references for verification or relies exclusively on non-medical sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be removed. (June 2016) (Learn how and when to remove this template message)

text: In a physiological context, the term is a misnomer because it refers to glucose, yet other sugars besides glucose are always present. Food contains several different types (e.g., fructose (largely from fruits/table sugar/industrial sweeteners), galactose (milk and dairy products), as well as several food additives such as sorbitol, xylose, maltose, etc.). But because these other sugars are largely inert with regard to the metabolic control system (i.e., that controlled by insulin secretion), since glucose is the dominant controlling signal for metabolic regulation, the term has gained currency, and is used by medical staff and lay folk alike. The table above reflects some of the more technical and closely defined terms used in the medical field.


document_title: Potter's wheel

question_text: where did the potter's wheel first develop

question_tokens: where did the potter 's wheel first develop

root

text: Potter's wheel

text: History[edit]

text: Much early ceramic ware was hand-built using a simple coiling technique in which clay was rolled into long threads that were then pinched and beaten together to form the body of a vessel. In the coiling method of construction, all the energy required to form the main part of a piece is supplied indirectly by the hands of the potter. Early ceramics built by coiling were often placed on mats or large leaves to allow them to be worked more conveniently. The evidence of this lies in mat or leaf impressions left in the clay of the base of the pot. This arrangement allowed the potter to rotate the vessel during construction, rather than walk around it to add coils of clay.

tag: p

text: The earliest forms of the potter's wheel (called tourneys or slow wheels) were probably developed as an extension to this procedure. Tournettes, in use around 4500 BC in the Near East, were turned slowly by hand or by foot while coiling a pot. Only a small range of vessels were fashioned on the tournette, suggesting that it was used by a limited number of potters.[1] The introduction of the slow wheel increased the efficiency of hand-powered pottery production.

text: In the mid to late 3rd millennium BCE the fast wheel was developed, which operated on the flywheel principle. It utilised energy stored in the rotating mass of the heavy stone wheel itself to speed the process. This wheel was wound up and charged with energy by kicking, or pushing it around with a stick, providing a centrifugal force. The fast wheel enabled a new process of pottery-making to develop, called throwing, in which a lump of clay was placed centrally on the wheel and then squeezed, lifted and shaped as the wheel turned. The process tends to leave rings on the inside of the pot and can be used to create thinner-walled pieces and a wider variety of shapes, including stemmed vessels, so wheel-thrown pottery can be distinguished from handmade. Potters could now produce many more pots per hour, a first step towards industrialization.

text: Many modern scholars suggest that the first potter's wheel was first developed by the ancient Sumerians in Mesopotamia.[2] A stone potter's wheel found at the Sumerian city of Ur in modern-day Iraq has been dated to about 3129 BC,[3] but fragments of wheel-thrown pottery of an even earlier date have been recovered in the same area.[3] However, southeastern Europe[4] and China[5] have also been claimed as possible places of origin. Furthermore, the wheel was also in popular use by potters starting around 3500 BC in major cities of the Indus Valley civilization in South Asia, namely Harappa and Mohenjo-daro (Kenoyer, 2005). Others consider Egypt as "being the place of origin of the potter's wheel. It was here that the turntable shaft was lengthened about 3000 BC and a flywheel added. The flywheel was kicked and later was moved by pulling the edge with the left hand while forming the clay with the right. This led to the counterclockwise motion for the potter's wheel which is almost universal."[6] Hence the exact origin of the wheel is not wholly clear yet.

text: In the Iron Age, the potter's wheel in common use had a turning platform about one metre (3 feet) above the floor, connected by a long axle to a heavy flywheel at ground level. This arrangement allowed the potter to keep the turning wheel rotating by kicking the flywheel with the foot, leaving both hands free for manipulating the vessel under construction. However, from an ergonomic standpoint, sweeping the foot from side to side against the spinning hub is rather awkward. At some point, an alternative solution was invented that involved a crankshaft with a lever that converted up-and-down motion into rotary motion.

text: The use of the motor-driven wheel has become common in modern times, particularly with craft potters and educational institutions, although human-powered ones are still in use and are preferred by some studio potters.

text: Techniques of throwing[edit]

text: There are many techniques in use for throwing ceramic containers, although this is a typical procedure:

text: A round, moist lumpy clump of clay body is thrown at a wheelhead or a bat attached to it. (The term "bat" refers to a secondary disc or square, made of wood – or more recently plastic – to which the lump of clay is attached instead of the wheel head, thereby permitting the finished piece to be more easily lifted from the wheel.) The lump or clump is made even and forced to the centre of the wheel by applying pressure with the hands. The thrower finds the centre of the clay by moving a thumb across the lump until no more friction is felt. The thumb is pressed into the centre of the lump, stopping about 5 mm (1⁄4 inch) from the wheel head. The hole made is widened. The sides thus defined are pulled up and made thinner by pressure between the hands. The vessel is shaped, and the mouth is smoothed. The vessel is cut from the wheelhead or bat with a cheese wire and left to stiffen. Sometimes the stiffened vessel is inverted on the wheel and trimmed with a sharp tool.

text:
The process of throwing a round pot

The clay is centred on the spinning wheel.

A depression is made in the centre, forming walls.

The walls are drawn up with the hands...

...and shaped into the desired form.

