document_title: The Bridges of Madison County (film)

question_text: where is the bridges of madison county located

text: The Bridges of Madison County (film)

text: Plot[edit]

text: In the present day, adult siblings Michael and Carolyn arrive at the Iowa farmhouse of Francesca Johnson, their recently deceased, elderly mother, to see about the settlement of their mother's estate. As they go through the contents of her safe deposit box and the will, they are baffled to discover that their mother left very specific instructions that her body be cremated and her ashes thrown off the nearby Roseman Covered Bridge, which is not in accordance with the burial arrangements their parents had made: side-by-side plots in the local cemetery. Michael initially refuses to comply with the cremation, while Carolyn discovers a set of photos of her mother and a letter. She manages to convince Michael to set aside his initial reaction so they can read the documents she has discovered. Once alone, they go through a series of letters from a man named Robert Kincaid to their mother. The siblings find their way to a chest where their mother left a letter, a series of diaries, photographs, old cameras and other mementos.

text: They discovered that in 1965, their mother, an Italian war bride, had a four-day affair with Robert Kincaid, a travelling professional photographer who had come to Madison County, Iowa, to shoot a photographic essay for National Geographic on the covered bridges in the area.[6] The affair took place while her husband and children were at the state fair in Illinois.

text: The story in the diaries also reveals the impact the affair had on the lives of Francesca and Robert, since they almost ran away together, so she could travel the world with him. However, after a wrenching period of decision-making, she decided to stay at the last minute after considering the bigger picture that includes the consequences leaving would have on the lives of her teenage children and husband, who was a good, loving man. Kincaid is very moved by meeting her. He finds meaning and his true calling as an artist. The story also has deep consequences on the lives of Michael and Carolyn, who are both experiencing marital problems. Their mother’s story helped them to find a sense of direction in their lives. At the end, the Johnson siblings comply with their mother’s request and scatter their mother's ashes at the covered bridge.

text: Cast[edit]

text:
Clint Eastwood as Robert Kincaid
Meryl Streep as Francesca Johnson
Annie Corley as Carolyn Johnson

Sarah Kathryn Schmitt as young Carolyn

Victor Slezak as Michael Johnson

Christopher Kroon as young Michael

Jim Haynie as Richard Johnson
Phyllis Lyons as Betty
Debra Monk as Madge
Richard Lage as Lawyer Peterson
Michelle Benes as Lucy Redfield

text: Production[edit]

text: Development[edit]

text:
"I've been that guy a little bit, going off by myself years ago in a pickup truck into Nevada, scouting locations for High Plains Drifter. But I didn't stop off with any housewives while doing that."

— Clint Eastwood on Robert Kincaid[3]

tag: div

text: Amblin Entertainment, a production company founded by Steven Spielberg, bought the film rights to Waller's novel for $25,000 in late 1991, before its publication—by the time of the film's release, the novel sold 9.5 million copies worldwide.[3] Spielberg first asked Sydney Pollack to direct, who got Kurt Luedtke to draft the first version of the adaptation but then bowed out; Ronald Bass was brought in by Kathleen Kennedy and Spielberg to work on the script, but they were unsatisfied with the results.[3] But a third draft by Richard LaGravenese was liked by Eastwood, who quite early had been cast for the male lead, and by Spielberg, who liked LaGravenese's version enough to consider making Bridges his next film after Schindler's List, which was in post-production at the time.[3] Both men liked that LaGravenese's script presented the story from Francesca's point of view; Spielberg then had LaGravenese introduce the framing device of having Francesca's adult children discover and read her diaries.[3] When Spielberg decided not to direct, he then brought in Bruce Beresford, who got Alfred Uhry to draft another version of the script; when Warner Bros., Spielberg, and Eastwood all preferred LaGravenese's draft, Beresford dropped out.[3]

text: Waller championed Isabella Rossellini to play Francesca; she was a "strong contender" in a list that also included Anjelica Huston, Jessica Lange, Mary McDonnell, Cher, and Susan Sarandon. But despite Spielberg's initial reluctance, Eastwood had advocated Meryl Streep for the role from the beginning.[3]

text: Filming[edit]

text: Principal photography took 42 days, ending on November 1, 1994, ten days ahead of Eastwood's 52-day schedule; Eastwood filmed it chronologically from Francesca's point of view, "because it was important to work that way. We were two people getting to know each other, in real time, as actors and as the characters."[3] It was filmed on location in Madison County, Iowa, including the town of Winterset, and in the Dallas County town of Adel.[2] The Bell's Mills Bridge, in Westmoreland County, Pennsylvania, was also a filming location.

