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Thursday, April 9, 2020

Car

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

Car
401 Gridlock.jpg
Cars and trucks driving on Highway 401 in Ontario, Canada
ClassificationVehicle
IndustryVarious
ApplicationTransportation
Fuel sourceGasoline, diesel, natural gas, electric, hydrogen, solar, vegetable oil
PoweredYes
Self-propelledYes
Wheels3–4
Axles2
InventorKarl Benz

A car (or automobile) is a wheeled motor vehicle used for transportation. Most definitions of cars say that they run primarily on roads, seat one to eight people, have four tires, and mainly transport people rather than goods.

Cars came into global use during the 20th century, and developed economies depend on them. The year 1886 is regarded as the birth year of the modern car when German inventor Karl Benz patented his Benz Patent-Motorwagen. Cars became widely available in the early 20th century. One of the first cars accessible to the masses was the 1908 Model T, an American car manufactured by the Ford Motor Company. Cars were rapidly adopted in the US, where they replaced animal-drawn carriages and carts, but took much longer to be accepted in Western Europe and other parts of the world.

Cars have controls for driving, parking, passenger comfort, and a variety of lights. Over the decades, additional features and controls have been added to vehicles, making them progressively more complex, but also more reliable and easier to operate. These include rear reversing cameras, air conditioning, navigation systems, and in-car entertainment. Most cars in use in the 2010s are propelled by an internal combustion engine, fueled by the combustion of fossil fuels. Electric cars, which were invented early in the history of the car, became commercially available in the 2000s and are predicted to cost less to buy than gasoline cars before 2025.

There are costs and benefits to car use. The costs to the individual include acquiring the vehicle, interest payments (if the car is financed), repairs and maintenance, fuel, depreciation, driving time, parking fees, taxes, and insurance. The costs to society include maintaining roads, land use, road congestion, air pollution, public health, health care, and disposing of the vehicle at the end of its life. Traffic collisions are the largest cause of injury-related deaths worldwide.

The personal benefits include on-demand transportation, mobility, independence, and convenience. The societal benefits include economic benefits, such as job and wealth creation from the automotive industry, transportation provision, societal well-being from leisure and travel opportunities, and revenue generation from the taxes. People's ability to move flexibly from place to place has far-reaching implications for the nature of societies. There are around 1 billion cars in use worldwide. The numbers are increasing rapidly, especially in China, India and other newly industrialized countries.

Etymology

The English word car is believed to originate from Latin carrus/carrum "wheeled vehicle" or (via Old North French) Middle English carre "two-wheeled cart," both of which in turn derive from Gaulish karros "chariot." It originally referred to any wheeled horse-drawn vehicle, such as a cart, carriage, or wagon.

"Motor car," attested from 1895, is the usual formal term in British English. "Autocar," a variant likewise attested from 1895 and literally meaning "self-propelled car," is now considered archaic. "Horseless carriage" is attested from 1895.

"Automobile," a classical compound derived from Ancient Greek autós (αὐτός) "self" and Latin mobilis "movable," entered English from French and was first adopted by the Automobile Club of Great Britain in 1897. It fell out of favour in Britain and is now used chiefly in North America, where the abbreviated form "auto" commonly appears as an adjective in compound formations like "auto industry" and "auto mechanic". Both forms are still used in everyday Dutch (auto/automobiel) and German (Auto/Automobil).

History

Steam Machine Of Verbiest, In 1678. (Ferdinand Verbiest)

The first working steam-powered vehicle was designed — and quite possibly built — by Ferdinand Verbiest, a Flemish member of a Jesuit mission in China around 1672. It was a 65-cm-long scale-model toy for the Chinese Emperor that was unable to carry a driver or a passenger. It is not known with certainty if Verbiest's model was successfully built or run.

Cugnot's 1771 fardier à vapeur, as preserved at the Musée des Arts et Métiers, Paris, France

Nicolas-Joseph Cugnot is widely credited with building the first full-scale, self-propelled mechanical vehicle or car in about 1769; he created a steam-powered tricycle. He also constructed two steam tractors for the French Army, one of which is preserved in the French National Conservatory of Arts and Crafts. His inventions were, however, handicapped by problems with water supply and maintaining steam pressure. In 1801, Richard Trevithick built and demonstrated his Puffing Devil road locomotive, believed by many to be the first demonstration of a steam-powered road vehicle. It was unable to maintain sufficient steam pressure for long periods and was of little practical use.

The development of external combustion engines is detailed as part of the history of the car but often treated separately from the development of true cars. A variety of steam-powered road vehicles were used during the first part of the 19th century, including steam cars, steam buses, phaetons, and steam rollers. Sentiment against them led to the Locomotive Acts of 1865. 

In 1807, Nicéphore Niépce and his brother Claude created what was probably the world's first internal combustion engine (which they called a Pyréolophore), but they chose to install it in a boat on the river Saone in France. Coincidentally, in 1807 the Swiss inventor François Isaac de Rivaz designed his own 'de Rivaz internal combustion engine' and used it to develop the world's first vehicle to be powered by such an engine. The Niépces' Pyréolophore was fuelled by a mixture of Lycopodium powder (dried spores of the Lycopodium plant), finely crushed coal dust and resin that were mixed with oil, whereas de Rivaz used a mixture of hydrogen and oxygen. Neither design was very successful, as was the case with others, such as Samuel Brown, Samuel Morey, and Etienne Lenoir with his hippomobile, who each produced vehicles (usually adapted carriages or carts) powered by internal combustion engines.

Gustave Trouvé's tricycle, the first ever electric automobile to be shown in public
Karl Benz, the inventor of the modern car

In November 1881, French inventor Gustave Trouvé demonstrated the first working (three-wheeled) car powered by electricity at the International Exposition of Electricity, Paris. Although several other German engineers (including Gottlieb Daimler, Wilhelm Maybach, and Siegfried Marcus) were working on the problem at about the same time, Karl Benz generally is acknowledged as the inventor of the modern car.