The finished pot.

tag: table

text: A skilled potter can quickly throw a vessel from up to 15 kg (30 lb) of clay.[7] Alternatively, by throwing and adding coils of clay then throwing again, pots up to four feet high may be made, the heat of a blowlamp being used to firm each thrown section before adding the next coil. In Chinese manufacture, very large pots are made by two throwers working simultaneously.

text: The potter's wheel in myth and legend[edit]

text: In Ancient Egyptian mythology, the deity Khnum was said to have formed the first humans on a potter's wheel.


document_title: Army–Navy Game

question_text: when's the last time army won the army navy game

question_tokens: when 's the last time army won the army navy game

text: Army–Navy Game

text: Series history[edit]

text: Army and Navy first met on the field on November 29, 1890. They played 30 times between that date and November 26, 1927. The series has been renewed annually since 1930. The game has been held at several locations throughout its history, including Baltimore and New York City, but has most frequently been played in Philadelphia, roughly equidistant from the two academies. Historically played on the Saturday after Thanksgiving (a date on which most other major college football teams end their regular seasons), the game is now played on the second Saturday in December and is traditionally the last game of the season for both teams and the last regular-season game played in Division I FBS football. With the permanent expansion of the regular season to 12 games starting in 2006, several conference championship games joined the Army–Navy Game on its then-current date of the first weekend of December. In 2009, the game was moved from the first Saturday in December to the second Saturday; this means that it no longer conflicts with conference championship games and once again is the last non-bowl contest in college football.[5]

text: This game has inter-service "bragging rights" at stake. For much of the first half of the 20th century, both Army and Navy were often national powers, and the game occasionally had national championship implications. However, as the level of play in college football improved nationally, and became fueled by prospects of playing in the National Football League (NFL), the high academic entrance requirements, height and weight limits, and the five-year military commitment required has reduced the overall competitiveness of both academies. Since 1963, only the 1996, 2010, 2016 and 2017 games have seen both teams enter with winning records. Nonetheless, the game is considered a college football institution. It has aired nationally on radio since 1930, and has been nationally televised every year since 1945. The tradition associated with the game assures that it remains nationally broadcast to this day.

text: Arguably, one of the reasons this game has maintained its appeal is that the players are playing solely for the love of the game. Most players are required to fulfill a post-graduation active duty military commitment and, by the time this ends, many players are deemed too old to consider playing competitively again. Nevertheless, some participants in the Army–Navy Game have gone on to professional football careers. Quarterback Roger Staubach (Navy, 1965) went on to a Hall of Fame career with the Dallas Cowboys that included starting at quarterback in two Super Bowl victories including being named the Most Valuable Player of Super Bowl VI. Wide receiver and return specialist Phil McConkey (Navy, 1979) was a popular player on the New York Giants squad that won Super Bowl XXI. Running back Napoleon McCallum (Navy, 1985) was able to complete his commitment to the Navy and play for the then-Los Angeles Raiders in 1986. After satisfying his Navy commitment, he joined the Raiders full-time.

text: The game is especially emotional for the seniors, called "first classmen" by both academies, since it is typically the last competitive regular season football game they will ever play (though they sometimes play in a subsequent bowl game). During wartime the game is even more emotional, as some seniors may face combat and perhaps die after they graduate. Recognition of those who share the uniform and are deployed overseas is an important part of the day.

text: At the end of the game, both teams' almae matres are played and sung. The winning team stands alongside the losing team and faces the losing academy's students; then the losing team accompanies the winning team, facing their students.[6] This is done in a show of mutual respect and solidarity. Since the winning team's alma mater is always played last, the phrase "to sing second" has become synonymous with winning the rivalry game.

text: The rivalry between Annapolis and West Point, while friendly, is intense. The cadets live and breathe the phrase "Beat Navy!" while for midshipmen the opposite phrase, "Beat Army!" is ingrained. They have become a symbol of competitiveness, not just in the Army–Navy Game, but in the service of their country, and are often used at the close of (informal) letters by graduates of both academies. A long-standing tradition at the Army-Navy football game is to conduct a formal "prisoner exchange" as part of the pre-game activities. The prisoners are the cadets and midshipmen currently spending the semester studying at the sister academy. After the exchange, students have a brief reprieve to enjoy the game with their comrades.[7]

text: The game is the last of three contests in the annual Commander-in-Chief's Trophy series, awarded to each season's winner of the triangular series between Army, Navy, and Air Force since 1972. In years when Navy and Army have each beaten Air Force before the Army–Navy Game (1972, 1977, 1978, 1996, 2005, 2012 and 2017) the Army-Navy game has also determined whether Army or Navy would win this trophy. In years when Air Force has split its two games, the Army-Navy game determines whether the trophy is shared or won outright by the winner of the game.

text: The rivalries Army and Navy have with Air Force are much less intense than the Army–Navy rivalry, primarily due to the relative youth of the USAFA, established in 1954, and the physical distance between the USAFA and the other two schools. The Army–Air Force and Navy–Air Force games are usually played at the academies' regular home fields, although on occasion they have been held at a neutral field.

text: Navy won 14 Army-Navy games in a row from 2002 to 2015, the longest winning streak in the history of the series.[8] On December 10, 2016, Army snapped its 14-game losing streak against Navy with a 21–17 victory.

text: Venues[edit]

text: Though the game has been played 118 times, only six of those games have ever been held on the campus of either academy. Neither team has ever played at an on-campus stadium nearly large enough to accommodate the large crowds that usually attend the game, as well as the media and dignitaries. Army's Michie Stadium only seats 38,000 people, while Navy's Navy–Marine Corps Memorial Stadium only seats 34,000. The game's popularity grew enough early on that when it was revived in 1899, it was played at a neutral site, the Franklin Field in Philadelphia. Except for the 1942 and 1943 games, which were played on-campus due to World War II travel restrictions, it has been played at a neutral site every year since.

text: Traditionally, the game is played in Philadelphia, due to the historic nature of the city and the fact that it is approximately halfway between West Point and Annapolis. Additionally, Philadelphia has always had a stadium large enough to accommodate the crowds. Philadelphia's John F. Kennedy Stadium (JFK) hosted the game from 1936 to 1979 (except for three years in World War II) – more than any other venue in the history of the series. It even hosted the game for several years after the 1971 construction of nearby Veterans Stadium, which finally became the game's host in 1980. The Pennsylvania Railroad and its successors offered game-day service to all Army–Navy games (except several during World War II) at John F. Kennedy Stadium, using a sprawling temporary station constructed each year on the railroad's nearby Greenwich freight yard. The service, with 40-odd trains serving as many as 30,000 attendees, was the single largest concentrated passenger rail movement in the country.[9][10]

text: Franklin Field, on the campus of the University of Pennsylvania, hosted the game in the early twentieth century before it was moved to JFK. New York's Polo Grounds holds the record for most games hosted outside of Philadelphia. The city of Baltimore has hosted a number of games throughout the history of the series as well, even though Baltimore is closer to Annapolis.

