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Glenn Miller changed the song title from "That's Where I Came In" to "Keep 'Em Flying". Recorded December 8, 1941. "Oh! So Good" – written by Jerry Gray "Soldier, Let Me Read Your Letter" – arranged by arranger/trumpeter Billy May; written by Sidney Lippman, Pvt. Pat Fallon and Pvt. Tim Pasma "I Got Rhythm" – Billy May, arranger /January 1, 1942 broadcast "Boom Shot" – composed by Glenn Miller and Billy May (under his wife's name Arletta May) for Orchestra Wives and arranged by George Williams. "Blues in the Night" "When Johnny Comes Marching Home" "Rainbow Rhapsody" "Polka Dots and Moonbeams" "Make Believe" "Twenty Four Robbers" "On A Little Street in Singapore" Harry Warren and Mack Gordon songs for Sun Valley Serenade and Orchestra Wives: Harry Warren and Mack Gordon were songwriters under contract with Twentieth Century Fox from 1940 to 1943.
During that time period they composed the songs for Miller's movies for Fox. "The Kiss Polka", used in Sun Valley Serenade and also appeared as a Bluebird 78. "The World is Waiting to Waltz Again" – vocal by John Payne, cut out of the release print of Sun Valley Serenade. "People Like You and Me" – Vocals by Marion Hutton, Tex Beneke, Ray Eberle, and the Modernaires in Orchestra Wives. Not recorded commercially or performed for broadcast. "That's Sabotage" – vocal by Marion Hutton. Cut out of the release print of Orchestra Wives supposedly by pressure from the United States government about how the war effort was being presented in the song.
The 35mm audio survives and has been released many times. Also recorded with Marion Hutton for RCA Victor. Radio format: In sharing air time with the Andrews Sisters for the early Chesterfield Shows, the Miller band had nine minutes to present its music. Miller instituted medleys of Something Old, Something New, Something Borrowed, Something Blue into the band's broadcasts to enable it to play as much as possible. This medley tradition continued into both later programs and the Army Air Force band's radio broadcasts.
Sample Glenn Miller medley, June 19, 1940 Cincinnati, Ohio, Chesterfield show with a Jerry Gray arrangement of all tracks: Old – "The Touch of Your Hand" (Generally an older song) New – "Basket Weaver Man" (A way to introduce a new song, written by Joe McCarthy and Walter Donaldson) Borrowed – "The Waltz You Saved For Me" (Themes or songs made famous by other bands/bandleaders; Borrowed from bandleader Wayne King, written by King, Gus Kahn and Emil Flindt) Blue – "Blue Danube" ("Blue" in title, written by Johann Strauss, Jr., 1867) Recordings as sideman, arranger, and leader: 1926–1938 The first authenticated recordings made by Glenn Miller were in 1926.
In the fall of 1926, Earl Baker, a cornetist, made recordings on cylinders using the Edison Standard Phonograph recording device, making the first recordings of Glenn Miller, Benny Goodman, and Fud Livingston. Miller and Goodman were both in the Ben Pollack and his Californians band at that time. The Ben Pollack band was in Chicago, Illinois, to make studio recordings for Victor. The Baker cylinders are available on the album "The Legendary Earl Baker Cylinders", released by the Jazz Archives record label as JA43 in 1979. The songs performed included "Sleepy Time Gal", "Sister Kate", "After I Say I'm Sorry", and "Sobbin' Blues".
"When I First Met Mary" – recorded on December 9, 1926 in Chicago as part of Ben Pollack and his Californians which featured Benny Goodman on clarinet. The recording was released as Victor 20394. "He's the Last Word" – recorded on December 12, 1926 with Ben Pollack and featuring a solo by Benny Goodman "Room 1411 (Goin' to Town)" – Miller's first known composition, written with Benny Goodman in 1928 and recorded with Miller's peers was released on 78 as Brunswick 4013. "Solo Hop" – composed by Glenn Miller in 1935 when he began recording under his own name which features a trumpet solo by Bunny Berigan.
The record reached number seven on the Billboard singles chart in 1935 becoming Miller's first hit record. "Dese Dem Dose" – with the Dorsey Brothers and Ray Noble. "When Icky Morgan Plays the Organ" – recorded with the Clark Randall Orchestra in 1935. Clark Randall was the pseudonym of Frank Tennille, the father of Toni Tennille of the Captain and Tennille. Most of the band members in the Clark Randall Orchestra were part of the Bob Crosby Orchestra. "Annie's Cousin Fanny" – with the Dorsey Brothers in 1934, vocal by Kay Weber and orchestra. This song was covered by Dick Pierce, Russ Carlton and his Orchestra, Marshall Royal and Maxwell Davis on the album Studio Cuts which includes two takes of the song and in 2000 by Mora's Modern Rhythmists Dance Orchestra, a ten-piece ensemble that plays jazz and swing from the 1920s and 1930s.
The record was banned by radio stations in 1934 because of suggestive lyrics relying on double entendre. "Every Day's a Holiday" was a 1938 Brunswick 78 single by Glenn Miller and his Orchestra that reached number 17 on Billboard, staying on the charts for one week. This was Glenn Miller's second hit record before he switched to the Bluebird label. "Doin' the Jive" "Community Swing" Pre-1938 charted recordings Army Air Force Band and V-Discs: 1943–1944 Navy V-Discs featured different color schemes than standard V-Discs. Unreleased V-Discs and addendum Other popular tracks, not recorded for or unreleased as V-Discs were: "7-0-5" or "Seven-O-Five" – written by Glenn Miller.
While recorded for V-Disc, it went unreleased. "Passage Interdit" - written by Jerry Gray. Released as V-Disc 587A in February, 1946. "Snafu Jump" – written by Jerry Gray "Long Ago (And Far Away)" vocal Johnny Desmond / Norman Leyden, arranger March 25, 1944, broadcast "People Will Say We're In Love" vocal Johnny Desmond / Norman Leyden, arranger "Flying Home", written by Benny Goodman, Eddie DeLange, and Lionel Hampton; arranged by Steve Steck; April 8, 1944, broadcast "Mission to Moscow" - Mel Powell, composer and arranger Songs that were in the civilian band and Army Air Force band libraries include: "Jeep Jockey Jump" – written by Jerry Gray and one broadcast of the song was done by the civilian band.
"It Must Be Jelly ('Cause Jam Don't Shake Like That)" – music written by Chummy MacGregor and George Williams and lyrics by Sunny Skylar. George Williams, arranger /Mar. 11, 1944 Chant by the band. This version is from the Army Air Force band. The civilian band played the same arrangement that was performed at least twice, available on a Victor 78 recording, Vi-20-1546-A, recorded July 15, 1942 or also taken from a radio remote broadcast from September 15, 1942 in Boston, Massachusetts and later re-released by RCA Victor on LPT 6700. According to the tsort.com website, the 78 single, Victor 20-1546, reached number twelve on the Billboard charts in January, 1944, where it stayed for eight weeks on the chart.
Moreover, the record was a crossover hit, reaching number two on the Billboard 'Harlem' Hit Parade Chart on February 19, 1944, the then equivalent of the later R&B chart, and number sixteen on the Billboard Juke Box Chart. Harry James, Johnny Long, and Frankie Ford also recorded versions. Woody Herman recorded a version that was also released as a V-Disc, No. 320B, in November, 1944. "Sun Valley Jump" – written by Jerry Gray. Released as a V-Disc, No. 281A, on October, 1944 by Glenn Miller and the AAFTC Orchestra. "Rhapsody in Blue" – written by George Gershwin. The civilian band version has Bobby Hackett solo in the middle.