text: Post-production[edit]

text: The MPAA ratings board initially gave the film an "R" rating, for the line "Or should we just fuck on the linoleum one last time?", a line of dialogue spoken sarcastically by Francesca; Eastwood appealed, and the rating was reduced to a PG-13.[3]

text: Release[edit]

text: Box office[edit]

text: The Bridges of Madison County opened theatrically on June 2, 1995 in 1,805 venues. It earned $10,519,257 in its opening weekend, ranking number two in the North American box office, behind Casper (which was in its second weekend).[7] At the end of its run, the film grossed $71,516,617 domestically and $110,500,000 overseas for a worldwide total of $182,016,617.[4]

text: Critical reception[edit]

text: Rotten Tomatoes reports a score of 89% based on 57 reviews, with an average rating of 7.4/10. The site's consensus states: "Sentimental, slow, schmaltzy, and very satisfying, The Bridges of Madison County finds Clint Eastwood adapting a bestseller with heft, wit, and grace."[8] On Metacritic, the film has a 66 out of 100 rating, based on 22 critics, indicating "generally favorable reviews".[9]

text: According to Janet Maslin, "Clint Eastwood, director and alchemist, has transformed The Bridges of Madison County into something bearable—no, something even better. Limited by the vapidity of this material while he trims its excesses with the requisite machete, Mr. Eastwood locates a moving, elegiac love story at the heart of Mr. Waller's self-congratulatory overkill. The movie has leanness and surprising decency, and Meryl Streep has her best role in years. Looking sturdy and voluptuous in her plain housedress (the year is 1965), Ms. Streep rises straight out of "Christina's World" to embody all the loneliness and fierce yearning Andrew Wyeth captured on canvas. And yet, despite the Iowa setting and the emphasis on down-home Americana, Mr. Eastwood's Bridges of Madison County has a European flavor. Its pace is unhurried, which is not the same as slow. It respects long silences and pays attention to small details. It sustains an austere tone and staves off weepiness until the last reel. It voices musings that would definitely sound better in French."[10] Richard Corliss said Eastwood is the "most reticent of directors—where the book ogles, the film discreetly observes—and, here, the courtliest of stars....As scripted by Richard LaGravenese (The Fisher King), the Madison County movie has a slightly riper theme than the book's. It is about the anticipation and consequences of passion—the slow dance of appraisal, of waiting to make a move that won't be rejected, of debating what to do when the erotic heat matures into love light. What is the effect of an affair on a woman who has been faithful to her husband, and on a rootless man who only now realizes he needs the one woman he can have but not hold?" Corliss concludes "Madison County is Eastwood's gift to women: to Francesca, to all the girls he's loved before—and to Streep, who alchemizes literary mawkishness into intelligent movie passion."[11]

text: Accolades[edit]

text:
Won

ASCAP Film and Television Music Awards:

Top Box Office Films

Blue Ribbon Awards (Japan):

Best Foreign Language Film

BMI Film & Television Awards:

BMI Film Music Award (Lennie Niehaus)

Kinema Junpo Awards (Japan):

Best Foreign Language Film Director (Clint Eastwood)

Mainichi Film Concours (Japan):

Best Foreign Language Film

Nominated

68th Academy Awards:

Best Actress in a Leading Role (Meryl Streep)

American Society of Cinematographers:

Outstanding Achievement in Theatrical Releases (Jack N. Green)

Awards of the Japanese Academy (Japan):

Best Foreign Film

César Awards (France):

Best Foreign Film

53rd Golden Globe Awards:

Best Actress in a Motion Picture – Drama (Meryl Streep)
Best Motion Picture – Drama

