Math Is Fun Forum

2231) Bullion

Bullion

Gist

Bullion is non-ferrous metal that has been refined to a high standard of elemental purity.

Summary

Bullion, the name applied to gold, silver, and platinum considered solely as metal without regard to any value arising from its form as coins or ornaments. The bullion value of a coin is determined by its weight, fineness (proportion of precious metal to total weight), and the current price of the metal.

When most countries dropped the silver standard for currency in the early 20th century, the silver bullion in subsidiary coins became worth considerably less than face value. The exception to this rule occurred when an issuing government inflated its paper currency and reduced its purchasing power to the point that it became profitable to melt coins for their bullion value. In the United States, the rising price of silver in the mid-1960s made it necessary to reduce the silver content of subsidiary coins to prevent their being melted down for their bullion value. Gold coins enjoy a value established by world markets for their bullion content.

The bulk of the world’s monetary gold is held in bars rather than coins, and it is kept as a reserve by countries and banks even though the era of the gold standard has passed. Individuals hoard gold when they fear either monetary or political instability. In doing so they lose any profit they might gain by investing the money and they incur storage costs. They also risk confiscation by the government of any profits resulting from currency devaluation, such as occurred during the Great Depression of the early 1930s. Nevertheless, the tangibility and ease of convertability of bullion made it an attractive option for some investors.

Details

Bullion is non-ferrous metal that has been refined to a high standard of elemental purity. The term is ordinarily applied to bulk metal used in the production of coins and especially to precious metals such as gold and silver. It comes from the Anglo-Norman term for a melting-house where metal was refined, and earlier from French bouillon, "boiling". Although precious metal bullion is no longer used to make coins for general circulation, it continues to be held as an investment with a reputation for stability in periods of economic uncertainty. To assess the purity of gold bullion, the centuries-old technique of fire assay is still employed, together with modern spectroscopic instrumentation, to accurately determine its quality.

As investment

The specifications of bullion are often regulated by market bodies or legislation. In the European Union, the minimum purity for gold to be referred to as "bullion", which is treated as investment gold with regard to taxation, is 99.5% for gold bullion bars and 90% for bullion coins. Investors may choose to purchase physical bullion for several reasons – to attempt to hedge against currency risks, inflation risks, geopolitical risks, or to add diversification to an investment portfolio.

London bullion market

The London bullion market is an over-the-counter market for wholesale trading of gold and silver. The London Bullion Market Association (LBMA) coordinates activities of its members and other participants in the London bullion market. The LBMA sets and promotes quality standards for gold and silver bullion bars. The minimum acceptable fineness of the Good Delivery Bars is 99.5% for gold bars and 99.9% for silver bars. Bars with a purity less than these may not be referred to as "bullion".

Coins

Bullion coins are contemporary precious metal coins minted by official agencies for investment purposes. Some bullion coins have been used as currency throughout the 20th century, such as the Maria Theresa thaler and the Krugerrand. Modern bullion coins generally do not enter common circulation despite having legal tender status and nominal face value. Some modern bullion coins are produced as business strike and collectible proof and uncirculated versions, such as the American Silver Eagle and American Gold Eagle coins. Private mint strikes called bullion rounds, bullion wafers or bullion bars are typically sold at prices slightly above the underlying prevailing precious metals spot price commensurate with their precious metal content, whereas collectible versions are sold at a significant premium over their precious metal bullion melt value. In some cases, the grade and mintages of privately struck rounds, bars or wafers can affect their value as a collectible too, they can at times be considered collectible numismatic pieces rather than bullion items.

Uses

Professional market participants participate in the bullion markets, such as banks, fabricators, refiners, and vault operators or transport companies, as well as brokers. They provide facilities for the refining, melting, assaying, transporting, trading and vaulting of gold and silver bullion. Other professional parties such as investment companies and jewelers use bullion in the context of products or services which they produce or offer to customers. Shares of the world's largest gold exchange-traded fund, the SPDR Gold Shares, represent a gold spot price mimicking derivative although shareholders in popular gold ETFs such as GLD are almost always unsecured creditors, meaning they own no vaulted gold bullion potentially underlying the exchange-traded fund (ETF).

Investors often prefer to own bullion outright over ETFs due to the minimization of counter-party risks inherent. Private individuals use bullion as an investment or as a store of value. Gold bullion and silver bullion are the most important forms of physical precious metals investments. Bullion investments can be considered as insurance against inflation or economic turmoil, their sole direct counterparty risk is theft or government confiscation. Compared to numismatic coins, bullion bars or bullion coins can typically be purchased and traded at lower price premiums over the fluctuating spot price and their trading bid/ask spreads or buy/sell price differences are closer to the values of the contained precious metals.

11) Muhammad Al-Karaji

Abū Bakr Muḥammad ibn al Ḥasan al-Karajī (c. 953 – c. 1029) was a 10th-century Persian mathematician and engineer who flourished at Baghdad. He was born in Karaj, a city near Tehran. His three principal surviving works are mathematical: Al-Badi' fi'l-hisab (Wonderful on calculation), Al-Fakhri fi'l-jabr wa'l-muqabala (Glorious on algebra), and Al-Kafi fi'l-hisab (Sufficient on calculation).