"Rhapsody in Blue" from the civilian band is not the entire work, but rather a section of the work arranged to fit on a 10" 78 rpm record. It was released as Victor 20-1529-A. "Blue Rain" – written by Johnny Mercer and Jimmy Van Heusen, Civilian band-arrangement with Ray Eberle vocal, unknown arranger. Army Air Force band: arrangement with strings, no vocal. "Are You Jumpin' Jack?" – written by Bill Finegan. First civilian band version, December 21, 1940 for a remote broadcast on NBC. " Enlisted Men's Mess" – written by Jerry Gray. In the civilian band's library but not performed or recorded.
Performed by the Army Air Forces Training Command Band and broadcast on the I Sustain the Wings radio program, May 5, 1944. Songs that were prepared for but went unreleased on V-Disc include: "Stardust" (breakdown) "(The End Of A) Perfect Day" "Blue Room" "Holiday for Strings", in two parts "Here We Go Again" "In An Eighteenth Century Drawing Room" "The Old Refrain" "Song Of The Volga Boatmen" "Moonlight Serenade" (AAF arrangement) A disc released in 2010 is called "The Final - His Last Recordings" and collects Miller's last known recorded performances (November, 1944) plus bonus spoken bits for the radio program "Music for the Wehrmacht", starring Major Miller with German speaker Ilse Weinberger.
The album also contains a September 1944 interview and - as final track - the BBC radio announcement of Miller's disappearance. Album discography, 1928–1944 References Bibliography Polic, Edward F. (1990). The Glenn Miller Army Air Force Band. The Scarecrow Press, Inc.; Sustineo Alas/I Sustain the Wings edition (June 1, 1990) Miller, Glenn (1943). Glenn Miller's Method for Orchestral Arranging. New York: Mutual Music Society. ASIN: B0007DMEDQ Miller, Glenn (1927). Glenn Miller's 125 Jazz Breaks For Trombone. Chicago: Melrose Brothers Music Company. Miller, Glenn (1939). Feist All-Star Series of Modern Rhythm Choruses Arranged By Glenn Miller For Trombone. New York: Leo J. Feist, Inc. Grudens, Richard (2004).
Chattanooga Choo Choo: The Life and Times of the World Famous Glenn Miller Orchestra. Stony Brook, NY: Celebrity Profiles, 2004. Sears, Richard S. (1980). V-Discs: A History and Discography. Greenwood Press; illustrated edition (December 23, 1980) Category:Discographies of American artists Category:Jazz discographies
Ulnar dimelia, also referred to simply as mirror hand, is a very rare congenital disorder characterized by the absence of the radial ray, duplication of the ulna, duplication of the carpal, metacarpal, and phalanx bones, and symmetric polydactyly. In some cases surgical amputation is performed to remove the duplicate carpals, metacarpals and phalanges. As of 2015, approximately 70 cases have been recorded in the medical literature. Bone deformity may also accompany nervous and arterial anomalies in some cases due to the duplication of the ulnar nerve, the presence of abnormal arterial arches, the duplication of the ulnar artery, the shortening of the radial nerve, and the absence of the radial artery.
The diagnosis of ulnar dimelia is based on laboratory tests of frontal and sagittal planes in individuals suspected of the condition. There are two types of ulnar dimelia noted in medical journals: Type 1 ulnar dimelia entails one lunate and one trapezoid bone as well as one index finger, while type 2 ulnar dimelia has two lunate and two trapezoid bones as well as two index fingers. The American Society for Surgery of the Hand and the International Federation of Societies for Surgery of the Hand classified ulnar dimelia in the third group of congenital hand deformities in accordance with the characteristics proposed in the Swanson classification (1976).
References Further reading Category:Congenital disorders
Freckles is a 1960 American drama film directed by Andrew McLaglen. It stars Martin West and Carol Christensen. It was filmed in CinemaScope and DeLuxe Color, and is the fourth of five adaptations of Gene Stratton-Porter's 1904 novel of the same name. Plot summary Handicapped by a missing hand since childhood, Freckles (Martin West) works for timber baron John McLean (Roy Barcroft). He rounds up a gang of lumber thieves headed by Duncan (Jack Lambert). John’s foreman, Duncan, gives Freckles a tour and points out the troubles they have been facing due to a gang of timber thieves, led by Jack Barbeau.
Freckles begs to be a guard that requires him to be alone in a small, isolated cabin. John eventually agrees, and Freckles is quick to start patrolling a large area of land on horseback with a rifle in hand. One day, Freckles meets a naturalist, Alice Cooper, who is photographing birds. Alice asks Freckles to watch her niece, Chris, who lives nearby. Meanwhile, Chris has fallen and hurt herself. A fisherman, who ends up being Barbeau, helps her. Freckles arrives and tells Barbeau he is on private property and must leave. Later in the day, Wessner, one of John’s men who is actually secretly working for Barbeau, tries to bribe Freckles while in his cabin.
Freckles refuses and a fistfight breaks out, which Freckles wins. John sees this confrontation, and is pleased with how Freckles acted and assures him that he will always have a job. A few days later, Chris and Freckles spend more time getting to know one another. While on the job, Freckles is approached by Barbeau, who tells him that his family was in the woods long before John, and they only cut what they need. He tells Freckles that he is working for the wrong side. When Freckles tells Duncan about this encounter, Duncan tells him not to listen to Barbeau’s story.
The next day, Freckles learns from Alice that Chris’s parents are sending her to college. Freckles stops by Chris's house and meets her father. At this point, Freckles and Chris are in love, and Freckles is worried that college will change her. They fight, and Freckles leaves. He returns to the Limberlost, where Barbeau and his men are cutting down trees. Freckles gathers MacLean and his crew to confront the lumber thieves, but they are too late. Freckles blames himself for both the theft and the thieves' escape. This story of love, competition, and rivalry ends with the death of Barbeau, guilt, and the union of Freckles and Chris.
Cast Martin West as Freckles Carol Christensen as Chris Cooper Jack Lambert as Duncan Steve Peck as Jack Barbeau Roy Barcroft as John McLean Lorna Thayer as Alice Cooper Ken Curtis as Wessner John Eldredge as Mr. Cooper Production The film was made by Robert L. Lippert's Associated Producers Inc. It was filmed on location in San Bernardino National Forest. See also List of American films of 1961 List of American films of 1960 References External links Category:1960 films Category:Films directed by Andrew McLaglen Category:English-language films Category:Films based on American novels Category:American drama films Category:1960 drama films Category:20th Century Fox films Category:American films Category:Films based on works by Gene Stratton-Porter Category:Films set in forests Category:American film remakes
Molecular imaging is broadly defined as the visualization of molecular and cellular processes on either a macro- or microscopic level. Because of its high spatial resolution and ability to noninvasively visualize internal organs, magnetic resonance (MR) imaging is widely believed to be an ideal platform for in vivo molecular imaging. For this reason, MR contrast agents that can detect molecular events are an active field of research. One group of compounds that has shown particular promise is enzyme-activated MR contrast agents. Enzyme-activated MR contrast agents are compounds that cause a detectable change in image intensity when in the presence of the active form of a certain enzyme.