2nd Screen Actors Guild Awards:

Outstanding Performance by a Female Actor in a Leading Role (Meryl Streep)

text: Others[edit]

text: The film tied with Goodbye South, Goodbye and Carlito's Way as the best film of the 1990s in a poll by Cahiers du cinéma.[12]

text: The film is recognized by American Film Institute in these lists:

text:
2002: AFI's 100 Years...100 Passions – #90[13]
2004: AFI's 100 Years...100 Songs:

"I See Your Face Before Me" – Nominated[14]


document_title: Fault (geology)

question_text: dip slip faults in which the hanging wall moves down relative to the footwall are called

root

text: Fault (geology)

text: Mechanisms of faulting[edit]

text: Because of friction and the rigidity of the constituent rocks, the planes cannot glide or flow past each other easily, and so occasionally all movement stops. Thus, stress builds up, and when it reaches a level that exceeds the strain threshold, the accumulated potential energy is released into the fault.

tag: p

text: Strain occurs accumulatively or instantaneously, depending on the liquid state of the rock; the ductile lower crust and mantle accumulate deformation gradually via shearing, whereas the brittle upper crust reacts by fracture – instantaneous stress release – resulting in motion along the fault. A fault in ductile rocks can also release instantaneously when the strain rate is too great. The energy released by instantaneous strain-release causes earthquakes.

text: Slip, heave, throw[edit]

text: Slip is defined as the relative movement of geological features present on either side of a fault plane. A fault's sense of slip is defined as the relative motion of the rock on each side of the fault with respect to the other side.[3] In measuring the horizontal or vertical separation, the throw of the fault is the vertical component of the separation and the heave of the fault is the horizontal component, as in "Throw up and heave out".[4]

text: The vector of slip can be qualitatively assessed by studying any drag folding of strata,[clarification needed] which may be visible on either side of the fault; the direction and magnitude of heave and throw can be measured only by finding common intersection points on either side of the fault (called a piercing point). In practice, it is usually only possible to find the slip direction of faults, and an approximation of the heave and throw vector.

text: Hanging wall and foot wall[edit]

text: The two sides of a non-vertical fault are known as the hanging wall and footwall. The hanging wall occurs above the fault plane and the footwall occurs below it.[5] This terminology comes from mining: when working a tabular ore body, the miner stood with the footwall under his feet and with the hanging wall above him.[6]

text: Fault types[edit]

text: Based on direction of slip, faults can be categorized as:

text:
strike-slip, where the offset is predominantly horizontal, parallel to the fault trace.
dip-slip, offset is predominantly vertical and/or perpendicular to the fault trace.
oblique-slip, combining strike and dip slip.

tag: ul

text: Strike-slip faults[edit]

text: In a strike-slip fault (also known as a wrench fault, tear fault or transcurrent fault),[7] the fault surface (plane) is usually near vertical and the footwall moves laterally either left or right with very little vertical motion. Strike-slip faults with left-lateral motion are also known as sinistral faults. Those with right-lateral motion are also known as dextral faults.[8] Each is defined by the direction of movement of the ground as would be seen by an observer on the opposite side of the fault.

text: A special class of strike-slip fault is the transform fault, when it forms a plate boundary. This class is related to an offset in a spreading center, such as a mid-ocean ridge, or, less common, within continental lithosphere, such as the Dead Sea Transform in the Middle East or the Alpine Fault in New Zealand. Transform faults are also referred to as "conservative" plate boundaries, inasmuch as lithosphere is neither created nor destroyed.

text: Dip-slip faults[edit]

text: Dip-slip faults can be either "normal" ("extensional") or "reverse".

text: In a normal fault, the hanging wall moves downward, relative to the footwall. A downthrown block between two normal faults dipping towards each other is a graben. An upthrown block between two normal faults dipping away from each other is a horst. Low-angle normal faults with regional tectonic significance may be designated detachment faults.

text: A reverse fault is the opposite of a normal fault—the hanging wall moves up relative to the footwall. Reverse faults indicate compressive shortening of the crust. The dip of a reverse fault is relatively steep, greater than 45°.