Work

Al-Karaji wrote on mathematics and engineering. Some consider him to be merely reworking the ideas of others (he was influenced by Diophantus) but most regard him as more original, in particular for the beginnings of freeing algebra from geometry. Among historians, his most widely studied work is his algebra book al-fakhri fi al-jabr wa al-muqabala, which survives from the medieval era in at least four copies.

In his book "Extraction of hidden waters" he has mentioned that earth is spherical in shape but considers it the centre of the universe long before Galileo Galilei, Johannes Kepler or Isaac Newton, but long after Aristotle and Ptolemy. He expounded the basic principles of hydrology and this book reveals his profound knowledge of this science and has been described as the oldest extant text in this field.

He systematically studied the algebra of exponents, and was the first to define the rules for monomials like x,x²,x³ and their reciprocals in the cases of multiplication and division. However, since for example the product of a square and a cube would be expressed, in words rather than in numbers, as a square-cube, the numerical property of adding exponents was not clear.

His work on algebra and polynomials gave the rules for arithmetic operations for adding, subtracting and multiplying polynomials; though he was restricted to dividing polynomials by monomials.

F. Woepcke was the first historian to realise the importance of al-Karaji's work and later historians mostly agree with his interpretation. He praised Al-Karaji for being the first who introduced the theory of algebraic calculus.

Al-Karaji gave the first formulation of the binomial coefficients and the first description of Pascal's triangle. He is also credited with the discovery of the binomial theorem.

Hi,

#2631. What does the medical term 'Hypoprothrombinemia' mean?

Hi,

#9285.

Determinant - IV

Definition

Let A be a square matrix with n rows and n columns, so that it can be written as

{\displaystyle A={\begin{bmatrix}a_{1,1}&a_{1,2}&\cdots &a_{1,n}\\a_{2,1}&a_{2,2}&\cdots &a_{2,n}\\\vdots &\vdots &\ddots &\vdots \\a_{n,1}&a_{n,2}&\cdots &a_{n,n}\end{bmatrix}}.}

gives

The entries

{\displaystyle a_{1,1}}

gives

The determinant of A is denoted by det(A), or it can be denoted directly in terms of the matrix entries by writing enclosing bars instead of brackets:

{\displaystyle {\begin{vmatrix}a_{1,1}&a_{1,2}&\cdots &a_{1,n}\\a_{2,1}&a_{2,2}&\cdots &a_{2,n}\\\vdots &\vdots &\ddots &\vdots \\a_{n,1}&a_{n,2}&\cdots &a_{n,n}\end{vmatrix}}.}

gives

There are various equivalent ways to define the determinant of a square matrix A, i.e. one with the same number of rows and columns: the determinant can be defined via the Leibniz formula, an explicit formula involving sums of products of certain entries of the matrix. The determinant can also be characterized as the unique function depending on the entries of the matrix satisfying certain properties. This approach can also be used to compute determinants by simplifying the matrices in question.

2230) Horse Management

Gist

A building in which horses are kept, fed, and cared for. Stable is a building where horses are kept.
She rode the horse back to the stable. A horse stable.

Summary

Horses were among the last species of livestock to be domesticated. Domestication took place at least as early as 3000 BCE, probably in the Near East. The wild math, which when domesticated is usually called a donkey, was first domesticated in Egypt about 3400 BCE.

Breeds

The Arabian, the oldest recognized breed of horse in the world, is thought to have originated in Arabia before 600 CE. Though its history is lost in the past, the breed probably descended from the Libyan horse, which in turn was probably preceded by horses of similar characteristics in Assyria, Greece, and Egypt as early as 1000 BCE. The Arabian may be bay, gray, chestnut, brown, black, or white in hair colour but always has a black skin. It ranges from 14.1 to 15.1 hands (4.7 to 5.0 feet, or 1.4 to 1.5 metres) in height. The Arabian horse has one lumbar vertebra less than other breeds of horse and is characterized by the high carriage of its head, long neck, and spirited action.

The Thoroughbred racing horse is descended from three desert stallions brought to England between 1689 and 1724; all of the Thoroughbreds of the world today trace their ancestry to one of these stallions.

The American Saddle Horse, which originated in the United States, was formed by crossing Thoroughbreds, Morgans, and Standardbreds on native mares possessing an easy gait. The American Saddle Horse is 15 to 16 hands (5 to 5.3 feet, or 1.5 to 1.6 metres) in height. Its colours are bay, brown, black, gray, and chestnut. There are two distinct types of the American Saddle Horse: three-gaited and five-gaited. The three natural gaits are walk, trot, and canter. Three-gaited saddle horses are shown with a short tail and cropped mane. They often have slightly less style and finish than the five-gaited horse. The five-gaited saddle horse has the three natural gaits plus the rack and a slow gait, which is usually a stepping pace. The American Saddle Horse is also used as a fine harness horse mainly for show.