This makes them useful for in vivo assays of enzyme activity. They are distinguished from current, clinical MR contrast agents that give only anatomical information, such as aqueous gadolinium compounds, by their ability to make molecular processes visible. Enzyme-activated contrast agents are powerful tools for molecular imaging. To date, β-galactosidase-activated contrast agents have attracted the most attention in the literature, although there no theoretical reason that other enzymes could not be used to activate contrast agents. Also, mechanisms other than enzyme activation, such as Ca2+-dependent activation, can theoretically be used. In general, enzyme-activated agents contain a paramagnetic metal ion which can affect the T1 or T2 relaxation times for nearby water molecules.
However, the metal ions are unable to interact with the water until an enzyme-catalyzed reaction takes place. Steric hindrance or coordination with other ions prevents water from accessing the paramagnetic center prior to the enzymatic reaction. Structure of β-galactosidase-activated contrast agents Two distinct β-galactosidase-activated contrast agents have been reported. Both consist of a Gd(III) ion complexed with a tetraazamacrocycle. At the N-10 position, a two-carbon chain links the gadolinium-tertaazamacrocycle complex to a molecule of galactose. The galactose is linked to the complex by a β-glycosidic bond at its C-1 position. The two forms of the contrast agent differ only in the location of a single methyl group.
The first class, known as the α-series, has a methyl group bound to the carbon that is α to the tetraazamacrocycle. The other class, called the β-series, has a methyl attached to the β carbon relative to the tetraazamacrocycle. The position of this methyl group is significant for the structure of the agent, and thus determines the mechanism by which the non-active compound shields the Gd(III) ion from interacting with water. The α-series adopts a conformation in which the sugar lies directly over the paramagnetic center, thus sterically prohibitting water from accessing the gadolinium. The β-series, on the other hand, blocks water from the gadolinium by coordinating with a carbonate ion.
There is no evidence that the stereochemical orientation of the methyl-bearing carbon affects the either the enzyme-catalyzed cleavage or the ability of the sugar to exclude water from the gadolinium ion. Studies have shown that the α-series is far more effective at blocking water from the paramagnetic center prior to cleavage. The need to coordinate with a carbonate ion and the lower level of signal suppression inherent to the β-series make the α-series a better candidate for use in research and clinical medicine. Mechanism of activation In a tissue where active β-galactosidase is present, the sugar will be cleaved from the rest of the compound.
This permits water to access the paramagnetic center, and causes the magnetic relaxation properties of the surrounding water molecules to change. This change in relaxation times will, in turn, visibly alter the signal intensity of images of the tissue obtained from MR scans. The mechanism proceeds in the same manner as all other β-galactosidase-catalyzed cleavages. The carboxyl group on a glutamic acid side chain within the enzyme acts as an acid catalyst, hastening the cleavage of the glycosidic bond at the C-1 position in the sugar. This cleavage gives water access to the paramagnetic center. The result of the enzyme-catalyzed reaction is a free galactose molecule and an activated contrast agent.
Uses There are obvious potential uses to this technology, both in research and clinical medicine. Basic research In a research context, the α-series of β-galactosidase-activated MR contrast agents has been used to visualize the development and gene expression of cells in a Xenopus laevis embryo. Researchers injected the agent into both cells of a two-cell stage embryo, and then injected only one of the cells with mRNA for the enzyme. Following a period of growth, they obtained MR images of the embryo that clearly displayed signal enhancement only in the cells derived from the parent cell that had been injected with both the enzyme and the contrast agent.
This study demonstrates the value of whole body, in vivo molecular imaging methods for basic research. Such techniques permit scientists to test for gene activity and enzyme function throughout an organism. In contrast, many existing assays (such as fixation of cells on paraffin wax followed by immunostaining) only permit the analysis of a few cells at a time. These methods kill the cells, thus making time-series studies difficult. They also require the researcher to have identified a tissue of interest before obtaining the cells. The rise of whole-body molecular imaging methods may permit scientists to see where in an organism an enzyme is active without damaging cells; imaging could be repeated at multiple time points to monitor changes in gene expression or enzyme activity.
Similar techniques have attracted considerable interest from researchers studying cancer and cardiovascular disease. Clinical medicine The ability to detect tissues that contain the active form of an enzyme at certain time has clear value in medicine. Specific contrast agents that provide enhancement only in the presence of active enzymes could allow doctors to conclusively and noninvasively assay for a wide variety of enzymatic diseases, such as fructose bisphosphatase deficiency. However, such diagnostic tools would require the development of contrast agents specific to the enzyme of interest, and would necessitate the development of methods for delivering the agents to cells (see “Limitations” below).
Limitations Once the contrast agent has been activated by cleavage of the sugar group, the signal enhancing effects will only diminish if the gadolinium is washed out of the compartment containing it, or if water’s access to the metal group is again inhibited. So, to prevent permanent enhancement of the MR signal, cells must either have a way to export the gadolinium group to the bloodstream, or they must be able to replace the cleaved sugar group. There is no data in the literature indicating that either approach is feasible in vivo, suggesting that these methods may result in permanent signal amplification.
Another challenge is the delivery of the contrast agents to target cells. In the sole paper describing in vivo use of enzyme-activated MR contrast agents, the agent was delivered to embryonic cells via a micropipette. However, the authors of the paper acknowledge that this is not a feasible approach for many research projects, and it presents a clear impediment to clinical use. There is active research in using the cell’s native import machinery to load contrast agents. References Category:Imaging
A dental drill or handpiece is a hand-held, mechanical instrument used to perform a variety of common dental procedures, including removing decay, polishing fillings, performing cosmetic dentistry, and altering prostheses. The handpiece itself consists of internal mechanical components which initiate a rotational force and provide power to the cutting instrument, usually a dental burr. The type of apparatus used clinically will vary depending on the required function dictated by the dental procedure. It is common for a light source and cooling water-spray system to also be incorporated into certain handpieces; this improves visibility, accuracy and overall success of the procedure.
High-speed handpiece High-speed handpieces work at cutting speeds over 180,000 rpm. They are technically categorised into air turbine and speed-increasing depending on their mechanisms. In a clinical setting, however, air turbine handpieces are most often referred to as "high-speeds". Handpieces have a chuck or collet, for holding a cutter, called a burr or bur. Mechanisms Power The turbine is powered by compressed air between 35 to 61 pounds per square inch (~2,4 to 4,2 bar), which passes up the centre of the instrument and rotates a windmill in the head of the handpiece. The centre of the windmill (chuck) is surrounded by bearing housing, which holds a friction-grip burr firmly & centrally within the instrument.
Inside the bearing housing are small, lubricated ball-bearings (stainless steel or ceramic) which allow the shank of the burr to rotate smoothly along a central axis with minimal friction. The complete rotor is fixed with O-Rings in the head of the high speed. The O-Rings allow the system to become perfect centric during the idle speed but allow a small movement of the rotor within the head. Failure of the burr to run centrally causes a number of clinical defects: The burr will judder; this will cause excessive, damaging vibrations leading to cracking and crazing in the material being cut.
It is also an unpleasant experience for the patient. Eccentric cutting - this will result in irregular removal of the surface, meaning more tissue than necessary is removed. Decreased control - due to irregular cutting, it is more difficult for the dentist to control movements Cooling The friction produced by high-speeds creates significant heat within the burr. It is therefore critical for high-speed handpieces to have an effective water-cooling system. The standard is a cooling water of minimum 50 ml/min that is delivered through 3to 5 spray hole jets. Illumination Many modern handpieces now have a light in close proximity to the burr.