The original Benz Patent-Motorwagen, first built in 1885 and awarded the patent for the concept
In 1879, Benz was granted a patent for his first engine, which had been designed in 1878. Many of his other inventions made the use of the internal combustion engine feasible for powering a vehicle. His first Motorwagen was built in 1885 in Mannheim, Germany. He was awarded the patent for its invention as of his application on 29 January 1886 (under the auspices of his major company, Benz & Cie., which was founded in 1883). Benz began promotion of the vehicle on 3 July 1886, and about 25 Benz vehicles were sold between 1888 and 1893, when his first four-wheeler was introduced along with a cheaper model. They also were powered with four-stroke engines of his own design. Emile Roger of France, already producing Benz engines under license, now added the Benz car to his line of products. Because France was more open to the early cars, initially more were built and sold in France through Roger than Benz sold in Germany. In August 1888 Bertha Benz, the wife of Karl Benz, undertook the first road trip by car, to prove the road-worthiness of her husband's invention.

Bertha Benz, the first long distance driver

In 1896, Benz designed and patented the first internal-combustion flat engine, called boxermotor. During the last years of the nineteenth century, Benz was the largest car company in the world with 572 units produced in 1899 and, because of its size, Benz & Cie., became a joint-stock company. The first motor car in central Europe and one of the first factory-made cars in the world, was produced by Czech company Nesselsdorfer Wagenbau (later renamed to Tatra) in 1897, the Präsident automobil. 

Daimler and Maybach founded Daimler Motoren Gesellschaft (DMG) in Cannstatt in 1890, and sold their first car in 1892 under the brand name Daimler. It was a horse-drawn stagecoach built by another manufacturer, which they retrofitted with an engine of their design. By 1895 about 30 vehicles had been built by Daimler and Maybach, either at the Daimler works or in the Hotel Hermann, where they set up shop after disputes with their backers. Benz, Maybach and the Daimler team seem to have been unaware of each other's early work. They never worked together; by the time of the merger of the two companies, Daimler and Maybach were no longer part of DMG. Daimler died in 1900 and later that year, Maybach designed an engine named Daimler-Mercedes that was placed in a specially ordered model built to specifications set by Emil Jellinek. This was a production of a small number of vehicles for Jellinek to race and market in his country. Two years later, in 1902, a new model DMG car was produced and the model was named Mercedes after the Maybach engine, which generated 35 hp. Maybach quit DMG shortly thereafter and opened a business of his own. Rights to the Daimler brand name were sold to other manufacturers.

Karl Benz proposed co-operation between DMG and Benz & Cie. when economic conditions began to deteriorate in Germany following the First World War, but the directors of DMG refused to consider it initially. Negotiations between the two companies resumed several years later when these conditions worsened and, in 1924 they signed an Agreement of Mutual Interest, valid until the year 2000. Both enterprises standardized design, production, purchasing, and sales and they advertised or marketed their car models jointly, although keeping their respective brands. On 28 June 1926, Benz & Cie. and DMG finally merged as the Daimler-Benz company, baptizing all of its cars Mercedes Benz, as a brand honoring the most important model of the DMG cars, the Maybach design later referred to as the 1902 Mercedes-35 hp, along with the Benz name. Karl Benz remained a member of the board of directors of Daimler-Benz until his death in 1929, and at times, his two sons also participated in the management of the company.

Émile Levassor
Armand Peugeot
In 1890, Émile Levassor and Armand Peugeot of France began producing vehicles with Daimler engines, and so laid the foundation of the automotive industry in France. In 1891, Auguste Doriot and his Peugeot colleague Louis Rigoulot completed the longest trip by a gasoline-powered vehicle when their self-designed and built Daimler powered Peugeot Type 3 completed 2,100 km (1,300 miles) from Valentigney to Paris and Brest and back again. They were attached to the first Paris–Brest–Paris bicycle race, but finished 6 days after the winning cyclist, Charles Terront.

The first design for an American car with a gasoline internal combustion engine was made in 1877 by George Selden of Rochester, New York. Selden applied for a patent for a car in 1879, but the patent application expired because the vehicle was never built. After a delay of sixteen years and a series of attachments to his application, on 5 November 1895, Selden was granted a United States patent (U.S. Patent 549,160) for a two-stroke car engine, which hindered, more than encouraged, development of cars in the United States. His patent was challenged by Henry Ford and others, and overturned in 1911.

In 1893, the first running, gasoline-powered American car was built and road-tested by the Duryea brothers of Springfield, Massachusetts. The first public run of the Duryea Motor Wagon took place on 21 September 1893, on Taylor Street in Metro Center Springfield. The Studebaker Automobile Company, subsidiary of a long-established wagon and coach manufacturer, started to build cars in 1897 and commenced sales of electric vehicles in 1902 and gasoline vehicles in 1904.

In Britain, there had been several attempts to build steam cars with varying degrees of success, with Thomas Rickett even attempting a production run in 1860. Santler from Malvern is recognized by the Veteran Car Club of Great Britain as having made the first gasoline-powered car in the country in 1894, followed by Frederick William Lanchester in 1895, but these were both one-offs. The first production vehicles in Great Britain came from the Daimler Company, a company founded by Harry J. Lawson in 1896, after purchasing the right to use the name of the engines. Lawson's company made its first car in 1897, and they bore the name Daimler.

In 1892, German engineer Rudolf Diesel was granted a patent for a "New Rational Combustion Engine". In 1897, he built the first diesel engine. Steam-, electric-, and gasoline-powered vehicles competed for decades, with gasoline internal combustion engines achieving dominance in the 1910s. Although various pistonless rotary engine designs have attempted to compete with the conventional piston and crankshaft design, only Mazda's version of the Wankel engine has had more than very limited success. 

All in all, it is estimated that over 100,000 patents created the modern automobile and motorcycle.