The American Quarter Horse traces to the Thoroughbred, and includes the blood of other breeds, such as the Morgan, the American Saddle Horse, and several strains of native horses. This fast, muscular horse has been raced, ridden in rodeos, and used for herding cattle.

The typical Quarter Horse is 15 to 16 hands tall and is of powerful build, suitable for both racing and the rough life of a cow pony. This horse is noted for its intelligence, easy disposition, and cow sense.

The Tennessee Walking Horse, or plantation horse, traces mainly to the Standardbred but also includes Thoroughbred and American Saddle Horse blood. The Tennessee Walking Horse is noted for its running walk, a slowgliding gait in which the hind foot oversteps the print of the front foot by as much as 24 inches (600 millimetres). This breed is 15.2 to 16 hands high and is bay, black, chestnut, roan, or gray in colour.

The Morgan traces directly to “the Justin Morgan horse,” foaled in 1793, of unknown breeding but no doubt tracing to Arabian stock. A dark bay in colour, Morgan stood 14 hands high and weighed 950 pounds (430 kilograms). He was a heavily muscled, short-legged horse of great style, quality, and endurance. He is the world’s best example of prepotency, since he alone founded the Morgan breed. The Morgan is used for both riding and driving. It ranges from 14 to 16 hands in height and resembles the Arabian in size, conformation, quality, and endurance.

The American Standardbred originated around New York City during the first half of the 19th century from Thoroughbred, Morgan, Norfolk Trotter, Arabian, Barb, and pacers of mixed breeding. The modern Standardbred is smaller than the Thoroughbred, ranging from 15 to 16 hands in height and averaging about 15.2 hands. In racing condition it weighs from 900 to 1,000 pounds (410–450 kilograms). Stallions in stud condition average from 1,100 to 1,200 pounds (500–545 kilograms). Compared with the Thoroughbred, the Standardbred is longer-bodied, shorter-legged, heavier-boned, and stockier in build. Prevailing colours are bay, brown, and chestnut.

Draft horses have largely been supplanted by trucks and tractors in the developed countries of the world. Major draft breeds include the Percheron, developed in France; the Clydesdale of Scotland; the Shire of England; the Suffolk of England; and the Belgian of Belgium. These breeds range from 151/2 to 17 hands in height at the withers; at maturity the mares weigh from 1,600 to 2,000 pounds (720–900 kilograms) and the stallions from 1,900 to 2,200 pounds (860–1000 kilograms).

The more popular pony breeds are the Shetland, which originated in the Shetland Islands, and the Hackney, of English origin. Ponies must be under 14.2 hands in height at the withers and are used both for show and for children’s pleasure.

Details

A stable is a building in which livestock, especially horses, are kept. It most commonly means a building that is divided into separate stalls for individual animals and livestock. There are many different types of stables in use today; the American-style barn, for instance, is a large barn with a door at each end and individual stalls inside or free-standing stables with top and bottom-opening doors.The term "stable" is additionally utilised to denote a collection of animals under the care of a single owner, irrespective of their housing or whereabouts.

The exterior design of a stable can vary widely, based on climate, building materials, historical period and cultural styles of architecture. A wide range of building materials can be used, including masonry (bricks or stone), wood and steel. Stables also range widely in size, from a small building housing one or two animals to facilities at agricultural shows or race tracks that can house hundreds of animals.

History

The stable is typically historically the second-oldest building type on the farm. The world's oldest horse stables were discovered in the ancient city of Pi-Ramesses in Qantir, in Ancient Egypt, and were established by Ramesses II (c. 1304–1213 BC). These stables covered approximately 182,986 square feet, had floors sloped for drainage, and could contain about 480 horses. Free-standing stables began to be built from the 16th century. They were well built and placed near the house because these animals were highly valued and carefully maintained. They were once vital to the economy and an indicator of their owners' position in the community. Relatively few examples survive of complete interiors (i.e. with stalls, mangers and feed racks) from the mid-19th century or earlier.

Traditionally, stables in Great Britain had a hayloft on their first (i.e. upper) floor and a pitching door at the front. Doors and windows were symmetrically arranged. Their interiors were divided into stalls and usually included a large stall for a foaling mare or sick horse. The floors were cobbled (or, later, bricked) and featured drainage channels. An outside stone stairway constructed against the side of the building was common for reaching the upper level.

Horses

For horses, stables are often part of a larger complex which includes trainers, vets and farriers.

Other uses

The word stable is also used metonymically to refer to the collection of horses that the building contains (for example, the college's stable includes a wide variety of breeds) and even, by extension, metaphorically to refer to a group of people—often (but not exclusively) athletes—trained, coached, supervised or managed by the same person or organisation. For example, art galleries typically refer to the artists they represent as their stable of artists. Analogously, car enthusiast magazines sometimes speak of collectible cars in this way, referring to the cars in a collector's stable (most especially when the metaphor can play on the word association of pony cars).

Historically, the headquarters of a unit of cavalry, not simply their horses' accommodation, was known as a "stable".