The light is directed at the cutting surface as to assist with intra-operative vision. Older handpieces used a system of halogen bulbs and fibre-optic rods, however, there are a number of disadvantages to this system: halogen bulbs deteriorate with time and are expensive to replace, and fibre-optic rods fracture easily if dropped and deteriorate during repeated autoclaving cycles. More modern handpieces now use LED systems. Advantages of LEDs include a longer working life, more intense light and minimal heat production. Speed-increasing handpiece Electric motors cannot turn as fast as air turbines. To power a high-speed handpiece, gears are needed to increase the speed of an electric motor, often by a ratio of 1:5.
For this reason, electric handpieces are also called speed-increasing handpieces, working at cutting speeds over 180,000 rpm. Speed-increasing handpiece is driven by electrical motor, also known as micromotor. The power to the handpiece is provided by the micromotor. Within the handpiece is internal gearings which allow the friction grip burr to rotate at a constant speed and torque. Therefore the power is provided by micromotor and internal gearings. Torque Torque is the ability of burr to continually rotate with the same speed and cut even when pressure is applied As the speed of a handpiece increases its torque subsequently decreases (slow-speed handpieces have high torque, whereas high-speed handpieces, like the air turbine system, have a low torque) The free running speed of 1:5 speed-increasing handpiece is the same as its cutting speed, thus 40,000 motor speed x5= 200,000 rpm burr speed.
Electrical motor maintains the 200,000 rpm speed and provides consistent power so torque will be maintained, depending on the electronic control parameters. Comparison of high speed and speed increasing handpieces Slow speed handpiece Slow speed handpieces work at a much slower rate that high speed and speed-increasing handpieces, and are usually driven by rotary vane motors, instead of air turbines. They work at a speed between 600 and 25,000 rpm. The internal gearings are very similar to that of a speed-increasing handpiece. The main difference between the two is that slow speed has internal gearing and they use a latch grip burr as opposed to a friction grip burr.
Indications for use Generally used for operative procedures such as the removal of dental caries or for polishing enamel or restorative materials. Straight slow speed handpiece is generally indicated for the extra oral adjustment and polishing of acrylic and metals. Speed decreasing handpiece Designed to work at slower speeds. Indications for use The main indications for use include endodontic canal preparation, implant placement and prophylaxis. Endodontic canal preparation Endodontic canals are prepared using a slow rotating file. It is imperative that torque is controlled in order to prevent endodontic file separation during use. Implant placement - In order to prevent heat damage to bone during implant placement speed decreasing handpiece is used.
Prophylaxis - Prophylaxis with the use of speed decreasing handpiece ensures that less heat is produced and thus less risk of pulpal damage by heat transmission. Dental burr A dental burr is a type of burr used in a handpiece. The burrs are usually made of tungsten carbide or diamond. The three parts to a burr are the head, the neck, and the shank. The heads of some burrs (such as tungsten carbide burrs) contain the blades which remove material. These blades may be positioned at different angles in order to change the property of the burr. More obtuse angles will produce a negative rake angle which increases the strength and longevity of the burr.
More acute angles will produce a positive rake angle which has a sharper blade, but which dulls more quickly. The heads of other commonly used burrs are covered in a fine grit which has a similar cutting function to blades (e.g. high speed diamond burrs). Diamond burrs seems to give better control and tactile feedback then carbide burs, due to the fact that the diamonds are always in contact with the milled tooth in comparison to the single blades at the carbide burrs. There are various shapes of burrs that include round, inverted cone, straight fissure, tapered fissure, and pear-shaped burrs.
Additional cuts across the blades of burrs were added to increase cutting efficiency, but their benefit has been minimized with the advent of high-speed handpieces. These extra cuts are called crosscuts. Due to the wide array of different burrs, numbering systems to categorise burrs are used and include a US numbering system and a numbering system used by the International Organisation for Standardisation (ISO). Maintenance The instrument needs to be disinfected or sterilized after every usage to prevent infection during succeeding incisions. Due to the mechanical structure of the device, this must not be done with alcoholic disinfectant, as that would destroy the lubricants.
Instead it has to be done in an autoclave after removing the drill, washing the instrument with hydrogen hydroxide and lubricating it. The United States Food and Drug Administration classes burrs as "single-use devices", although they can be sterilised with proper procedures. History The Indus Valley Civilization has yielded evidence of dentistry being practiced as far back as 7000 BC. This earliest form of dentistry involved curing tooth related disorders with bow drills operated, perhaps, by skilled bead craftsmen. The reconstruction of this ancient form of dentistry showed that the methods used were reliable and effective. Cavities of 3.5 mm depth with concentric grooves indicate use of a drill tool.
The age of the teeth has been estimated at 9000 years. In later times, mechanical hand drills were used. Like most hand drills, they were quite slow, with speeds of up to 15 rpm. In 1864, British dentist George Fellows Harrington invented a clockwork dental drill named Erado. The device was much faster than earlier drills, but also very noisy. In 1868, American dentist George F. Green came up with a pneumatic dental drill powered with pedal-operated bellows. James B. Morrison devised a pedal-powered burr drill in 1871. The first electric dental drill was patented in 1875 by Green, a development that revolutionized dentistry.
By 1914, electric dental drills could reach speeds of up to 3000 rpm. A second wave of rapid development occurred in the 1950s and 60s, including the development of the air turbine drill. The modern incarnation of the dental drill is the air turbine (or air rotor) handpiece, developed by John Patrick Walsh (later knighted) and members of the staff of the Dominion Physical Laboratory (DPL) Wellington, New Zealand. The first official application for a provisional patent for the handpiece was granted in October 1949. This handpiece was driven by compressed air. The final model is held by the Commonwealth Inventions development Board in Canada.
The New Zealand patent number is No/104611. The patent was granted in November to John Patrick Walsh who conceived the idea of the contra angle air-turbine handpiece after he had used a small commercial-type air grinder as a straight handpiece. Dr. John Borden developed it in America and it was first commercially manufactured and distributed by the DENTSPLY Company as the Borden Airotor in 1957. Borden Airotors soon were also manufactured by different other companies like KaVo Dental, which built their first one in 1959. Current iterations can operate at up to 800,000 rpm, however, most common is a 400,000 rpm "high speed" handpiece for precision work complemented with a "low speed" handpiece operating at a speed that is dictated by a micromotor which creates the momentum (max up to 40,000 rpm) for applications requiring higher torque than a high-speed handpiece can deliver.
Alternatives Starting in the 1990s, a number of alternatives to conventional rotary dental drills have been developed. These include laser ablation systems and air abrasion devices (essentially miniature sand blasters) or dental treatments with ozone. References MedTerms definition for Drill, dental "Dental drills - enemy of the people?" from the British Dental Association museum Australian Dental Journal:1 p59-62 Category:Dental equipment
Channelrhodopsins are a subfamily of retinylidene proteins (rhodopsins) that function as light-gated ion channels. They serve as sensory photoreceptors in unicellular green algae, controlling phototaxis: movement in response to light. Expressed in cells of other organisms, they enable light to control electrical excitability, intracellular acidity, calcium influx, and other cellular processes. Channelrhodopsin-1 (ChR1) and Channelrhodopsin-2 (ChR2) from the model organism Chlamydomonas reinhardtii are the first discovered channelrhodopsins. Variants have been cloned from other algal species, and more are expected. Structure In terms of structure, channelrhodopsins are retinylidene proteins. They are seven-transmembrane proteins like rhodopsin, and contain the light-isomerizable chromophore all-trans-retinal (an aldehyde derivative of vitamin A).
