info sains

2007-11-19T00:40:00.001-08:00

my friends

2007-11-19T00:37:00.001-08:00

wanted

2007-11-19T00:30:00.001-08:00

my face

2007-11-19T00:25:00.001-08:00

my love

2007-11-19T00:13:00.000-08:00

full expression

2007-11-19T00:07:00.001-08:00

i n my little brother

MOMENTUM

2007-11-17T21:18:00.000-08:00

classical mechanics, momentum (pl. momenta; SI unit kg m/s, or, equivalently, N·s) is the product of the mass and velocity of an object. For more accurate measures of momentum, see the section "modern definitions of momentum" on this page. It is sometimes referred to as linear momentum to distinguish it from the related subject of angular momentum. Linear momentum is a vector quantity, as it takes into account the direction of the value.

Momentum is a conserved quantity, meaning that the total momentum of any closed system (one not affected by external forces) cannot change.

The concept of momentum in classical mechanics was originated by a number of great thinkers and experimentalists. The first of these was Ibn Sina (Avicenna) circa 1000, who referred to impetus as proportional to weight times velocity.^[1] René Descartes later referred to mass times velocity as the fundamental force of motion. Galileo in his Two New Sciences used the term "impeto" (Italian), while Newton's Laws of Motion uses motus (Latin), which has been interpreted by subsequent scholars to mean momentum.^{[citation needed]}

[hide]

Momentum in Newtonian mechanics

If an object is moving in any reference frame, then it has momentum in that frame. It is important to note that momentum is frame dependent. That is, the same object may have a certain momentum in one frame of reference, but a different amount in another frame. For example, a moving object has momentum in a reference frame fixed to a spot on the ground, while at the same time having 0 momentum in a reference frame attached to the object's center of mass.

The amount of momentum that an object has depends on two physical quantities: the mass and the velocity of the moving object in the frame of reference. In physics, the symbol for momentum is usually denoted by a small bold p (bold because it is a vector); so this can be written:

where:

p is the momentum

m is the mass

v the velocity

(using bold text for vectors).

The origin of the use of p for momentum is unclear. It has been suggested that, since m had already been used for "mass", the p may be derived from the Latin petere ("to go") or from "progress" (a term used by Leibniz).^{[citation needed]}

The velocity of an object at a particular instant is given by its speed and the direction of its motion at that instant. Because momentum depends on and includes the physical quantity of velocity, it too has a magnitude and a direction and is a vector quantity. For example the momentum of a 5-kg bowling ball would have to be described by the statement that it was moving westward at 2 m/s. It is insufficient to say that the ball has 10 kg m/s of momentum because momentum is not fully described unless its direction is given.

Momentum for a system

Relating to mass and velocity

The momentum of a system of objects is the vector sum of the momenta of all the individual objects in the system.

where

is the momentum

m i

is the mass of object i

the vector velocity of object i

is the number of objects in the system

It can be shown that, in the center of mass frame the momentum of a system is zero. Additionally, the momentum in a frame of reference that is moving at a speed with respect to that frame is simply:

where:

Relating to force

Force is equal to the rate of change of momentum:

In the case of constant mass, and velocities much less than the speed of light, this definition results in the equation , commonly known as Newton's second law.

If a system is in equilibrium, then the change in momentum with respect to time is equal to 0:

Conservation of momentum

The law of conservation of momentum is a fundamental law of nature, and it states that the total momentum of a closed system of objects (which has no interactions with external agents) is constant. One of the consequences of this is that the centre of mass of any system of objects will always continue with the same velocity unless acted on by a force outside the system.

Conservation of momentum is a mathematical consequence of the homogeneity (shift symmetry) of space (position in space is canonical conjugate quantity to momentum). So, momentum conservation can be philosophically stated as "nothing depends on location per se".

In an isolated system (one where external forces are absent) the total momentum will be constant: this is implied by Newton's first law of motion. Newton's third law of motion, the law of reciprocal actions, which dictates that the forces acting between systems are equal in magnitude, but opposite in sign, is due to the conservation of momentum.

Since position in space is a vector quantity, momentum (being canonical conjugate of position) is a vector quantity as well - it has direction. Thus, when a gun is fired, the final total momentum of the system (the gun and the bullet) is the vector sum of the momentums of these two objects. Assuming that the gun and bullet were at rest prior to firing (meaning the initial momentum of the system was zero), the final total momentum must also equal 0.

In an isolated system with only two objects, the amount of momentum gained by one object must equal the loss of momentum by the other object. Mathematically,

Momentum has the special property that, in a closed system, it is always conserved, even in collisions and separations caused by explosive forces. Kinetic energy, on the other hand, is not conserved in collisions if they are inelastic. Since momentum is conserved it can be used to calculate an unknown velocity following a collision or a separation if all the other masses and velocities are known.

A common problem in physics that requires the use of this fact is the collision of two particles. Since momentum is always conserved, the sum of the momenta before the collision must equal the sum of the momenta after the collision:

where:

u signifies vector velocity before the collision

v signifies vector velocity after the collision.

Usually, we either only know the velocities before or after a collision and would like to also find out the opposite. Correctly solving this problem means you have to know what kind of collision took place. There are two basic kinds of collisions, both of which conserve momentum:

Elastic collisions conserve kinetic energy as well as total momentum before and after collision.
Inelastic collisions don't conserve kinetic energy, but total momentum before and after collision is conserved.

Elastic collisions

A collision between two pool or snooker balls is a good example of an almost totally elastic collision. In addition to momentum being conserved when the two balls collide, the sum of kinetic energy before a collision must equal the sum of kinetic energy after:

Since the 1/2 factor is common to all the terms, it can be taken out right away.

[edit] Head-on collision (1 dimensional)

In the case of two objects colliding head on we find that the final velocity

which can then easily be rearranged to

Special Case: m1>>m2

Now consider if the mass of one body, say m1, is far greater than that of m2 (m1>>m2). In that case m1+m2 is approximately equal to m1. And m1-m2 is approximately equal to m1.

Put these values in the above equation to calculate the value of v2 after collision. The expression changes to v2 final is 2*v1-v2. Its physical interpretation is in case of collision between two body one of which is very heavy, the lighter body moves with twice the velocity of the heavier body less its actual velocity but in opposite direction.

Special Case: m1==m2

Another special case is when the collision is between two bodies of equal mass.

Say body m1 moving at velocity v1 strikes body m2 that is at rest (v2). Putting this case in the equation derived above we will see that after the collision, the body that was moving (m1) will start moving with velocity v2 and the mass m2 will start moving with velocity v1. So there will be an exchange of velocities.

Now suppose one of the masses, say m2, was at rest. In that case after the collision the moving body, m1, will come to rest and the body that was at rest, m2, will start moving with the velocity that m1 had before the collision.

Note that all of these observations are for an elastic collision.

This phenomenon is demonstrated by Newton's cradle, one of the best known examples of conservation of momentum, a real life example of this special case.

Multi-dimensional collisions

In the case of objects colliding in more than one dimension, as in oblique collisions, the velocity is resolved into orthogonal components with one component perpendicular to the plane of collision and the other component or components in the plane of collision. The velocity components in the plane of collision remain unchanged, while the velocity perpendicular to the plane of collision is calculated in the same way as the one-dimensional case.

For example, in a two-dimensional collision, the momenta can be resolved into x and y components. We can then calculate each component separately, and combine them to produce a vector result. The magnitude of this vector is the final momentum of the isolated system.

See the elastic collision page for more details.

Inelastic collisions

A common example of a perfectly inelastic collision is when two snowballs collide and then stick together afterwards. This equation describes the conservation of momentum:

It can be shown that a perfectly inelastic collision is one in which the maximum amount of kinetic energy is converted into other forms. For instance, if both objects stick together after the collision and move with a final common velocity, one can always find a reference frame in which the objects are brought to rest by the collision and 100% of the kinetic energy is converted. This is true even in the relativistic case and utilized in particle accelerators to efficiently convert kinetic energy into new forms of mass-energy (i.e. to create massive particles).

See the inelastic collision page for more details.

Modern definitions of momentum

Momentum in relativistic mechanics

In relativistic mechanics, in order to be conserved, momentum must be defined as:

where

is the invariant mass of the object moving,

is the Lorentz factor

is the relative velocity between an object and an observer

is the speed of light.

Relativistic momentum becomes Newtonian momentum: at low speed .

