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Lung

The lungs are the central organs of the respiratory system in humans and some other animals, including tetrapods, some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of the heart. Their function in the respiratory system is to extract oxygen from the air and transfer it into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere, in a process of gas exchange. The pleurae, which are thin, smooth, and moist, serve to reduce friction between the lungs and chest wall during breathing, allowing for easy and effortless movements of the lungs.

Respiration is driven by different muscular systems in different species. Mammals, reptiles and birds use their different muscles to support and foster breathing. In earlier tetrapods, air was driven into the lungs by the pharyngeal muscles via buccal pumping, a mechanism still seen in amphibians. In humans, the main muscle of respiration that drives breathing is the diaphragm. The lungs also provide airflow that makes vocal sounds including human speech possible.

Humans have two lungs, one on the left and one on the right. They are situated within the thoracic cavity of the chest. The right lung is bigger and heavier than the left, which shares space in the chest with the heart. The lungs together weigh approximately 1.3 kg. The lungs are part of the lower respiratory tract that begins at the trachea and branches into the bronchi and bronchioles, and which receive air breathed in via the conducting zone. The conducting zone ends at the terminal bronchioles. These divide into the respiratory bronchioles of the respiratory zone which divide into alveolar ducts that give rise to the alveolar sacs that contain the alveoli, where gas exchange takes place. Alveoli are also sparsely present on the walls of the respiratory bronchioles and alveolar ducts. Together, the lungs contain approximately 2400 km of airways and 300 to 500 million alveoli. Each lung is enclosed within a pleural sac of two membranes called pleurae; the membranes are separated by a film of pleural fluid, which allows the inner and outer membranes to slide over each other whilst breathing takes place, without much friction. The inner pleura also divides each lung into sections called lobes. The right lung has three lobes and the left has two. The lobes are further divided into bronchopulmonary segments and pulmonary lobules. The lungs have a unique blood supply, receiving deoxygenated blood from the heart in the pulmonary circulation for the purposes of receiving oxygen and releasing carbon dioxide, and a separate supply of oxygenated blood to the tissue of the lungs, in the bronchial circulation. Deoxygenated blood travels from the heart through the pulmonary artery to the lungs to be oxygenated in capillaries of alveoli. After the blood is oxygenated, it returns to the heart through the pulmonary vein to be sent to the rest of the body.

The tissue of the lungs can be affected by a number of respiratory diseases, including pneumonia and lung cancer. Chronic obstructive pulmonary disease includes chronic bronchitis and emphysema, and can be related to smoking or exposure to harmful substances. A number of occupational lung diseases can be caused by substances such as coal dust, asbestos fibres, and crystalline silica dust. Diseases such as bronchitis can also affect the respiratory tract. Medical terms related to the lung often begin with pulmo-, from the Latin pulmonarius (of the lungs) as in pulmonology, or with pneumo- (from Greek πνεύμων "lung") as in pneumonia.

In embryonic development, the lungs begin to develop as an outpouching of the foregut, a tube which goes on to form the upper part of the digestive system. When the lungs are formed the fetus is held in the fluid-filled amniotic sac and so they do not function to breathe. Blood is also diverted from the lungs through the ductus arteriosus. At birth, however, air begins to pass through the lungs, and the diversionary duct closes, so that the lungs can begin to respire. The lungs only fully develop in early childhood.

Anatomy
The lungs are located in the chest on either side of the heart in the rib cage. They are conical in shape with a narrow rounded apex at the top, and a broad concave base that rests on the convex surface of the diaphragm. The apex of the lung extends into the root of the neck, reaching shortly above the level of the sternal end of the first rib. The lungs stretch from close to the backbone in the rib cage to the front of the chest and downwards from the lower part of the trachea to the diaphragm.

The left lung shares space with the heart, and has an indentation in its border called the cardiac notch of the left lung to accommodate this. The front and outer sides of the lungs face the ribs, which make light indentations on their surfaces. The medial surfaces of the lungs face towards the centre of the chest, and lie against the heart, great vessels, and the carina where the trachea divides into the two main bronchi. The cardiac impression is an indentation formed on the surfaces of the lungs where they rest against the heart.

Both lungs have a central recession called the hilum, where the blood vessels and airways pass into the lungs making up the root of the lung. There are also bronchopulmonary lymph nodes on the hilum.

The lungs are surrounded by the pulmonary pleurae. The pleurae are two serous membranes; the outer parietal pleura lines the inner wall of the rib cage and the inner visceral pleura directly lines the surface of the lungs. Between the pleurae is a potential space called the pleural cavity containing a thin layer of lubricating pleural fluid.

Lobes
Each lung is divided into sections called lobes by the infoldings of the visceral pleura as fissures. Lobes are divided into segments, and segments have further divisions as lobules. There are three lobes in the right lung and two lobes in the left lung.

Fissures
The fissures are formed in early prenatal development by invaginations of the visceral pleura that divide the lobar bronchi, and section the lungs into lobes that helps in their expansion. The right lung is divided into three lobes by a horizontal fissure, and an oblique fissure. The left lung is divided into two lobes by an oblique fissure which is closely aligned with the oblique fissure in the right lung. In the right lung the upper horizontal fissure, separates the upper (superior) lobe from the middle lobe. The lower, oblique fissure separates the lower lobe from the middle and upper lobes.

Variations in the fissures are fairly common being either incompletely formed or present as an extra fissure as in the azygos fissure, or absent. Incomplete fissures are responsible for interlobar collateral ventilation, airflow between lobes which is unwanted in some lung volume reduction procedures.

Segments
The main or primary bronchi enter the lungs at the hilum and initially branch into secondary bronchi also known as lobar bronchi that supply air to each lobe of the lung. The lobar bronchi branch into tertiary bronchi also known as segmental bronchi and these supply air to the further divisions of the lobes known as bronchopulmonary segments. Each bronchopulmonary segment has its own (segmental) bronchus and arterial supply. Segments for the left and right lung are shown in the table. The segmental anatomy is useful clinically for localising disease processes in the lungs. A segment is a discrete unit that can be surgically removed without seriously affecting surrounding tissue.

Right lung
The right lung has both more lobes and segments than the left. It is divided into three lobes, an upper, middle, and a lower lobe by two fissures, one oblique and one horizontal. The upper, horizontal fissure, separates the upper from the middle lobe. It begins in the lower oblique fissure near the posterior border of the lung, and, running horizontally forward, cuts the anterior border on a level with the sternal end of the fourth costal cartilage; on the mediastinal surface it may be traced back to the hilum. The lower, oblique fissure, separates the lower from the middle and upper lobes and is closely aligned with the oblique fissure in the left lung.

The mediastinal surface of the right lung is indented by a number of nearby structures. The heart sits in an impression called the cardiac impression. Above the hilum of the lung is an arched groove for the azygos vein, and above this is a wide groove for the superior vena cava and right brachiocephalic vein; behind this, and close to the top of the lung is a groove for the brachiocephalic artery. There is a groove for the esophagus behind the hilum and the pulmonary ligament, and near the lower part of the esophageal groove is a deeper groove for the inferior vena cava before it enters the heart.

The weight of the right lung varies between individuals, with a standard reference range in men of 155-720 g and in women of 100-590 g.

Left lung
The left lung is divided into two lobes, an upper and a lower lobe, by the oblique fissure, which extends from the costal to the mediastinal surface of the lung both above and below the hilum. The left lung, unlike the right, does not have a middle lobe, though it does have a homologous feature, a projection of the upper lobe termed the lingula. Its name means "little tongue". The lingula on the left lung serves as an anatomic parallel to the middle lobe on the right lung, with both areas being predisposed to similar infections and anatomic complications. There are two bronchopulmonary segments of the lingula: superior and inferior.

The mediastinal surface of the left lung has a large cardiac impression where the heart sits. This is deeper and larger than that on the right lung, at which level the heart projects to the left.

On the same surface, immediately above the hilum, is a well-marked curved groove for the aortic arch, and a groove below it for the descending aorta. The left subclavian artery, a branch off the aortic arch, sits in a groove from the arch to near the apex of the lung. A shallower groove in front of the artery and near the edge of the lung, lodges the left brachiocephalic vein. The esophagus may sit in a wider shallow impression at the base of the lung.

By standard reference range, the weight of the left lung is 110-675 g in men and 105-515 g in women.

Microanatomy
The lungs are part of the lower respiratory tract, and accommodate the bronchial airways when they branch from the trachea. The bronchial airways terminate in alveoli which make up the functional tissue (parenchyma) of the lung, and veins, arteries, nerves, and lymphatic vessels. The trachea and bronchi have plexuses of lymph capillaries in their mucosa and submucosa. The smaller bronchi have a single layer of lymph capillaries, and they are absent in the alveoli. The lungs are supplied with the largest lymphatic drainage system of any other organ in the body. Each lung is surrounded by a serous membrane of visceral pleura, which has an underlying layer of loose connective tissue attached to the substance of the lung.

Connective tissue
The connective tissue of the lungs is made up of elastic and collagen fibres that are interspersed between the capillaries and the alveolar walls. Elastin is the key protein of the extracellular matrix and is the main component of the elastic fibres. Elastin gives the necessary elasticity and resilience required for the persistent stretching involved in breathing, known as lung compliance. It is also responsible for the elastic recoil needed. Elastin is more concentrated in areas of high stress such as the openings of the alveoli, and alveolar junctions. The connective tissue links all the alveoli to form the lung parenchyma which has a sponge-like appearance. The alveoli have interconnecting air passages in their walls known as the pores of Kohn.