text: The Rose Bowl is the only site west of the Mississippi River to host the Army–Navy game; it did so in 1983. The city of Pasadena, California, paid for the travel expenses of all the students and supporters of both academies – 9,437 in all.[11] A substitute, however, for Bill XXII – the Navy mascot – and four rented Army mules were brought in.[11] The attendance was 81,000.[12][13] The game was held at the Rose Bowl that year because there are a large number of military installations and servicemen and women, along with many retired military personnel, on the West Coast.[11] The game has been held one other time in a non-East Coast venue, at Chicago's Soldier Field, which played host to the 1926 game. In October 1984, the $100,000 in costs to transport the cadets and midshipmen to the California game earned the Department of Defense a "Golden Fleece Award" from United States Senator William Proxmire, a Democrat from Wisconsin.[14]

text: Currently the game is played primarily at Lincoln Financial Field in Philadelphia, the home of the Philadelphia Eagles. Since the 1980s, the game has been held roughly once every three or four years at a site other than Philadelphia. In addition to the Rose Bowl, these sites have included Giants Stadium in East Rutherford, New Jersey (replaced in 2010 by MetLife Stadium, which is scheduled to host the game for the first time in 2021), M&T Bank Stadium in Baltimore and FedExField in Landover, Maryland. These are still considered neutral-site games, but provide locations that are closer to one academy or the other.

text: Future venues[edit]

text: All games through 2020 will be held at Lincoln Financial Field in Philadelphia. MetLife Stadium in East Rutherford, New Jersey will host the 2021 game. The game will then return to Lincoln Financial Field for 2022. Games beyond 2022 have yet to be awarded.[15]

text: Total games by venue and geography[edit]

text:
Venue
Games
Army victories
Navy victories
Tie games
First game
Most recent game

John F. Kennedy Stadium (Philadelphia)
41
16
22
3
1936
1979

Franklin Field
18
11
7
0
1899
1935

Veterans Stadium
17
11
5
1
1980
2001

Lincoln Financial Field
11
1
10
0
2003
2017

Polo Grounds
9
5
3
1
1913
1927

Giants Stadium
4
1
3
0
1989
2002

M&T Bank Stadium
4
1
3
0
2000
2016

The Plain
2
0
2
0
1890
1892

Worden Field
2
1
1
0
1891
1893

Municipal Stadium (Baltimore)
2
2
0
0
1924
1944

Yankee Stadium
2
2
0
0
1930
1931

Osborne Field
1
0
0
1
1905
1905

Soldier Field
1
0
0
1
1926
1926

Thompson Stadium
1
0
1
0
1942
1942

Michie Stadium
1
0
1
0
1943
1943

Rose Bowl
1
0
1
0
1983
1983

FedExField
1
0
1
0
2011
2011

text:
City
Games
Army victories
Navy victories
Tie games
First game
Most recent game

Philadelphia
87
39
44
4
1899
2017

New York City
11
7
3
1
1913
1931

Baltimore
6
3
3
0
1924
2016

East Rutherford, New Jersey
4
1
3
0
1989
2002

West Point, New York
3
0
3
0
1890
1943

Annapolis, Maryland
3
1
2
0
1891
1942

Princeton, New Jersey
1
0
0
1
1905
1905

Chicago
1
0
0
1
1926
1926

Pasadena, California
1
0
1
0
1983
1983

Landover, Maryland
1
0
1
0
2011
2011

text:
State
Games
Army victories
Navy victories
Tie games
First game
Most recent game

Pennsylvania
87
39
44
4
1899
2017

New York
14
7
6
1
1890
1943

Maryland
10
4
6
0
1891
2016

New Jersey
5
1
3
1
1905
2002

Illinois
1
0
0
1
1926
1926

California
1
0
1
0
1983
1983

text:
CSA
Games
Army victories
Navy victories
Tie games
First game
Most recent game

Philadelphia–Reading–Camden, PA–NJ–DE–MD
87
39
44
4
1899
2017

New York–Newark, NY–NJ–CT–PA
19
8
9
2
1890
2002

Washington–Baltimore–Arlington, DC–MD–VA–WV–PA
10
4
6
0
1891
2016

Chicago–Naperville, IL–IN–WI
1
0
0
1
1926
1926

Los Angeles–Long Beach, CA
1
0
1
0
1983
1983

text: Game results[edit]