Additional Information

There are many aspects to horse management. Horses, ponies, mules, donkeys and other domesticated equids require attention from humans for optimal health and long life.

Living environment

Horses require both shelter from natural elements like wind and precipitation, as well as room to exercise. Worldwide, horses and other equids usually live outside with access to shelter for protection from the elements. In some cases, animals are kept in a barn or stable for ease of access by managers, or for protection from the weather for various reasons. For horse owners who do not own their own land, fields and barns can be rented from a private land owner or space for an individual horse may be rented from a boarding farm. Horses that are not on full-time turnout in a field or pasture normally require some form of regular exercise, whether it is being ridden, longed or turned out for free time. However, if a horse is ill or injured it may need to be confined to a stable, usually in a box stall.

As equines are herd animals, most have better mental behavior when in proximity to other equine company. However, this is not always possible, and it has been known for companionship bonds to develop between horses and cats, goats and other species. There are exceptions. Some horses, particularly stallions are often kept separated from other horses, particularly other males they may challenge for dominance. For safety and monitoring, Mares may be separated from a herd prior to foaling.

Horses require access to clean fresh water at all times, and access to adequate forage such as grass or hay. Unless an animal can be fully maintained on pasture with a natural open water source, horses must be fed daily. As horses evolved as continuous grazers, it is better to feed small amounts of feed throughout the day than to feed a large amount at one time.

Horses in blankets

In the winter, horses grow a heavy hair coat to keep warm and usually stay warm if well-fed and allowed access to shelter. But if kept artificially clipped for show, or if under stress from age, sickness or injury, a horse blanket may need to be added to protect the horse from cold weather. In the summer, access to shade is well-advised.

Pastures

If a horse is kept in a pasture, the amount of land needed for basic maintenance varies with climate, an animal needs more land for grazing in a dry climate than in a moist one. An average of between one and 3 acres (12,000 m^2) of land per horse will provide adequate forage in much of the world, though hay or other feed may have to be supplemented in winter or during periods of drought. To lower the risk of laminitis, horses also may need to be removed from lush, rapidly changing grass for short periods in the spring and fall (autumn), when the grass is particularly high in non-structural carbohydrates such as fructans. Horses turned out to pasture full-time still need to be checked frequently for evidence of injury, parasites, sickness or weight loss.

If the terrain does not provide natural shelter in the form of heavy trees or other windbreaks, an artificial shelter must be provided; a horse's insulating hair coat works less efficiently when wet or when subjected to wind, horses that cannot get away from wind and precipitation put unnecessary energy into maintaining core body warmth and may become susceptible to illness.

Horses cannot live for more than a few days without water. Therefore, even in a natural, semi-feral setting, a check every day is recommended; a stream or irrigation source can dry up, ponds may become stagnant or develop toxic blue-green algae, a fence can break and allow escape, poisonous plants can take root and grow; windstorms, precipitation, or even human vandalism can create unsafe conditions.

Pastures should be rotated when plants are grazed down to avoid overgrazing or deterioration of pasture quality. Manure management is also improved by pasture rotation; horses will not eat grass that contains too much of their own manure and such areas are a breeding ground for parasites. Decomposition of the manure needs to be allowed while the horses are kept in an alternative paddock.

Fences and pens

Horses evolved to live on prairie grasslands and to cover long distances unfettered by artificial barriers. Therefore, when fenced in, accident potential must be considered. Horses will put their heads and legs through fences in an attempt to reach forage on the other side. They may run into fences if chased by another animal, or even when running at play if the fence (such as a wire fence) is not particularly visible. The smaller the area, the more visible and substantial a fence needs to be.

For exercise alone, a pen, run, corral or "dry lot" without forage can be much smaller than a pasture, and this is a common way that many horses are managed; kept in a barn with a turnout run, or in a dry lot with a shelter, feeding hay, allowing either no pasture access, or grazing for only a few hours per day. Outdoor turnout pens range greatly in size, but 12 feet (4 m) by 20 to 30 feet (9 m) is a bare minimum for a horse that does not get ridden daily. To gallop for short stretches, a horse needs a "run" of at least 50 to 100 feet (30 m). When kept in a dry lot, a barn or shelter is a must. If kept in a small pen, a horse needs to be worked regularly or turned out in a larger area for free exercise.

Fences in pens must be sturdy. In close quarters, a horse may contact the fence frequently. Wire is very dangerous in any small pen. Pens are often made of metal pipe, or wood. Larger pens are sometimes enclosed in closely woven mesh, sometimes called "no climb" fencing. However, if a wire mesh is used in a small pen, the openings must be too small for a horse hoof to pass through.

Types of fencing

Over vast areas, barbed wire is often seen in some parts of the world, but it is the most dangerous fencing material that can be used around horses, even in a large pasture. If a horse is caught in barbed wire, it can quickly become severely hurt, often leaving lasting scars or even permanent injuries. Horse management books and periodicals are nearly universal in stating that barbed wire should never be used to contain horses. However, this advice is widely ignored, particularly in the western United States.