The diagram can serve as a useful mnemonic for remembering the above relations involving relativistic energy , invariant mass , and relativistic momentum . Please note that in the notation used by the diagram's creator, the invariant mass is subscripted with a zero, .

Relativistic four-momentum as proposed by Albert Einstein arises from the invariance of four-vectors under Lorentzian translation. The four-momentum is defined as:

where

is the component of the relativistic momentum,

is the total energy of the system:

The "length" of the vector is the mass times the speed of light, which is invariant across all reference frames:

Momentum of massless objects

Massless objects such as photons also carry momentum. The formula is:

where

is Planck's constant,

is the wavelength of the photon,

is the energy the photon carries and

is the speed of light.

Generalization of momentum

Momentum is the Noether charge of translational invariance. As such, even fields as well as other things can have momentum, not just particles. However, in curved space-time which is not asymptotically Minkowski, momentum isn't defined at all.

Momentum in quantum mechanics

In quantum mechanics, momentum is defined as an operator on the wave function. The Heisenberg uncertainty principle defines limits on how accurately the momentum and position of a single observable system can be known at once. In quantum mechanics, position and momentum are conjugate variables.

For a single particle with no electric charge and no spin, the momentum operator can be written in the position basis as

where:

is the gradient operator

is the reduced Planck constant.

is the imaginary unit.

This is a commonly encountered form of the momentum operator, though not the most general one.

Momentum in electromagnetism

When electric and/or magnetic fields move, they carry momenta. Light (visible, UV, radio) is an electromagnetic wave and also has momentum. Even though photons (the particle aspect of light) have no mass, they still carry momentum. This leads to applications such as the solar sail.

Momentum is conserved in an electrodynamic system (it may change from momentum in the fields to mechanical momentum of moving parts). The treatment of the momentum of a field is usually accomplished by considering the so-called energy-momentum tensor and the change in time of the Poynting vector integrated over some volume. This is a tensor field which has components related to the energy density and the momentum density.

The definition canonical momentum corresponding to the momentum operator of quantum mechanics when it interacts with the electromagnetic field is, using the principle of least coupling:

instead of the customary

where:

is the electromagnetic vector potential

m

the charged particle's invariant mass

its velocity

q

its charge.

Figurative use

A process may be said to gain momentum. The terminology implies that it requires effort to start such a process, but that it is relatively easy to keep it going. Alternatively, the expression can be seen to reflect that the process is adding adherents, or general acceptance, and thus has more mass at the same velocity; hence, it gained momentum.

Wikipedia.com

Medical ultrasonography

2007-11-17T21:08:00.001-08:00

Medical ultrasonography (sonography) is an ultrasound-based diagnostic imaging technique used to visualize muscles and internal organs, their size, structures and possible pathologies or lesions. Obstetric sonography is commonly used during pregnancy and is widely recognized by the public. There are a plethora of diagnostic and therapeutic applications practiced in medicine.

In physics the term "ultrasound" applies to all acoustic energy with a frequency above human hearing (20,000 hertz or 20 kilohertz). Typical diagnostic sonographic scanners operate in the frequency range of 2 to 18 megahertz, hundreds of times greater than this limit. The choice of frequency is a trade-off between spatial resolution of the image and imaging depth: lower frequencies produce less resolution but image deeper into the body.

A fetus in the womb, viewed in a sonogram

"3D ultrasound" of a developing fetus at 29 weeks

Diagnostic applications

Sonography (ultrasonography) is widely used in medicine. It is possible to perform diagnosis or therapeutic procedures with the guidance of sonography (for instance biopsies or drainage of fluid collections). Sonographers are medical professionals who perform scans for diagnostic purposes. Sonographers typically use a hand-held probe (called a transducer) that is placed directly on and moved over the patient. A water-based gel is used to couple the ultrasound between the transducer and patient.

Sonography is effective for imaging soft tissues of the body. Superficial structures such as muscles, tendons, testes, breast and the neonatal brain are imaged at a higher frequency (7-18 MHz), which provides better axial and lateral resolution. Deeper structures such as liver and kidney are imaged at a lower frequency 1-6 MHz with lower axial and lateral resolution but greater penetration.

Medical sonography is used in, for example:

Cardiology; see echocardiography
Endocrinology
Gastroenterology
Gynaecology; see gynecologic ultrasonography
Obstetrics; see obstetric ultrasonography
Ophthalmology; see A-scan ultrasonography, B-scan ultrasonography
Urology, to determine, for example, the amount of fluid retained in a patient's bladder.
Musculoskeletal, tendons, muscles, and nerves
Vascular, arteries and veins
Intravascular ultrasound (e.g. ultrasound guided fluid aspiration, fine needle aspiration, guided injections)
Intervenional; biopsy, emptying fluids, intrauterine transfusion (Hemolytic disease of the newborn)
Contrast-enhanced ultrasound

A general-purpose sonographic machine may be able to be used for most imaging purposes. Usually specialty applications may be served only by use of a specialty transducer. The dynamic nature of many studies generally requires specialized features in a sonographic machine for it to be effective; such as endovaginal, endorectal, or transesophageal transducers.

Sonograph showing the image of a fetal head in the womb

Obstetrical ultrasound is commonly used during pregnancy to check on the development of the fetus.

In a pelvic sonogram, organs of the pelvic region are imaged. This includes the uterus and ovaries or urinary bladder. Men are sometimes given a pelvic sonogram to check on the health of their bladder and prostate. There are two methods of performing a pelvic sonography - externally or internally. The internal pelvic sonogram is performed either transvaginally (in a woman) or transrectally (in a man). Sonographic imaging of the pelvic floor can produce important diagnostic information regarding the precise relationship of abnormal structures with other pelvic organs and it represents a useful hint to treat patients with symptoms related to pelvic prolapse, double incontinence and obstructed defecation.^[1]

In abdominal sonography, the solid organs of the abdomen such as the pancreas, aorta, inferior vena cava, liver, gall bladder, bile ducts, kidneys, and spleen are imaged. Sound waves are blocked by gas in the bowel, therefore there are limited diagnostic capabilities in this area. The appendix can sometimes be seen when inflamed eg: appendicitis.

Therapeutic applications

Therapeutic applications use ultrasound to bring heat or agitation into the body. Therefore much higher energies are used than in diagnostic ultrasound. In many cases the range of frequencies used are also very different.

Ultrasound may be used to clean teeth in dental hygiene.
Ultrasound sources may be used to generate regional heating in biological tissue, e.g. in occupational therapy, physical therapy and cancer treatment.
Focused ultrasound may be used to generate highly localized heating to treat cysts and tumors (benign or malignant), This is known as Focused Ultrasound Surgery (FUS) or High Intensity Focused Ultrasound (HIFU). These procedures generally use lower frequencies than medical diagnostic ultrasound (from 250 kHz to 2000 kHz), but significantly higher energies. HIFU treatment is often guided by MRI.
Focused ultrasound may be used to break up kidney stones by lithotripsy.
Ultrasound may be used for cataract treatment by phacoemulsification.
Additional physiological effects of low-intensity ultrasound have recently been discovered, e.g. its ability to stimulate bone-growth and its potential to disrupt the blood-brain barrier for drug delivery.

From sound to image

The creation of an image from sound is done in three steps - producing a sound wave, receiving echoes, and interpreting those echoes.

Producing a sound wave

Medical Sonographic Scanner

A sound wave is typically produced by a piezoelectric transducer encased in a probe. Strong, short electrical pulses from the ultrasound machine make the transducer ring at the desired frequency. The frequencies can be anywhere between 2 and 15 MHz. The sound is focused either by the shape of the transducer, a lens in front of the transducer, or a complex set of control pulses from the ultrasound scanner machine. This focusing produces an arc-shaped sound wave from the face of the transducer. The wave travels into the body and comes into focus at a desired depth.

Older technology transducers focus their beam with physical lenses. Newer technology transducers use phased array techniques to enable the sonographic machine to change the direction and depth of focus. Almost all piezoelectric transducers are made of ceramic.

Materials on the face of the transducer enable the sound to be transmitted efficiently into the body (usually seeming to be a rubbery coating, a form of impedance matching). In addition, a water-based gel is placed between the patient's skin and the probe.

The sound wave is partially reflected from the layers between different tissues. In detail, sound is reflected anywhere there are density changes in the body: e.g. blood cells in blood plasma, small structures in organs, etc. Some of the reflections return to the transducer.