Mass production

Ransom E. Olds founded Olds Motor Vehicle Company (Oldsmobile) in 1897
Henry Ford founded Ford Motor Company in 1903
Kiichiro Toyoda, president of the Toyota Motor Corporation 1941–1950
Mass production at a Toyota plant in the 1950s
Large-scale, production-line manufacturing of affordable cars was started by Ransom Olds in 1901 at his Oldsmobile factory in Lansing, Michigan and based upon stationary assembly line techniques pioneered by Marc Isambard Brunel at the Portsmouth Block Mills, England, in 1802. The assembly line style of mass production and interchangeable parts had been pioneered in the U.S. by Thomas Blanchard in 1821, at the Springfield Armory in Springfield, Massachusetts. This concept was greatly expanded by Henry Ford, beginning in 1913 with the world's first moving assembly line for cars at the Highland Park Ford Plant

As a result, Ford's cars came off the line in fifteen-minute intervals, much faster than previous methods, increasing productivity eightfold, while using less manpower (from 12.5-man-hours to 1 hour 33 minutes). It was so successful, paint became a bottleneck. Only Japan black would dry fast enough, forcing the company to drop the variety of colors available before 1913, until fast-drying Duco lacquer was developed in 1926. This is the source of Ford's apocryphal remark, "any color as long as it's black". In 1914, an assembly line worker could buy a Model T with four months' pay.

Ford's complex safety procedures—especially assigning each worker to a specific location instead of allowing them to roam about—dramatically reduced the rate of injury. The combination of high wages and high efficiency is called "Fordism," and was copied by most major industries. The efficiency gains from the assembly line also coincided with the economic rise of the United States. The assembly line forced workers to work at a certain pace with very repetitive motions which led to more output per worker while other countries were using less productive methods.

In the automotive industry, its success was dominating, and quickly spread worldwide seeing the founding of Ford France and Ford Britain in 1911, Ford Denmark 1923, Ford Germany 1925; in 1921, Citroen was the first native European manufacturer to adopt the production method. Soon, companies had to have assembly lines, or risk going broke; by 1930, 250 companies which did not, had disappeared.

Development of automotive technology was rapid, due in part to the hundreds of small manufacturers competing to gain the world's attention. Key developments included electric ignition and the electric self-starter (both by Charles Kettering, for the Cadillac Motor Company in 1910–1911), independent suspension, and four-wheel brakes.

Since the 1920s, nearly all cars have been mass-produced to meet market needs, so marketing plans often have heavily influenced car design. It was Alfred P. Sloan who established the idea of different makes of cars produced by one company, called the General Motors Companion Make Program, so that buyers could "move up" as their fortunes improved. 

Reflecting the rapid pace of change, makes shared parts with one another so larger production volume resulted in lower costs for each price range. For example, in the 1930s, LaSalles, sold by Cadillac, used cheaper mechanical parts made by Oldsmobile; in the 1950s, Chevrolet shared hood, doors, roof, and windows with Pontiac; by the 1990s, corporate powertrains and shared platforms (with interchangeable brakes, suspension, and other parts) were common. Even so, only major makers could afford high costs, and even companies with decades of production, such as Apperson, Cole, Dorris, Haynes, or Premier, could not manage: of some two hundred American car makers in existence in 1920, only 43 survived in 1930, and with the Great Depression, by 1940, only 17 of those were left.

In Europe, much the same would happen. Morris set up its production line at Cowley in 1924, and soon outsold Ford, while beginning in 1923 to follow Ford's practice of vertical integration, buying Hotchkiss (engines), Wrigley (gearboxes), and Osberton (radiators), for instance, as well as competitors, such as Wolseley: in 1925, Morris had 41% of total British car production. Most British small-car assemblers, from Abbey to Xtra, had gone under. Citroen did the same in France, coming to cars in 1919; between them and other cheap cars in reply such as Renault's 10CV and Peugeot's 5CV, they produced 550,000 cars in 1925, and Mors, Hurtu, and others could not compete. Germany's first mass-manufactured car, the Opel 4PS Laubfrosch (Tree Frog), came off the line at Russelsheim in 1924, soon making Opel the top car builder in Germany, with 37.5% of the market.

In Japan, car production was very limited before World War II. Only a handful of companies were producing vehicles in limited numbers, and these were small, three-wheeled for commercial uses, like Daihatsu, or were the result of partnering with European companies, like Isuzu building the Wolseley A-9 in 1922. Mitsubishi was also partnered with Fiat and built the Mitsubishi Model A based on a Fiat vehicle. Toyota, Nissan, Suzuki, Mazda, and Honda began as companies producing non-automotive products before the war, switching to car production during the 1950s. Kiichiro Toyoda's decision to take Toyoda Loom Works into automobile manufacturing would create what would eventually become Toyota Motor Corporation, the largest automobile manufacturer in the world. Subaru, meanwhile, was formed from a conglomerate of six companies who banded together as Fuji Heavy Industries, as a result of having been broken up under keiretsu legislation.

Fuel and propulsion technologies

The Nissan Leaf is an all-electric car launched in December 2010
According to the European Environment Agency, the transport sector is a major contributor to air pollution, noise pollution and climate change.

Most cars in use in the 2010s run on gasoline burnt in an internal combustion engine (ICE). The International Organization of Motor Vehicle Manufacturers says that, in countries that mandate low sulfur gasoline, gasoline-fuelled cars built to late 2010s standards (such as Euro-6) emit very little local air pollution. Some cities ban older gasoline-fuelled cars and some countries plan to ban sales in future. However some environmental groups say this phase-out of fossil fuel vehicles must be brought forward to limit climate change. Production of gasoline fueled cars peaked in 2017.

Other hydrocarbon fossil fuels also burnt by deflagration (rather than detonation) in ICE cars include diesel, Autogas and CNG. Removal of fossil fuel subsidies, concerns about oil dependence, tightening environmental laws and restrictions on greenhouse gas emissions are propelling work on alternative power systems for cars. This includes hybrid vehicles, plug-in electric vehicles and hydrogen vehicles. 2.1 million light electric vehicles (of all types but mainly cars) were sold in 2018, over half in China: this was an increase of 64% on the previous year, giving a global total on the road of 5.4 million. Vehicles using alternative fuels such as ethanol flexible-fuel vehicles and natural gas vehicles are also gaining popularity in some countries. Cars for racing or speed records have sometimes employed jet or rocket engines, but these are impractical for common use.

Oil consumption has increased rapidly in the 20th and 21st centuries because there are more cars; the 1985–2003 oil glut even fuelled the sales of low-economy vehicles in OECD countries. The BRIC countries are adding to this consumption.