text: A thrust fault has the same sense of motion as a reverse fault, but with the dip of the fault plane at less than 45°.[9][10] Thrust faults typically form ramps, flats and fault-bend (hanging wall and foot wall) folds.

text: Flat segments of thrust fault planes are known as flats, and inclined sections of the thrust are known as ramps. Typically, thrust faults move within formations by forming flats and climb up sections with ramps.

text: Fault-bend folds are formed by movement of the hanging wall over a non-planar fault surface and are found associated with both extensional and thrust faults.

text: Faults may be reactivated at a later time with the movement in the opposite direction to the original movement (fault inversion). A normal fault may therefore become a reverse fault and vice versa.

text: Thrust faults form nappes and klippen in the large thrust belts. Subduction zones are a special class of thrusts that form the largest faults on Earth and give rise to the largest earthquakes.

text: Oblique-slip faults[edit]

text: A fault which has a component of dip-slip and a component of strike-slip is termed an oblique-slip fault. Nearly all faults have some component of both dip-slip and strike-slip, so defining a fault as oblique requires both dip and strike components to be measurable and significant. Some oblique faults occur within transtensional and transpressional regimes, and others occur where the direction of extension or shortening changes during the deformation but the earlier formed faults remain active.

text: The hade angle is defined as the complement of the dip angle; it is the angle between the fault plane and a vertical plane that strikes parallel to the fault.

text: Listric fault[edit]

text: Listric faults are similar to normal faults but the fault plane curves, the dip being steeper near the surface, then shallower with increased depth. The dip may flatten into a sub-horizontal décollement, resulting in horizontal slip on a horizontal plane. The illustration shows slumping of the hanging wall along a listric fault. Where the hanging wall is absent (such as on a cliff) the footwall may slump in a manner that creates multiple listric faults.

text: Ring fault[edit]

text: Ring faults, also known as caldera faults, are faults that occur within collapsed volcanic calderas[11] and the sites of bolide strikes, such as the Chesapeake Bay impact crater. Ring faults are result of a series of overlapping normal faults, forming a circular outline. Fractures created by ring faults may be filled by ring dikes[11].

text: Synthetic and antithetic faults[edit]

text: Synthetic and antithetic faults are terms used to describe minor faults associated with a major fault. Synthetic faults dip in the same direction as the major fault while the antithetic faults dip in the opposite direction. These faults may be accompanied by rollover anticlines (e.g. the Niger Delta Structural Style).

text: Fault rock[edit]

text: All faults have a measurable thickness, made up of deformed rock characteristic of the level in the crust where the faulting happened, of the rock types affected by the fault and of the presence and nature of any mineralising fluids. Fault rocks are classified by their textures and the implied mechanism of deformation. A fault that passes through different levels of the lithosphere will have many different types of fault rock developed along its surface. Continued dip-slip displacement tends to juxtapose fault rocks characteristic of different crustal levels, with varying degrees of overprinting. This effect is particularly clear in the case of detachment faults and major thrust faults.

text: The main types of fault rock include:

text:
Cataclasite – a fault rock which is cohesive with a poorly developed or absent planar fabric, or which is incohesive, characterised by generally angular clasts and rock fragments in a finer-grained matrix of similar composition.

Tectonic or Fault breccia – a medium- to coarse-grained cataclasite containing >30% visible fragments.
Fault gouge – an incohesive, clay-rich fine- to ultrafine-grained cataclasite, which may possess a planar fabric and containing <30% visible fragments. Rock clasts may be present

Clay smear - clay-rich fault gouge formed in sedimentary sequences containing clay-rich layers which are strongly deformed and sheared into the fault gouge.