Various types of smooth wire fencing, particularly when supported by a strand of electric fence, can be used to enclose a large pasture of several acres, and is one of the least expensive fencing options. A wire fence should have at least four, preferably five strands to provide adequate security. However, even without sharp barbs, wire has the highest potential for horses to become tangled in the fence and injured. If used, it must be properly installed and kept tight through regular maintenance. Visibility is also an issue; a horse galloping in an unfamiliar pasture may not see a wire fence until it is too late to stop.

Woven mesh wire is safer but more expensive than strands of smooth wire. It is more difficult to install, and has some visibility issues, but horses are less likely to become tangled in it or be injured if they run into it. Adding a top rail of wood or synthetic material increases visibility of the fence and prevents it from being bent by horses reaching over it. A strand of electric fence may also keep horses from pushing on a mesh fence. Mesh fencing needs to be heavy-gauge wire, woven, not welded, and the squares of the mesh should be too small for a horse to put a foot through. "Field fence" or "no-climb" fence are safer designs than more widely woven "sheep fence." Chain link fence is occasionally seen, but horses can bend chain link almost as easily as a thinner-gauge wire, so the additional expense is often not justified by any gain over good-quality woven wire.

Electric fence comes in many styles of wire, rope and webbing, and is particularly useful for internal division of pastures. It carries only a mild charge that causes a noticeable shock, but no permanent injury to animals or people. It is relatively inexpensive and is easy to install, but if electricity fails, it is easily broken. It is excellent both as a temporary fence and, in single strands, as a top or middle barrier to keep horses away from conventional fencing. There is some danger that horses can become tangled in an electric fence, though because the materials are finer, it usually breaks, stopping the current, though injuries are still possible. Because electricity can fail, it should not be the sole fencing used on property boundaries, particularly next to roads, though a strand on top may be used to keep a horse from leaning over a fence made of other materials. Nor should it be used alone in small pens where horses may accidentally bump into it on a regular basis. However, small single-horse enclosures are sometimes seen at endurance riding competition, where temporary fencing must be set up in remote areas. In residential areas, warning signs should be posted on any boundary fences with electrified sections to keep people from touching the fence and accidentally being shocked.

Wood is the "classic" form of horse fencing, either painted planks or natural round rails. It is one of the safest materials for containing horses. Wood or a synthetic material with similar properties is the best option for small paddocks, pens and corrals. It can be used to fence pastures and has some ability to give or break if a horse collides with it. However, wood is expensive, high maintenance and not completely without safety concerns; boards can splinter, nails can stick out and cause lacerations. Wood-like synthetics are even more expensive, but are often safer and lower maintenance.

Cable of various sorts is sometimes used for horse fencing, and, especially if combined with a top rail or pipe or wood, can be reasonably safe. However, if cable is not kept tight, like wire, horses can be tangled in it. However, it not only cannot break but unlike wire, it also cannot easily be cut by humans. Its advantage over wire is that it poses less of a risk of entanglement. It is often less expensive than wood or pipe, has some give if a horse runs into it, and requires relatively little maintenance.

Metal pipe is often used for fences instead of wood and if properly installed, can be fairly safe in the right circumstances. Pipe is often the most expensive fencing option, but is low maintenance and is very strong. Pipe will generally not give or break if it is run into or if the horse puts a foot through it, which can itself be a potential injury risk; horse owners debate the relative merits and dangers of pipe versus wood for horse fencing. Usually pipe is most suitable for very small areas such as pens where a horse may often bump or test the fence, but will not be at risk of colliding with the fence at full speed.

Barns and stables

Horses are sometimes kept indoors.

A horse can be kept in a box stall. Mares with foals often are kept in double stalls.

Feeding

A horse or pony needs approximately 1.5% to 2.5% of its body weight in food per day, depending on its age and level of work.

Grooming

Horses groomed regularly have healthier and more attractive coats. Many horse management handbooks recommend grooming a horse daily, though for the average modern horse owner, this is not always possible. However, a horse should always be groomed before being ridden to avoid chafing and rubbing of dirt and other material, which can cause sores on the animal and also grind dirt into horse tack. Grooming also allows the horse handler to check for injuries and is a good way to gain the trust of the animal.

2000) Kary Mullis

Summary

Kary Mullis (born December 28, 1944, Lenoir, North Carolina, U.S.—died August 7, 2019, Newport Beach, California) was an American biochemist, cowinner of the 1993 Nobel Prize for Chemistry for his invention of the polymerase chain reaction (PCR), a simple technique that allows a specific stretch of DNA to be copied billions of times in a few hours.

After receiving a doctorate in biochemistry from the University of California, Berkeley, in 1973, Mullis held research posts at various universities. In 1979 he joined Cetus Corp., a California biotechnology firm, where he carried out his prizewinning research. From 1986 to 1988 he was director of molecular biology for Xytronyx, Inc., in San Diego, California; thereafter he worked as a freelance consultant.