Receiving the echoes

The return of the sound wave to the transducer results in the same process that it took to send the sound wave, except in reverse. The return sound wave vibrates the transducer, the transducer turns the vibrations into electrical pulses that travel to the ultrasonic scanner where they are processed and transformed into a digital image.

Forming the image

The sonographic scanner must determine three things from each received echo:

The direction of the echo.
How strong the echo was.
How long it took the echo to be received from when the sound was transmitted.

Once the ultrasonic scanner determines these three things, it can locate which pixel in the image to light up and to what intensity.

Transforming the received signal into a digital image may be explained by using a blank spreadsheet as an analogy. We imagine our transducer is a long, flat transducer at the top of the sheet. We will send pulses down the 'columns' of our spreadsheet (A, B, C, etc.). We listen at each column for any return echoes. When we hear an echo, we note how long it took for the echo to return. The longer the wait, the deeper the row (1,2,3, etc.). The strength of the echo determines the brightness setting for that cell (white for a strong echo, black for a weak echo, and varying shades of grey for everything in between.) When all the echoes are recorded on the sheet, we have a greyscale image.

Sound in the body

Linear Array Transducer

Ultrasonography (sonography) uses a probe containing one or more acoustic transducers to send pulses of sound into a material. Whenever a sound wave encounters a material with a different density (acoustical impedance), part of the sound wave is reflected back to the probe and is detected as an echo. The time it takes for the echo to travel back to the probe is measured and used to calculate the depth of the tissue interface causing the echo. The greater the difference between acoustic impedances, the larger the echo is. If the pulse hits gases or solids, the density difference is so great that most of the acoustic energy is reflected and it becomes impossible to see deeper.

The frequencies used for medical imaging are generally in the range of 1 to 18 MHz. Higher frequencies have a correspondingly smaller wavelength, and can be used to make sonograms with smaller details. However, the attenuation of the sound wave is increased at higher frequencies, so in order to have better penetration of deeper tissues, a lower frequency (3-5 MHz) is used.

Seeing deep into the body with sonography is very difficult. Some acoustic energy is lost every time an echo is formed, but most of it (approximately )is lost from acoustic absorption.

The speed of sound is different in different materials, and is dependent on the acoustical impedance of the material. However, the sonographic instrument assumes that the acoustic velocity is constant at 1540 m/s. An effect of this assumption is that in a real body with non-uniform tissues, the beam become somewhat de-focused and image resolution is reduced.

To generate a 2D-image, the ultrasonic beam is swept. A transducer may be swept mechanically by rotating or swinging. Or a 1D phased array transducer may be use to sweep the beam electronically. The received data is processed and used to construct the image. The image is then a 2D representation of the slice into the body.

3D images can be generated by acquiring a series of adjacent 2D images. Commonly a specialised probe that mechanically scans a conventional 2D-image transducer is used. However, since the mechanical scanning is slow, it is difficult to make 3D images of moving tissues. Recently, 2D phased array transducers that can sweep the beam in 3D have been developed. These can image faster and can even be used to make live 3D images of a beating heart.

Doppler ultrasonography is used to study blood flow and muscle motion. The different detected speeds are represented in color for ease of interpretation, for example leaky heart valves: the leak shows up as a flash of unique color. Colors may alternatively be used to represent the amplitudes of the received echoes.

Modes of Sonography

Four different modes of ultrasound are used in medical imaging^[2]. These are:

A-mode: A-mode is the simplest type of ultrasound. A single transducer scans a line through the body with the echoes plotted on screen as a function of depth. Therapeutic ultrasound aimed at a specific tumor or calculus is also A-mode, to allow for pinpoint accurate focus of the destructive wave energy.
B-mode: In B-mode ultrasound, a linear array of transducers simultaneously scans a plane through the body that can be viewed as a two-dimensional image on screen.
M-mode: M stands for motion. In m-mode a rapid sequence of B-mode scans whose images follow each other in sequence on screen enables doctors to see and measure range of motion, as the organ boundaries that produce reflections move relative to the probe.
Doppler mode: This mode makes use of the Doppler effect.

Doppler sonography

Spectral Doppler of Common Carotid Artery

Colour Doppler of Common Carotid Artery

Sonography can be enhanced with Doppler measurements, which employ the Doppler effect to assess whether structures (usually blood) are moving towards or away from the probe, and its relative velocity. By calculating the frequency shift of a particular sample volume, for example a jet of blood flow over a heart valve, its speed and direction can be determined and visualised. This is particularly useful in cardiovascular studies (sonography of the vasculature system and heart) and essential in many areas such as determining reverse blood flow in the liver vasculature in portal hypertension. The Doppler information is displayed graphically using spectral Doppler, or as an image using color Doppler (directional Doppler) or power Doppler (non directional Doppler). This Doppler shift falls in the audible range and is often presented audibly using stereo speakers: this produces a very distinctive, although synthetic, pulsing sound.

Strictly speaking, most modern sonographic machines do not use the Doppler effect to measure velocity, as they rely on pulsed wave Doppler (PW). Pulsed wave machines transmit pulses of ultrasound, and then switch to receive mode. As such, the reflected pulse that they receive is not subject to a frequency shift, as the insonation is not continuous. However, by making several measurements, the phase change in subsequent measurements can be used to obtain the frequency shift (since frequency is the rate of change of phase). To obtain the phase shift between the received and transmitted signals, one of two algorithms is typically used: the Kasai algorithm or cross-correlation. Older machines, that use continuous wave (CW) Doppler, exhibit the Doppler effect as described above. To do this, they must have separate transmission and reception transducers. The major drawback of CW machines, is that no distance information can be obtained (this is the major advantage of PW systems - the time between the transmitted and received pulses can be converted into a distance with knowledge of the speed of sound).

In the sonographic community (although not in the signal processing community), the terminology "Doppler" ultrasound, has been accepted to apply to both PW and CW Doppler systems despite the different mechanisms by which the velocity is measured.

Microbubbles

The use of microbubble contrast media in medical sonography to improve ultrasound signal backscatter is known as contrast-enhanced ultrasound. This technique is currently used in echocardiography, and may have future applications in molecular imaging and drug delivery.

Strengths of sonography

It images muscle and soft tissue very well and is particularly useful for delineating the interfaces between solid and fluid-filled spaces.
It renders "live" images, where the operator can dynamically select the most useful section for diagnosing and documenting changes, often enabling rapid diagnoses.
It shows the structure of organs.
It has no known long-term side effects and rarely causes any discomfort to the patient.
Equipment is widely available and comparatively flexible.
Small, easily carried scanners are available; examinations can be performed at the bedside.
Relatively inexpensive compared to other modes of investigation (e.g. computed X-ray tomography, DEXA or magnetic resonance imaging).

Weaknesses of ultrasonic imaging

Sonographic devices have trouble penetrating bone. For example, sonography of the adult brain is very limited.
Sonography performs very poorly when there is a gas between the transducer and the organ of interest, due to the extreme differences in acoustic impedance. For example, overlying gas in the gastrointestinal tract often makes ultrasound scanning of the pancreas difficult, and lung imaging is not possible (apart from demarcating pleural effusions).
Even in the absence of bone or air, the depth penetration of ultrasound is limited, making it difficult to image structures deep in the body, especially in obese patients.
The method is operator-dependent. A high level of skill and experience is needed to acquire good-quality images and make accurate diagnoses.
There is no scout image as there is with CT and MR. Once an image has been acquired there is no exact way to tell which part of the body was imaged.

Risks and side-effects

Ultrasonography is generally considered a "safe" imaging modality.^{[citation needed]} However slight detrimental effects have been occasionally observed (see below). Diagnostic ultrasound studies of the fetus are generally considered to be safe during pregnancy. This diagnostic procedure should be performed only when there is a valid medical indication, and the lowest possible ultrasonic exposure setting should be used to gain the necessary diagnostic information under the "as low as reasonably achievable" or ALARA principle.

The promotion, selling, or leasing of ultrasound equipment for making "keepsake fetal videos" is considered by the US Food and Drug Administration to be an unapproved use of a medical device. Use of a diagnostic ultrasound system for these purposes, without a physician’s order, may be in violation of state laws or regulations.