Mylonite - a fault rock which is cohesive and characterized by a well-developed planar fabric resulting from tectonic reduction of grain size, and commonly containing rounded porphyroclasts and rock fragments of similar composition to minerals in the matrix
Pseudotachylite – ultrafine-grained glassy-looking material, usually black and flinty in appearance, occurring as thin planar veins, injection veins or as a matrix to pseudoconglomerates or breccias, which infills dilation fractures in the host rock.

text: Impacts on structures and people[edit]

text: In geotechnical engineering a fault often forms a discontinuity that may have a large influence on the mechanical behavior (strength, deformation, etc.) of soil and rock masses in, for example, tunnel, foundation, or slope construction.

text: The level of a fault's activity can be critical for (1) locating buildings, tanks, and pipelines and (2) assessing the seismic shaking and tsunami hazard to infrastructure and people in the vicinity. In California, for example, new building construction has been prohibited directly on or near faults that have moved within the Holocene Epoch (the last 11,700 years) of the Earth's geological history.[12] Also, faults that have shown movement during the Holocene plus Pleistocene Epochs (the last 2.6 million years) may receive consideration, especially for critical structures such as power plants, dams, hospitals, and schools. Geologists assess a fault's age by studying soil features seen in shallow excavations and geomorphology seen in aerial photographs. Subsurface clues include shears and their relationships to carbonate nodules, eroded clay, and iron oxide mineralization, in the case of older soil, and lack of such signs in the case of younger soil. Radiocarbon dating of organic material buried next to or over a fault shear is often critical in distinguishing active from inactive faults. From such relationships, paleoseismologists can estimate the sizes of past earthquakes over the past several hundred years, and develop rough projections of future fault activity.


document_title: Hemoglobin

question_text: portion of hemoglobin associated with the production of bilirubin

question_tokens: portion of hemoglobin associated with the production of bilirubin

text: Hemoglobin

text: Research history[edit]

text: In 1825 J. F. Engelhard discovered that the ratio of iron to protein is identical in the hemoglobins of several species.[14] From the known atomic mass of iron he calculated the molecular mass of hemoglobin to n × 16000 (n = number of iron atoms per hemoglobin, now known to be 4), the first determination of a protein's molecular mass. This "hasty conclusion" drew a lot of ridicule at the time from scientists who could not believe that any molecule could be that big. Gilbert Smithson Adair confirmed Engelhard's results in 1925 by measuring the osmotic pressure of hemoglobin solutions.[15]

text: The oxygen-carrying protein hemoglobin was discovered by Hünefeld in 1840.[16] In 1851,[17] German physiologist Otto Funke published a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein solution.[18] Hemoglobin's reversible oxygenation was described a few years later by Felix Hoppe-Seyler.[19]

text: In 1959, Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography.[20][21] This work resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry for their studies of the structures of globular proteins.

text: The role of hemoglobin in the blood was elucidated by French physiologist Claude Bernard. The name hemoglobin is derived from the words heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme group. Each heme group contains one iron atom, that can bind one oxygen molecule through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits.

text: Genetics[edit]

text: Hemoglobin consists of protein subunits (the "globin" molecules), and these proteins, in turn, are folded chains of a large number of different amino acids called polypeptides. The amino acid sequence of any polypeptide created by a cell is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid sequence that determines the protein's chemical properties and function.

text: There is more than one hemoglobin gene: in humans, hemoglobin A (the main form of hemoglobin present) is coded for by the genes, HBA1, HBA2, and HBB.[22] The amino acid sequences of the globin proteins in hemoglobins usually differ between species. These differences grow with evolutionary distance between species. For example, the most common hemoglobin sequences in humans and chimpanzees are nearly identical, differing by only one amino acid in both the alpha and the beta globin protein chains.[citation needed] These differences grow larger between less closely related species.

text: Even within a species, different variants of hemoglobin always exist, although one sequence is usually a "most common" one in each species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants.[23][24] Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease, which was the first human disease whose mechanism was understood at the molecular level. A (mostly) separate set of diseases called thalassemias involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. All these diseases produce anemia.[25]