Mullis developed PCR in 1983. Earlier methods for obtaining a specific sequence of DNA in quantities sufficient for study were difficult, time-consuming, and expensive. PCR uses four ingredients: the double-stranded DNA segment to be copied, called the template DNA; two oligonucleotide primers (short segments of single-stranded DNA, each of which is complementary to a short sequence on one of the strands of the template DNA); nucleotides, the chemical building blocks that make up DNA; and a polymerase enzyme that copies the template DNA by joining the free nucleotides in the correct order. These ingredients are heated, causing the template DNA to separate into two strands. The mixture is cooled, allowing the primers to attach themselves to the complementary sites on the template strands. The polymerase is then able to begin copying the template strands by adding nucleotides onto the end of the primers, producing two molecules of double-stranded DNA. Repeating this cycle increases the amount of DNA exponentially: some 30 cycles, each lasting only a few minutes, will produce more than a billion copies of the original DNA sequence.

PCR has extremely wide applications. In medical diagnostics the technique made it possible to identify the causative agent of a bacterial or viral infection directly from a very small sample of genetic material; it was also used to screen patients for genetic disorders such as sickle cell anemia and Huntington’s chorea.

Details

Kary Banks Mullis (December 28, 1944 – August 7, 2019) was an American biochemist. In recognition of his role in the invention of the polymerase chain reaction (PCR) technique, he shared the 1993 Nobel Prize in Chemistry with Michael Smith and was awarded the Japan Prize in the same year. PCR became a central technique in biochemistry and molecular biology, described by The New York Times as "highly original and significant, virtually dividing biology into the two epochs of before PCR and after PCR."

Mullis downplayed humans' role in climate change, expressed doubt that HIV is the cause of AIDS, and professed a belief in astrology and the paranormal. Mullis's unscientific statements about topics outside his area of expertise have been named by Skeptical Inquirer as an instance of "Nobel disease".

Early life and education

Mullis was born in Lenoir, North Carolina, near the Blue Ridge Mountains, on December 28, 1944, to Cecil Banks Mullis and Bernice Barker Mullis. His family had a background in farming in this rural area. As a child, Mullis said, he was interested in observing organisms in the countryside. He and his cousins would often taunt livestock by feeding them through electric fences, and Kary was mostly interested in the spiders in his grandparents' basement. He grew up in Columbia, South Carolina, where he attended Dreher High School, graduating in the class of 1962. He recalled his interest in chemistry beginning when he learned how to chemically synthesize and build solid fuel propulsion rockets as a high school student during the 1960s.

He earned a Bachelor of Science in chemistry from the Georgia Institute of Technology in Atlanta in 1966, during which time he married his first wife, Richards Haley, and started a business. He earned his PhD in 1973 in biochemistry at the University of California, Berkeley (UC Berkeley), in J. B. Neilands' laboratory, which focused on synthesis and structure of bacterial iron transporter molecules. Although he published a sole-author paper in Nature in the field of astrophysics in 1968, he struggled to pass his oral exams (with a colleague recalling that "He didn’t get his propositions right. He didn’t know general biochemistry"), and his dissertation was accepted only after several friends pitched in to "cut all the whacko stuff out of it" while his advisor lobbied the committee to reconsider its initial decision.

His doctoral dissertation was on the structure of the bacterial siderophore schizokinen. J. B. Neilands was known for his groundbreaking work on siderophores, and Mullis was a part of that with his characterization of schizokinen. Following his graduation, Mullis completed postdoctoral fellowships in pediatric cardiology at the University of Kansas Medical Center (1973–1977) and pharmaceutical chemistry at the University of California, San Francisco (1977–1979).

Career

After receiving his doctorate, Mullis briefly left science to write fiction before accepting the University of Kansas fellowship. During his postdoctoral work, he managed a bakery for two years. Mullis returned to science at the encouragement of UC Berkeley friend and colleague Thomas White, who secured Mullis's UCSF position and later helped Mullis land a position with the biotechnology company Cetus Corporation of Emeryville, California. Despite little experience in molecular biology, Mullis worked as a DNA chemist at Cetus for seven years, ultimately serving as head of the DNA synthesis lab under White, then the firm's director of molecular and biological research; it was there, in 1983, that Mullis invented the polymerase chain reaction (PCR) procedure.

Mullis acquired a reputation for erratic behavior at Cetus, once threatening to bring a gun to work; he also engaged in "public lovers' quarrels" with his then-girlfriend (a fellow chemist at the company) and "nearly came to blows with another scientist" at a staff party, according to California Magazine. White recalled: "It definitely put me in a tough spot. His behavior was so outrageous that the other scientists thought that the only reason I didn't fire him outright was that he was a friend of mine."

After resigning from Cetus in 1986, Mullis served as director of molecular biology for Xytronyx, Inc. in San Diego for two years. While inventing a UV-sensitive ink at Xytronyx, he became skeptical of the existence of the ozone hole.

Thereafter, Mullis worked intermittently as a consultant for multiple corporations and institutions on nucleic acid chemistry and as an expert witness specializing in DNA profiling. In 1992, Mullis founded a business to sell pieces of jewelry containing the amplified DNA of deceased famous people such as Elvis Presley and Marilyn Monroe. In the same year, he also founded Atomic Tags in La Jolla, California. The venture sought to develop technology using atomic-force microscopy and bar-coded antibodies tagged with heavy metals to create highly multiplexed, parallel immunoassays.