text:
Army victories
Navy victories
Ties

text:
Year
Winner
Score
Location
City
Series

1890
Navy
24–0
"The Plain" USMA
West Point, New York
Navy 1–0

1891
Army
32–16
Worden Field USNA
Annapolis, Maryland
Tied 1–1

1892
Navy
12–4
"The Plain"
West Point, New York
Navy 2–1

1893
Navy
6–4
Worden Field
Annapolis, Maryland
Navy 3–1

1899
Army
17–5
Franklin Field
Philadelphia
Navy 3–2

1900
Navy
11–7
Franklin Field
Philadelphia
Navy 4–2

1901
Army
11–5
Franklin Field
Philadelphia
Navy 4–3

1902
Army
22–8
Franklin Field
Philadelphia
Tied 4–4

1903
Army
40–5
Franklin Field
Philadelphia
Army 5–4

1904
Army
11–0
Franklin Field
Philadelphia
Army 6–4

1905
Tie
6–6
Osborne Field
Princeton, New Jersey
Army 6–4–1

1906
Navy
10–0
Franklin Field
Philadelphia
Army 6–5–1

1907
Navy
6–0
Franklin Field
Philadelphia
Tied 6–6–1

1908
Army
6–4
Franklin Field
Philadelphia
Army 7–6–1

1910
Navy
3–0
Franklin Field
Philadelphia
Tied 7–7–1

1911
Navy
3–0
Franklin Field
Philadelphia
Navy 8–7–1

1912
Navy
6–0
Franklin Field
Philadelphia
Navy 9–7–1

1913
Army
22–9
Polo Grounds
New York
Navy 9–8–1

1914
Army
20–0
Franklin Field
Philadelphia
Tied 9–9–1

1915
Army
14–0
Polo Grounds
New York
Army 10–9–1

1916
Army
15–7
Polo Grounds
New York
Army 11–9–1

1919
Navy
6–0
Polo Grounds
New York
Army 11–10–1

1920
Navy
7–0
Polo Grounds
New York
Tied 11–11–1

1921
Navy
7–0
Polo Grounds
New York
Navy 12–11–1

1922
Army
17–14
Franklin Field
Philadelphia
Tied 12–12–1

1923
Tie
0–0
Polo Grounds
New York
Tied 12–12–2

1924
Army
12–0
Municipal Stadium
Baltimore
Army 13–12–2

1925
Army
10–3
Polo Grounds
New York
Army 14–12–2

1926
Tie
21–21
Soldier Field
Chicago
Army 14–12–3

1927
Army
14–9
Polo Grounds
New York
Army 15–12–3

1930
Army
6–0
Yankee Stadium
Bronx, New York
Army 16–12–3

1931
Army
17–7
Yankee Stadium
Bronx, New York
Army 17–12–3

1932
Army
20–0
Franklin Field
Philadelphia
Army 18–12–3

1933
Army
12–7
Franklin Field
Philadelphia
Army 19–12–3

1934
Navy
3–0
Franklin Field
Philadelphia
Army 19–13–3

1935
Army
28–6
Franklin Field
Philadelphia
Army 20–13–3

1936
Navy
7–0
Municipal Stadium
Philadelphia
Army 20–14–3

1937
Army
6–0
Municipal Stadium
Philadelphia
Army 21–14–3

1938
Army
14–7
Municipal Stadium
Philadelphia
Army 22–14–3

1939
Navy
10–0
Municipal Stadium
Philadelphia
Army 22–15–3

1940
Navy
14–0
Municipal Stadium
Philadelphia
Army 22–16–3

1941
#11 Navy
14–6
Municipal Stadium
Philadelphia
Army 22–17–3

1942
Navy
14–0
Thompson Stadium
Annapolis, Maryland
Army 22–18–3

1943
#6 Navy
13–0
Michie Stadium
West Point, New York
Army 22–19–3

1944
#1 Army
23–7
Municipal Stadium
Baltimore
Army 23–19–3

1945
#1 Army
32–13
Municipal Stadium
Philadelphia
Army 24–19–3

1946
#1 Army
21–18
Municipal Stadium
Philadelphia
Army 25–19–3

1947
#12 Army
21–0
Municipal Stadium
Philadelphia
Army 26–19–3

1948
Tie
21–21
Municipal Stadium
Philadelphia
Army 26–19–4

1949
#4 Army
38–0
Municipal Stadium
Philadelphia
Army 27–19–4

1950
Navy
14–2
Municipal Stadium
Philadelphia
Army 27–20–4

1951
Navy
42–7
Municipal Stadium
Philadelphia
Army 27–21–4

1952
Navy
7–0
Municipal Stadium
Philadelphia
Army 27–22–4

1953
#18 Army
20–7
Municipal Stadium
Philadelphia
Army 28–22–4

1954
#6 Navy
27–20
Municipal Stadium
Philadelphia
Army 28–23–4

1955
Army
14–6
Municipal Stadium
Philadelphia
Army 29–23–4

1956
Tie
7–7
Municipal Stadium
Philadelphia
Army 29–23–5

1957
#8 Navy
14–0
Municipal Stadium
Philadelphia
Army 29–24–5

1958
#5 Army
22–6
Municipal Stadium
Philadelphia
Army 30–24–5

1959
Navy
43–12
Municipal Stadium
Philadelphia
Army 30–25–5

1960
#7 Navy
17–12
Philadelphia Stadium
Philadelphia
Army 30–26–5

1961
Navy
13–7
Philadelphia Stadium
Philadelphia
Army 30–27–5

1962
Navy
34–14
Philadelphia Stadium
Philadelphia
Army 30–28–5

1963
#2 Navy
21–15
Philadelphia Stadium
Philadelphia
Army 30–29–5

1964
Army
11–8
John F. Kennedy Stadium
Philadelphia
Army 31–29–5

1965
Tie
7–7
John F. Kennedy Stadium
Philadelphia
Army 31–29–6

1966
Army
20–7
John F. Kennedy Stadium
Philadelphia
Army 32–29–6

1967
Navy
19–14
John F. Kennedy Stadium
Philadelphia
Army 32–30–6

1968
Army
21–14
John F. Kennedy Stadium
Philadelphia
Army 33–30–6

1969
Army
27–0
John F. Kennedy Stadium
Philadelphia
Army 34–30–6

1970
Navy
11–7
John F. Kennedy Stadium
Philadelphia
Army 34–31–6

1971
Army
24–23
John F. Kennedy Stadium
Philadelphia
Army 35–31–6

1972
Army
23–15
John F. Kennedy Stadium
Philadelphia
Army 36–31–6

1973
Navy
51–0
John F. Kennedy Stadium
Philadelphia
Army 36–32–6

1974
Navy
19–0
John F. Kennedy Stadium
Philadelphia
Army 36–33–6

1975
Navy
30–6
John F. Kennedy Stadium
Philadelphia
Army 36–34–6

1976
Navy
38–10
John F. Kennedy Stadium
Philadelphia
Army 36–35–6

1977
Army
17–14
John F. Kennedy Stadium
Philadelphia
Army 37–35–6

1978
Navy
28–0
John F. Kennedy Stadium
Philadelphia
Army 37–36–6

1979
Navy
31–7
John F. Kennedy Stadium
Philadelphia
Tied 37–37–6

1980
Navy
33–6
Veterans Stadium
Philadelphia
Navy 38–37–6

1981
Tie
3–3
Veterans Stadium
Philadelphia
Navy 38–37–7

1982
Navy
24–7
Veterans Stadium
Philadelphia
Navy 39–37–7

1983
Navy
42–13
Rose Bowl
Pasadena, California
Navy 40–37–7

1984
Army
28–11
Veterans Stadium
Philadelphia
Navy 40–38–7

1985
Navy
17–7
Veterans Stadium
Philadelphia
Navy 41–38–7

1986
Army
27–7
Veterans Stadium
Philadelphia
Navy 41–39–7

1987
Army
17–3
Veterans Stadium
Philadelphia
Navy 41–40–7

1988
Army
20–15
Veterans Stadium
Philadelphia
Tied 41–41–7

1989
Navy
19–17
Giants Stadium
East Rutherford, New Jersey
Navy 42–41–7

1990
Army
30–20
Veterans Stadium
Philadelphia
Tied 42–42–7

1991
Navy
24–3
Veterans Stadium
Philadelphia
Navy 43–42–7

1992
Army
25–24
Veterans Stadium
Philadelphia
Tied 43–43–7

1993
Army
16–14
Giants Stadium
East Rutherford, New Jersey
Army 44–43–7

1994
Army
22–20