User interface

In the Ford Model T the left-side hand lever sets the rear wheel parking brakes and puts the transmission in neutral. The lever to the right controls the throttle. The lever on the left of the steering column is for ignition timing. The left foot pedal changes the two forward gears while the centre pedal controls reverse. The right pedal is the brake.
Cars are equipped with controls used for driving, passenger comfort and safety, normally operated by a combination of the use of feet and hands, and occasionally by voice on 21st century cars. These controls include a steering wheel, pedals for operating the brakes and controlling the car's speed (and, in a manual transmission car, a clutch pedal), a shift lever or stick for changing gears, and a number of buttons and dials for turning on lights, ventilation and other functions. Modern cars' controls are now standardized, such as the location for the accelerator and brake, but this was not always the case. Controls are evolving in response to new technologies, for example the electric car and the integration of mobile communications.

Some of the original controls are no longer required. For example, all cars once had controls for the choke valve, clutch, ignition timing, and a crank instead of an electric starter. However new controls have also been added to vehicles, making them more complex. These include air conditioning, navigation systems, and in car entertainment. Another trend is the replacement of physical knobs and switches by secondary controls with touchscreen controls such as BMW's iDrive and Ford's MyFord Touch. Another change is that while early cars' pedals were physically linked to the brake mechanism and throttle, in the 2010s, cars have increasingly replaced these physical linkages with electronic controls.

Lighting


Cars are typically fitted with multiple types of lights. These include headlights, which are used to illuminate the way ahead and make the car visible to other users, so that the vehicle can be used at night; in some jurisdictions, daytime running lights; red brake lights to indicate when the brakes are applied; amber turn signal lights to indicate the turn intentions of the driver; white-colored reverse lights to illuminate the area behind the car (and indicate that the driver will be or is reversing); and on some vehicles, additional lights (e.g., side marker lights) to increase the visibility of the car. Interior lights on the ceiling of the car are usually fitted for the driver and passengers. Some vehicles also have a trunk light and, more rarely, an engine compartment light.

Weight

The Smart Fortwo car from 1998-2002, weighing 730 kg (1,610 lb)
A Chevrolet Suburban extended-length SUV weighs 3,300 kg (7,200 lb) (gross weight)[44]

During the late 20th and early 21st century cars increased in weight due to batteries, modern steel safety cages, anti-lock brakes, airbags, and "more-powerful—if more-efficient—engines" and, as of 2019, typically weigh between 1 and 3 tonnes. Heavier cars are safer for the driver from a crash perspective, but more dangerous for other vehicles and road users. The weight of a car influences fuel consumption and performance, with more weight resulting in increased fuel consumption and decreased performance. The SmartFortwo, a small city car, weighs 750–795 kg (1,655–1,755 lb). Heavier cars include full-size cars, SUVs and extended-length SUVs like the Suburban

According to research conducted by Julian Allwood of the University of Cambridge, global energy use could be greatly reduced by using lighter cars, and an average weight of 500 kg (1,100 lb) has been said to be well achievable. In some competitions such as the Shell Eco Marathon, average car weights of 45 kg (99 lb) have also been achieved. These cars are only single-seaters (still falling within the definition of a car, although 4-seater cars are more common), but they nevertheless demonstrate the amount by which car weights could still be reduced, and the subsequent lower fuel use (i.e. up to a fuel use of 2560 km/l).

Seating and body style

Most cars are designed to carry multiple occupants, often with four or five seats. Cars with five seats typically seat two passengers in the front and three in the rear. Full-size cars and large sport utility vehicles can often carry six, seven, or more occupants depending on the arrangement of the seats. On the other hand, sports cars are most often designed with only two seats. The differing needs for passenger capacity and their luggage or cargo space has resulted in the availability of a large variety of body styles to meet individual consumer requirements that include, among others, the sedan/saloon, hatchback, station wagon/estate, and minivan.

Safety

Result of a serious car collision

Traffic collisions are the largest cause of injury-related deaths worldwide. Mary Ward became one of the first documented car fatalities in 1869 in Parsonstown, Ireland, and Henry Bliss one of the United States' first pedestrian car casualties in 1899 in New York City. There are now standard tests for safety in new cars, such as the EuroNCAP and the US NCAP tests, and insurance-industry-backed tests by the Insurance Institute for Highway Safety (IIHS).

Costs and benefits

Road congestion is an issue in many major cities. (pictured is Chang'an Avenue in Beijing)
The costs of car usage, which may include the cost of: acquiring the vehicle, repairs and auto maintenance, fuel, depreciation, driving time, parking fees, taxes, and insurance, are weighed against the cost of the alternatives, and the value of the benefits – perceived and real – of vehicle usage. The benefits may include on-demand transportation, mobility, independence and convenience. During the 1920s, cars had another benefit: "[c]ouples finally had a way to head off on unchaperoned dates, plus they had a private space to snuggle up close at the end of the night."

Similarly the costs to society of car use may include; maintaining roads, land use, air pollution, road congestion, public health, health care, and of disposing of the vehicle at the end of its life; and can be balanced against the value of the benefits to society that car use generates. Societal benefits may include: economy benefits, such as job and wealth creation, of car production and maintenance, transportation provision, society wellbeing derived from leisure and travel opportunities, and revenue generation from the tax opportunities. The ability of humans to move flexibly from place to place has far-reaching implications for the nature of societies.

Environmental impact

Vehicles in use per country from 2001 to 2007. It shows the significant growth in BRIC.

Cars are a major cause of urban air pollution, with all types of cars producing dust from brakes, tyres and road wear. As of 2018 the average diesel car has a worse effect on air quality than the average gasoline car But both gasoline and diesel cars pollute more than electric cars. While there are different ways to power cars most rely on gasoline or diesel, and they consume almost a quarter of world oil production as of 2019. In 2018 passenger road vehicles emitted 3.6 gigatonnes of carbon dioxide. As of 2019, due to greenhouse gases emitted during battery production, electric cars must be driven tens of thousands of kilometers before their lifecycle carbon emissions are less than fossil fuel cars: but this is expected to improve in future due to longer lasting batteries being produced in larger factories, and lower carbon electricity. Many governments are using fiscal policies, such as road tax, to discourage the purchase and use of more polluting cars; and many cities are doing the same with low-emission zones. Fuel taxes may act as an incentive for the production of more efficient, hence less polluting, car designs (e.g. hybrid vehicles) and the development of alternative fuels. High fuel taxes or cultural change may provide a strong incentive for consumers to purchase lighter, smaller, more fuel-efficient cars, or to not drive.