Mullis was a member of the USA Science and Engineering Festival's Advisory Board. In 2014, he was named a distinguished researcher at the Children's Hospital Oakland Research Institute in Oakland, California.

PCR (Polymerase Chain Reaction) and other inventions

In 1983, Mullis was working for Cetus Corporation as a chemist. Mullis recalled that, while driving in the vicinity of his country home in Mendocino County (with his girlfriend, who also was a chemist at Cetus), he had the idea to use a pair of primers to bracket the desired DNA sequence and to copy it using DNA polymerase; a technique that would allow rapid amplification of a small stretch of DNA and become a standard procedure in molecular biology laboratories. Longtime professional benefactor and supervisor Thomas White reassigned Mullis from his usual projects to concentrate on PCR full-time after the technique was met with skepticism by their colleagues. Mullis succeeded in demonstrating PCR on December 16, 1983, but the staff remained circumspect as he continued to produce ambiguous results amid alleged methodological problems, including a perceived lack of "appropriate controls and repetition." In his Nobel Prize lecture, he remarked that the December 16 breakthrough did not make up for his girlfriend breaking up with him: "I was sagging as I walked out to my little silver Honda Civic. Neither [assistant] Fred, empty Beck's bottles, nor the sweet smell of the dawn of the age of PCR could replace Jenny. I was lonesome."

Other Cetus scientists who were regarded as "top-notch experimentalists", including Randall Saiki, Henry Erlich, and Norman Arnheim, were placed on parallel PCR projects to work on determining if PCR could amplify a specific human gene (betaglobin) from genomic DNA. Saiki generated the needed data and Erlich authored the first paper to include use of the technique, while Mullis was still working on the paper that would describe PCR itself. Mullis's 1985 paper with Saiki and Erlich, "Enzymatic Amplification of β-globin Genomic Sequences and Restriction Site Analysis for Diagnosis of Sickle Cell Anemia" — the polymerase chain reaction invention (PCR) — was honored by a Citation for Chemical Breakthrough Award from the Division of History of Chemistry of the American Chemical Society in 2017.

A drawback of the technique was that the DNA polymerase in the reaction was destroyed by the high heat used at the start of each replication cycle and had to be replaced. In 1986, Saiki started to use Thermophilus aquaticus (Taq) DNA polymerase to amplify segments of DNA. The Taq polymerase was heat resistant and needed to be added to the reaction only once, making the technique dramatically more affordable and subject to automation. This modification of Mullis's invention revolutionized biochemistry, molecular biology, genetics, medicine, and forensics. UC Berkeley biologist David Bilder said, "PCR revolutionized everything. It really superpowered molecular biology—which then transformed other fields, even distant ones like ecology and evolution. … It’s impossible to overstate PCR’s impact. The ability to generate as much DNA of a specific sequence as you want, starting from a few simple chemicals and some temperature changes—it’s just magical." Although he received a $10,000 bonus from Cetus for the invention, the company's later sale of the patent to Roche Molecular Systems for $300 million would lead Mullis to condemn White and members of the parallel team as "vultures."

Mullis also invented a UV-sensitive plastic that changes color in response to light.

He founded Altermune LLC in 2011 to pursue new ideas on the immune system. Mullis described the company's product thusly:

It is a method using specific synthetic chemical linkers to divert an immune response from its nominal target to something completely different which you would right now like to be temporarily immune to. Let's say you just got exposed to a new strain of the flu. You’re already immune to alpha-1,3-galactosyl-galactose bonds. All humans are. Why not divert a fraction of those antibodies to the influenza strain you just picked up. A chemical linker synthesized with an alpha-1,3-gal-gal bond on one end and a DNA aptamer devised to bind specifically to the strain of influenza you have on the other end, will link anti-alpha-Gal antibodies to the influenza virus and presto, you have fooled your immune system into attacking the new virus.

In a TED Talk, Mullis describes how the US Government paid $500,000 for Mullis to use this new technology against anthrax. He said the treatment was 100% effective, compared to the previous anthrax treatment which was 40% effective.

Another proof-of-principle of this technology, re-targeting pre-existing antibodies to the surface of a pathogenic strep bacterium using an alpha-gal modified aptamer ("alphamer"), was published in 2015 in collaboration with scientists at the University of California, San Diego. Mullis said he was inspired to fight this particular strep bacterium because it had killed his friend.

Accreditation of the PCR technique

A concept similar to that of PCR had been described before Mullis's work. Nobel laureate H. Gobind Khorana and Kjell Kleppe, a Norwegian scientist, authored a paper 17 years earlier describing a process they termed "repair replication" in the Journal of Molecular Biology. Using repair replication, Kleppe duplicated and then quadrupled a small synthetic molecule with the help of two primers and DNA polymerase. The method developed by Mullis used repeated thermal cycling, which allowed the rapid and exponential amplification of large quantities of any desired DNA sequence from an extremely complex template. Later a heat-stable DNA polymerase was incorporated into the process.