Veterans Stadium
Philadelphia
Army 45–43–7

1995
Army
14–13
Veterans Stadium
Philadelphia
Army 46–43–7

1996
#23 Army
28–24
Veterans Stadium
Philadelphia
Army 47–43–7

1997
Navy
39–7
Giants Stadium
East Rutherford, New Jersey
Army 47–44–7

1998
Army
34–30
Veterans Stadium
Philadelphia
Army 48–44–7

1999
Navy
19–9
Veterans Stadium
Philadelphia
Army 48–45–7

2000
Navy
30–28
PSINet Stadium
Baltimore
Army 48–46–7

2001
Army
26–17
Veterans Stadium
Philadelphia
Army 49–46–7

2002
Navy
58–12
Giants Stadium
East Rutherford, New Jersey
Army 49–47–7

2003
Navy
34–6
Lincoln Financial Field
Philadelphia
Army 49–48–7

2004
Navy
42–13
Lincoln Financial Field
Philadelphia
Tied 49–49–7

2005
Navy
42–23
Lincoln Financial Field
Philadelphia
Navy 50–49–7

2006
Navy
26–14
Lincoln Financial Field
Philadelphia
Navy 51–49–7

2007
Navy
38–3
M&T Bank Stadium
Baltimore
Navy 52–49–7

2008
Navy
34–0
Lincoln Financial Field
Philadelphia
Navy 53–49–7

2009
Navy
17–3
Lincoln Financial Field
Philadelphia
Navy 54–49–7

2010
Navy
31–17
Lincoln Financial Field
Philadelphia
Navy 55–49–7

2011
Navy
27–21
FedExField
Landover, Maryland
Navy 56–49–7

2012
Navy
17–13
Lincoln Financial Field
Philadelphia
Navy 57–49–7

2013
Navy
34–7
Lincoln Financial Field
Philadelphia
Navy 58–49–7

2014
Navy
17–10
M&T Bank Stadium
Baltimore
Navy 59–49–7

2015
#21 Navy
21–17
Lincoln Financial Field
Philadelphia
Navy 60–49–7

2016
Army
21–17
M&T Bank Stadium
Baltimore
Navy 60–50–7

2017
Army
14–13
Lincoln Financial Field
Philadelphia
Navy 60–51–7

2018

Lincoln Financial Field
Philadelphia

2019

Lincoln Financial Field
Philadelphia

2020

Lincoln Financial Field
Philadelphia

2021

MetLife Stadium
East Rutherford, New Jersey

2022

Lincoln Financial Field
Philadelphia

text: Notable games[edit]

text: Navy Midshipman (and later Admiral) Joseph Mason Reeves wore what is widely regarded as the first football helmet in the 1893 Army–Navy Game. He had been advised by a Navy doctor that another kick to his head would result in intellectual disability or even death, so he commissioned an Annapolis shoemaker to make him a helmet out of leather.[16]

text: On November 27, 1926, the Army–Navy Game was held in Chicago for the National Dedication of Soldier Field as a monument to American servicemen who had fought in World War I. Navy came to the game undefeated, while West Point had only lost to Notre Dame, so the game would decide the National Championship. Played before a crowd of over 100,000, the teams fought to a 21–21 tie, but Navy was awarded the national championship.[17]

text: In both the 1944 and 1945 contests, Army and Navy entered the game ranked #1 and #2 respectively.[18] The 1945 game was labeled the "game of the century" before it was played. Army defeated a 7–0–1 Navy team 32–13. Navy's lone tie was against Notre Dame.[19]

text: In 1963, shortly after the assassination of President John F. Kennedy, Jacqueline Kennedy urged the academies to play after there had been talk of cancellation. Originally scheduled for November 30, 1963, the game was played on December 7, 1963 also coinciding with the 22nd anniversary of Pearl Harbor Day.[20] In front of a crowd of 102,000 people in Philadelphia's Municipal Stadium, later named John F. Kennedy Stadium, junior (second class Midshipman) quarterback Roger Staubach led number two ranked Navy to victory which clinched a Cotton Bowl national championship matchup with Texas played on January 1, 1964. Army was led by junior (second class Cadet) quarterback Rollie Stichweh. Stichweh led off the game with a touchdown drive that featured the first use of instant replay on television. Army nearly won the game after another touchdown and two point conversion, Stichweh recovered the onside kick and drove the ball to the Navy 2 yard line. On 4th down and no timeouts, crowd noise prevented Stichweh from calling a play and time expired with the 21–15 final score. Staubach won the Heisman Trophy that year and was bumped off the scheduled cover of Life magazine due to the coverage of the assassination. Stichweh and Staubach would meet again in 1964 as First Class where Stichweh's Army would defeat Staubach's Navy. Staubach went on to serve in the Navy and afterward became a Pro Football Hall of Fame quarterback with the Dallas Cowboys. Stichweh served five years in Vietnam with the 173rd Airborne Brigade. Stichweh was inducted into the Army Sports Hall of Fame in 2012.[21][22]

text: On December 10, 2016, Army beat Navy 21–17, snapping Navy's 14-year winning streak. This followed the death earlier in the season of Brandon Jackson, a defensive back from the Army side who died in a car accident on September 11, 2016.[23] Army players wore Jackson's number 28 on their uniforms in remembrance of their late teammate.[24]


document_title: Touchback

question_text: what is the new touchback rule in the nfl

text: Touchback

text: American football[edit]

text: In standard outdoor American football, the team awarded the touchback receives possession of the ball at its own 20-yard line in college football, and the 20 yard-line for professional football, on kickoffs and free kicks after a safety as of the 2012 season. In arena football, and other indoor football games, a touchback results in the team awarded the touchback receiving the football at its own 3-yard line. This can result from any of the above events except for punting, which is not a part of arena football. (In arena football, a kicked ball usually bounces back into play off of the rebound nets, but the above can still occur when the ball lands in the slack nets behind the goalposts after a kickoff, passes under the rebound nets and out of play, or in the event of fumbles and interceptions.)