Studies on the safety of ultrasound

A study at the Yale Medical School found a correlation between prolonged and frequent use of ultrasound and abnormal neuronal migration in mice.^[3]
A study published in 2001 by a team working at the Karolinska Institute in Stockholm found a correlation between the number of scans received by male fetuses and subsequent left-handedness. ^[4]
A meta-analysis of several ultrasonography studies found no statistically significant harmful effects from ultrasonography, but mentioned that there was a lack of data on long-term substantive outcomes such as neurodevelopment.^[5]

Regulation

Diagnostic sonography is regulated in the USA by the FDA, and world-wide by other national regulatory agencies. The FDA limits acoustic output using several metrics. Generally other regulatory agencies around the world accept the FDA-established guidelines.

The primary regulated metrics are MI (Mechanical Index) a metric associated with the cavitation bio-effect, and TI (Thermal Index) a metric associated with the tissue heating bio-effect. The FDA requires that the machine not exceed limits that they have established. This requires self-regulation on the part of the manufacturer in terms of the calibration of the machine. The established limits are reasonably conservative so as to maintain diagnostic ultrasound as a safe imaging modality.^{[citation needed]}

History

United States

Ultrasonic energy was first applied to the human body for medical purposes by Dr. George Ludwig at the Naval Medical Research Institute, Bethesda, Maryland in the late 1940s.^[6]^[7]

The first demonstration of color Doppler was by Geoff Stevenson, who was involved in the early developments and medical use of Doppler shifted ultrasonic energy.^[8]

Sweden

Medical ultrasonography was used 1953 at Lund University by cardiologist Inge Edler and Carl Hellmuth Hertz, the son of Gustav Ludwig Hertz, who was a graduate student at the department of nuclear physics.

Edler had asked Hertz if it was possible to use radar to look into the body, but Hertz said this was impossible. However, he said, it might be possible to use ultrasonography. Hertz was familiar with using ultrasonic reflectoscopes for nondestructive materials testing, and together they developed the idea of using this method in medicine.

The first successful measurement of heart activity was made on October 29, 1953 using a device borrowed from the ship construction company Kockums in Malmö. On December 16 the same year, the method was used to generate an echo-encephalogram (ultrasonic probe of the brain). Edler and Hertz published their findings in 1954.

Scotland

Parallel developments in Glasgow, Scotland (coincidentally also a major shipbuilding centre) by Professor Ian Donald and colleagues at the Glasgow Royal Maternity Hospital (GRMH) led to the first diagnostic applications of the technique. Donald was an obstetrician with a self-confessed "childish interest in machines, electronic and otherwise", who, having treated the wife of one of the company's directors, was invited to visit the Research Department of boilermakers Babcock & Wilcox at Renfrew, where he used their industrial ultrasound equipment to conduct experiments on various morbid anatomical specimens and assess their ultrasonic characteristics. Together with the medical physicist Tom Brown and fellow obstetrician Dr John MacVicar, Donald refined the equipment to enable differentiation of pathology in live volunteer patients. These findings were reported in The Lancet on 7th June 1958 as "Investigation of Abdominal Masses by Pulsed Ultrasound" - possibly one of the most important papers ever published in the field of diagnostic medical imaging.

At GRMH, Professor Donald and Dr James Willocks then refined their techniques to obstetric applications including fetal head measurement to assess the size and growth of the foetus. With the opening of the new Queen Mother's Hospital on Yorkhill in 1964, it became possible to improve these methods even further. Dr Stuart Campbell's pioneering work on fetal cephalometry led to it acquiring long-term status as the definitive method of study of fetal growth. As the technical quality of the scans was further developed, it soon became possible to study pregnancy from start to finish and diagnose its many complications such as multiple pregnancy, fetal abnormality and placenta praevia. Diagnostic ultrasound has since been imported into practically every other area of medicine.

WIKIPEDIA.COM

Medical ultrasonography

2007-11-17T21:08:00.000-08:00

A fetus in the womb, viewed in a sonogram

"3D ultrasound" of a developing fetus at 29 weeks

[edit] Diagnostic applications

Medical sonography is used in, for example:

Cardiology; see echocardiography
Endocrinology
Gastroenterology
Gynaecology; see gynecologic ultrasonography
Obstetrics; see obstetric ultrasonography
Ophthalmology; see A-scan ultrasonography, B-scan ultrasonography
Urology, to determine, for example, the amount of fluid retained in a patient's bladder.
Musculoskeletal, tendons, muscles, and nerves
Vascular, arteries and veins
Intravascular ultrasound (e.g. ultrasound guided fluid aspiration, fine needle aspiration, guided injections)
Intervenional; biopsy, emptying fluids, intrauterine transfusion (Hemolytic disease of the newborn)
Contrast-enhanced ultrasound

Sonograph showing the image of a fetal head in the womb

Obstetrical ultrasound is commonly used during pregnancy to check on the development of the fetus.

[edit] Therapeutic applications

Ultrasound may be used to clean teeth in dental hygiene.
Ultrasound sources may be used to generate regional heating in biological tissue, e.g. in occupational therapy, physical therapy and cancer treatment.
Focused ultrasound may be used to generate highly localized heating to treat cysts and tumors (benign or malignant), This is known as Focused Ultrasound Surgery (FUS) or High Intensity Focused Ultrasound (HIFU). These procedures generally use lower frequencies than medical diagnostic ultrasound (from 250 kHz to 2000 kHz), but significantly higher energies. HIFU treatment is often guided by MRI.
Focused ultrasound may be used to break up kidney stones by lithotripsy.
Ultrasound may be used for cataract treatment by phacoemulsification.
Additional physiological effects of low-intensity ultrasound have recently been discovered, e.g. its ability to stimulate bone-growth and its potential to disrupt the blood-brain barrier for drug delivery.

[edit] From sound to image

The creation of an image from sound is done in three steps - producing a sound wave, receiving echoes, and interpreting those echoes.

[edit] Producing a sound wave

Medical Sonographic Scanner

[edit] Receiving the echoes

[edit] Forming the image

The sonographic scanner must determine three things from each received echo:

The direction of the echo.
How strong the echo was.
How long it took the echo to be received from when the sound was transmitted.

Once the ultrasonic scanner determines these three things, it can locate which pixel in the image to light up and to what intensity.

[edit] Sound in the body

Linear Array Transducer

Seeing deep into the body with sonography is very difficult. Some acoustic energy is lost every time an echo is formed, but most of it (approximately )is lost from acoustic absorption.

[edit] Modes of Sonography

Four different modes of ultrasound are used in medical imaging^[2]. These are:

A-mode: A-mode is the simplest type of ultrasound. A single transducer scans a line through the body with the echoes plotted on screen as a function of depth. Therapeutic ultrasound aimed at a specific tumor or calculus is also A-mode, to allow for pinpoint accurate focus of the destructive wave energy.
B-mode: In B-mode ultrasound, a linear array of transducers simultaneously scans a plane through the body that can be viewed as a two-dimensional image on screen.
M-mode: M stands for motion. In m-mode a rapid sequence of B-mode scans whose images follow each other in sequence on screen enables doctors to see and measure range of motion, as the organ boundaries that produce reflections move relative to the probe.
Doppler mode: This mode makes use of the Doppler effect.

[edit] Doppler sonography

Spectral Doppler of Common Carotid Artery

Colour Doppler of Common Carotid Artery

[edit] Microbubbles

[edit] Strengths of sonography

It images muscle and soft tissue very well and is particularly useful for delineating the interfaces between solid and fluid-filled spaces.
It renders "live" images, where the operator can dynamically select the most useful section for diagnosing and documenting changes, often enabling rapid diagnoses.
It shows the structure of organs.
It has no known long-term side effects and rarely causes any discomfort to the patient.
Equipment is widely available and comparatively flexible.
Small, easily carried scanners are available; examinations can be performed at the bedside.
Relatively inexpensive compared to other modes of investigation (e.g. computed X-ray tomography, DEXA or magnetic resonance imaging).

[edit] Weaknesses of ultrasonic imaging

Sonographic devices have trouble penetrating bone. For example, sonography of the adult brain is very limited.
Sonography performs very poorly when there is a gas between the transducer and the organ of interest, due to the extreme differences in acoustic impedance. For example, overlying gas in the gastrointestinal tract often makes ultrasound scanning of the pancreas difficult, and lung imaging is not possible (apart from demarcating pleural effusions).
Even in the absence of bone or air, the depth penetration of ultrasound is limited, making it difficult to image structures deep in the body, especially in obese patients.
The method is operator-dependent. A high level of skill and experience is needed to acquire good-quality images and make accurate diagnoses.
There is no scout image as there is with CT and MR. Once an image has been acquired there is no exact way to tell which part of the body was imaged.