On average, today's cars are about 75 percent recyclable, and using recycled steel helps reduce energy use and pollution. According to the International Energy Agency fuel economy improved 0.7% in 2017, but an annual improvement of 3.7% is needed to meet the Global Fuel Economy Initiative 2030 target. The increase in sales of SUVs is bad for fuel economy. Many cities in Europe, have banned older fossil fuel cars and all fossil fuel vehicles will be banned in Amsterdam from 2030. Many Chinese cities limit licensing of fossil fuel cars, and many countries plan to stop selling them between 2025 and 2050.

The manufacture of vehicles is resource intensive, and many manufacturers now report on the environmental performance of their factories, including energy usage, waste and water consumption. Manufacturing each kWh of battery emits a similar amount of carbon as burning through one full tank of gasoline. The growth in popularity of the car allowed cities to sprawl, therefore encouraging more travel by car resulting in inactivity and obesity, which in turn can lead to increased risk of a variety of diseases.

Animals and plants are often negatively impacted by cars via habitat destruction and pollution. Over the lifetime of the average car the "loss of habitat potential" may be over 50,000 m2 (540,000 sq ft) based on primary production correlations. Animals are also killed every year on roads by cars, referred to as roadkill. More recent road developments are including significant environmental mitigation in their designs, such as green bridges (designed to allow wildlife crossings) and creating wildlife corridors

Growth in the popularity of vehicles and commuting has led to traffic congestion. Moscow, Istanbul, Bogota, Mexico City and Sao Paulo were the world's most congested cities in 2018 according to INRIX, a data analytics company.

Emerging car technologies

Although intensive development of conventional battery electric vehicles is continuing into the 2020s, other car propulsion technologies that are under development include wheel hub motors, wireless charging, hydrogen cars, and hydrogen/electric hybrids. Research into alternative forms of power includes using ammonia instead of hydrogen in fuel cells.

New materials which may replace steel car bodies include duralumin, fiberglass, carbon fiber, biocomposites, and carbon nanotubes. Telematics technology is allowing more and more people to share cars, on a pay-as-you-go basis, through car share and carpool schemes. Communication is also evolving due to connected car systems.

Autonomous car

Fully autonomous vehicles, also known as driverless cars, already exist in prototype (such as the Google driverless car), but have a long way to go before they are in general use.

Open source development

There have been several projects aiming to develop a car on the principles of open design, an approach to designing in which the plans for the machinery and systems are publicly shared, often without monetary compensation. The projects include OScar, Riversimple (through 40fires.org) and c,mm,n. None of the projects have reached significant success in terms of developing a car as a whole both from hardware and software perspective and no mass production ready open-source based design have been introduced as of late 2009. Some car hacking through on-board diagnostics (OBD) has been done so far.

Car sharing

Car-share arrangements and carpooling are also increasingly popular, in the US and Europe. For example, in the US, some car-sharing services have experienced double-digit growth in revenue and membership growth between 2006 and 2007. Services like car sharing offering a residents to "share" a vehicle rather than own a car in already congested neighborhoods.

Industry

A car being assembled in a factory
The automotive industry designs, develops, manufactures, markets, and sells the world's motor vehicles, more than three-quarters of which are cars. In 2018 there were 70 million cars manufactured worldwide, down 2 million from the previous year.

The automotive industry in China produces by far the most (24 million in 2018), followed by Japan (8 million), Germany (5 million) and India (4 million). The largest market is China, followed by the USA. 

Around the world there are about a billion cars on the road; they burn over a trillion liters of gasoline and diesel fuel yearly, consuming about 50 EJ (nearly 300 terawatt-hours) of energy. The numbers of cars are increasing rapidly in China and India. In the opinion of some, urban transport systems based around the car have proved unsustainable, consuming excessive energy, affecting the health of populations, and delivering a declining level of service despite increasing investment. Many of these negative impacts fall disproportionately on those social groups who are also least likely to own and drive cars. The sustainable transport movement focuses on solutions to these problems. The car industry is also facing increasing competition from the public transport sector, as some people re-evaluate their private vehicle usage.

Alternatives

The Vélib' in Paris, France is the largest bikesharing system outside China
Established alternatives for some aspects of car use include public transport such as buses, trolleybuses, trains, subways, tramways, light rail, cycling, and walking. Bicycle sharing systems have been established in China and many European cities, including Copenhagen and Amsterdam. Similar programs have been developed in large US cities. Additional individual modes of transport, such as personal rapid transit could serve as an alternative to cars if they prove to be socially accepted.

Other meanings

The term motorcar was formerly also used in the context of electrified rail systems to denote a car which functions as a small locomotive but also provides space for passengers and baggage. These locomotive cars were often used on suburban routes by both interurban and intercity railroad systems.

Tuesday, April 7, 2020

Fusion gene

From Wikipedia, the free encyclopedia
 
A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neoplasia. The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker.

A schematic showing the ways a fusion gene can occur at a chromosomal level.

History

The first fusion gene was described in cancer cells in the early 1980s. The finding was based on the discovery in 1960 by Peter Nowell and David Hungerford in Philadelphia of a small abnormal marker chromosome in patients with chronic myeloid leukemia—the first consistent chromosome abnormality detected in a human malignancy, later designated the Philadelphia chromosome. In 1973, Janet Rowley in Chicago showed that the Philadelphia chromosome had originated through a translocation between chromosomes 9 and 22, and not through a simple deletion of chromosome 22 as was previously thought. Several investigators in the early 1980s showed that the Philadelphia chromosome translocation led to the formation of a new BCR/ABL1 fusion gene, composed of the 3' part of the ABL1 gene in the breakpoint on chromosome 9 and the 5' part of a gene called BCR in the breakpoint in chromosome 22. In 1985 it was clearly established that the fusion gene on chromosome 22 produced an abnormal chimeric BCR/ABL1 protein with the capacity to induce chronic myeloid leukemia.