text: On March 23, 2016, the NFL announced that it would award a touchback on kickoffs at the 25-yard line instead of the previous 20-yard line and much discussion and analysis on the impact of this change has emerged.[2] This new rule was to be re-evaluated after the 2016 NFL season.[3]

text: If a defensive player gains possession of the ball during a play between his own five-yard line and goal line and the player's original momentum carries him into the end zone, there is no touchback. Instead, the ball is dead at the point where possession changed. In the National Football League, this rule applies regardless of whether possession is gained inside the five-yard line.

text: In July 2016, the NCAA announced that it had approved the Ivy League to test an experimental kickoff rule in conference play in the 2016 season. Under this rule, kickoffs will be taken from the 40-yard line instead of the 35, and touchbacks will be marked at the 20-yard line instead of the 25. The rule will be re-evaluated in February 2017.[4]

text: Canadian football[edit]

text: In Canadian football the term touchback is not used. The failure to advance a kicked ball out of the goal area results in a single point being scored by the kickers, as well as possession by the receivers at their 35-yard line or at the point the ball was kicked from. A turn-over by fumble or interception in the defense's goal area that is not advanced back into the field of play, or a kickoff untouched out of bounds in the end zone, or a kick that touches the goal posts, crossbar, or goal assembly results in a scrimmage on the 25-yard line with no points awarded. If a player's momentum causes the ball to be in the end zone, the ball is treated as if it was recovered in the end zone.

text: Six- and eight-man football[edit]

text: For high schools which play six-man football and eight-man football on an 30-yard long field, a touchback is brought out to the 15-yard line.

text: Differences[edit]

text: A special rule applies in college football and the NFL with regard to field goal attempts. If a missed field goal occurs in these leagues, where the other team receives possession of the ball depends on the spot from which the ball has been kicked. In NCAA football, the ball will be placed either on the twenty or the line of scrimmage of the play in which the attempt was made; in the NFL, either the twenty or the place from which the ball was kicked. (In either case, the ball goes to the spot which is further from the goal line.) The purpose of this rule is to discourage low-percentage, long-range field goal attempts and to deemphasize the advantage which can accrue when only one team has a kicker who has a reasonable possibility of success from a great distance. In American high school football (except in Massachusetts and Texas, which use college football rules), the missed field goal, regardless of where attempted on the field, results in a touchback as long as the attempt breaks the plane of the goal line, and in arena football, the field goal is treated as if it were a punt.


document_title: Peter Ostrum

question_text: where is the boy who played charlie in willy wonka

text: Peter Ostrum

text: Acting career[edit]

text: Ostrum was in the sixth grade and performing at the Cleveland Play House children's theatre, when he was noticed by talent agents who were searching nationwide for the actor to portray Charlie Bucket in Willy Wonka & the Chocolate Factory. The agents took Polaroid photos of Ostrum and recorded him reading from the original novel, then returned to New York. Two months later Ostrum was called to New York for a screen test where he sang "My Country, 'Tis of Thee",[4] and a month after that he was contacted and given ten days to prepare to leave for filming.[6]

text: In 2000, Ostrum recalled that shooting Willy Wonka in Munich was "sort of like being an exchange student for five months". Fond memories of his five months in West Germany included watching the construction of Olympiapark, Munich, for the 1972 Summer Olympics, and working with Gene Wilder and Jack Albertson.[5][6] Ostrum was tutored on-set for three hours a day, though sometimes only for 30–60 minutes at a time.[7] Though in his audition he had been assured that his singing would probably be cut and dubbed, it was Ostrum's own singing voice that made it to the screen—albeit significantly cut.[5] In a 2011 interview, Ostrum told the story of how director Mel Stuart gave him a clapperboard from the film, and later on asked him how he got it because he had forgotten that he had done so; it is Ostrum's only souvenir from the set.[8] After he finished shooting Willy Wonka, the then 13-year-old Ostrum declined the offer of a three-film contract, later recalling that "[e]verybody thinks that acting is such a glamorous profession, but it's a difficult profession."[6] In January 2018, Ostrum said he sometimes misses acting—though not its hurry-up-and-wait nature—but feels he dodged having to make the transition from child- to adult-actor.[7]

text: As of January 2018[update], Ostrum still received US$8–9 in royalty payments about every three months.[7]

text: Lasting effect[edit]

text: In his senior year, Ostrum was involved in film class and, at the interest of one of his instructors, looked back into theatre and acting. After auditioning for, but not landing, several roles (including Equus on Broadway), Ostrum decided not to pursue it further.[9] After putting his short film career behind him, Ostrum declined reporters and interviews, preferring not to speak on the subject;[6] "I wanted people to judge me on who I was, not what I’d done".[10] For some time, Ostrum even lied and told people that his brother, and not he, had starred in the film.[1] It took Ostrum years after moving to Lowville before he told anybody there about his one-time stardom; even his wife Loretta did not know about his role until he warned her about it just before she met his mother.[5]