Respiratory epithelium
All of the lower respiratory tract including the trachea, bronchi, and bronchioles is lined with respiratory epithelium. This is a ciliated epithelium interspersed with goblet cells which produce mucin the main component of mucus, ciliated cells, basal cells, and in the terminal bronchioles–club cells with actions similar to basal cells, and macrophages. The epithelial cells, and the submucosal glands throughout the respiratory tract secrete airway surface liquid (ASL), the composition of which is tightly regulated and determines how well mucociliary clearance works.

Pulmonary neuroendocrine cells are found throughout the respiratory epithelium including the alveolar epithelium, though they only account for around 0.5 percent of the total epithelial population. PNECs are innervated airway epithelial cells that are particularly focused at airway junction points. These cells can produce serotonin, dopamine, and norepinephrine, as well as polypeptide products. Cytoplasmic processes from the pulmonary neuroendocrine cells extend into the airway lumen where they may sense the composition of inspired gas.

Bronchial airways
In the bronchi there are incomplete tracheal rings of cartilage and smaller plates of cartilage that keep them open. Bronchioles are too narrow to support cartilage and their walls are of smooth muscle, and this is largely absent in the narrower respiratory bronchioles which are mainly just of epithelium. The absence of cartilage in the terminal bronchioles gives them an alternative name of membranous bronchioles.

Respiratory zone
The conducting zone of the respiratory tract ends at the terminal bronchioles when they branch into the respiratory bronchioles. This marks the beginning of the terminal respiratory unit called the acinus which includes the respiratory bronchioles, the alveolar ducts, alveolar sacs, and alveoli. An acinus measures up to 10 mm in diameter. A primary pulmonary lobule is the part of the lung distal to the respiratory bronchiole. Thus, it includes the alveolar ducts, sacs, and alveoli but not the respiratory bronchioles.

The unit described as the secondary pulmonary lobule is the lobule most referred to as the pulmonary lobule or respiratory lobule. This lobule is a discrete unit that is the smallest component of the lung that can be seen without aid. The secondary pulmonary lobule is likely to be made up of between 30 and 50 primary lobules. The lobule is supplied by a terminal bronchiole that branches into respiratory bronchioles. The respiratory bronchioles supply the alveoli in each acinus and is accompanied by a pulmonary artery branch. Each lobule is enclosed by an interlobular septum. Each acinus is incompletely separated by an intralobular septum.

The respiratory bronchiole gives rise to the alveolar ducts that lead to the alveolar sacs, which contain two or more alveoli. The walls of the alveoli are extremely thin allowing a fast rate of diffusion. The alveoli have interconnecting small air passages in their walls known as the pores of Kohn.

Alveoli
Alveoli consist of two types of alveolar cell and an alveolar macrophage. The two types of cell are known as type I and type II cells (also known as pneumocytes). Types I and II make up the walls and alveolar septa. Type I cells provide 95% of the surface area of each alveoli and are flat ("squamous"), and Type II cells generally cluster in the corners of the alveoli and have a cuboidal shape. Despite this, cells occur in a roughly equal ratio of 1:1 or 6:4.

Type I are squamous epithelial cells that make up the alveolar wall structure. They have extremely thin walls that enable an easy gas exchange. These type I cells also make up the alveolar septa which separate each alveolus. The septa consist of an epithelial lining and associated basement membranes. Type I cells are not able to divide, and consequently rely on differentiation from Type II cells.

Type II are larger and they line the alveoli and produce and secrete epithelial lining fluid, and lung surfactant. Type II cells are able to divide and differentiate to Type I cells.

The alveolar macrophages have an important role in the immune system. They remove substances which deposit in the alveoli including loose red blood cells that have been forced out from blood vessels.

Microbiota
There is a large presence of microorganisms in the lungs known as the lung microbiota that interacts with the airway epithelial cells; an interaction of probable importance in maintaining homeostasis. The microbiota is complex and dynamic in healthy people, and altered in diseases such as asthma and COPD. For example significant changes can take place in COPD following infection with rhinovirus. Fungal genera that are commonly found as mycobiota in the microbiota include Candida, Malassezia, Saccharomyces, and Aspergillus.

Respiratory tract
The lower respiratory tract is part of the respiratory system, and consists of the trachea and the structures below this including the lungs. The trachea receives air from the pharynx and travels down to a place where it splits (the carina) into a right and left primary bronchus. These supply air to the right and left lungs, splitting progressively into the secondary and tertiary bronchi for the lobes of the lungs, and into smaller and smaller bronchioles until they become the respiratory bronchioles. These in turn supply air through alveolar ducts into the alveoli, where the exchange of gases take place. Oxygen breathed in, diffuses through the walls of the alveoli into the enveloping capillaries and into the circulation, and carbon dioxide diffuses from the blood into the lungs to be breathed out.

Estimates of the total surface area of lungs vary from 50 to 75 sqm; although this is often quoted in textbooks and the media being "the size of a tennis court", it is actually less than half the size of a singles court.

The bronchi in the conducting zone are reinforced with hyaline cartilage in order to hold open the airways. The bronchioles have no cartilage and are surrounded instead by smooth muscle. Air is warmed to 37 °C, humidified and cleansed by the conducting zone. Particles from the air being removed by the cilia on the respiratory epithelium lining the passageways, in a process called mucociliary clearance.

Pulmonary stretch receptors in the smooth muscle of the airways initiate a reflex known as the Hering–Breuer reflex that prevents the lungs from over-inflation, during forceful inspiration.

Blood supply
The lungs have a dual blood supply provided by a bronchial and a pulmonary circulation. The bronchial circulation supplies oxygenated blood to the airways of the lungs, through the bronchial arteries that leave the aorta. There are usually three arteries, two to the left lung and one to the right, and they branch alongside the bronchi and bronchioles. The pulmonary circulation carries deoxygenated blood from the heart to the lungs and returns the oxygenated blood to the heart to supply the rest of the body.

The blood volume of the lungs is about 450 millilitres on average, about 9% of the total blood volume of the entire circulatory system. This quantity can easily fluctuate from between one-half and twice the normal volume. Also, in the event of blood loss through hemorrhage, blood from the lungs can partially compensate by automatically transferring to the systemic circulation.

Nerve supply
The lungs are supplied by nerves of the autonomic nervous system. Input from the parasympathetic nervous system occurs via the vagus nerve. When stimulated by acetylcholine, this causes constriction of the smooth muscle lining the bronchus and bronchioles, and increases the secretions from glands. The lungs also have a sympathetic tone from norepinephrine acting on the beta 2 adrenoceptors in the respiratory tract, which causes bronchodilation.

The action of breathing takes place because of nerve signals sent by the respiratory center in the brainstem, along the phrenic nerve from the cervical plexus to the diaphragm.

Variation
The lobes of the lung are subject to anatomical variations. A horizontal interlobar fissure was found to be incomplete in 25% of right lungs, or even absent in 11% of all cases. An accessory fissure was also found in 14% and 22% of left and right lungs, respectively. An oblique fissure was found to be incomplete in 21% to 47% of left lungs. In some cases a fissure is absent, or extra, resulting in a right lung with only two lobes, or a left lung with three lobes.

A variation in the airway branching structure has been found specifically in the central airway branching. This variation is associated with the development of COPD in adulthood.

Development
The development of the human lungs arise from the laryngotracheal groove and develop to maturity over several weeks in the foetus and for several years following birth.

The larynx, trachea, bronchi and lungs that make up the respiratory tract, begin to form during the fourth week of embryogenesis from the lung bud which appears ventrally to the caudal portion of the foregut. The respiratory tract has a branching structure, and is also known as the respiratory tree. In the embryo this structure is developed in the process of branching morphogenesis, and is generated by the repeated splitting of the tip of the branch. In the development of the lungs (as in some other organs) the epithelium forms branching tubes. The lung has a left-right symmetry and each bud known as a bronchial bud grows out as a tubular epithelium that becomes a bronchus. Each bronchus branches into bronchioles. The branching is a result of the tip of each tube bifurcating. The branching process forms the bronchi, bronchioles, and ultimately the alveoli. The four genes mostly associated with branching morphogenesis in the lung are the intercellular signalling protein – sonic hedgehog (SHH), fibroblast growth factors FGF10 and FGFR2b, and bone morphogenetic protein BMP4. FGF10 is seen to have the most prominent role. FGF10 is a paracrine signalling molecule needed for epithelial branching, and SHH inhibits FGF10. The development of the alveoli is influenced by a different mechanism whereby continued bifurcation is stopped and the distal tips become dilated to form the alveoli.

At the end of the fourth week the lung bud divides into two, the right and left primary bronchial buds on each side of the trachea. During the fifth week the right bud branches into three secondary bronchial buds and the left branches into two secondary bronchial buds. These give rise to the lobes of the lungs, three on the right and two on the left. Over the following week, the secondary buds branch into tertiary buds, about ten on each side. From the sixth week to the sixteenth week, the major elements of the lungs appear except the alveoli. From week 16 to week 26, the bronchi enlarge and lung tissue becomes highly vascularised. Bronchioles and alveolar ducts also develop. By week 26 the terminal bronchioles have formed which branch into two respiratory bronchioles. During the period covering the 26th week until birth the important blood–air barrier is established. Specialised type I alveolar cells where gas exchange will take place, together with the type II alveolar cells that secrete pulmonary surfactant, appear. The surfactant reduces the surface tension at the air-alveolar surface which allows expansion of the alveolar sacs. The alveolar sacs contain the primitive alveoli that form at the end of the alveolar ducts, and their appearance around the seventh month marks the point at which limited respiration would be possible, and the premature baby could survive.