Oncogenes

It has been known for 30 years that the corresponding gene fusion plays an important role in tumorgenesis. Fusion genes can contribute to tumor formation because fusion genes can produce much more active abnormal protein than non-fusion genes. Often, fusion genes are oncogenes that cause cancer; these include BCR-ABL, TEL-AML1 (ALL with t(12 ; 21)), AML1-ETO (M2 AML with t(8 ; 21)), and TMPRSS2-ERG with an interstitial deletion on chromosome 21, often occurring in prostate cancer. In the case of TMPRSS2-ERG, by disrupting androgen receptor (AR) signaling and inhibiting AR expression by oncogenic ETS transcription factor, the fusion product regulates the prostate cancer. Most fusion genes are found from hematological cancers, sarcomas, and prostate cancer. BCAM-AKT2 is a fusion gene that is specific and unique to high-grade serous ovarian cancer.

Oncogenic fusion genes may lead to a gene product with a new or different function from the two fusion partners. Alternatively, a proto-oncogene is fused to a strong promoter, and thereby the oncogenic function is set to function by an upregulation caused by the strong promoter of the upstream fusion partner. The latter is common in lymphomas, where oncogenes are juxtaposed to the promoters of the immunoglobulin genes. Oncogenic fusion transcripts may also be caused by trans-splicing or read-through events.

Since chromosomal translocations play such a significant role in neoplasia, a specialized database of chromosomal aberrations and gene fusions in cancer has been created. This database is called Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Diagnostics

Presence of certain chromosomal aberrations and their resulting fusion genes is commonly used within cancer diagnostics in order to set a precise diagnosis. Chromosome banding analysis, fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) are common methods employed at diagnostic laboratories. These methods all have their distinct shortcomings due to the very complex nature of cancer genomes. Recent developments such as high-throughput sequencing and custom DNA microarrays bear promise of introduction of more efficient methods.

Evolution

Gene fusion plays a key role in the evolution of gene architecture. We can observe its effect if gene fusion occurs in coding sequences. Duplication, sequence divergence, and recombination are the major contributors at work in gene evolution. These events can probably produce new genes from already existing parts. When gene fusion happens in non-coding sequence region, it can lead to the misregulation of the expression of a gene now under the control of the cis-regulatory sequence of another gene. If it happens in coding sequences, gene fusion cause the assembly of a new gene, then it allows the appearance of new functions by adding peptide modules into multi domain protein. The detecting methods to inventory gene fusion events on a large biological scale can provide insights about the multi modular architecture of proteins.

Detection

In recent years, next generation sequencing technology has already become available to screen known and novel gene fusion events on a genome wide scale. However, the precondition for large scale detection is a paired-end sequencing of the cell's transcriptome. The direction of fusion gene detection is mainly towards data analysis and visualization. Some researchers already developed a new tool called Transcriptome Viewer (TViewer) to directly visualize detected gene fusions on the transcript level.

Research applications

Biologists may also deliberately create fusion genes for research purposes. The fusion of reporter genes to the regulatory elements of genes of interest allows researches to study gene expression. Reporter gene fusions can be used to measure activity levels of gene regulators, identify the regulatory sites of genes (including the signals required), identify various genes that are regulated in response to the same stimulus, and artificially control the expression of desired genes in particular cells. For example, by creating a fusion gene of a protein of interest and green fluorescent protein, the protein of interest may be observed in cells or tissue using fluorescence microscopy. The protein synthesized when a fusion gene is expressed is called a fusion protein.

Chromosomal translocation

From Wikipedia, the free encyclopedia
 
Chromosomal reciprocal translocation of the 4th and 20th chromosome.

In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translocation is a chromosome abnormality caused by exchange of parts between non-homologous chromosomes. Two detached fragments of two different chromosomes are switched. Robertsonian translocation occurs when two non-homologous chromosomes get attached, meaning that given two healthy pairs of chromosomes, one of each pair "sticks" together.

A gene fusion may be created when the translocation joins two otherwise-separated genes. It is detected on cytogenetics or a karyotype of affected cells. Translocations can be balanced (in an even exchange of material with no genetic information extra or missing, and ideally full functionality) or unbalanced (where the exchange of chromosome material is unequal resulting in extra or missing genes).

Reciprocal translocations

Reciprocal translocations are usually an exchange of material between non-homologous chromosomes. Estimates of incidence range from about 1 in 500 to 1 in 625 human newborns. Such translocations are usually harmless and may be found through prenatal diagnosis. However, carriers of balanced reciprocal translocations have increased risks of creating gametes with unbalanced chromosome translocations, leading to Infertility, miscarriages or children with abnormalities. Genetic counseling and genetic testing are often offered to families that may carry a translocation. Most balanced translocation carriers are healthy and do not have any symptoms.

It is important to distinguish between chromosomal translocations occurring in gametogenesis, due to errors in meiosis, and translocations that occur in cellular division of somatic cells, due to errors in mitosis. The former results in a chromosomal abnormality featured in all cells of the offspring, as in translocation carriers. Somatic translocations, on the other hand, result in abnormalities featured only in the affected cell line, as in chronic myelogenous leukemia with the Philadelphia chromosome translocation.

Nonreciprocal translocation

Nonreciprocal translocation involves the one-way transfer of genes from one chromosome to another nonhomologous chromosome.

Robertsonian translocations

Robertsonian translocation is a type of translocation caused by breaks at or near the centromeres of two acrocentric chromosomes. The reciprocal exchange of parts gives rise to one large metacentric chromosome and one extremely small chromosome that may be lost from the organism with little effect because it contains few genes. The resulting karyotype in humans leaves only 45 chromosomes, since two chromosomes have fused together. This has no direct effect on the phenotype, since the only genes on the short arms of acrocentrics are common to all of them and are present in variable copy number (nucleolar organiser genes).