[edit] Risks and side-effects

[edit] Studies on the safety of ultrasound

A study at the Yale Medical School found a correlation between prolonged and frequent use of ultrasound and abnormal neuronal migration in mice.^[3]
A study published in 2001 by a team working at the Karolinska Institute in Stockholm found a correlation between the number of scans received by male fetuses and subsequent left-handedness. ^[4]
A meta-analysis of several ultrasonography studies found no statistically significant harmful effects from ultrasonography, but mentioned that there was a lack of data on long-term substantive outcomes such as neurodevelopment.^[5]

[edit] Regulation

[edit] History

[edit] United States

Ultrasonic energy was first applied to the human body for medical purposes by Dr. George Ludwig at the Naval Medical Research Institute, Bethesda, Maryland in the late 1940s.^[6]^[7]

The first demonstration of color Doppler was by Geoff Stevenson, who was involved in the early developments and medical use of Doppler shifted ultrasonic energy.^[8]

[edit] Sweden

[edit] Scotland

WIKIPEDIA.COM

Metabolism

2007-11-17T21:06:00.000-08:00

Metabolism is the complete set of chemical reactions that occur in living cells. These processes are the basis of life, allowing cells to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism yields energy, an example being the breakdown of food in cellular respiration. Anabolism, on the other hand, uses this energy to construct components of cells such as proteins and nucleic acids.

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed into another by a sequence of enzymes. Enzymes are crucial to metabolism because they allow cells to drive desirable but thermodynamically unfavorable reactions by coupling them to favorable ones. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell's environment or signals from other cells.

The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.^[1] The speed of metabolism, the metabolic rate, also influences how much food an organism will require.

A striking feature of metabolism is the similarity of the basic metabolic pathways between even vastly different species. For example, the set of chemical intermediates in the citric acid cycle are found universally, among living cells as diverse as the unicellular bacteria Escherichia coli and huge multicellular organisms like elephants.^[2] This shared metabolic structure is most likely the result of the high efficiency of these pathways, and of their early appearance in evolutionary history.^[3]^[4]

Key biochemicals

Further information: Biomolecule, cell (biology) and biochemistry

Structure of a triacylglycerol lipid.

Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydrates and lipids (often called fats). As these molecules are vital for life, metabolism focuses on making these molecules, in the construction of cells and tissues, or breaking them down and using them as a source of energy, in the digestion and use of food. Many important biochemicals can be joined together to make polymers such as DNA and proteins. These macromolecules are essential parts of all living organisms. Some of the most common biological polymers are listed in the table below.

Type of molecule	Name of monomer forms	Name of polymer forms	Examples of polymer forms
Amino acids	Amino acids	Proteins (also called polypeptides)	Fibrous proteins and globular proteins
Carbohydrates	Monosaccharides	Polysaccharides	Starch, glycogen and cellulose
Nucleic acids	Nucleotides	Polynucleotides	DNA and RNA

Amino acids and proteins

Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are the enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as the proteins in the cytoskeleton that form a system of scaffolding to maintain cell shape.^[5] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes and the cell cycle.^[6]

Lipids

Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes such as the cell membrane, or as a source of energy.^[6] Lipids are usually defined as hydrophobic or amphipathic biological molecules that will dissolve in organic solvents such as benzene or chloroform.^[7] The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a triacylglyceride.^[8] Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, and hydrophilic groups such as phosphate in phospholipids. Steroids such as cholesterol are another major class of lipids that are made in cells.^[9]

Carbohydrates

Glucose can exist in both a straight-chain and ring form.

Carbohydrates are straight-chain aldehydes or ketones with many hydroxyl groups that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals).^[6] The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways.^[10]

Nucleotides

The polymers DNA and RNA are long chains of nucleotides. These molecules are critical for the storage and use of genetic information, through the processes of transcription and protein biosynthesis.^[6] This information is protected by DNA repair mechanisms and propagated through DNA replication. A few viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template from its viral RNA genome.^[11] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic group transfer reactions.^[12]

Coenzymes

Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to the sulphur atom at the extreme left.

Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups.^[13] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.^[12] These group-transfer intermediates are called coenzymes. Each class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously being made, consumed and then recycled.^[14]

The most central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day.^[14] ATP acts as a bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions consuming it. It also serves as a carrier of phosphate groups in phosphorylation reactions.

A vitamin is an organic compound needed in small quantities that cannot be made in the cells. In human nutrition, most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells.^[15] Nicotinamide adenine dinucleotide (NADH), a derivative of vitamin B₃ (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD⁺ into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.^[16] Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD⁺/NADH form is more important in catabolic reactions, while NADP⁺/NADPH is used in anabolic reactions.

Structure of hemoglobin. The protein subunits are in red and blue, and the iron-containing heme groups in green. From PDB 1GZX.

Minerals and cofactors

Further information: Physiology, bioinorganic chemistry and iron metabolism

Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of mammals' mass are the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, oxygen and sulfur.^[17] The organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water.^[17]

The abundant inorganic elements act as ionic electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate, and the organic ion bicarbonate. The maintenance of precise gradients across cell membranes maintains osmotic pressure and pH.^[18] Ions are also critical for nerves and muscles, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cytosol.^[19] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.^[20]

The transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant.^[21]^[22] These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin.^[23] These cofactors are bound tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place. The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as ferritin or metallothionein when not being used.^[24]^[25]

CATABOLISM

Further information: Catabolism

Catabolism is the set of metabolic processes that release energy. These include breaking down and oxidising food molecules as well as reactions that trap the energy in sunlight. The purpose of these catabolic reactions is to provide the energy and components needed by anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism, with organic molecules being used as a source of energy in organotrophs, while lithotrophs use inorganic substrates and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulphate.^[26] In animals these reactions involve complex organic molecules being broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms such as plants and cyanobacteria, these electron-transfer reactions do not release energy, but are used as a way of storing energy absorbed from sunlight.^[6]

The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large organic molecules such as proteins, polysaccharides or lipids are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually acetyl coenzyme A (CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD⁺) into NADH.

Digestion

Further information: Digestion and gastrointestinal tract

Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into monosaccharides.

Microbes simply secrete digestive enzymes into their surroundings,^[27]^[28] while animals only secrete these enzymes from specialized cells in their guts.^[29] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by specific active transport proteins.^[30]^[31]

A simplified outline of the catabolism of proteins, carbohydrates and fats.

Energy from organic compounds

Further information: Cellular respiration, fermentation, carbohydrate catabolism, fat catabolism and protein catabolism

Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides.^[32] Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated.^[33] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD⁺ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.

Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures.

Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy.^[34] The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate.^[35] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).^[36]

Oxidative phosphorylation

Structure of ATP synthase, the proton channel and rotating stalk are shown in blue and the synthase subunits in red.

Further information: Oxidative phosphorylation, chemiosmosis and mitochondrion

In oxidative phosphorylation, the electrons removed from food molecules in pathways such as the citric acid cycle are transferred to oxygen and the energy released used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane.^[37] These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.^[38]

Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates a electrochemical gradient.^[39] This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate - turning it into ATP.^[14]

Energy from inorganic compounds

Further information: Microbial metabolism and nitrogen cycle

Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen,^[40] reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate),^[41] ferrous iron (FeII)^[42] or ammonia^[43] as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite.^[44] These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.^[45]^[46]

Energy from light

Further information: Phototroph, photophosphorylation, chloroplast

The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.^[47]^[48]

The capture of solar energy is a process that is similar in principle to oxidative phosphorylation, as it involves energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis.^[14] The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres. These structures are classed into two types depending on the type of photosynthetic pigment present, with most photosynthetic bacteria only having one type of reaction center, while plants and cyanobacteria have two.^[49]

In plants, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast.^[50] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to reduce the coenzyme NADP⁺, for use in the Calvin cycle which is discussed below, or recycled for further ATP generation.^[51]

Anabolism

Further information: Anabolism

Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids.

Organisms differ in how many of the molecules in their cells they can construct for themselves. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.

Carbon fixation

Further information: Photosynthesis, carbon fixation and chemosynthesis

Plant cells (bounded by purple walls) filled with chloroplasts (green), which are the site of photosynthesis.