His co-workers at Cetus contested the notion that Mullis was solely responsible for the idea of using Taq polymerase in PCR. However, biochemist Richard T. Pon has written that the "full potential [of PCR] was not realized" until Mullis's work in 1983, and journalist Michael Gross states that Mullis's colleagues failed to see the potential of the technique when he presented it to them. As a result, some controversy surrounds the balance of credit that should be given to Mullis versus the team at Cetus. In practice, credit has accrued to both the inventor and the company (although not its individual workers) in the form of a Nobel Prize and a $10,000 Cetus bonus for Mullis and $300 million for Cetus when the company sold the patent to Roche Molecular Systems. After DuPont lost out to Roche on that sale, the company unsuccessfully disputed Mullis's patent on the alleged grounds that PCR had been previously described in 1971. Mullis and Erlich took Cetus' side in the case, and Khorana refused to testify for DuPont; the jury upheld Mullis's patent in 1991. However, in February 1999, the patent of Hoffman-La Roche (United States Patent No. 4,889,818) was found by the courts to be unenforceable, after Dr. Thomas Kunkel testified in the case Hoffman-La Roche v. Promega Corporation on behalf of the defendants (Promega Corporation) that "prior art" (i.e. articles on the subject of Taq polymerase published by other groups prior to the work of Gelfand and Stoffel, and their patent application covering the purification of Taq polymerase) existed, in the form of two articles, published by Alice Chien et al. in 1976, and A. S. Kaledin et al. in 1980.

The anthropologist Paul Rabinow wrote a book on the history of the PCR method in 1996, in which he discusses whether Mullis "invented" PCR or merely came up with the concept of it.

Views on HIV/AIDS and climate change

In his 1998 autobiography, Mullis expressed disagreement with the scientific evidence for humans' role in climate change and ozone depletion. Mullis claimed that scientific theories about ozone depletion and climate change were the product of scientists and government bureaucrats conspiring to secure funding, saying that "science is being practiced by people who are dependent on being paid for what they are going to find out" instead of searching for the truth. The New York Times listed Mullis as one of several scientists who, after success in their area of research, go on to make unfounded, sometimes bizarre statements in other areas, especially in regard to contradicting the scientific consensus on climate change and ozone depletion.

Mullis also questioned the scientific validity of the link between HIV and AIDS, despite never having done any scientific research on either subject, leading Seth Kalichman and Paroma Basu to call him an AIDS denialist. He wrote that he began to question the AIDS consensus while compiling a report for a project's sponsor and being unable to find a published reference for HIV being the cause of AIDS. Mullis published an alternative hypothesis for AIDS in 1994, claiming that AIDS is an arbitrary diagnosis used when HIV antibodies are found in a patient's blood. Seth Kalichman, AIDS researcher and author of Denying AIDS, names Mullis "among the who's who of AIDS pseudoscientists". Mullis was often cited in the press as a supporter of molecular biologist and AIDS denialist Peter Duesberg. According to California Magazine, Mullis's HIV skepticism influenced Thabo Mbeki's denialist policymaking throughout his tenure as president of South Africa from 1999 to 2008, contributing to as many as 330,000 unnecessary deaths.

According to Skeptical Inquirer, Mullis's statements on HIV/AIDS and human-caused climate change are an instance of "Nobel disease", i.e. the tendency of some Nobel laureates to go on to embrace ideas that are scientifically implausible, rejected by most scientific experts, and based mostly on anecdotal or uncorroborated evidence.

Use of hallucinogens

Mullis practiced clandestine chemistry throughout his graduate studies, specializing in the synthesis of LSD; according to his friend Tom White, "I knew he was a good chemist because he'd been synthesizing hallucinogenic drugs at UC Berkeley." He detailed his experiences synthesizing and testing various psychedelic amphetamines and a difficult trip on DET in his autobiography.  In a Q&A interview published in the September 1994 issue of California Monthly, Mullis said, "Back in the 1960s and early 1970s I took plenty of LSD. A lot of people were doing that in Berkeley back then. And I found it to be a mind-opening experience. It was certainly much more important than any courses I ever took." During a symposium held for centenarian Albert Hofmann, Hofmann said Mullis had told him that LSD had "helped him develop the polymerase chain reaction that helps amplify specific DNA sequences".

Interest in the supernatural

Mullis expressed interest in the paranormal. For example, he said that he had witnessed the "non-substantial form" of his deceased grandfather, even offering it a beer. In his autobiography, Mullis professed a belief in astrology and wrote about an encounter with a fluorescent, talking raccoon that he suggested might have been an extraterrestrial alien.

Personal life

Mullis was a surfer as well as a musician, being both a guitarist and vocalist. He married four times, and he had three children by two of his wives. At the time of his death, he had two grandchildren and was survived by his fourth wife, Nancy (née Cosgrove). Mullis died on August 7, 2019, at his home in Newport Beach, California, from complications of pneumonia.

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#2630. What does the medical term 'Heat stroke' mean?

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#9284.