The retinal chromophore is covalently linked to the rest of the protein through a protonated Schiff base. Whereas most 7-transmembrane proteins are G protein-coupled receptors that open other ion channels indirectly via second messengers (i.e., they are metabotropic), channelrhodopsins directly form ion channels (i.e., they are ionotropic). This makes cellular depolarization extremely fast, robust, and useful for bioengineering and neuroscience applications, including photostimulation. Function The natural ("wild-type") ChR2 absorbs blue light with an absorption and action spectrum maximum at 480 nm. When the all-trans-retinal complex absorbs a photon, it induces a conformational change from all-trans to 13-cis-retinal. This change introduces a further one in the transmembrane protein, opening the pore to at least 6 Å.
Within milliseconds, the retinal relaxes back to the all-trans form, closing the pore and stopping the flow of ions. Most natural channelrhodopsins are nonspecific cation channels, conducting H+, Na+, K+, and Ca2+ ions. Recently, anion-conducting channelrhodopsins have been discovered. Designer-channelrhodopsins Channelrhodopsins are key tools in optogenetics. The C-terminal end of Channelrhodopsin-2 extends into the intracellular space and can be replaced by fluorescent proteins without affecting channel function. This kind of fusion construct can be useful to visualize the morphology of ChR2 expressing cells. Point mutations close to the retinal binding pocket have been shown to affect the biophysical properties of the channelrhodopsin, resulting in a variety of different tools.
Kinetics Closing of the channel after optical activation can be substantially delayed by mutating the protein residues C128 or D156. This modification results in super-sensitive channelrhodopsins that can be opened by a blue light pulse and closed by a green or yellow light pulse (Step-function opsins). Mutating the E123 residue accelerates channel kinetics (ChETA), and the resulting ChR2 mutants have been used to spike neurons at up to 200 Hz. In general, channelrhodopsins with slow kinetics are more light-sensitive on the population level, as open channels accumulate over time even at low light levels. Photocurrent amplitude H134R and T159C mutants display increased photocurrents, and a combination of T159 and E123 (ET/TC) has slightly larger photocurrents and slightly faster kinetics than wild-type ChR2.
Among ChR variants, ChIEF, a chimera and point mutant of ChR1 and ChR2, demonstrates the largest photocurrents and the least desensitization and has kinetics similar to wild-type ChR2. Wavelength Chimeric channelrhodopsins have been developed by combining transmembrane helices from ChR1 and VChR1, leading to the development of ChRs with red spectral shifts (such as C1V1 and ReaChR). ReaChR has improved membrane trafficking and strong expression in mammalian cells, and has been used for minimally invasive, transcranial activation of brainstem motoneurons. Searches for homologous sequences in other organisms has yielded spectrally improved and stronger red-shifted channelrhodpsins (Chrimson). In combination with ChR2, these yellow/red light-sensitive channelrhodopsins allow controlling two populations of neurons independently with light pulses of different colors.
A blue-shifted channelrhodopsin has been discovered in the alga Scherffelia dubia. After some engineering to improve membrane trafficking and speed, the resulting tool (CheRiff) produced large photocurrents at 460 nm excitation. It has been combined with the Genetically Encoded Calcium Indicator jRCaMP1b in an all-optical system called the OptoCaMP. Ion selectivity The L132C mutation (CatCh) increases the permeability for calcium and generates very large currents. Mutating E90 to the positively charged amino acid arginine turns channelrhodopsin from an unspecific cation channel into a chloride-conducting channel (ChloC). The selectivity for Cl- was further improved by replacing negatively charged residues in the channel pore, making the reversal potential more negative.
Selective chloride-conducting channelrhodopsins (iChloC, iC++, GtACR) inhibit neuronal spiking in cell culture and in intact animals when illuminated with blue light. Applications Channelrhodopsins can be readily expressed in excitable cells such as neurons using a variety of transfection techniques (viral transfection, electroporation, gene gun) or transgenic animals. The light-absorbing pigment retinal is present in most cells (of vertebrates) as Vitamin A, making it possible to photostimulate neurons without adding any chemical compounds. Before the discovery of channelrhodopsins, neuroscientists were limited to recording the activity of neurons in the brain and correlate this activity with behavior. This is not sufficient to prove that the recorded neural activity actually caused that behavior.
Controlling networks of genetically modified cells with light, an emerging field known as Optogenetics., allows researchers now to explore the causal link between activity in a specific group of neurons and mental events, e.g. decision making. Optical control of behavior has been demonstrated in nematodes, fruit flies, zebrafish, and mice. Recently, chloride-conducting channelrhodopsins have been engineered and were also found in nature. These tools can be used to silence neurons in cell culture and in live animals by shunting inhibition. Using multiple colors of light expands the possibilities of optogenetic experiments. The blue-light sensitive ChR2 and the yellow light-activated chloride pump halorhodopsin together enable multiple-color optical activation and silencing of neural activity.
VChR1 from the colonial alga Volvox carteri absorbs maximally at 535 nm and had been used to stimulate cells with yellow light (580 nm), although photocurrents generated by VChR1 are typically very small. However, VChR1-ChR2 hybrids have been developed using directed evolution that display maximal excitation at 560 nm, and 50% of peak absorbance at wavelengths over 600 nm. Using fluorescently labeled ChR2, light-stimulated axons and synapses can be identified. This is useful to study the molecular events during the induction of synaptic plasticity. Transfected cultured neuronal networks can be stimulated to perform some desired behaviors for applications in robotics and control.
ChR2 has also been used to map long-range connections from one side of the brain to the other, and to map the spatial location of inputs on the dendritic tree of individual neurons. Visual function in blind mice can be partially restored by expressing ChR2 in inner retinal cells. In the future, ChR2 might find medical applications, e.g. in forms of retinal degeneration or for deep-brain stimulation. Optical cochlear implants have been shown to work well in animal experiments and might lead to the first application of optogenetics in human patients. History Motility and photoorientation of microalgae (phototaxis) have been studied over more than hundred years in many laboratories worldwide.
In 1980, Ken Foster developed the first consistent theory about the functionality of algal eyes. He also analyzed published action spectra and complemented blind cells with retinal and retinal analogues, which led to the conclusion that the photoreceptor for motility responses in Chlorophyceae is rhodopsin. Photocurrents of the Chlorophyceae Heamatococcus pluvialis and Chlamydomonas reinhardtii were studied over many years in the groups of Oleg Sineshchekov and Peter Hegemann, resulting in two seminal publications in the years 1978 and 1991. Based on action spectroscopy and simultaneous recordings of photocurrents and flagellar beating, it was determined that the photoreceptor currents and subsequent flagellar movements are mediated by rhodopsin and control phototaxis and photophobic responses.
The extremely fast rise of the photoreceptor current after a brief light flash led to the conclusion that the rhodopsin and the channel are intimately linked in a protein complex, or even within one single protein. However, biochemical purification of the rhodopsin-photoreceptor(s) was unsuccessful for many years. The nucleotide sequences of the rhodopsins now called channelrhodopsins ChR1 and ChR2 were finally uncovered in a large-scale EST sequencing project in C. reinhardtii. Independent submission of the same sequences to GenBank by three research groups generated confusion about their naming: The names cop-3 and cop-4 were used for initial submission by Hegemann's group; csoA and csoB by Spudich's group; and acop-1 and acop-2 by Takahashi's group.