Photosynthesis is the synthesis of glucose from sunlight, carbon dioxide (CO₂) and water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO₂ into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle.^[52] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO₂ directly, while C4 and CAM photosynthesis incorporate the CO₂ into other compounds first, as adaptations to deal with intense sunlight and dry conditions.^[53]

In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle,^[54] or the carboxylation of acetyl-CoA.^[55]^[56] Prokaryotic chemoautotrophs also fix CO₂ through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction.^[57]

Carbohydrates and glycans

Further information: Gluconeogenesis, glyoxylate cycle, glycogenesis and glycosylation

In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.^[33] However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways from running simultaneously in a futile cycle.^[58]^[59]

Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate.^[60] As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.^[61] In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.^[62]^[60]

Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.^[63] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.^[64]^[65]

Fatty acids, isoprenoids and steroids

Further information: Fatty acid synthesis, mevalonate pathway and non-mevalonate pathway

Simplified version of the steroid synthesis pathway with the intermediates isopentenyl pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate (GPP) and squalene shown. Some intermediates are omitted for clarity.

Fatty acids are made by fatty acid synthases that polymerize and reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the actyl group, reduce it to the alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional type I protein,^[66] while in plant plastids and bacteria separate type II enzymes perform each step in the pathway.^[67]^[68]

Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products.^[69] These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.^[70] These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA,^[71] while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.^[72]^[70] One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.^[73] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.^[74]^[73]

Proteins

Further information: Protein biosynthesis, Amino acid synthesis

Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can synthesize only the ten nonessential amino acids.^[6] Thus, the essential amino acids must be obtained from food. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.^[75]

Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.^[76] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.^[77]

[edit] Nucleotide synthesis and salvage

Further information: Nucleotide salvage, Pyrimidine biosynthesis, and Purine metabolism

Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy.^[78] Consequently, most organisms have efficient systems to salvage preformed nucleotides.^[78]^[79] Purines are synthesized as nucleosides (bases attached to ribose). Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.^[80]

Xenobiotics and redox metabolism

Further information: Detoxification, Drug metabolism and Antioxidants

All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics.^[81] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,^[82] UDP-glucuronosyltransferasess,^[83] and glutathione S-transferases.^[84] This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills.^[85] Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even persistent organic pollutants such as organochloride compounds.^[86]

A related problem for aerobic organisms is oxidative stress.^[87] Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide.^[88] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases.^[89]^[90]

Thermodynamics of living organisms

Further information: Biological thermodynamics

Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any closed system, the amount of entropy (disorder) will tend to increase. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments.^[91] The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.^[92]

Regulation and control

Further information: Metabolic pathway, metabolic control analysis, hormone and cell signaling

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis.^[93]^[94] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.^[95] Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway).^[96] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.^[97]

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate.^[96] This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway.^[98] Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface.^[99] These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins.^[100]

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin.^[101] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen.^[102] The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.^[103]

Evolution

Further information: Molecular evolution and Phylogenetics

Evolutionary tree showing the common ancestry of organisms from all three domains of life. Bacteria are colored blue, eukaryotes red, and archaea green. Relative positions of some of the phyla included are shown around the tree.

The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal ancestor.^[104]^[2] This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.^[105]^[106] The retention of these ancient pathways during later evolution may be the result of these reactions being an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.^[3]^[4] The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of the ancient RNA world.^[107]

Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway.^[108] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions being created from pre-existing steps in the pathway.^[109] An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the MANET database) ^[110] These recruitment processes result in an evolutionary enzymatic mosaic. ^[111] A third possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.^[112]

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host.^[113] Similar reduced metabolic capabilities are seen in endosymbiotic organisms.^[114]

Investigation and manipulation

Further information: Protein methods, proteomics, metabolomics and metabolic network modelling

Metabolic network of the Arabidopsis thaliana citric acid cycle. Enzymes and metabolites are shown as red squares and the interactions between them as black lines.

Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively-labelled intermediates and products.^[115] The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.^[116]

An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 45,000 genes.^[117] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior.^[118] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies.^[119]

A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically-modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.^[120] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.^[121]

History

Further information: History of biochemistry and History of molecular biology

Santorio Santorio in his steelyard balance, from Ars de statica medecina, first published 1614

The term metabolism is derived from the Greek Μεταβολισμός – "Metabolismos" for "change", or "overthrow".^[122] The history of the scientific study of metabolism spans 400 years and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medecina.^[123] He described how he weighed himself before and after eating, sleeping, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".

In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue.^[124] In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."^[125] This discovery, along with the publication by Friedrich Wöhler in 1828 of the chemical synthesis of urea,^[126] proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry.^[127] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism.^[128] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle.^[129]^[62] Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.

WIKIPEDIA.COM

DNA

2007-11-17T20:54:00.000-08:00

Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms. The main role of DNA molecules is the long-term storage of information and DNA is often compared to a set of blueprints, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information.

Chemically, DNA is a long polymer of simple units called nucleotides, with a backbone made of sugars and phosphate groups joined by ester bonds. Attached to each sugar is one of four types of molecules called bases. It is the sequence of these four bases along the backbone that encodes information. This information is read using the genetic code, which specifies the sequence of the amino acids within proteins. The code is read by copying stretches of DNA into the related nucleic acid RNA, in a process called transcription. Most of these RNA molecules are used to synthesize proteins, but others are used directly in structures such as ribosomes and spliceosomes.

Within cells, DNA is organized into structures called chromosomes. These chromosomes are duplicated before cells divide, in a process called DNA replication. Eukaryotic organisms such as animals, plants, and fungi store their DNA inside the cell nucleus, while in prokaryotes such as bacteria it is found in the cell's cytoplasm. Within the chromosomes, chromatin proteins such as histones compact and organize DNA, which helps control its interactions with other proteins and thereby control which genes are transcribed.

Physical and chemical properties

The chemical structure of DNA.

DNA is a long polymer made from repeating units called nucleotides.^[1]^[2] The DNA chain is 22 to 26 Ångströms wide (2.2 to 2.6 nanometres), and one nucleotide unit is 3.3 Ångstroms (0.33 nanometres) long.^[3] Although each individual repeating unit is very small, DNA polymers can be enormous molecules containing millions of nucleotides. For instance, the largest human chromosome, chromosome number 1, is 220 million base pairs long.^[4]

In living organisms, DNA does not usually exist as a single molecule, but instead as a tightly-associated pair of molecules.^[5]^[6] These two long strands entwine like vines, in the shape of a double helix. The nucleotide repeats contain both the segment of the backbone of the molecule, which holds the chain together, and a base, which interacts with the other DNA strand in the helix. In general, a base linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. If multiple nucleotides are linked together, as in DNA, this polymer is referred to as a polynucleotide.^[7]

The backbone of the DNA strand is made from alternating phosphate and sugar residues.^[8] The sugar in DNA is 2-deoxyribose, which is a pentose (five carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bonds mean a strand of DNA has a direction. In a double helix the direction of the nucleotides in one strand is opposite to their direction in the other strand. This arrangement of DNA strands is called antiparallel. The asymmetric ends of DNA strands are referred to as the 5′ (five prime) and 3′ (three prime) ends. One of the major differences between DNA and RNA is the sugar, with 2-deoxyribose being replaced by the alternative pentose sugar ribose in RNA.^[6]

The DNA double helix is stabilized by hydrogen bonds between the bases attached to the two strands. The four bases found in DNA are adenine (abbreviated A), cytosine (C), guanine (G) and thymine (T). These four bases are shown below and are attached to the sugar/phosphate to form the complete nucleotide, as shown for adenosine monophosphate.

These bases are classified into two types; adenine and guanine are fused five- and six-membered heterocyclic compounds called purines, while cytosine and thymine are six-membered rings called pyrimidines.^[6] A fifth pyrimidine base, called uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine, but a very rare exception to this rule is a bacterial virus called PBS1 that contains uracil in its DNA.^[9] In contrast, following synthesis of certain RNA molecules, a significant number of the uracils are converted to thymines by the enzymatic addition of the missing methyl group. This occurs mostly on structural and enzymatic RNAs like transfer RNAs and ribosomal RNA.^[10]

Major and minor grooves

Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. Large version^[11]

The double helix is a right-handed spiral. As the DNA strands wind around each other, they leave gaps between each set of phosphate backbones, revealing the sides of the bases inside (see animation). There are two of these grooves twisting around the surface of the double helix: one groove, the major groove, is 22 Å wide and the other, the minor groove, is 12 Å wide.^[12] The narrowness of the minor groove means that the edges of the bases are more accessible in the major groove. As a result, proteins like transcription factors that can bind to specific sequences in double-stranded DNA usually make contacts to the sides of the bases exposed in the major groove.^[13]

Base pairing

Further information: Base pair

At top, a GC base pair with three hydrogen bonds. At the bottom, AT base pair with two hydrogen bonds. Hydrogen bonds are shown as dashed lines.