text: Since 1990, Ostrum has since spoken to students at Lowville Academy once a year—on the last day of school, as a special treat—about his experience in Willy Wonka as well as his work in veterinary medicine.[1] The students chiefly ask about the film's special effects, and Ostrum describes to them "what happened to Veruca, how did Violet blow up like a blueberry, how did Charlie fly with Grandpa Joe, all those types of questions."[5] Ostrum also accepted an invitation to appear at the 2018 Snowtown Film Festival in Watertown, New York, answering audience questions after a screening of the film; "it’s in my backyard — it's become a popular event in January and I like to support local events." Ostrum said of the 2018 event that he enjoyed re-watching the film, and that people ask him "great questions."[7] Ostrum has been called "the most famous man in Lowville", where the local video rental shop has twice worn out its VHS copy of Willy Wonka & the Chocolate Factory.[1]

text: In the run-up to the release of Charlie and the Chocolate Factory in 2005, Ostrum garnered a spate of attention that included seeing the film in New York City with NPR as well as being included in VH1's list of "100 Greatest Kid Stars" (placing 78th).[1] On the new film, Ostrum quoted fellow Wonka actor Julie Dawn Cole, saying that "It's sort of like going back to a house that you once lived in and it's been redecorated." Ultimately, the media attention was so pervasive that Ostrum stopped answering his phone, and requested "please, no more interviews."[5]

text: In January 2009, Ostrum teamed up with Dunkin' Donuts to hand out free rides on the Massachusetts Bay Transportation Authority (MBTA) at South Station in Boston, Massachusetts; Ostrum's participation connected the MBTA's CharlieCards he was handing out with his portrayal of Charlie Bucket in Willy Wonka. The promotion also gave out one "golden ticket", worth unlimited rides on MBTA and unlimited Dunkin' Donuts coffee for 2009.[11]

text: In October 2000, Ostrum and some of his co-stars from the film were scheduled to record an audio commentary for a special edition DVD.[6] In a 2010 interview, Wonka co-star Denise Nickerson (Violet Beauregarde) revealed that Ostrum had agreed to join her and Paris Themmen (Wonka's Mike Teevee) for a reunion commemorating the 40th anniversary of the film's release in 2011.[12]

text: Veterinary career[edit]

text:
I can remember the veterinarian coming out and taking care of the horses, and it made a huge impression on me, [...] This person really enjoyed what he did for a living. My father was a lawyer, and I really didn't have a clue what he did all day. But I knew exactly what the veterinarian did. Someone making a living from something he enjoyed so much really sparked my interest.

2000 interview with Peter Ostrum[6]

tag: div

text: Soon after Ostrum returned home from filming Willy Wonka, his family acquired a horse; while the teenaged Ostrum was interested in the horse, it was the animal's veterinarian that left a lasting impression on him. Taking a hiatus from school between high school and college, Ostrum groomed horses and worked at the Delaware Equine Center in Pennsylvania. Ostrum contemplated a return to Hollywood, and even visited California for a week to "test the waters" there. He ultimately decided to pursue a degree in veterinary medicine instead, feeling that he would forever berate himself if he didn't. In 1984, Peter Ostrum received his Doctorate of Veterinary Medicine from Cornell University College of Veterinary Medicine.[6]

text: As of February 2018[update], Ostrum worked out of the Countryside Veterinary Clinic in Lowville, New York, where he works mainly with horses and cows.[13][14] He has taken part in the video series Veterinarians on Call, funded by Pfizer, highlighting the work of large animal veterinarians.[13]

text: Personal life[edit]

text: Ostrum married Loretta M. Lepkowski in 1987 or 1988. The couple has two children, Helenka and Leif, with the latter following his father onto stage as the leading actor in several South Lewis Central School musicals.[7]


document_title: Cell cycle

question_text: the resting stage of the cell cycle is

question_tokens: the resting stage of the cell cycle is

text: Cell cycle

text: Phases[edit]

text: The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis). M phase is itself composed of two tightly coupled processes: karyokinesis, in which the cell's chromosomes are divided, and cytokinesis, in which the cell's cytoplasm divides forming two daughter cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.

text:
State
Phase
Abbreviation
Description

Resting
Gap 0
G0
A phase where the cell has left the cycle and has stopped dividing.

Interphase
Gap 1
G1
Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.

Synthesis
S
DNA replication occurs during this phase.

Gap 2
G2
During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.

Cell division
Mitosis
M
Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.

text: After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

text: G0 phase (quiescence)[edit]

text: G0 is a resting phase where the cell has left the cycle and has stopped dividing. The cell cycle starts with this phase. The word "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Non-proliferative (non-dividing) cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence occurs in response to DNA damage and external stress and usually constitutes an arrest in G1. Some cells enter the G0 phase semi-permanently and are considered post-mitotic, e.g., some liver, kidney, and stomach cells. Many cells do not enter G0 and continue to divide throughout an organism's life, e.g., epithelial cells.

text: Cellular senescence is also a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis.

text: Interphase (intermitosis)[edit]

text: Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during interphase. Interphase is a series of changes that takes place in a newly formed cell and its nucleus, before it becomes capable of division again. It is also called preparatory phase or intermitosis. Previously it was called resting stage because there is no apparent activity related to cell division.Typically interphase lasts for at least 91% of the total time required for the cell cycle.

text: Interphase proceeds in three stages, G1, S, and G2, followed by the cycle of mitosis and cytokinesis. The cell's nuclear DNA contents are duplicated during S phase but may continue till G2 in case of heterochromatin.

text: G1 phase (First growth phase or Post mitotic gap phase)[edit]

text: The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called G1 (G indicating gap). It is also called the growth phase. During this phase, the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate. The duration of G1 is highly variable, even among different cells of the same species.[3] In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size. In G1 phase, a cell has three options. (1) To continue cell cycle and enter S phase (2) Stop cell cycle and enter G0 phase for undergoing differentiation. (3) Get arrested in G1 phase hence it may enter G0 phase or re-enter cell cycle. The deciding factor is availability of nitrogens and storage of energy rich compounds at the deciding point called check point. This check point is called G1 cyclin or CG1. It causes transition of G1 to S phase. Once the check point of G1 phase is crossed, cell cycle will go uninterrupted till it is completed.