Both sequences were found to function as single-component light-activated cation channels in a Xenopus oocytes and human kidney cells (HEK) by Georg Nagel, Ernst Bamberg, Peter Hegemann and others. The name "channelrhodopsin" was coined to highlight this unusual property, and the sequences were renamed accordingly. Meanwhile, their roles in generation of photoreceptor currents in algal cells were characterized by Oleg Sineshchekov, Kwang-Hwan Jung and John Spudich, and Peter Berthold and Peter Hegemann. In November 2004, Zhuo-Hua Pan submitted a paper to Nature reporting restoration of eyesight in blind mice transfected with Channelrhodopsin, but the paper was rejected and ultimately published in Neuron in 2006.
Meanwhile, in 2005, three groups sequentially established ChR2 as a tool for genetically targeted optical remote control (optogenetics) of neurons, neural circuits and behavior. At first, Karl Deisseroth's lab (in a paper published in August 2005) demonstrated that ChR2 could be deployed to control mammalian neurons in vitro, achieving temporal precision on the order of milliseconds (both in terms of delay to spiking and in terms of temporal jitter).
This was a significant finding, since, first, all opsins (microbial as well as vertebrate) require retinal as the light-sensing co-factor and it was unclear whether central mammalian nerve cells would contain sufficient retinal levels, but they do; second, it showed, despite the small single-channel conductance, sufficient potency to drive mammalian neurons above action potential threshold; and, third, it demonstrated channelrhodopsin to be the first optogenetic tool, with which neural activity could be controlled with the temporal precision at which neurons operate (milliseconds). An earlier tool for photostimulation, cHARGe, demonstrated proof of principle in cultured neurons but was never used by other groups since it operated with a precision on the order of seconds, was highly variable, and did not allow control of individual action potentials.
A second study was published later by Peter Hegemann's and Stefan Herlitze's groups confirming the ability of ChR2 to control the activity of vertebrate neurons, at this time in the chick spinal cord. This study was the first wherein ChR2 was expressed alongside an optical silencer, vertebrate rhodopsin-4 in this case, demonstrating for the first time that excitable cells could be activated and silenced using these two tools simultaneously, illuminating the tissue at different wavelengths. The groups of Alexander Gottschalk and Ernst Bamberg (with Georg Nagel taking the experimental lead) demonstrated that ChR2, if expressed in specific neurons or muscle cells, can evoke predictable behaviors, i.e.
can control the nervous system of an intact animal, in this case the invertebrate C. elegans. This was the first using ChR2 to steer the behavior of an animal in an optogenetic experiment, rendering a genetically specified cell type subject to optical remote control. Although both aspects had been illustrated earlier that year by another group, the Miesenböck lab, deploying the indirectly light-gated ion channel P2X2, it was henceforth microbial opsins like channelrhodopsin that dominated the field of genetically targeted remote control of excitable cells, due to the power, speed, targetability, ease of use, and temporal precision of direct optical activation, not requiring any external chemical compound such as caged ligands.
To overcome its principal downsides — the small single-channel conductance (especially in steady-state), the limitation to one optimal excitation wavelength (~470 nm, blue) as well as the relatively long recovery time, not permitting controlled firing of neurons above 20–40 Hz — ChR2 has been optimized using genetic engineering. A point mutation H134R (exchanging the amino acid Histidine in position 134 of the native protein for an Arginine) resulted in increased steady-state conductance, as described in a 2005 paper that also established ChR2 as an optogenetic tool in C. elegans. In 2009, Roger Tsien's lab optimized ChR2 for further increases in steady-state conductance and dramatically reduced desensitization by creating chimeras of ChR1 and ChR2 and mutating specific amino acids, yielding ChEF and ChIEF, which allowed the driving of trains of action potentials up to 100 Hz.
In 2010, the groups of Hegemann and Deisseroth introduced an E123T mutation into native ChR2, yielding ChETA, which has faster on- and off-kinetics, permitting the control of individual action potentials at frequencies up to 200 Hz (in appropriate cell types). The groups of Hegemann and Deisseroth also discovered that the introduction of the point mutation C128S makes the resulting ChR2-derivative a step-function tool: Once "switched on" by blue light, ChR2(C128S) stays in the open state until it is switched off by yellow light – a modification that deteriorates temporal precision, but increases light sensitivity by two orders of magnitude. They also discovered and characterized VChR1 in the multicellular algae Volvox carteri.
VChR1 produces only tiny photocurrents, but with an absorption spectrum that is red-shifted relative to ChR2. Using parts of the ChR1 sequence, photocurrent amplitude was later improved to allow excitation of two neuronal populations at two distinct wavelengths. Deisseroth's group has pioneered many applications in live animals such as genetically targeted remote control in rodents in vivo, the optogenetic induction of learning in rodents, the experimental treatment of Parkinson's disease in rats, and the combination with fMRI (opto-fMRI). Other labs have pioneered the combination of ChR2 stimulation with calcium imaging for all-optical experiments, mapping of long-range and local neural circuits, ChR2 expression from a transgenic locus – directly or in the Cre-lox conditional paradigm – as well as the two-photon excitation of ChR2, permitting the activation of individual cells.
In March 2013, the Brain Prize (Grete Lundbeck European Brain Research Prize) was jointly awarded to Ernst Bamberg, Edward Boyden, Karl Deisseroth, Peter Hegemann, Gero Miesenböck, and Georg Nagel for "their invention and refinement of optogenetics". The same year, Peter Hegemann and Georg Nagel received the Louis-Jeantet Prize for Medicine for "the discovery of channelrhodopsin". In 2015, Edward Boyden and Karl Deisseroth received the Breakthrough Prize in Life Sciences for "the development and implementation of optogenetics". References Further reading (Naturel function of channelrhodopsins and other photoreceptors in green) (Using channelrhodopsin in transgenic mice to study brain circuitry) (Using channelrhodopsin potentially to treat blindness) External links OpenOptogenetics.org, a comprehensive wiki about optogenetics.
Optogenetics Resource Center / Deisseroth lab Boyden lab Lab of Zhuo-Hua Pan Hegemann lab The Brain Prize 2013 for the invention of optogenetics Category:Ion channels Category:Integral membrane proteins Category:Neurotechnology
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltrasferases, however, examples of other methyl donors are seen in nature.
The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the nucleophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA. Function Genetics Methylation, as well as other epigenetic modifications, affects transcription, gene stability, and parental imprinting.
It directly impacts chromatin structure and can modulate gene transcription, or even completely silence or activate genes, without mutation to the gene itself. Though the mechanisms of this genetic control are complex, hypo- and hypermethylation of DNA is implicated in many diseases. Protein regulation Methylation of proteins has a regulatory role in protein–protein interactions, protein–DNA interactions, and protein activation. Examples: RCC1, an important mitotic protein, is methylated so that it can interact with centromeres of chromosomes. This is an example of regulation of protein-protein interaction, as methylation regulates the attachment of RCC1 to histone proteins H2A and H2B. The RCC1-chromatin interaction is also an example of a protein-DNA interaction, as another domain of RCC1 interacts directly with DNA when this protein is methylated.