Each type of base on one strand forms a bond with just one type of base on the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with A bonding only to T, and C bonding only to G. This arrangement of two nucleotides binding together across the double helix is called a base pair. In a double helix, the two strands are also held together via forces generated by the hydrophobic effect and pi stacking, which are not influenced by the sequence of the DNA.^[14] As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical force or high temperature.^[15] As a result of this complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. Indeed, this reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.^[1]

The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, left). The GC base pair is therefore stronger than the AT base pair. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determine the strength of the association between the two strands of DNA. Long DNA helices with a high GC content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands.^[16] Parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in bacterial promoters, tend to have sequences with a high AT content, making the strands easier to pull apart.^[17] In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the hydrogen bonds, their melting temperature (also called T_m value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.^[18]

Sense and antisense

Further information: Sense (molecular biology)

A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into protein. The sequence on the opposite strand is complementary to the sense sequence and is therefore called the "antisense" sequence. Since RNA polymerases work by making a complementary copy of their templates, it is this antisense strand that is the template for producing the sense messenger RNA. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear.^[19] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.^[20]

A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction made above between sense and antisense strands by having overlapping genes.^[21] In these cases, some DNA sequences do double duty, encoding one protein when read 5′ to 3′ along one strand, and a second protein when read in the opposite direction (still 5′ to 3′) along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,^[22] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.^[23] Another way of reducing genome size is seen in some viruses that contain linear or circular single-stranded DNA as their genetic material.^[24]^[25]

Supercoiling

Further information: DNA supercoil

DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.^[26] If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases.^[27] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.^[28]

From left to right, the structures of A, B and Z DNA

Alternative double-helical structures

Further information: Mechanical properties of DNA

DNA exists in several possible conformations. The conformations so far identified are: A-DNA, B-DNA, C-DNA, D-DNA,^[29] E-DNA,^[30] H-DNA,^[31] L-DNA,^[29] P-DNA,^[32] and Z-DNA.^[8]^[33] However, only A-DNA, B-DNA, and Z-DNA have been observed in naturally occurring biological systems. Which conformation DNA adopts depends on the sequence of the DNA, the amount and direction of supercoiling, chemical modifications of the bases and also solution conditions, such as the concentration of metal ions and polyamines.^[34] Of these three conformations, the "B" form described above is most common under the conditions found in cells.^[35] The two alternative double-helical forms of DNA differ in their geometry and dimensions.

The A form is a wider right-handed spiral, with a shallow and wide minor groove and a narrower and deeper major groove. The A form occurs under non-physiological conditions in dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in enzyme-DNA complexes.^[36]^[37] Segments of DNA where the bases have been chemically-modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.^[38] These unusual structures can be recognised by specific Z-DNA binding proteins and may be involved in the regulation of transcription.^[39]

Structure of a DNA quadruplex formed by telomere repeats. The conformation of the DNA backbone diverges significantly from the typical helical structure^[40]

Quadruplex structures

Further information: G-quadruplex

At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes.^[41] As a result, if a chromosome lacked telomeres it would become shorter each time it was replicated. These specialized chromosome caps also help protect the DNA ends from exonucleases and stop the DNA repair systems in the cell from treating them as damage to be corrected.^[42] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.^[43]

These guanine-rich sequences may stabilize chromosome ends by forming very unusual structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure.^[44] These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. The structure shown to the left is a top view of the quadruplex formed by a DNA sequence found in human telomere repeats. The single DNA strand forms a loop, with the sets of four bases stacking in a central quadruplex three plates deep. In the space at the centre of the stacked bases are three chelated potassium ions.^[45] Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.

In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins.^[46] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.^[44]

Chemical modifications


cytosine	5-methylcytosine	thymine

Structure of cytosine with and without the 5-methyl group. After deamination the 5-methylcytosine has the same structure as thymine

Base modifications

Further information: DNA methylation

The expression of genes is influenced by the chromatin structure of a chromosome and regions of heterochromatin (low or no gene expression) correlate with the methylation of cytosine. For example, cytosine methylation, to produce 5-methylcytosine, is important for X-chromosome inactivation.^[47] The average level of methylation varies between organisms, with Caenorhabditis elegans lacking cytosine methylation, while vertebrates show higher levels, with up to 1% of their DNA containing 5-methylcytosine.^[48] Despite the biological role of 5-methylcytosine it is susceptible to spontaneous deamination to leave the thymine base, and methylated cytosines are therefore mutation hotspots.^[49] Other base modifications include adenine methylation in bacteria and the glycosylation of uracil to produce the "J-base" in kinetoplastids.^[50]^[51]

DNA damage

Further information: Mutation

Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA.^[52]

DNA can be damaged by many different sorts of mutagens. These include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and x-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light mostly damages DNA by producing thymine dimers, which are cross-links between adjacent pyrimidine bases in a DNA strand.^[53] On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, as well as double-strand breaks.^[54] It has been estimated that in each human cell, about 500 bases suffer oxidative damage per day.^[55]^[56] Of these oxidative lesions, the most dangerous are double-strand breaks, as these lesions are difficult to repair and can produce point mutations, insertions and deletions from the DNA sequence, as well as chromosomal translocations.^[57]

Many mutagens intercalate into the space between two adjacent base pairs. Intercalators are mostly aromatic and planar molecules, and include ethidium, daunomycin, doxorubicin and thalidomide. In order for an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. These structural changes inhibit both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators are often carcinogens, with benzopyrene diol epoxide, acridines, aflatoxin and ethidium bromide being well-known examples.^[58]^[59]^[60] Nevertheless, due to their properties of inhibiting DNA transcription and replication, they are also used in chemotherapy to inhibit rapidly-growing cancer cells.^[61]

Overview of biological functions

DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes.^[62] The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation which depends on the same interaction between RNA nucleotides. Alternatively, a cell may simply copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here we focus on the interactions between DNA and other molecules that mediate the function of the genome.

Genome structure

Further information: Cell nucleus, Chromatin, Chromosome, Gene, Non-coding DNA

Genomic DNA is located in the cell nucleus of eukaryotes, as well as small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.^[63] The genetic information in a genome is held within genes. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the expression of the open reading frame.

In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.^[64] The reasons for the presence of so much non-coding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle known as the "C-value enigma."^[65] However, DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.^[66]

T7 RNA polymerase (blue) producing a mRNA (green) from a DNA template (orange).^[67]

Some non-coding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes.^[42]^[68] An abundant form of non-coding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.^[69] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.^[70]

Transcription and translation

Further information: Genetic code, Transcription (genetics), Protein biosynthesis

A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).

In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons ( $43$ combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA and TAG codons.

DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.

Replication

Further information: DNA replication

Cell division is essential for an organism to grow, but when a cell divides it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix.^[71] In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.

Interactions with proteins

All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.

DNA-binding proteins

Interaction of DNA with histones (shown in white, top). These proteins' basic amino acids (below left, blue) bind to the acidic phosphate groups on DNA (below right, red).

Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved.^[72]^[73] The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence.^[74] Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation.^[75] These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription.^[76] Other non-specific DNA-binding proteins found in chromatin include the high-mobility group proteins, which bind preferentially to bent or distorted DNA.^[77] These proteins are important in bending arrays of nucleosomes and arranging them into more complex chromatin structures.^[78]

A distinct group of DNA-binding proteins are the single-stranded-DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-characterised member of this family and is essential for most processes where the double helix is separated, including DNA replication, recombination and DNA repair.^[79] These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem loops or being degraded by nucleases.

The lambda repressor helix-turn-helix transcription factor bound to its DNA target^[80]

In contrast, other proteins have evolved to specifically bind particular DNA sequences. The most intensively studied of these are the various classes of transcription factors, which are proteins that regulate transcription. Each one of these proteins bind to one particular set of DNA sequences and thereby activates or inhibits the transcription of genes with these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription.^[81] Alternatively, transcription factors can bind enzymes that modify the histones at the promoter; this will change the accessibility of the DNA template to the polymerase.^[82]

As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes.^[83] Consequently, these proteins are often the targets of the signal transduction processes that mediate responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.^[84]

The restriction enzyme EcoRV (green) in a complex with its substrate DNA^[85]

DNA-modifying enzymes

Nucleases and ligases

Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently-used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GAT|ATC-3′ and makes a cut at the vertical line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.^[86] In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.