Vitamin A deficiency
The developing lung is particularly vulnerable to changes in the levels of vitamin A. Vitamin A deficiency has been linked to changes in the epithelial lining of the lung and in the lung parenchyma. This can disrupt the normal physiology of the lung and predispose to respiratory diseases. Severe nutritional deficiency in vitamin A results in a reduction in the formation of the alveolar walls (septa) and to notable changes in the respiratory epithelium; alterations are noted in the extracellular matrix and in the protein content of the basement membrane. The extracellular matrix maintains lung elasticity; the basement membrane is associated with alveolar epithelium and is important in the blood-air barrier. The deficiency is associated with functional defects and disease states. Vitamin A is crucial in the development of the alveoli which continues for several years after birth.

After birth
At birth, the baby's lungs are filled with fluid secreted by the lungs and are not inflated. After birth the infant's central nervous system reacts to the sudden change in temperature and environment. This triggers the first breath, within about 10 seconds after delivery. Before birth, the lungs are filled with fetal lung fluid. After the first breath, the fluid is quickly absorbed into the body or exhaled. The resistance in the lung's blood vessels decreases giving an increased surface area for gas exchange, and the lungs begin to breathe spontaneously. This accompanies other changes which result in an increased amount of blood entering the lung tissues.

At birth the lungs are very undeveloped with only around one sixth of the alveoli of the adult lung present. The alveoli continue to form into early adulthood, and their ability to form when necessary is seen in the regeneration of the lung. Alveolar septa have a double capillary network instead of the single network of the developed lung. Only after the maturation of the capillary network can the lung enter a normal phase of growth. Following the early growth in numbers of alveoli there is another stage of the alveoli being enlarged.

Gas exchange
The major function of the lungs is gas exchange between the lungs and the blood. The alveolar and pulmonary capillary gases equilibrate across the thin blood–air barrier. This thin membrane (about 0.5 –2 μm thick) is folded into about 300 million alveoli, providing an extremely large surface area (estimates varying between 70 and 145 m2) for gas exchange to occur.

The lungs are not capable of expanding to breathe on their own, and will only do so when there is an increase in the volume of the thoracic cavity. This is achieved by the muscles of respiration, through the contraction of the diaphragm, and the intercostal muscles which pull the rib cage upwards as shown in the diagram. During breathing out the muscles relax, returning the lungs to their resting position. At this point the lungs contain the functional residual capacity (FRC) of air, which, in the adult human, has a volume of about 2.5–3.0 litres.

During heavy breathing as in exertion, a large number of accessory muscles in the neck and abdomen are recruited, that during exhalation pull the ribcage down, decreasing the volume of the thoracic cavity. The FRC is now decreased, but since the lungs cannot be emptied completely there is still about a litre of residual air left. Lung function testing is carried out to evaluate lung volumes and capacities.

Protection
The lungs possess several characteristics which protect against infection. The respiratory tract is lined by respiratory epithelium or respiratory mucosa, with hair-like projections called cilia that beat rhythmically and carry mucus. This mucociliary clearance is an important defence system against air-borne infection. The dust particles and bacteria in the inhaled air are caught in the mucosal surface of the airways, and are moved up towards the pharynx by the rhythmic upward beating action of the cilia. The lining of the lung also secretes immunoglobulin A which protects against respiratory infections; goblet cells secrete mucus which also contains several antimicrobial compounds such as defensins, antiproteases, and antioxidants. A rare type of specialised cell called a pulmonary ionocyte that is suggested may regulate mucus viscosity has been described. In addition, the lining of the lung also contains macrophages, immune cells which engulf and destroy debris and microbes that enter the lung in a process known as phagocytosis; and dendritic cells which present antigens to activate components of the adaptive immune system such as T cells and B cells.

The size of the respiratory tract and the flow of air also protect the lungs from larger particles. Smaller particles deposit in the mouth and behind the mouth in the oropharynx, and larger particles are trapped in nasal hair after inhalation.

Other
In addition to their function in respiration, the lungs have a number of other functions. They are involved in maintaining homeostasis, helping in the regulation of blood pressure as part of the renin–angiotensin system. The inner lining of the blood vessels secretes angiotensin-converting enzyme (ACE) an enzyme that catalyses the conversion of angiotensin I to angiotensin II. The lungs are involved in the blood's acid–base homeostasis by expelling carbon dioxide when breathing.

The lungs also serve a protective role. Several blood-borne substances, such as a few types of prostaglandins, leukotrienes, serotonin and bradykinin, are excreted through the lungs. Drugs and other substances can be absorbed, modified or excreted in the lungs. The lungs filter out small blood clots from veins and prevent them from entering arteries and causing strokes.

The lungs also play a pivotal role in speech by providing air and airflow for the creation of vocal sounds, and other paralanguage communications such as sighs and gasps.

Research suggests a role of the lungs in the production of blood platelets.

Gene and protein expression
About 20,000 protein coding genes are expressed in human cells and almost 75% of these genes are expressed in the normal lung. A little less than 200 of these genes are more specifically expressed in the lung with less than 20 genes being highly lung specific. The highest expression of lung specific proteins are different surfactant proteins, such as SFTPA1, SFTPB and SFTPC, and napsin, expressed in type II pneumocytes. Other proteins with elevated expression in the lung are the dynein protein DNAH5 in ciliated cells, and the secreted SCGB1A1 protein in mucus-secreting goblet cells of the airway mucosa.

Clinical significance
Lungs can be affected by a number of diseases and disorders. Pulmonology is the medical speciality that deals with respiratory diseases involving the lungs and respiratory system. Cardiothoracic surgery deals with surgery of the lungs including lung volume reduction surgery, lobectomy, pneumectomy and lung transplantation.

Inflammation and infection
Inflammatory conditions of the lung tissue are pneumonia, of the respiratory tract are bronchitis and bronchiolitis, and of the pleurae surrounding the lungs pleurisy. Inflammation is usually caused by infections due to bacteria or viruses. When the lung tissue is inflamed due to other causes it is called pneumonitis. One major cause of bacterial pneumonia is tuberculosis. Chronic infections often occur in those with immunodeficiency and can include a fungal infection by Aspergillus fumigatus that can lead to an aspergilloma forming in the lung. In the US certain species of rat can transmit a hantavirus to humans that can cause untreatable hantavirus pulmonary syndrome with a similar presentation to that of acute respiratory distress syndrome (ARDS).

Alcohol affects the lungs and can cause inflammatory alcoholic lung disease. Acute exposure to alcohol stimulates the beating of cilia in the respiratory epithelium. However, chronic exposure has the effect of desensitising the ciliary response which reduces mucociliary clearance (MCC). MCC is an innate defense system protecting against pollutants and pathogens, and when this is disrupted the numbers of alveolar macrophages are decreased. A subsequent inflammatory response is the release of cytokines. Another consequence is the susceptibility to infection.

Blood-supply changes
A pulmonary embolism is a blood clot that becomes lodged in the pulmonary arteries. The majority of emboli arise because of deep vein thrombosis in the legs. Pulmonary emboli may be investigated using a ventilation/perfusion scan, a CT scan of the arteries of the lung, or blood tests such as the D-dimer. Pulmonary hypertension describes an increased pressure at the beginning of the pulmonary artery that has a large number of differing causes. Other rarer conditions may also affect the blood supply of the lung, such as granulomatosis with polyangiitis, which causes inflammation of the small blood vessels of the lungs and kidneys.

A lung contusion is a bruise caused by chest trauma. It results in hemorrhage of the alveoli causing a build-up of fluid which can impair breathing, and this can be either mild or severe. The function of the lungs can also be affected by compression from fluid in the pleural cavity pleural effusion, or other substances such as air (pneumothorax), blood (hemothorax), or rarer causes. These may be investigated using a chest X-ray or CT scan, and may require the insertion of a surgical drain until the underlying cause is identified and treated.

Obstructive lung diseases
Asthma, bronchiectasis, and chronic obstructive pulmonary disease (COPD) that includes chronic bronchitis, and emphysema, are all obstructive lung diseases characterised by airway obstruction. This limits the amount of air that is able to enter alveoli because of constriction of the bronchial tree, due to inflammation. Obstructive lung diseases are often identified because of symptoms and diagnosed with pulmonary function tests such as spirometry.

Many obstructive lung diseases are managed by avoiding triggers (such as dust mites or smoking), with symptom control such as bronchodilators, and with suppression of inflammation (such as through corticosteroids) in severe cases. A common cause of chronic bronchitis, and emphysema, is smoking; and common causes of bronchiectasis include severe infections and cystic fibrosis. The definitive cause of asthma is not yet known, but it has been linked to other atopic diseases.

The breakdown of alveolar tissue, often as a result of tobacco-smoking leads to emphysema, which can become severe enough to develop into COPD. Elastase breaks down the elastin in the lung's connective tissue that can also result in emphysema. Elastase is inhibited by the acute-phase protein, alpha-1 antitrypsin, and when there is a deficiency in this, emphysema can develop. With persistent stress from smoking, the airway basal cells become disarranged and lose their regenerative ability needed to repair the epithelial barrier. The disorganised basal cells are seen to be responsible for the major airway changes that are characteristic of COPD, and with continued stress can undergo a malignant transformation. Studies have shown that the initial development of emphysema is centred on the early changes in the airway epithelium of the small airways. Basal cells become further deranged in a smoker's transition to clinically defined COPD.