Robertsonian translocations have been seen involving all combinations of acrocentric chromosomes. The most common translocation in humans involves chromosomes 13 and 14 and is seen in about 0.97 / 1000 newborns. Carriers of Robertsonian translocations are not associated with any phenotypic abnormalities, but there is a risk of unbalanced gametes that lead to miscarriages or abnormal offspring. For example, carriers of Robertsonian translocations involving chromosome 21 have a higher risk of having a child with Down syndrome. This is known as a 'translocation Downs'. This is due to a mis-segregation (nondisjunction) during gametogenesis. The mother has a higher (10%) risk of transmission than the father (1%). Robertsonian translocations involving chromosome 14 also carry a slight risk of uniparental disomy 14 due to trisomy rescue.

Role in disease

Some human diseases caused by translocations are:
Chromosomal translocations between the sex chromosomes can also result in a number of genetic conditions, such as

By chromosome

Overview of some chromosomal translocations involved in different cancers, as well as implicated in some other conditions, e.g. schizophrenia, with chromosomes arranged in standard karyogram order. Abbreviations:
ALL – Acute lymphoblastic leukemia
AML – Acute myeloid leukemia
CML – Chronic myelogenous leukemia
DFSP – Dermatofibrosarcoma protuberans

Denotation

The International System for Human Cytogenetic Nomenclature (ISCN) is used to denote a translocation between chromosomes. The designation t(A;B)(p1;q2) is used to denote a translocation between chromosome A and chromosome B. The information in the second set of parentheses, when given, gives the precise location within the chromosome for chromosomes A and B respectively—with p indicating the short arm of the chromosome, q indicating the long arm, and the numbers after p or q refers to regions, bands and subbands seen when staining the chromosome with a staining dye. See also the definition of a genetic locus. The translocation is the mechanism that can cause a gene to move from one linkage group to another.

Examples

Translocation Associated diseases Fused genes/proteins
First Second
t(8;14)(q24;q32) Burkitt's lymphoma c-myc on chromosome 8,
gives the fusion protein lymphocyte-proliferative ability
IGH@ (immunoglobulin heavy locus) on chromosome 14,
induces massive transcription of fusion protein
t(11;14)(q13;q32) Mantle cell lymphoma cyclin D1 on chromosome 11,
gives fusion protein cell-proliferative ability
IGH@ (immunoglobulin heavy locus) on chromosome 14,
induces massive transcription of fusion protein
t(14;18)(q32;q21) Follicular lymphoma (~90% of cases) IGH@ (immunoglobulin heavy locus) on chromosome 14,
induces massive transcription of fusion protein
Bcl-2 on chromosome 18,
gives fusion protein anti-apoptotic abilities
t(10;(various))(q11;(various)) Papillary thyroid cancer RET proto-oncogene[15] on chromosome 10 PTC (Papillary Thyroid Cancer) – Placeholder for any of several other genes/proteins
t(2;3)(q13;p25) Follicular thyroid cancer PAX8 – paired box gene 8 on chromosome 2 PPARγ1 (peroxisome proliferator-activated receptor γ 1) on chromosome 3
t(8;21)(q22;q22)[14] Acute myeloblastic leukemia with maturation ETO on chromosome 8 AML1 on chromosome 21
found in ~7% of new cases of AML, carries a favorable prognosis and predicts good response to cytosine arabinoside therapy
t(9;22)(q34;q11) Philadelphia chromosome Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) Abl1 gene on chromosome 9 BCR ("breakpoint cluster region" on chromosome 22
t(15;17)(q22;q21)[14] Acute promyelocytic leukemia PML protein on chromosome 15 RAR-α on chromosome 17
persistent laboratory detection of the PML-RARA transcript is strong predictor of relapse
t(12;15)(p13;q25) Acute myeloid leukemia, congenital fibrosarcoma, secretory breast carcinoma, mammary analogue secretory carcinoma of salivary glands, cellular variant of mesoblastic nephroma TEL on chromosome 12 TrkC receptor on chromosome 15
t(9;12)(p24;p13) CML, ALL JAK on chromosome 9 TEL on chromosome 12
t(12;16)(q13;p11) Myxoid liposarcoma DDIT3 (formerly CHOP) on chromosome 12 FUS gene on chromosome 16
t(12;21)(p12;q22) ALL TEL on chromosome 12 AML1 on chromosome 21
t(11;18)(q21;q21) MALT lymphoma BIRC3 (API-2) MLT
t(1;11)(q42.1;q14.3) Schizophrenia

t(2;5)(p23;q35) Anaplastic large cell lymphoma ALK NPM1
t(11;22)(q24;q11.2-12) Ewing's sarcoma FLI1 EWS
t(17;22) DFSP Collagen I on chromosome 17 Platelet derived growth factor B on chromosome 22
t(1;12)(q21;p13) Acute myelogenous leukemia

t(X;18)(p11.2;q11.2) Synovial sarcoma

t(1;19)(q10;p10) Oligodendroglioma and oligoastrocytoma

t(17;19)(q22;p13) ALL

t(7,16) (q32-34;p11) or t(11,16) (p11;p11) Low-grade fibromyxoid sarcoma FUS CREB3L2 or CREB3L1

History

In 1938, Karl Sax, at the Harvard University Biological Laboratories, published a paper entitled "Chromosome Aberrations Induced by X-rays", which demonstrated that radiation could induce major genetic changes by affecting chromosomal translocations. The paper is thought to mark the beginning of the field of radiation cytology, and led him to be called "the father of radiation cytology".

Hematopoietic stem cell

From Wikipedia, the free encyclopedia
 
Haematopoietic stem cell
Hematopoiesis simple.svg
Overview of normal human haematopoiesis
Details
SystemHematopoietic system
LocationBone marrow
FunctionStem cells that give rise to other blood cells
Identifiers
LatinCellula haematopoietica praecursoria
Acronym(s)HSC
MeSHD006412
THH2.00.01.0.00006

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. This process occurs in the red bone marrow, in the core of most bones. In embryonic development, the red bone marrow is derived from the layer of the embryo called the mesoderm.

Haematopoiesis is the process by which all mature blood cells are produced. It must balance enormous production needs (the average person produces more than 500 billion blood cells every day) with the need to regulate the number of each blood cell type in the circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are multipotent and capable of extensive self-renewal.