text: S phase (DNA replication)[edit]

text: The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase.[4][5][6]

text: G2 phase (growth)[edit]

text: G2 phase occurs after DNA replication and is a period of protein synthesis and rapid cell growth to prepare the cell for mitosis. During this phase microtubules begin to reorganize to form a spindle.

text: Mitotic phase (chromosome separation)[edit]

text: The relatively brief M phase consists of nuclear division (karyokinesis). It is a relatively short period of the cell cycle. M phase is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These phases are sequentially known as:

text:
prophase,
metaphase,
anaphase,
telophase

tag: ul

text: Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei.[7] During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell.[8]

text: Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.[9] Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.

text: Cytokinesis phase (separation of all cell components)[edit]

text: Mitosis is immediately followed by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.

text: Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called endoreplication. This occurs most notably among the fungi and slime moulds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.[10] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.

text: The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells.[8]

text: Regulation of eukaryotic cell cycle[edit]

text: Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.

text: Role of cyclins and CDKs[edit]

text:
Nobel Laureate
Paul Nurse

Nobel Laureate
Tim Hunt

text: Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle.[11] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules.[12] Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae;[13] genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g. cdc25 or cdc20.

text: Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.[14]

text: General mechanism of cyclin-CDK interaction[edit]

text: Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. However, results from a recent study of E2F transcriptional dynamics at the single-cell level argue that the role of G1 cyclin-CDK activities, in particular cyclin D-CDK4/6, is to tune the timing rather than the commitment of cell cycle entry.[15]

text: Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells.

text: Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.[16]

text: Specific action of cyclin-CDK complexes[edit]

text: Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (e.g. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (Rb). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S, which initiates the G2/M transition).[17] Cyclin B-cdk1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.[14] A quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells provided a quantitative framework for understanding the control logic of cell cycle entry, challenging the canonical textbook model. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment in cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression.[15]

text: Inhibitors[edit]

text: Two families of genes, the cip/kip (CDK interacting protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.

text: The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor of β (TGF β), a growth inhibitor.

text: The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14ARF which prevents p53 degradation.

text: Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.[18]

text: Transcriptional regulatory network[edit]

text: Current evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in Saccharomyces cerevisiae have identified 800–1200 genes that change expression over the course of the cell cycle.[13][19][20] They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated.[21]

text: Many periodically expressed genes are driven by transcription factors that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects.[22] Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression.[19][23] The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression).[20][24]

text: Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando et al. used microarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1 and S phase. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events.[20] Other work indicates that phosphorylation, a post-translational modification, of cell cycle transcription factors by Cdk1 may alter the localization or activity of the transcription factors in order to tightly control timing of target genes.[22][25][26]

text: While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded mRNA.[27]

text: DNA replication and DNA replication origin activity[edit]

text: Analyses of synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes.[28] This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression,[29][30][31] and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

text: Checkpoints[edit]

text: Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle.[32] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met. Checkpoints typically consist of a network of regulatory proteins that monitor and dictate the progression of the cell through the different stages of the cell cycle.

text: There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint.

text: G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[14] This is where the cell checks whether it has enough raw materials to fully replicate its DNA (nucleotide bases, DNA synthase, chromatin, etc.). An unhealthy or malnourished cell will get stuck at this checkpoint.

text: The G2/M checkpoint is where the cell ensures that it has enough cytoplasm and phospholipids for two daughter cells. But sometimes more importantly, it checks to see if it is the right time to replicate. There are some situations where many cells need to all replicate simultaneously (for example, a growing embryo should have a symmetric cell distribution until it reaches the mid-blastula transition). This is done by controlling the G2/M checkpoint.

text: The metaphase checkpoint is a fairly minor checkpoint, in that once a cell is in metaphase, it has committed to undergoing mitosis. However that's not to say it isn't important. In this checkpoint, the cell checks to ensure that the spindle has formed and that all of the chromosomes are aligned at the spindle equator before anaphase begins.[33]

text: While these are the three "main" checkpoints, not all cells have to pass through each of these checkpoints in this order to replicate. Many types of cancer are caused by mutations that allow the cells to speed through the various checkpoints or even skip them altogether. Going from S to M to S phase almost consecutively. Because these cells have lost their checkpoints, any DNA mutations that may have occurred are disregarded and passed on to the daughter cells. This is one reason why cancer cells have a tendency to exponentially accrue mutations. Aside from cancer cells, many fully differentiated cell types no longer replicate so they leave the cell cycle and stay in G0 until their death. Thus removing the need for cellular checkpoints. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.

text: Checkpoint regulation plays an important role in an organism's development. In sexual reproduction, when egg fertilization occurs, when the sperm binds to the egg, it releases signalling factors that notify the egg that it has been fertilized. Among other things, this induces the now fertilized oocyte to return from its previously dormant, G0, state back into the cell cycle and on to mitotic replication and division.

text: p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints. In addition to p53, checkpoint regulators are being heavily researched for their roles in cancer growth and proliferation.

text: Fluorescence imaging of the cell cycle[edit]

text: Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator (FUCCI), which enables fluorescence imaging of the cell cycle. Originally, a green fluorescent protein, mAG, was fused to hGem(1/110) and an orange fluorescent protein (mKO2) was fused to hCdt1(30/120). Note, these fusions are fragments that contain a nuclear localization signal and ubiquitination sites for degradation, but are not functional proteins. The green fluorescent protein is made during the S, G2, or M phase and degraded during the G0 or G1 phase, while the orange fluorescent protein is made during the G0 or G1 phase and destroyed during the S, G2, or M phase.[34] A far-red and near-infrared FUCCI was developed using a cyanobacteria-derived fluorescent protein (smURFP) and a bacteriophytochrome-derived fluorescent protein (movie found at this link).[35]

text: Role in tumor formation[edit]

text: A disregulation of the cell cycle components may lead to tumor formation.[36] As mentioned above, when some genes like the cell cycle inhibitors, RB, p53 etc. mutate, they may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue[citation needed]. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

text: The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle.[14]

text: The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.

text: In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S phase.

text: For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1.

text: The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural substances that protect cells from radiation damage and tend to be at their highest levels in S and at their lowest near mitosis.