Restrictive lung diseases
Some types of chronic lung diseases are classified as restrictive lung disease, because of a restriction in the amount of lung tissue involved in respiration. These include pulmonary fibrosis which can occur when the lung is inflamed for a long period of time. Fibrosis in the lung replaces functioning lung tissue with fibrous connective tissue. This can be due to a large variety of occupational lung diseases such as Coalworker's pneumoconiosis, autoimmune diseases or more rarely to a reaction to medication. Severe respiratory disorders, where spontaneous breathing is not enough to maintain life, may need the use of mechanical ventilation to ensure an adequate supply of air.

Cancers
Lung cancer can either arise directly from lung tissue or as a result of metastasis from another part of the body. There are two main types of primary tumour described as either small-cell or non-small-cell lung carcinomas. The major risk factor for cancer is smoking. Once a cancer is identified it is staged using scans such as a CT scan and a sample of tissue from a biopsy is taken. Cancers may be treated surgically by removing the tumour, the use of radiotherapy, chemotherapy or a combination, or with the aim of symptom control. Lung cancer screening is being recommended in the United States for high-risk populations.

Congenital disorders
Congenital disorders include cystic fibrosis, pulmonary hypoplasia (an incomplete development of the lungs) congenital diaphragmatic hernia, and infant respiratory distress syndrome caused by a deficiency in lung surfactant. An azygos lobe is a congenital anatomical variation which though usually without effect can cause problems in thoracoscopic procedures.

Pleural space pressure
A pneumothorax (collapsed lung) is an abnormal collection of air in the pleural space that causes an uncoupling of the lung from the chest wall. The lung cannot expand against the air pressure inside the pleural space. An easy to understand example is a traumatic pneumothorax, where air enters the pleural space from outside the body, as occurs with puncture to the chest wall. Similarly, scuba divers ascending while holding their breath with their lungs fully inflated can cause air sacs (alveoli) to burst and leak high pressure air into the pleural space.

Examination
As part of a physical examination in response to respiratory symptoms of shortness of breath, and cough, a lung examination may be carried out. This exam includes palpation and auscultation. The areas of the lungs that can be listened to using a stethoscope are called the lung fields, and these are the posterior, lateral, and anterior lung fields. The posterior fields can be listened to from the back and include: the lower lobes (taking up three quarters of the posterior fields); the anterior fields taking up the other quarter; and the lateral fields under the axillae, the left axilla for the lingual, the right axilla for the middle right lobe. The anterior fields can also be auscultated from the front. An area known as the triangle of auscultation is an area of thinner musculature on the back which allows improved listening. Abnormal breathing sounds heard during a lung exam can indicate the presence of a lung condition; wheezing for example is commonly associated with asthma and COPD.

Function testing
Lung function testing is carried out by evaluating a person's capacity to inhale and exhale in different circumstances. The volume of air inhaled and exhaled by a person at rest is the tidal volume (normally 500–750 mL); the inspiratory reserve volume and expiratory reserve volume are the additional amounts a person is able to forcibly inhale and exhale respectively. The summed total of forced inspiration and expiration is a person's vital capacity. Not all air is expelled from the lungs even after a forced breath out; the remainder of the air is called the residual volume. Together these terms are referred to as lung volumes.

Pulmonary plethysmographs are used to measure functional residual capacity. Functional residual capacity cannot be measured by tests that rely on breathing out, as a person is only able to breathe a maximum of 80% of their total functional capacity. The total lung capacity depends on the person's age, height, weight, and sex, and normally ranges between 4 and 6 litres. Females tend to have a 20–25% lower capacity than males. Tall people tend to have a larger total lung capacity than shorter people. Smokers have a lower capacity than nonsmokers. Thinner persons tend to have a larger capacity. Lung capacity can be increased by physical training as much as 40% but the effect may be modified by exposure to air pollution.

Other lung function tests include spirometry, measuring the amount (volume) and flow of air that can be inhaled and exhaled. The maximum volume of breath that can be exhaled is called the vital capacity. In particular, how much a person is able to exhale in one second (called forced expiratory volume (FEV1)) as a proportion of how much they are able to exhale in total (FEV). This ratio, the FEV1/FEV ratio, is important to distinguish whether a lung disease is restrictive or obstructive. Another test is that of the lung's diffusing capacity – this is a measure of the transfer of gas from air to the blood in the lung capillaries.

Human uses
Mammal lung is one of the main types of offal, or pluck, alongside the heart and trachea, and is consumed as a foodstuff around the world in dishes such as Scottish haggis. The United States Food and Drug Administration legally prohibits the sale of animal lungs due concerns such as fungal spores or cross-contamination with other organs, although this has been criticised as unfounded.

Birds
The lungs of birds are relatively small, but are connected to 8 or 9 air sacs that extend through much of the body, and are in turn connected to air spaces within the bones. On inhalation, air travels through the trachea of a bird into the air sacs. Air then travels continuously from the air sacs at the back, through the lungs, which are relatively fixed in size, to the air sacs at the front. From here, the air is exhaled. These fixed size lungs are called "circulatory lungs", as distinct from the "bellows-type lungs" found in most other animals.

The lungs of birds contain millions of tiny parallel passages called parabronchi. Small sacs called atria radiate from the walls of the tiny passages; these, like the alveoli in other lungs, are the site of gas exchange by simple diffusion. The blood flow around the parabronchi and their atria forms a cross-current process of gas exchange (see diagram on the right).

The air sacs, which hold air, do not contribute much to gas exchange, despite being thin-walled, as they are poorly vascularised. The air sacs expand and contract due to changes in the volume in the thorax and abdomen. This volume change is caused by the movement of the sternum and ribs and this movement is often synchronised with movement of the flight muscles.

Parabronchi in which the air flow is unidirectional are called paleopulmonic parabronchi and are found in all birds. Some birds, however, have, in addition, a lung structure where the air flow in the parabronchi is bidirectional. These are termed neopulmonic parabronchi.

Reptiles
The lungs of most reptiles have a single bronchus running down the centre, from which numerous branches reach out to individual pockets throughout the lungs. These pockets are similar to alveoli in mammals, but much larger and fewer in number. These give the lung a sponge-like texture. In tuataras, snakes, and some lizards, the lungs are simpler in structure, similar to that of typical amphibians.

Snakes and limbless lizards typically possess only the right lung as a major respiratory organ; the left lung is greatly reduced, or even absent. Amphisbaenians, however, have the opposite arrangement, with a major left lung, and a reduced or absent right lung.

Both crocodilians and monitor lizards have lungs similar to those of birds, providing a unidirectional airflow and even possessing air sacs. The now extinct pterosaurs have seemingly even further refined this type of lung, extending the airsacs into the wing membranes and, in the case of lonchodectids, tupuxuara, and azhdarchoids, the hindlimbs.

Reptilian lungs typically receive air via expansion and contraction of the ribs driven by axial muscles and buccal pumping. Crocodilians also rely on the hepatic piston method, in which the liver is pulled back by a muscle anchored to the pubic bone (part of the pelvis) called the diaphragmaticus, which in turn creates negative pressure in the crocodile's thoracic cavity, allowing air to be moved into the lungs by Boyle's law. Turtles, which are unable to move their ribs, instead use their forelimbs and pectoral girdle to force air in and out of the lungs.

Amphibians
The lungs of most frogs and other amphibians are simple and balloon-like, with gas exchange limited to the outer surface of the lung. This is not very efficient, but amphibians have low metabolic demands and can also quickly dispose of carbon dioxide by diffusion across their skin in water, and supplement their oxygen supply by the same method. Amphibians employ a positive pressure system to get air to their lungs, forcing air down into the lungs by buccal pumping. This is distinct from most higher vertebrates, who use a breathing system driven by negative pressure where the lungs are inflated by expanding the rib cage. In buccal pumping, the floor of the mouth is lowered, filling the mouth cavity with air. The throat muscles then presses the throat against the underside of the skull, forcing the air into the lungs.

Due to the possibility of respiration across the skin combined with small size, all known lungless tetrapods are amphibians. The majority of salamander species are lungless salamanders, which respirate through their skin and tissues lining their mouth. This necessarily restricts their size: all are small and rather thread-like in appearance, maximising skin surface relative to body volume. Other known lungless tetrapods are the Bornean flat-headed frog and Atretochoana eiselti, a caecilian.

The lungs of amphibians typically have a few narrow internal walls (septa) of soft tissue around the outer walls, increasing the respiratory surface area and giving the lung a honeycomb appearance. In some salamanders even these are lacking, and the lung has a smooth wall. In caecilians, as in snakes, only the right lung attains any size or development.

Fish
Lungs are found in three groups of fish; the coelacanths, the bichirs and the lungfish. Like in tetrapods, but unlike fish with swim bladder, the opening is at the ventral side of the esophagus. The coelacanth has a nonfunctional and unpaired vestigial lung surrounded by a fatty organ. Bichirs, the only group of ray-finned fish with lungs, have a pair which are hollow unchambered sacs, where the gas-exchange occurs on very flat folds that increase their inner surface area. The lungs of lungfish show more resemblance to tetrapod lungs. There is an elaborate network of parenchymal septa, dividing them into numerous respiration chambers. In the Australian lungfish, there is only a single lung, albeit divided into two lobes. Other lungfish, however, have traditionally been considered having two lungs, but newer research defines paired lungs as bilateral lung buds that arise simultaneously and are both connected directly to the foregut, which is only seen in tetrapods. In all lungfish, including the Australian, the lungs are located in the upper dorsal part of the body, with the connecting duct curving around and above the esophagus. The blood supply also twists around the esophagus, suggesting that the lungs originally evolved in the ventral part of the body, as in other vertebrates.