Enzymes called DNA ligases can rejoin cut or broken DNA strands, using the energy from either adenosine triphosphate or nicotinamide adenine dinucleotide.^[87] Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.^[87]

Topoisomerases and helicases

Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzyme work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break.^[27] Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix.^[88] Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.^[28]

Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single strands.^[89] These enzymes are essential for most processes where enzymes need to access the DNA bases.

Polymerases

Polymerases are enzymes that synthesise polynucleotide chains from nucleoside triphosphates. They function by adding nucleotides onto the 3′ hydroxyl group of the previous nucleotide in the DNA strand. As a consequence, all polymerases work in a 5′ to 3′ direction.^[90] In the active site of these enzymes, the nucleoside triphosphate substrate base-pairs to a single-stranded polynucleotide template: this allows polymerases to accurately synthesise the complementary strand of this template. Polymerases are classified according to the type of template that they use.

In DNA replication, a DNA-dependent DNA polymerase makes a DNA copy of a DNA sequence. Accuracy is vital in this process, so many of these polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed.^[91] In most organisms DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.^[92]

RNA-dependent DNA polymerases are a specialised class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres.^[93]^[41] Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure.^[42]

Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.^[94]

Genetic recombination

Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are coloured red, blue, green and yellow.^[95]

Further information: Genetic recombination

Recombination involves the breakage and rejoining of two chromosomes (M and F) to produce two re-arranged chromosomes (C1 and C2).

A DNA helix usually does not interact with other segments of DNA, and in human cells the different chromosomes even occupy separate areas in the nucleus called "chromosome territories".^[96] This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is during chromosomal crossover when they recombine. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.

Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins.^[97] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.^[98]

The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51.^[99] The first step in recombination is a double-stranded break either caused by an endonuclease or damage to the DNA.^[100] A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA.^[101]

Evolution of DNA metabolism

Further information: RNA world hypothesis

DNA contains the genetic information that allows all modern living things to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material.^[90]^[102] RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes.^[103] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur since the number of unique bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.^[104]

Unfortunately, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible. This is because DNA will survive in the environment for less than one million years and slowly degrades into short fragments in solution.^[105] Although claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250-million years old,^[106] these claims are controversial and have been disputed.^[107]^[108]

Uses in technology

Genetic engineering

Further information: Molecular biology and genetic engineering

Modern biology and biochemistry make intensive use of recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector.^[109] The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research,^[110] or be grown in agriculture.^[111]^[112]

Forensics

Further information: Genetic fingerprinting

Forensic scientists can use DNA in blood, semen, skin, saliva or hair at a crime scene to identify a perpetrator. This process is called genetic fingerprinting, or more accurately, DNA profiling. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a criminal.^[113] However, identification can be complicated if the scene is contaminated with DNA from several people.^[114] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,^[115] and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.^[116] People convicted of certain types of crimes may be required to provide a sample of DNA for a database. This has helped investigators solve old cases where only a DNA sample was obtained from the scene. DNA profiling can also be used to identify victims of mass casualty incidents.^[117]

Bioinformatics

Further information: Bioinformatics

Bioinformatics involves the manipulation, searching, and data mining of DNA sequence data. The development of techniques to store and search DNA sequences have led to widely-applied advances in computer science, especially string searching algorithms, machine learning and database theory.^[118] String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides.^[119] In other applications such as text editors, even simple algorithms for this problem usually suffice, but DNA sequences cause these algorithms to exhibit near-worst-case behaviour due to their small number of distinct characters. The related problem of sequence alignment aims to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function.^[120] Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without annotations, which label the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products in an organism even before they have been isolated experimentally.^[121]

DNA and computation

Further information: DNA computing

DNA was first used in computing to solve a small version of the directed Hamiltonian path problem, an NP-complete problem.^[122] DNA computing is advantageous over electronic computers in power use, space use, and efficiency, due to its ability to compute in a highly parallel fashion (see parallel computing). A number of other problems, including simulation of various abstract machines, the boolean satisfiability problem, and the bounded version of the travelling salesman problem, have since been analysed using DNA computing.^[123] Due to its compactness, DNA also has a theoretical role in cryptography, where in particular it allows unbreakable one-time pads to be efficiently constructed and used.^[124]

History and anthropology

Further information: Phylogenetics and Genetic genealogy

Because DNA collects mutations over time, which are then inherited, it contains historical information and by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.^[125] This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology; for example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel.^[126]^[127]

DNA has also been used to look at modern family relationships, such as establishing family relationships between the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime scenes has matched relatives of the guilty individual.^[128]

History

Francis Crick

James Watson

Further information: History of molecular biology

DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein".^[129] In 1919 this discovery was followed by Phoebus Levene's identification of the base, sugar and phosphate nucleotide unit.^[130] Levene suggested that DNA consisted of a string of nucleotide units linked together through the phosphate groups. However, Levene thought the chain was short and the bases repeated in a fixed order. In 1937 William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.^[131]

In 1943, Oswald Theodore Avery discovered that traits of the "smooth" form of the Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form. Avery, along with coworkers Colin MacLeod and Maclyn McCarty, identified DNA as this transforming principle.^[132] DNA's role in heredity was confirmed in 1953, when Alfred Hershey and Martha Chase in the Hershey-Chase experiment showed that DNA is the genetic material of the T2 phage.^[133]

In 1953, based on X-ray diffraction images^[134] taken by Rosalind Franklin and the information that the bases were paired, James D. Watson and Francis Crick suggested^[134] what is now accepted as the first accurate model of DNA structure in the journal Nature.^[5] Experimental evidence for Watson and Crick's model were published in a series of five articles in the same issue of Nature.^[135] Of these, Franklin and Raymond Gosling's paper was the first publication of X-ray diffraction data that supported the Watson and Crick model,^[136]^[137] this issue also contained an article on DNA structure by Maurice Wilkins and his colleagues.^[138] In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.^[139] However, speculation continues on who should have received credit for the discovery, as it was based on Franklin's data.

In an influential presentation in 1957, Crick laid out the "Central Dogma" of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".^[140] Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson-Stahl experiment.^[141] Further work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall Warren Nirenberg to decipher the genetic code.^[142] These findings represent the birth of molecular biology.

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MOMENTUM

Contents

Momentum in Newtonian mechanics

Momentum for a system

Relating to mass and velocity

Relating to force

Conservation of momentum

Elastic collisions

[edit] Head-on collision (1 dimensional)

Multi-dimensional collisions

Inelastic collisions

Modern definitions of momentum

Momentum in relativistic mechanics

Momentum in quantum mechanics

Momentum in electromagnetism

Figurative use

Medical ultrasonography

Contents

Diagnostic applications

Therapeutic applications

From sound to image

Producing a sound wave

Receiving the echoes

Forming the image

Sound in the body

Modes of Sonography

Doppler sonography

Microbubbles

Strengths of sonography

Weaknesses of ultrasonic imaging

Risks and side-effects

Studies on the safety of ultrasound

Regulation

History

United States

Sweden

Scotland

Medical ultrasonography

Contents

[edit] Diagnostic applications

[edit] Therapeutic applications

[edit] From sound to image

[edit] Producing a sound wave

[edit] Receiving the echoes

[edit] Forming the image

[edit] Sound in the body

[edit] Modes of Sonography

[edit] Doppler sonography

[edit] Microbubbles

[edit] Strengths of sonography

[edit] Weaknesses of ultrasonic imaging

[edit] Risks and side-effects

[edit] Studies on the safety of ultrasound

[edit] Regulation

[edit] History

[edit] United States

[edit] Sweden

[edit] Scotland

Metabolism

Contents

Key biochemicals

Amino acids and proteins

Lipids

Carbohydrates

Nucleotides

Coenzymes

Minerals and cofactors

CATABOLISM

Digestion

Energy from organic compounds

Oxidative phosphorylation

Energy from inorganic compounds

Energy from light

Anabolism

Carbon fixation

Carbohydrates and glycans

Fatty acids, isoprenoids and steroids

Proteins

[edit] Nucleotide synthesis and salvage