When RCC1 is not methylated, dividing cells have multiple spindle poles and usually cannot survive. p53 methylated on lysine to regulate its activation and interaction with other proteins in the DNA damage response. This is an example of regulation of protein-protein interactions and protein activation. p53 is a known tumor suppressor that activates DNA repair pathways, initiates apoptosis, and pauses the cell cycle. Overall, it responds to mutations in DNA, signaling to the cell to fix them or to initiate cell death so that these mutations cannot contribute to cancer. NF-κB (a protein involved in inflammation) is a known methylation target of the methyltransferase SETD6, which turns off NF-κB signaling by inhibiting of one of its subunits, RelA.
This reduces the transcriptional activation and inflammatory response, making methylation of NF-κB a regulatory process by which cell signaling through this pathway is reduced. Natural product methyltransferases provide a variety of inputs into metabolic pathways, including the availability of cofactors, signalling molecules, and metabolites. This regulates various cellular pathways by controlling protein activity. Types Histone methyltransferases Histone methyltransferases are critical for genetic regulation at the epigenetic level. They modify mainly lysine on the ε-nitrogen and the arginine guanidinium group on histone tails. Lysine methyltransferases and Arginine methyltransferases are unique classes of enzymes, but both bind SAM as a methyl donor for their histone substrates.
Lysine amino acids can be modified with one, two, or three methyl groups, while Arginine amino acids can be modified with one or two methyl groups. This increases the strength of the positive charge and residue hydrophobicity, allowing other proteins to recognize methyl marks. The effect of this modification depends on the location of the modification on the histone tail and the other histone modifications around it. The location of the modifications can be partially determined by DNA sequence, as well as small non-coding RNAs and the methylation of the DNA itself. Most commonly, it is histone H3 or H4 that is methylated in vertebrates.
Either increased or decreased transcription of genes around the modification can occur. Increased transcription is a result of decreased chromatin condensation, while decreased transcription results from increased chromatin condensation. Methyl marks on the histones contribute to these changes by serving as sites for recruitment of other proteins that can further modify chromatin. N-terminal methyltransferases N-alpha methyltransferases transfer a methyl group from SAM to the N-terminal nitrogen on protein targets. The N-terminal methionine is first cleaved by another enzyme and the X-Proline-Lysine consensus sequence is recognized by the methyltransferase. For all known substrates, the X amino acid is Alanine, Serine, or Proline.
This reaction yields a methylated protein and SAH. Known targets of these methyltransferases in humans include RCC-1 (a regulator of nuclear transport proteins) and Retinoblastoma protein (a tumor suppressor protein that inhibits excessive cell division). RCC-1 methylation is especially important in mitosis as it coordinates the localization of some nuclear proteins in the absence of the nuclear envelope. When RCC-1 is not methylated, cell division is abnormal following the formation of extra spindle poles. The function of Retinoblastoma protein N-terminal methylation is not known. DNA/RNA methyltransferases DNA methylation, a key component of genetic regulation, occurs primarily at the 5-carbon of the base cytosine, forming 5’methylcytosine (see left).
Methylation is an epigenetic modification catalyzed by DNA methyltransferase enzymes, including DNMT1, DNMT2, and DNMT3. These enzymes use S-adenosylmethionine as a methyl donor and contain several highly conserved structural features between the three forms; these include the S-adenosylmethionine binding site, a vicinal proline-cysteine pair which forms a thiolate anion important for the reaction mechanism, and the cytosine substrate binding pocket. Many features of DNA methyltransferases are highly conserved throughout many classes of life, from bacteria to mammals. In addition to controlling the expression of certain genes, there are a variety of protein complexes, many with implications for human health, which only bind to methylated DNA recognition sites.
Many of the early DNA methyltransferases have been thought to be derived from RNA methyltransferases that were supposed to be active in the RNA world to protect many species of primitive RNA. RNA methylation has been observed in different types of RNA species viz.mRNA, rRNA, tRNA, snoRNA, snRNA, miRNA, tmRNA as well as viral RNA species. Specific RNA methyltransferases are employed by cells to mark these on the RNA species according to the need and environment prevailing around the cells, which form a part of field called molecular epigenetics. 2'-O-methylation, m6A methylation, m1G methylation as well as m5C are most commonly methylation marks observed in different types of RNA.
6A is an enzyme that catalyzes chemical reaction as following: S-adenosyl-L-methionine + DNA adenine S-adenosyl-L-homocysteine + DNA 6-methylaminopurine m6A was primarily found in prokaryotes until 2015 when it was also identified in some eukaryotes. m6A methyltransferases methylate the amino group in DNA at C-6 position specifically to prevent the host system to digest own genome through restriction enzymes. m5C plays a role to regulate gene transcription. m5C transferases are the enzymes that produce C5-methylcytosine in DNA at C-5 position of cytosine and are found in most plants and some eukaryotes. Natural product methyltransferases Natural product methyltransferases (NPMTs) are a diverse group of enzymes that add methyl groups to naturally-produced small molecules.
Like many methyltransferases, SAM is utilized as a methyl donor and SAH is produced. Methyl groups are added to S, N, O, or C atoms, and are classified by which of these atoms are modified, with O-methyltransferases representing the largest class. The methylated products of these reactions serve a variety of functions, including co-factors, pigments, signalling compounds, and metabolites. NPMTs can serve a regulatory role by modifying the reactivity and availability of these compounds. These enzymes are not highly conserved across different species, as they serve a more specific function in providing small molecules for specialized pathways in species or smaller groups of species.
Reflective of this diversity is the variety of catalytic strategies, including general acid-base catalysis, metal-based catalysis, and proximity and desolvation effects not requiring catalytic amino acids. NPMTs are the most functionally diverse class of methyltransferases. Important examples of this enzyme class in humans include phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, and histamine N-methyltransferase (HNMT), which methylates histamine in the process of histamine metabolism. Catechol-O-methyltransferase (COMT) degrades a class of molecules known as catcholamines that includes dopamine, epinephrine, and norepenepherine. Non-SAM dependent methyltransferases Methanol, methyl tetrahydrofolate, mono-, di-, and trimethylamine, methanethiol, methyltetrahydromethanopterin, and chloromethane are all methyl donors found in biology as methyl group donors, typically in enzymatic reactions using the cofactor vitamin B12.
These substrates contribute to methyl transfer pathways including methionine biosynthesis, methanogenesis, and acetogenesis. Radical SAM methyltransferases Based on different protein structures and mechanisms of catalysis, there are 3 different types of radical SAM (RS) methylases: Class A, B, and C. Class A RS methylases are the best characterized of the 4 enzymes and are related to both RlmN and Cfr. RlmN is ubiquitous in bacteria which enhances translational fidelity and RlmN catalyzes methylation of C2 of adenosine 2503 (A2503) in 23 S rRNA and C2 of adenosine (A37). Cfr, on the other hand, catalyzes methylation of C8 of A2503 as well and it also catalyzes C2 methylation.
Class B is currently the largest class of radical SAM methylases which can mathylate both sp2-hybridized and sp3-hybridized carbon atoms in different sets of substrates unlike Class A which only catalyzes sp2-hybridized carbon atoms. The main difference that distinguishes Class B from others is the additional N-terminal cobalamin-binding domain that binds to the RS domain. Class C methylase has homologous sequence with the RS enzyme, coproporphyrinogen III oxidase (HemN), which also catalyzes the methylation of sp2-hybridized carbon centers yet it lacks the 2 cysteines required for methylation in mechanism of Class A. Clinical significance As with any biological process which regulates gene expression and/or function, anomalous DNA methylation is associated with genetic disorders such as ICF, Rett syndrome, and Fragile X syndrome.