Invertebrates
A number of invertebrates have lung-like structures that serve a similar respiratory purpose to true vertebrate lungs, but are not evolutionarily related and only arise out of convergent evolution. Some arachnids, such as spiders and scorpions, have structures called book lungs used for atmospheric gas exchange. Some species of spider have four pairs of book lungs but most have two pairs. Scorpions have spiracles on their body for the entrance of air to the book lungs.

The coconut crab is terrestrial and uses structures called branchiostegal lungs to breathe air. Juveniles are released into the ocean, however adults cannot swim and possess an only rudimentary set of gills. The adult crabs can breathe on land and hold their breath underwater. The branchiostegal lungs are seen as a developmental adaptive stage from water-living to enable land-living, or from fish to amphibian.

Pulmonates are mostly land snails and slugs that have developed a simple lung from the mantle cavity. An externally located opening called the pneumostome allows air to be taken into the mantle cavity lung.

Evolutionary origins
The lungs of today's terrestrial vertebrates and the gas bladders of today's fish are believed to have evolved from simple sacs, as outpocketings of the esophagus, that allowed early fish to gulp air under oxygen-poor conditions. These outpocketings first arose in the bony fish. In most of the ray-finned fish the sacs evolved into closed off gas bladders, while a number of carp, trout, herring, catfish, and eels have retained the physostome condition with the sac being open to the esophagus. In more basal bony fish, such as the gar, bichir, bowfin and the lobe-finned fish, the bladders have evolved to primarily function as lungs. The lobe-finned fish gave rise to the land-based tetrapods. Thus, the lungs of vertebrates are homologous to the gas bladders of fish (but not to their gills).

title: Lung


text:
Hepburn romanization

Hepburn romanization (ヘボン式ローマ字) is the main system of romanization for the Japanese language. The system was originally published in 1867 by American Christian missionary and physician James Curtis Hepburn as the standard in the first edition of his Japanese–English dictionary. The system is distinct from other romanization methods in its use of English orthography to phonetically transcribe sounds: for example, the syllable (し) is written as ' and  (ちゃ) is written as ', reflecting their spellings in English (compare to ' and ' in the more systematic Nihon-shiki and Kunrei-shiki systems).

In 1886, Hepburn published the third edition of his dictionary, codifying a revised version of the system that is known today as "traditional Hepburn". A version with additional revisions, known as "modified Hepburn", was published in 1908.

Although Kunrei-shiki romanization is the style favored by the Japanese government, Hepburn remains the most popular method of Japanese romanization. It is learned by most foreign students of the language, and is used within Japan for romanizing personal names, locations, and other information, such as train tables and road signs. Because the system's orthography is based on English phonology instead of a systematic transcription of the Japanese syllabary, individuals who do not speak Japanese will generally be more accurate when pronouncing unfamiliar words romanized in the Hepburn style compared to other systems.

History
In 1867, American Presbyterian missionary doctor James Curtis Hepburn published the first Japanese–English dictionary, in which he introduced a new system for the romanization of Japanese into Latin script. He published a second edition in 1872 and a third edition in 1886, which introduced minor changes. The third edition's system had been adopted in the previous year by the "Romanization Club" (羅馬字会), a group of Japanese and foreign scholars who promoted a replacement of the Japanese script with a romanized system.

Hepburn romanization, loosely based on the conventions of English orthography (spelling), stood in opposition to Nihon-shiki romanization, which had been developed in Japan in 1881 as a script replacement. Compared to Hepburn, Nihon-shiki is more systematic in its representation of the Japanese syllabary (kana), as each symbol corresponds to a phoneme. However, the notation requires further explanation for accurate pronunciation by non-Japanese speakers: for example, the syllables and, which are written as ' and ' in Hepburn, are rendered as ' and ' in Nihon-shiki. After Nihon-shiki was presented to the in 1886, a dispute began between the supporters of the two systems, which resulted in a standstill and an eventual halt to the organization's activities in 1892.

After the Russo-Japanese War of 1904–1905, the two factions resurfaced as the "Society for the Spread of Romanization" (ローマ字ひろめ会), which supported Hepburn's style, and the "Romanization Society of Japan" (日本のローマ字社), which supported Nihon-shiki. In 1908, Hepburn was revised by educator Kanō Jigorō and others of the Rōmaji Hirome-kai, which began calling it the "modified Hepburn system" (修正ヘボン式) or "standard system" (標準式).

In 1930, a Special Romanization Study Commission, headed by the Minister of Education, was appointed by the government to devise a standardized form of romanization. The Commission eventually decided on a slightly modified "compromise" version of Nihon-shiki, which was chosen for official use by cabinet ordinance on September 21, 1937; this system is known today as Kunrei-shiki romanization. On September 3, 1945, at the beginning of the occupation of Japan after World War II, Supreme Commander for the Allied Powers Douglas MacArthur issued a directive mandating the use of modified Hepburn by occupation forces. The directive had no legal force, however, and a revised version of Kunrei-shiki was reissued by cabinet ordinance on December 9, 1954, after the end of occupation.

Although it lacks de jure status, Hepburn remains the de facto standard for some applications in Japan. As of 1977, many government organizations used Hepburn, including the Ministry of International Trade and Industry; the Ministry of Foreign Affairs requires the use of Hepburn on passports, and the Ministry of Land, Infrastructure and Transport requires its use on transport signs, including road signs and railway station signs. According to a survey by the Japanese Agency for Cultural Affairs in 2022, the Japanese primarily use Hepburn to spell place names. Hepburn is also used by private organizations, including The Japan Times and the Japan Travel Bureau.

American National Standard System for the Romanization of Japanese (ANSI Z39.11-1972), based on modified Hepburn, was approved in 1971 and published in 1972 by the American National Standards Institute. In 1989, it was proposed for International Organization for Standardization (ISO) standard 3602, but was rejected in favor of Kunrei-shiki. ANSI Z39.11-1972 was deprecated as a standard in 1994.

In January 2024, the Cultural Affairs Agency proposed revising the 1954 Cabinet ordinance to make Hepburn the standard romanization system of Japan.

Variants
There are many variants of the Hepburn romanization. The two most common styles are as follows: In Japan itself, there are some variants officially mandated for various uses:
 * Traditional Hepburn, as defined in various editions of Hepburn's dictionary, with the third edition (1886) often considered authoritative (although changes in kana usage must be accounted for). It is characterized by the rendering of syllabic n as m before the consonants b, m and p: for example, for 新橋.
 * Modified Hepburn, also known as Revised Hepburn, in which (among other changes) the rendering of syllabic n as m before bilabial consonants is no longer used:  for 新橋. The version of the system published in the third (1954) and later editions of Kenkyusha's New Japanese-English Dictionary are often considered authoritative; it was adopted in 1989 by the Library of Congress as one of its ALA-LC romanizations, and is the most common variant of Hepburn romanization used today.
 * Railway Standard (鉄道掲示基準規程), which mostly follows Modified Hepburn, except syllabic n is rendered as in Traditional. Japan Railways and other major railways use it for station names.
 * Road Sign Romaji (Hepburn) (道路標識のローマ字（ヘボン式)), used for road signs, which otherwise follows Modified Hepburn closely but specifies that macrons are not to be used.
 * Ministry of Foreign Affairs Passport Standard (外務省旅券規定), a permissive standard that renders the syllabic n as m before b, m and p. Most of the long vowels are not rendered. Moreover, this standard explicitly allows the use of "non-Hepburn romaji" (非ヘボン式ローマ字) in personal names, notably for passports. In particular, the long vowel ō can be romanized oh, oo or ou (Satoh, Satoo or Satou for 佐藤).

Details of the variants can be found below.

Obsolete variants
The romanizations set out in the first and second versions of Hepburn's dictionary are primarily of historical interest. Notable differences from the third and later versions include:

Second version

 * エ and ヱ were written as ye: Yedo
 * ズ and ヅ were written as dzu: kudzu, tsudzuku
 * キャ, キョ, and キュ were written as kiya, kiyo and kiu
 * クヮ (modern: カ) was written as kuwa

First version
The following differences are in addition to those in the second version:
 * ス was written as sz.
 * ツ was written as tsz.
 * ズ and ヅ were written as du.

Features
The main feature of Hepburn is that its orthography is based on English phonology. More technically, when syllables that are constructed systematically according to the Japanese syllabary contain an "unstable" consonant in the modern spoken language, the orthography is changed to something that better matches the real sound as an English-speaker would pronounce it. For example, し is written shi not si. This transcription is thus only partly phonological.

Some linguists such as Harold E. Palmer, Daniel Jones and Otto Jespersen object to Hepburn since the pronunciation-based spellings can obscure the systematic origins of Japanese phonetic structures, inflections, and conjugations. Since the vowel sounds in Hepburn are similar to the vowel sounds in Italian, and the consonants similar to those of many other languages, in particular English, speakers unfamiliar with Japanese will generally be more accurate when pronouncing unfamiliar words romanized in the Hepburn style compared to other systems.

Long vowels
In Hepburn, vowel combinations that form a long sound are usually indicated with a macron (◌̄). Other adjacent vowels, such as those separated by a morpheme boundary, are written separately:

All other vowel combinations are always written separately:
 * E + I: – sei + fuku – seifuku 'uniform' (despite E + I often being pronounced as a long E)
 * U + I: い – karu + i – karui 'light (in weight)'
 * O + I: – oi – oi 'nephew'

Loanwords
In foreign loanwords, long vowels followed by a chōonpu (ー) are indicated with macrons:
 * セーラー: se + (ー) + ra + (ー) = sērā 'sailor'
 * タクシー: ta + ku + shi + (ー) = takushī 'taxi'
 * コンクール: ko + n + ku + (ー) + ru = konkūru 'competition'
 * バレーボール: ba + re + (ー) + bo + (ー) + ru = barēbōru 'volleyball'
 * ソール: so + (ー) + ru = sōru 'sole (of a shoe, etc.)'