Hematopoietic stem cells give rise to different types of blood cells, in lines called myeloid and lymphoid. Myeloid and lymphoid lineages both are involved in dendritic cell formation. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells. The definition of hematopoietic stem cell has evolved since they were first discovered in 1961. The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent, oligopotent, and unipotent progenitors. Hematopoietic stem cells constitute 1:10,000 of cells in myeloid tissue.

HSC transplants are used in the treatment of cancers and other immune system disorders.

Structure

They are round, non-adherent, with a rounded nucleus and low cytoplasm-to-nucleus ratio. In shape, hematopoietic stem cells resemble lymphocytes.

Location

Hematopoietic stem cells are found in the bone marrow of adults, especially in the pelvis, femur, and sternum. They are also found in umbilical cord blood and, in small numbers, in peripheral blood.

Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe. The cells can be removed as liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone).

Subtypes

A colony-forming unit is a subtype of HSC. (This sense of the term is different from colony-forming units of microbes, which is a cell counting unit.) There are various kinds of HSC colony-forming units:
The above CFUs are based on the lineage. Another CFU, the colony-forming unit–spleen (CFU-S), was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in the spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or transit-amplifying cells rather than stem cells.

Isolating stem cells

Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope. Hematopoietic stem cells can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers (particularly CD34) are used to separate the rare Hematopoietic stem cells from the surrounding blood cells. Hematopoietic stem cells lack expression of mature blood cell markers and are thus called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate hematopoietic stem cells. In addition, hematopoietic stem cells are characterised by their small size and low staining with vital dyes such as rhodamine 123 (rhodamine lo) or Hoechst 33342 (side population).

Function

Diagram of cells that arise from Hematopoetic stem cells during the process of hematopoiesis.

Haematopoiesis

Hematopoietic stem cells are essential to haematopoiesis, the formation of the cells within blood. Hematopoietic stem cells can replenish all blood cell types (i.e., are multipotent) and self-renew. A small number of Hematopoietic stem cells can expand to generate a very large number of daughter Hematopoietic stem cells. This phenomenon is used in bone marrow transplantation, when a small number of Hematopoietic stem cells reconstitute the hematopoietic system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter Hematopoietic stem cells must occur.

Stem cell self-renewal is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal. There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically.

Quiescence

Hematopoietic stem cells, like all adult stem cells, mostly exist in a state of quiescence, or reversible growth arrest. The altered metabolism of quiescent HCSs helps the cells survive for extended periods of time in the hypoxic bone marrow environment. When provoked by cell death or damage, Hematopoietic stem cells exit quiescence and begin actively dividing again. The transition from dormancy to propagation and back is regulated by the MEK/ERK pathway and PI3K/AKT/mTOR pathway. Dysregulation of these transitions can lead to stem cell exhaustion, or the gradual loss of active Hematopoietic stem cells in the blood system.

Mobility

Hematopoietic stem cells have a higher potential than other immature blood cells to pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus, they may develop into T cells. In the case of fetuses and other extramedullary hematopoiesis, Hematopoietic stem cells may also settle in the liver or spleen and develop. 

This enables Hematopoietic stem cells to be harvested directly from the blood.

DNA damage with aging

DNA strand breaks accumulate in long term Hematopoietic stem cells during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template. The NHEJ pathway depends on several proteins including ligase 4, DNA polymerase mu and NHEJ factor 1 (NHEJ1, also known as Cernunnos or XLF).

DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes a progressive loss of Hematopoietic stem cells during aging. Deficiency of lig4 in pluripotent stem cells results in accumulation of DNA double-strand breaks and enhanced apoptosis.

In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations with about a 40% decrease in bone marrow cell number that includes several hematopoietic lineages. Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue. 

Deficiency of NHEJ factor 1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time. Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors. These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation.

The sensitivity of haematopoietic stem cells to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time. Rossi et al. found that endogenous DNA damage accumulates with age even in wild type Hematopoietic stem cells, and suggested that DNA damage accrual may be an important physiological mechanism of stem cell aging.

Clinical significance

Transplant

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).

It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia. In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.

In order to harvest stem cells from the circulating peripheral blood, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), that induces cells to leave the bone marrow and circulate in the blood vessels. In mammalian embryology, the first definitive Hematopoietic stem cells are detected in the AGM (aorta-gonad-mesonephros), and then massively expanded in the fetal liver prior to colonising the bone marrow before birth.

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to autoimmune diseases and hereditary skeletal dysplasias; notably malignant infantile osteopetrosis and mucopolysaccharidosis.

Research

Behavior in culture

A cobblestone area-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated onto a confluent culture of stromal feeder layer, a fraction of Hematopoietic stem cells creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g. thymocytes into thymic nurse cells); on the other hand, when in vitro, lymphoid lineage cells creep beneath nurse-like cells, the process is called pseudoemperipolesis. This similar phenomenon is more commonly known in the HSC field by the cell culture terminology cobble stone area-forming cells (CAFC), which means areas or clusters of cells look dull cobblestone-like under phase contrast microscopy, compared to the other Hematopoietic stem cells, which are refractile. This happens because the cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and, thus, not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1) and α4β1 integrins.

Repopulation kinetics

Hematopoietic stem cells (HSC) cannot be easily observed directly, and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely the closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series is defined as the repopulation kinetic of the HSC.

The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes. To prove this, several hundred experimental repopulation kinetics from clonal Thy-1lo SCA-1+ lin c-kit+ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria. 

It was originally believed that all Hematopoietic stem cells were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego, who illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1lo Sca-1+ lin c-kit+ HSC. The results of these clonal studies led to the notion of lineage bias. Using the ratio of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) Hematopoietic stem cells repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3 ≤ ρ ≤ 10). Myeloid-biased (My-bi) Hematopoietic stem cells give rise to very few lymphocytes resulting in ratios 0 < ρ < 3, while lymphoid-biased (Ly-bi) Hematopoietic stem cells generate very few myeloid cells, which results in lymphoid-to-myeloid ratios of ρ > 10. All three types are normal types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin interleukin 7 (IL-7).

Subsequently, other groups confirmed and highlighted the original findings. For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties. In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1+ lin c-kit+ HSC. As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.

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