Cancer cells typically exhibit less DNA methylation activity in general, though often hypermethylation at sites which are unmethylated in normal cells; this overmethylation often functions as a way to inactivate tumor-suppressor genes. Inhibition of overall DNA methyltransferase activity has been proposed as a treatment option, but DNMT inhibitors, analogs of their cytosine substrates, have been found to be highly toxic due to their similarity to cytosine (see right); this similarity to the nucleotide causes the inhibitor to be incorporated into DNA translation, causing non-functioning DNA to be synthesized. A methylase which alters the ribosomal RNA binding site of the antibiotic linezolid causes cross-resistance to other antibiotics that act on the ribosomal RNA.
Plasmid vectors capable of transmitting this gene are a cause of potentially dangerous cross resistance. Examples of methyltransferase enzymes relevant to disease: thiopurine methyltransferase: defects in this gene causes toxic accumulation of thiopurine compounds, drugs used in chemotherapy and immunosuppressant therapy methionine synthase: pernicious anemia, caused by Vitamin B12 deficiency, is caused by a lack of cofactor for the methionine synthase enzyme Applications in drug discovery and development Recent work has revealed the methyltransferases involved in methylation of naturally occurring anticancer agents to use S-Adenosyl methionine (SAM) analogs that carry alternative alkyl groups as a replacement for methyl. The development of the facile chemoenzymatic platform to generate and utilize differentially alkylated SAM analogs in the context of drug discovery and drug development is known as alkylrandomization.
Applications in cancer treatment In human cells, it was found that m5C was associated with abnormal tumor cells in cancer. The role and potential application of m5C includes to balance the impaired DNA in cancer both hypermethylation and hypomethylation. An epigenetic repair of DNA can be applied by changing the m5C amount in both types of cancer cells (hypermethylation/ hypomethylation) and as well as the environment of the cancers to reach an equivalent point to inhibit tumor cells. Examples Examples include: Catechol-O-methyltransferase DNA methyltransferase Histone methyltransferase 5-Methyltetrahydrofolate-homocysteine methyltransferase O-methyltransferase methionine synthase corrinoid-iron sulfur protein References Further reading 3-D Structure of DNA Methyltransferase A novel methyltransferase : the 7SK snRNA Methylphosphate Capping Enzyme as seen on Flintbox "The Role of Methylation in Gene Expression" on Nature Scitable "Nutrition and Depression: Nutrition, Methylation, and Depression" on Psychology Today "DNA Methylation - What is DNA Methylation?"
from News-Medical.net "Histone Lysine Methylation" Genetic pathways involving Histone Methyltransferases from Cell Signaling Technology Category:EC 2.1.1 Category:Methylation
In differential geometry, the two principal curvatures at a given point of a surface are the eigenvalues of the shape operator at the point. They measure how the surface bends by different amounts in different directions at that point. Discussion At each point p of a differentiable surface in 3-dimensional Euclidean space one may choose a unit normal vector. A normal plane at p is one that contains the normal vector, and will therefore also contain a unique direction tangent to the surface and cut the surface in a plane curve, called normal section. This curve will in general have different curvatures for different normal planes at p. The principal curvatures at p, denoted k1 and k2, are the maximum and minimum values of this curvature.
Here the curvature of a curve is by definition the reciprocal of the radius of the osculating circle. The curvature is taken to be positive if the curve turns in the same direction as the surface's chosen normal, and otherwise negative. The directions in the normal plane where the curvature takes its maximum and minimum values are always perpendicular, if k1 does not equal k2, a result of Euler (1760), and are called principal directions. From a modern perspective, this theorem follows from the spectral theorem because these directions are as the principal axes of a symmetric tensor—the second fundamental form.
A systematic analysis of the principal curvatures and principal directions was undertaken by Gaston Darboux, using Darboux frames. The product k1k2 of the two principal curvatures is the Gaussian curvature, K, and the average (k1 + k2)/2 is the mean curvature, H. If at least one of the principal curvatures is zero at every point, then the Gaussian curvature will be 0 and the surface is a developable surface. For a minimal surface, the mean curvature is zero at every point. Formal definition Let M be a surface in Euclidean space with second fundamental form . Fix a point p∈M, and an orthonormal basis X1, X2 of tangent vectors at p. Then the principal curvatures are the eigenvalues of the symmetric matrix If X1 and X2 are selected so that the matrix is a diagonal matrix, then they are called the principal directions.
If the surface is oriented, then one often requires that the pair (X1, X2) be positively oriented with respect to the given orientation. Without reference to a particular orthonormal basis, the principal curvatures are the eigenvalues of the shape operator, and the principal directions are its eigenvectors. Generalizations For hypersurfaces in higher-dimensional Euclidean spaces, the principal curvatures may be defined in a directly analogous fashion. The principal curvatures are the eigenvalues of the matrix of the second fundamental form in an orthonormal basis of the tangent space. The principal directions are the corresponding eigenvectors. Similarly, if M is a hypersurface in a Riemannian manifold N, then the principal curvatures are the eigenvalues of its second-fundamental form.
If k1, ..., kn are the n principal curvatures at a point p ∈ M and X1, ..., Xn are corresponding orthonormal eigenvectors (principal directions), then the sectional curvature of M at p is given by for all with . Classification of points on a surface At elliptical points, both principal curvatures have the same sign, and the surface is locally convex. At umbilic points, both principal curvatures are equal and every tangent vector can be considered a principal direction. These typically occur in isolated points. At hyperbolic points, the principal curvatures have opposite signs, and the surface will be locally saddle shaped.
At parabolic points, one of the principal curvatures is zero. Parabolic points generally lie in a curve separating elliptical and hyperbolic regions. At flat umbilic points both principal curvatures are zero. A generic surface will not contain flat umbilic points. The monkey saddle is one surface with an isolated flat umbilic. Line of curvature The lines of curvature or curvature lines are curves which are always tangent to a principal direction (they are integral curves for the principal direction fields). There will be two lines of curvature through each non-umbilic point and the lines will cross at right angles. In the vicinity of an umbilic the lines of curvature typically form one of three configurations star, lemon and monstar (derived from lemon-star).
These points are also called Darbouxian Umbilics, in honor to Gaston Darboux, the first to make a systematic study in Vol. 4, p 455, of his Leçons (1896). In these figures, the red curves are the lines of curvature for one family of principal directions, and the blue curves for the other. When a line of curvature has a local extremum of the same principal curvature then the curve has a ridge point. These ridge points form curves on the surface called ridges. The ridge curves pass through the umbilics. For the star pattern either 3 or 1 ridge line pass through the umbilic, for the monstar and lemon only one ridge passes through.
Applications Principal curvature directions along with the surface normal, define a 3D orientation frame at a surface point. For example, in case of a cylindrical surface, by physically touching or visually observing, we know that along one specific direction the surface is flat (parallel to the axis of the cylinder) and hence take note of the orientation of the surface. The implication of such an orientation frame at each surface point means any rotation of the surfaces over time can be determined simply by considering the change in the corresponding orientation frames. This has resulted in single surface point motion estimation and segmentation algorithms in computer vision.
See also Earth radius#Principal sections References Further reading External links Historical Comments on Monge's Ellipsoid and the Configuration of Lines of Curvature on Surfaces Immersed in R3 Category:Curvature (mathematics) Category:Differential geometry of surfaces Category:Surfaces