Adjacent vowels in loanwords are written separately:
 * バレエ: ba + re + e – baree 'ballet'
 * ミイラ: mi + i + ra – miira 'mummy'
 * ソウル: so + u + ru – souru 'soul', 'Seoul'

Variations
There are many variations on the Hepburn system for indicating long vowels with a macron. For example, 東京 (とうきょう) is properly romanized as Tōkyō, but can also be written as:
 * Tokyo – not indicated at all. Common for Japanese words that have been adopted into English, and the de facto convention for Hepburn used in signs and other English-language information around Japan.
 * Tôkyô – indicated with circumflex accents, as in the alternative Nihon-shiki and Kunrei-shiki romanizations. They are often used when macrons are unavailable or difficult to input, due to their visual similarity.
 * Tohkyoh – indicated with an h (only applies after o). This is sometimes known as "passport Hepburn", as the Japanese Foreign Ministry has authorized (but not required) it in passports.
 * Toukyou – written using kana spelling: ō as ou or oo (depending on the kana). This is also known as wāpuro style, as it reflects how text is entered into a Japanese word processor by using a keyboard with Roman characters. Wāpuro more accurately represents the way that ō is written in kana by differentiating between おう (as in とうきょう (東京), Toukyou in wāpuro) and おお (as in とおい (遠い), tooi in wāpuro); however, it fails to differentiate between long vowels and vowels separated by a morpheme boundary.
 * Tookyoo – written by doubling the long vowels. Some dictionaries such as the Pocket Kenkyusha Japanese Dictionary and Basic English Writers' Japanese-English Wordbook follow this style, and it is also used in the JSL form of romanization.

Particles
In traditional and modified:
 * When は is used as a particle, it is written wa.

In traditional Hepburn:
 * When へ is used as a particle, Hepburn originally recommended ye. This spelling is obsolete, and it is commonly written as e (Romaji-Hirome-Kai, 1974 ).
 * When を is used as a particle, it is written wo.

In modified Hepburn:
 * When へ is used as a particle, it is written e.
 * When を is used as a particle, it is written o.

Syllabic n
In traditional Hepburn:
 * Syllabic n (ん) is written as n before consonants, but as m before labial consonants: b, m, and p. It is sometimes written as n- (with a hyphen) before vowels and y (to avoid confusion between, for example, んあ n + a and な na, and んや n + ya and にゃ nya), but its hyphen usage is not clear.

 * 案内（あんない）: annai – guide
 * 群馬（ぐんま）: Gumma – Gunma
 * 簡易（かんい）: kan-i – simple
 * 信用（しんよう）: shin-yō – trust

In modified Hepburn:
 * The rendering m before labial consonants is not used and is replaced with n. It is written n' (with an apostrophe) before vowels and y.

 * 案内（あんない）: annai – guide
 * 群馬（ぐんま）: Gunma – Gunma
 * 簡易（かんい）: kan'i – simple
 * 信用（しんよう）: shin'yō – trust

Long consonants
Elongated (or "geminate") consonant sounds are marked by doubling the consonant following a sokuon, っ; for consonants that are digraphs in Hepburn (sh, ch, ts), only the first consonant of the set is doubled, except for ch, which is replaced by tch.
 * 結果（けっか）: kekka – result
 * さっさと: sassato – quickly
 * ずっと: zutto – all the time
 * 切符（きっぷ）: kippu – ticket
 * 雑誌（ざっし）: zasshi – magazine
 * 一緒（いっしょ）: issho – together
 * こっち: kotchi (not kocchi) – this way
 * 抹茶（まっちゃ）: matcha (not maccha) – matcha
 * 三つ（みっつ）: mittsu – three

Romanization charts

 * Each entry contains hiragana, katakana, and Hepburn romanization, in that order.
 * † — The characters in are historical characters and are obsolete in modern Japanese.  In modern Hepburn romanization, they are often undefined.
 * ‡ — The characters in are rarely used outside of their status as a particle in modern Japanese, and romanization follows the rules above.

Extended katakana
These combinations are used mainly to represent the sounds in words in other languages.

Digraphs with orange backgrounds are the general ones used for loanwords or foreign places or names, and those with blue backgrounds are used for more accurate transliterations of foreign sounds, suggested by the Cabinet of Japan's Ministry of Education, Culture, Sports, Science and Technology. Katakana combinations with beige backgrounds are suggested by the American National Standards Institute and the British Standards Institution as possible uses. Ones with purple backgrounds appear on the 1974 version of the Hyōjun-shiki formatting.

 * * — The use of ウ in these two cases to represent w is rare in modern Japanese except for Internet slang and transcription of the Latin sound into katakana. E.g.: ミネルウァ (Mineruwa "Minerva", from Latin MINERVA ); ウゥルカーヌス (Wurukānusu "Vulcan", from Latin VVLCANVS, Vulcānus ). The wa-type of foreign sounds (as in watt or white) is usually transcribed to ワ (wa), while the wu-type (as in wood or woman) is usually to ウ (u) or ウー (ū).
 * ⁑ — ヴ has a rarely used hiragana form in ゔ that is also vu in Hepburn romanization systems.
 * ⁂ — The characters in are obsolete in modern Japanese and very rarely used.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Hepburn romanization


text:
Soldier of Fortune (video game)

Soldier of Fortune is a first-person shooter video game developed by Raven Software and published by Activision in 2000 for Microsoft Windows. It was later released for the PlayStation 2 (as Soldier of Fortune: Gold Edition), as well as the Dreamcast, while Loki Software also made a port for Linux. It was digitally re-released on GOG.com on October 2, 2018, along with its two successors. The player takes on the role of a U.S. mercenary as he trots around the globe hoping to halt a terrorist nuclear weapons plot.

The game, which was built with the Quake II engine, is notable for its realistic depictions of violence, made possible by the GHOUL engine, including the dismemberment of human bodies. This was the game's stylistic attraction and it caused considerable controversy, especially in Canada and Germany, where it was classified as a restricted-rated film and listed on the Federal Department for Media Harmful to Young Persons, respectively. The technology creates 26 different zones on the bodies of enemies, allowing for vastly different reactions depending upon which one is targeted.

The game sold well initially and critical reception was positive. Two sequels were released: Soldier of Fortune II: Double Helix (2002) and Soldier of Fortune: Payback (2007). Soldier of Fortune Online, a massively multiplayer online first-person shooter game, was published in Korea in 2010, but its servers were shut down shortly after its release.

Gameplay

Soldier of Fortune is best known for its graphic depictions of firearms dismembering the human body. This graphic violence is the game's main stylistic attraction, much like the destructible environments of Red Faction or bullet time of Max Payne. The GHOUL engine enables depiction of extreme graphic violence, in which character models are based on body parts that can each independently sustain damage (gore zones). There are 26 zones in total: a shot to the head with a powerful gun will often make the target's head explode, leaving nothing but the bloody stump of the neck remaining; a close-range shot to the stomach with a shotgun will leave an enemy's bowels in a bloody mess, and a shot to the nether regions will cause the victims to clutch their groin in agony for a few seconds before kneeling over dead. It is possible to shoot off an enemy's limbs (head, arms, legs) leaving nothing left but a bloody torso. In the last mission there is also a fictional microwave weapon, causing the enemies to fry or explode, depending on the firing mode. However, nonviolence is a possibility, if the player is a good shot it is possible to shoot an enemy's weapon out of their hand, causing them to cower on the floor to surrender. The game also came with password-protected options to disable all gore and there is even a version of the game with the extreme violence permanently locked-out, titled Soldier of Fortune: Tactical Low-Violence Version.

Multiplayer
In multiplayer mode, there are seven gametypes: Arsenal, Assassination, Capture the Flag, Conquer the Bunker, Control, Deathmatch and Realistic Deathmatch.

Plot
The story involves the theft of nuclear weapons, and the main enemy turns out to be an Afrikaner neo-fascist group based in Germany, led by South African exile Sergei Dekker. At the beginning of the game, terrorists steal four nuclear weapons from a storage facility in Russia, and proceed to sell them to various nations. This is a prelude to the acquisition of advanced weapons of mass destruction by this terrorist group. John Mullins, working for a U.S.-based mercenary ("soldier of fortune") organization known only as "The Shop", and his partner, Aaron "Hawk" Parsons, are assigned to prevent the nukes from falling into the wrong hands, and stop the terrorists in their plans. His missions take him to New York City, Sudan, Siberia, Tokyo, Kosovo, Iraq, Uganda and finally Germany.

Development
Raven Software acquired a license from the mercenary magazine Soldier of Fortune to produce a video game based on the publication. The game was built around a modified version of the Quake II game engine. It was the first game to utilize the GHOUL damage model engine developed by Raven Software. This introduced the ability to dismember enemies in combat, adding to the realism of the game. Upgraded versions of the GHOUL system were later used in other Raven titles, such as Soldier of Fortune II: Double Helix and Star Wars Jedi Knight II: Jedi Outcast.

The game was originally supposed to be much more realistic, featuring mostly real weapons, and the players taking damage would impede their movement and dexterity, depending on where and how many times they were hit. In 1998 (prior to the Kosovo War) the game was also supposed to be partially based in Bosnia instead of Kosovo.

The game is AMD Eyefinity validated. The game also made use of the Aureal Semiconductor A3D and Creative Labs EAX technology.

Rerelease
GOG.com re-released Soldier of Fortune alongside its two successors digitally on October 1, 2018.

Reception
The Dreamcast version and the Gold Edition received "mixed or average reviews" according to the review aggregation website Metacritic. Robert Howarth of GameFan gave the PC version 91% and wrote, "for those adults looking for extreme action, Soldier of Fortune could be just what the doctor ordered." Howarth considered its story to be "on par" with many action movies; he also commented that the GHOUL damage model rendering system was "an amazing technology".

Chris Kramer of NextGen's June 2000 issue wrote of the PC original, "Sure, it's not for kids, but it's as good an FPS as you could ever ask for." 15 issues later, Jim Preston called the Dreamcast version "An OK port of an OK game."

Robert Mayer of Computer Games Strategy Plus gave the PC version four stars out of five, saying, "Raven Software set out to make a shooter, and they've made a damn fine one. Just be sure you're up to it before you dive in. It gets mighty bloody in there." Edge gave the same PC version seven out of ten, calling it "an above-average firstperson shooter. It doesn't bring much to the genre, save for its gory depiction of violence."

Cal Nguyen of AllGame gave the PC version four-and-a-half stars out of five, saying, "If you're bent on eliminating terrorist threats by skinheads, Saddam Hussein's army, Russian mafias or even New York mobsters, then take a lesson from the Soldier of Fortune [sic] and tear open a new one." Later, J.C. Barnes gave the Dreamcast version three-and-a-half stars out of five, calling it "a solid shooter that doesn't break new ground in graphics, sound or artificial intelligence, but it's a solid shooter worth some attention. Aside from the tricky controls and lighting issues, FPS fans shouldn't be too disappointed with this single-player adventure."

Nash Werner of GamePro said of the PC version, "With its well-written storyline and thought-provoking missions, SoF's singleplayer will keep you thrilled for hours, and you'll probably be playing the Assassin mode for months. Despite ridiculously long load times, Soldier of Fortune is recommended for everyone who appreciates a good FPS." Jake the Snake said of the Dreamcast version, "If you're longing for some over-the-top shooting with real weapons, Soldier of Fortune hits its mark with extreme prejudice, but less gonzo gamers should steer clear." However, The D-Pad Destroyer said of the PlayStation 2 version, "with all its faults, Fortune is fairly fun for hardcore soldier types, but everyone else will just want to keep their membership in Red Faction." Nick Valentino of GameZone gave the same console version 6 out of 10, saying that it was "just another FPS trying to jump on the bandwagon of other successful titles and sorely misses the mark. With very little to offer in terms of design or new features, it fails to capture the right FPS feel which other games have effectively achieved.  In other words, look someplace else."

According to PC Data, a firm that tracked sales in the U.S., the PC version sold 100,919 units by November 2000. NPD Techworld, which also covered the U.S., reported 298,563 units sold for said PC version by December 2002.

Violence controversy
In 2000, after receiving a complaint from a member of the public about the explicit content of the game, the British Columbia Film Classification Office (BCFCO) investigated and decided the violence, gore and acts of torture were not suitable for persons under 18 years of age. In a controversial decision, the game was labeled an "adult motion picture" and was rated as a pornographic film. In Germany, the game was placed on the Index List of the Federal Department for Media Harmful to Young Persons.

Sequels
Based on its success, Raven Software and Activision later published Soldier of Fortune II: Double Helix in 2002, based on the Quake III: Team Arena engine. Initially released for Windows, the sequel was later ported to the Xbox.

A third game in the series, Soldier of Fortune: Payback was made by Cauldron HQ and released on November 14, 2007.

An MMOFPS based on the series, Soldier of Fortune Online, was published in South Korea by Dragonfly and went in Closed Beta on August 12, 2010 and ended on August 16, 2010.

title: Soldier of Fortune (video game)


text:
CIS

CIS may refer to:

Computing

 * Card information structure, formatting and organization data stored on a PC card
 * Center for Internet Security, cybersecurity benchmarks, controls, practices and tools
 * Center for Internet and Society (disambiguation)
 * Comodo Internet Security suite
 * CompuServe Information Service, a US commercial online service
 * Computer information systems, technologies which process data to solve business problems
 * Configuration interaction singles, a quantum-chemical method for computing electronic states
 * Contact image sensor, a technology developed for optical flatbed scanners
 * Continuous ink system, for ink-jet printers

Education

 * Calcutta International School, in India
 * Canadian International School (disambiguation)
 * Canadian International School (Bangalore)
 * Canadian International School Vietnam
 * Canadian International School of Sanya, in China
 * Canadian International School (Singapore)
 * Canadian International School (Tokyo)
 * Cayman International School in Grand Cayman, Cayman Islands
 * Cebu International School, in the Philippines
 * Chinese International School, in Hong Kong
 * Clifford International School, in Guangzhou, Guangdong, China
 * College in the Schools, a program for high school students run by the University of Minnesota, U.S.
 * Colombo International School, in Sri Lanka
 * Communities In Schools, a U.S. federation of organizations combating educational dropout
 * Copenhagen International School, in Denmark
 * Council of International Schools, an international educational community organizations
 * MIT Center for International Studies, in Massachusetts, U.S.

Health

 * Cancer Information Service, a program of the US National Institutes of Health
 * Carcinoma in situ, group of abnormal cells which may be cancer
 * Clinically isolated syndrome, an initial neurological episode related to nerve tissue
 * Combined intracavernous injection and stimulation test, a diagnostic procedure for erectile dysfunction

United States

 * Center for Immigration Studies, an American anti-immigration think tank
 * United States Citizenship and Immigration Services, a US government agency

British

 * Christians in Science, a UK organization
 * Co-operative Insurance Society, a British insurance company

Canadian

 * Canadian Ice Service, a division of the Meteorological Service of Canada
 * Canadian Identification Society, of police and civilians in crime scene investigation
 * Canadian Interuniversity Sport, a former name of the national governing body of university sport

Eurasian

 * Commonwealth of Independent States, a Eurasian intergovernmental organization
 * CIS national football team, a National association football team

Other

 * Centre for Independent Studies, an Australian libertarian think tank
 * Centro de Investigaciones Sociológicas, a Spanish public research institute
 * CIS Corps (Ireland), Communications and Information Services Corps, Irish combat support corps
 * Cisalpino, Swiss–Italian railway company (CIS in timetables)
 * Commonwealth Police (Commonwealth Investigation Service), an Australian security service, 1945 to 1960

Other uses

 * Canton Island Airport, Kanton Island, Phoenix Islands, Kiribati, IATA code
 * Capital Indoor Stadium, an indoor arena in Beijing, China
 * Case Information Statement, a document used in US civil lawsuits
 * cis (mathematics), a trigonometric mathematical function
 * CIS Tower, a building in Manchester, England
 * Common Intelligibility Scale, for speech intelligibility
 * Community Innovation Survey, a series of surveys throughout the European Union
 * Confederacy of Independent Systems, a fictional entity in the Star Wars universe
 * Continuous Injection System, a fuel injection system developed by the Robert Bosch Group
 * Copper indium selenide (CuInSe2), used in solar cells and semiconductors
 * Corpus Inscriptionum Semiticarum, a corpus of Semitic inscriptions

title: CIS


text:
Cell division

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis (division of the nucleus) is preceded by the S stage of interphase (during which the DNA replication occurs) and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

Prokaryotes (bacteria and archaea) usually undergo a vegetative cell division known as binary fission, where their genetic material is segregated equally into two daughter cells, but there are alternative manners of division, such as budding, that have been observed. All cell divisions, regardless of organism, are preceded by a single round of DNA replication.

For simple unicellular microorganisms such as the amoeba, one cell division is equivalent to reproduction – an entire new organism is created. On a larger scale, mitotic cell division can create progeny from multicellular organisms, such as plants that grow from cuttings. Mitotic cell division enables sexually reproducing organisms to develop from the one-celled zygote, which itself is produced by fusion of two gametes, each having been produced by meiotic cell division. After growth from the zygote to the adult, cell division by mitosis allows for continual construction and repair of the organism. The human body experiences about 10 quadrillion cell divisions in a lifetime.

The primary concern of cell division is the maintenance of the original cell's genome. Before division can occur, the genomic information that is stored in chromosomes must be replicated, and the duplicated genome must be cleanly divided between progeny cells. A great deal of cellular infrastructure is involved in ensuring consistency of genomic information among generations.

In bacteria

Bacterial cell division happens through binary fission or sometimes through budding. The divisome is a protein complex in bacteria that is responsible for cell division, constriction of inner and outer membranes during division, and remodeling of the peptidoglycan cell wall at the division site. A tubulin-like protein, FtsZ plays a critical role in formation of a contractile ring for the cell division.

In eukaryotes
Cell division in eukaryotes is more complicated than in prokaryotes. If the chromosomal number is reduced, eukaryotic cell division is classified as meiosis (reductional division). If the chromosomal number is not reduced, eukaryotic cell division is classified as mitosis (equational division). A primitive form of cell division, called amitosis, also exists. The amitotic or mitotic cell divisions are more atypical and diverse among the various groups of organisms, such as protists (namely diatoms, dinoflagellates, etc.) and fungi.

In the mitotic metaphase (see below), typically the chromosomes (each containing 2 sister chromatids that developed during replication in the S phase of interphase) align themselves on the metaphase plate. Then, the sister chromatids split and are distributed between two daughter cells.

In meiosis I, the homologous chromosomes are paired before being separated and distributed between two daughter cells. On the other hand, meiosis II is similar to mitosis. The chromatids are separated and distributed in the same way. In humans, other higher animals, and many other organisms, the process of meiosis is called gametic meiosis, during which meiosis produces four gametes. Whereas, in several other groups of organisms, especially in plants (observable during meiosis in lower plants, but during the vestigial stage in higher plants), meiosis gives rise to spores that germinate into the haploid vegetative phase (gametophyte). This kind of meiosis is called sporic meiosis.

Interphase
Interphase is the process through which a cell must go before mitosis, meiosis, and cytokinesis. Interphase consists of three main phases: G1, S, and G2. G1 is a time of growth for the cell where specialized cellular functions occur in order to prepare the cell for DNA replication. There are checkpoints during interphase that allow the cell to either advance or halt further development. One of the checkpoint is between G1 and S, the purpose for this checkpoint is to check for appropriate cell size and any DNA damage. The second check point is in the G2 phase, this checkpoint also checks for cell size but also the DNA replication. The last check point is located at the site of metaphase, where it checks that the chromosomes are correctly connected to the mitotic spindles. In S phase, the chromosomes are replicated in order for the genetic content to be maintained. During G2, the cell undergoes the final stages of growth before it enters the M phase, where spindles are synthesized. The M phase can be either mitosis or meiosis depending on the type of cell. Germ cells, or gametes, undergo meiosis, while somatic cells will undergo mitosis. After the cell proceeds successfully through the M phase, it may then undergo cell division through cytokinesis. The control of each checkpoint is controlled by cyclin and cyclin-dependent kinases. The progression of interphase is the result of the increased amount of cyclin. As the amount of cyclin increases, more and more cyclin dependent kinases attach to cyclin signaling the cell further into interphase. At the peak of the cyclin, attached to the cyclin dependent kinases this system pushes the cell out of interphase and into the M phase, where mitosis, meiosis, and cytokinesis occur. There are three transition checkpoints the cell has to go through before entering the M phase. The most important being the G1-S transition checkpoint. If the cell does not pass this checkpoint, it results in the cell exiting the cell cycle.

Prophase
Prophase is the first stage of division. The nuclear envelope begins to be broken down in this stage, long strands of chromatin condense to form shorter more visible strands called chromosomes, the nucleolus disappears, and the mitotic spindle begins to assemble from the two centrosomes. Microtubules associated with the alignment and separation of chromosomes are referred to as the spindle and spindle fibers. Chromosomes will also be visible under a microscope and will be connected at the centromere. During this condensation and alignment period in meiosis, the homologous chromosomes undergo a break in their double-stranded DNA at the same locations, followed by a recombination of the now fragmented parental DNA strands into non-parental combinations, known as crossing over. This process is evidenced to be caused in a large part by the highly conserved Spo11 protein through a mechanism similar to that seen with topoisomerase in DNA replication and transcription.

Prometaphase
Prometaphase is the second stage of cell division. This stage begins with the complete breakdown of the nuclear envelope which exposes various structures to the cytoplasm. This breakdown then allows the spindle apparatus growing from the centrosome to attach to the kinetochores on the sister chromatids. Stable attachment of the spindle apparatus to the kinetochores on the sister chromatids will ensure error-free chromosome segregation during anaphase. Prometaphase follows prophase and precedes metaphase.

Metaphase
In metaphase, the centromeres of the chromosomes align themselves on the metaphase plate (or equatorial plate), an imaginary line that is at equal distances from the two centrosome poles and held together by complexes known as cohesins. Chromosomes line up in the middle of the cell by microtubule organizing centers (MTOCs) pushing and pulling on centromeres of both chromatids thereby causing the chromosome to move to the center. At this point the chromosomes are still condensing and are currently one step away from being the most coiled and condensed they will be, and the spindle fibers have already connected to the kinetochores. During this phase all the microtubules, with the exception of the kinetochores, are in a state of instability promoting their progression toward anaphase. At this point, the chromosomes are ready to split into opposite poles of the cell toward the spindle to which they are connected.

Anaphase
Anaphase is a very short stage of the cell cycle and it occurs after the chromosomes align at the mitotic plate. Kinetochores emit anaphase-inhibition signals until their attachment to the mitotic spindle. Once the final chromosome is properly aligned and attached the final signal dissipates and triggers the abrupt shift to anaphase. This abrupt shift is caused by the activation of the anaphase-promoting complex and its function of tagging degradation of proteins important toward the metaphase-anaphase transition. One of these proteins that is broken down is securin which through its breakdown releases the enzyme separase that cleaves the cohesin rings holding together the sister chromatids thereby leading to the chromosomes separating. After the chromosomes line up in the middle of the cell, the spindle fibers will pull them apart. The chromosomes are split apart while the sister chromatids move to opposite sides of the cell. As the sister chromatids are being pulled apart, the cell and plasma are elongated by non-kinetochore microtubules. Additionally, in this phase, the activation of the anaphase promoting complex through the association with Cdh-1 begins the degradation of mitotic cyclins.

Telophase
Telophase is the last stage of the cell cycle in which a cleavage furrow splits the cells cytoplasm (cytokinesis) and chromatin. This occurs through the synthesis of a new nuclear envelope that forms around the chromatin gathered at each pole. The nucleolus reforms as the chromatin reverts back to the loose state it possessed during interphase. The division of the cellular contents is not always equal and can vary by cell type as seen with oocyte formation where one of the four daughter cells possess the majority of the duckling.

Cytokinesis
The last stage of the cell division process is cytokinesis. In this stage there is a cytoplasmic division that occurs at the end of either mitosis or meiosis. At this stage there is a resulting irreversible separation leading to two daughter cells. Cell division plays an important role in determining the fate of the cell. This is due to there being the possibility of an asymmetric division. This as a result leads to cytokinesis producing unequal daughter cells containing completely different amounts or concentrations of fate-determining molecules.

In animals the cytokinesis ends with formation of a contractile ring and thereafter a cleavage. But in plants it happen differently. At first a cell plate is formed and then a cell wall develops between the two daughter cells.

In Fission yeast (S. pombe) the cytokinesis happens in G1 phase.

Variants
Cells are broadly classified into two main categories: simple non-nucleated prokaryotic cells and complex nucleated eukaryotic cells. Due to their structural differences, eukaryotic and prokaryotic cells do not divide in the same way. Also, the pattern of cell division that transforms eukaryotic stem cells into gametes (sperm cells in males or egg cells in females), termed meiosis, is different from that of the division of somatic cells in the body.

In 2022, scientists discovered a new type of cell division called asynthetic fission found in the squamous epithelial cells in the epidermis of juvenile zebrafish. When juvenile zebrafish are growing, skin cells must quickly cover the rapidly increasing surface area of the zebrafish. These skin cells divide without duplicating their DNA (the S phase of mitosis) causing up to 50% of the cells to have a reduced genome size. These cells are later replaced by cells with a standard amount of DNA. Scientists expect to find this type of division in other vertebrates.

DNA Damage Repair in the Cell Cycle
DNA damage is detected and repaired at various points in the cell cycle. The G1/S checkpoint, G2/M checkpoint, and the checkpoint between metaphase and anaphase all monitor for DNA damage and halt cell division by inhibiting different cyclin-CDK complexes. The p53 tumor-suppressor protein plays a crucial role at the G1/S checkpoint and the G2/M checkpoint. Activated p53 proteins result in the expression of many proteins that are important in cell cycle arrest, repair, and apoptosis. At the G1/S checkpoint, p53 acts to ensure that the cell is ready for DNA replication, while at the G2/M checkpoint p53 acts to ensure that the cells have properly duplicated their content before entering mitosis.

Specifically, when DNA damage is present, ATM and ATR kinases are activated, activating various checkpoint kinases. These checkpoint kinases phosphorylate p53, which stimulates the production of different enzymes associated with DNA repair. Activated p53 also upregulates p21, which inhibits various cyclin-cdk complexes. These cyclin-cdk complexes phosphorylate the Retinoblastoma (Rb) protein, a tumor suppressor bound with the E2F family of transcription factors. The binding of this Rb protein ensures that cells do not enter the S phase prematurely; however, if it is not able to be phosphorylated by these cyclin-cdk complexes, the protein will remain, and the cell will be halted in the G1 phase of the cell cycle.

If DNA is damaged, the cell can also alter the Akt pathway in which BAD is phosphorylated and dissociated from Bcl2, thus inhibiting apoptosis. If this pathway is altered by a loss of function mutation in Akt or Bcl2, then the cell with damaged DNA will be forced to undergo apoptosis. If the DNA damage cannot be repaired, activated p53 can induce cell death by apoptosis. It can do so by activating the p53 upregulated modulator of apoptosis (PUMA). PUMA is a pro-apoptotic protein that rapidly induces apoptosis by inhibiting the anti-apoptotic Bcl-2 family members.

Degradation
Multicellular organisms replace worn-out cells through cell division. In some animals, however, cell division eventually halts. In humans this occurs, on average, after 52 divisions, known as the Hayflick limit. The cell is then referred to as senescent. With each division the cells telomeres, protective sequences of DNA on the end of a chromosome that prevent degradation of the chromosomal DNA, shorten. This shortening has been correlated to negative effects such as age-related diseases and shortened lifespans in humans. Cancer cells, on the other hand, are not thought to degrade in this way, if at all. An enzyme complex called telomerase, present in large quantities in cancerous cells, rebuilds the telomeres through synthesis of telomeric DNA repeats, allowing division to continue indefinitely.

History

A cell division under microscope was first discovered by German botanist Hugo von Mohl in 1835 as he worked over the green alga Cladophora glomerata.

In 1943, cell division was filmed for the first time by Kurt Michel using a phase-contrast microscope.

title: Cell division