text: Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example, hemoglobin has been found to adapt in different ways to high altitudes. Organisms living at high elevations experience lower partial pressures of oxygen compared to those at sea level. This presents a challenge to the organisms that inhabit such environments because hemoglobin, which normally binds oxygen at high partial pressures of oxygen, must be able to bind oxygen when it is present at a lower pressure. Different organisms have adapted to such a challenge. For example, recent studies have suggested genetic variants in deer mice that help explain how deer mice that live in the mountains are able to survive in the thin air that accompanies high altitudes. A researcher from the University of Nebraska-Lincoln found mutations in four different genes that can account for differences between deer mice that live in lowland prairies versus the mountains. After examining wild mice captured from both highlands and lowlands, it was found that: the genes of the two breeds are "virtually identical—except for those that govern the oxygen-carrying capacity of their hemoglobin". "The genetic difference enables highland mice to make more efficient use of their oxygen", since less is available at higher altitudes, such as those in the mountains.[26] Mammoth hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the Pleistocene.[27] This was also found in hummingbirds that inhabit the Andes. Hummingbirds already expend a lot of energy and thus have high oxygen demands and yet Andean hummingbirds have been found to thrive in high altitudes. Non-synonymous mutations in the hemoglobin gene of multiple species living at high elevations (Oreotrochilus, A. castelnaudii, C. violifer, P. gigas, and A. viridicuada) have caused the protein to have less of an affinity for inositol hexaphosphate (IHP), a molecule found in birds that has a similar role as 2,3-BPG in humans; this results in the ability to bind oxygen in lower partial pressures.[28]

text: Birds' unique circulatory lungs also promote efficient use of oxygen at low partial pressures of O2. These two adaptations reinforce each other and account for birds' remarkable high-altitude performance.

text: Hemoglobin adaptation extends to humans, as well. Studies have found that a small number of native Tibetan women have a genotype which codes for hemoglobin to be more highly saturated with oxygen.[29] Natural selection seems to be the main force working on this gene because the mortality rate of offspring is significantly lower for women with higher hemoglobin-oxygen affinity when compared to the mortality rate of offspring from women with low hemoglobin-oxygen affinity. While the exact genotype and mechanism by which this occurs is not yet clear, selection is acting on these women's ability to bind oxygen in low partial pressures, which overall allows them to better sustain crucial metabolic processes.

text: Synthesis[edit]

text: Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol.[30] Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).[31]

text: Structure[edit]

text: Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins.[32] Most of the amino acids in hemoglobin form alpha helices, and these helices are connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, which then causes each polypeptide chain to fold into a specific shape.[33] Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.[32]

text: In most vertebrates, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein prosthetic heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement. Such a name is given because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin.[34][35] This folding pattern contains a pocket that strongly binds the heme group.

text: A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. This porphyrin ring consists of four pyrrole molecules cyclically linked together (by methine bridges) with the iron ion bound in the center.[36] The iron ion, which is the site of oxygen binding, coordinates with the four nitrogen atoms in the center of the ring, which all lie in one plane. The iron is bound strongly (covalently) to the globular protein via the N atoms of the imidazole ring of F8 histidine residue (also known as the proximal histidine) below the porphyrin ring. A sixth position can reversibly bind oxygen by a coordinate covalent bond,[37] completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds to Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.

text: Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions but is bound to the protein chains of the structure.

text: The iron ion may be either in the Fe2+ or in the Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen.[38] In binding, oxygen temporarily and reversibly oxidizes (Fe2+) to (Fe3+) while oxygen temporarily turns into the superoxide ion, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe3+ is protonated, the hemoglobin iron will remain oxidized and incapable of binding oxygen. In such cases, the enzyme methemoglobin reductase will be able to eventually reactivate methemoglobin by reducing the iron center.

text: In adult humans, the most common hemoglobin type is a tetramer (which contains four subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 16,000 daltons,[39] for a total molecular weight of the tetramer of about 64,000 daltons (64,458 g/mol).[40] Thus, 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

text: In human infants, the hemoglobin molecule is made up of 2 α chains and 2 γ chains. The gamma chains are gradually replaced by β chains as the infant grows.[41]

text: The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and the hydrophobic effect.

text: Oxygen saturation[edit]

text: In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).[42]

text: Oxyhemoglobin[edit]

text: Oxyhemoglobin is formed during physiological respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized as a terminal electron acceptor in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH.[43]

text: Hemoglobin exists in two forms, a taut (tense) form (T) and a relaxed form (R). Various factors such as low pH, high CO2 and high 2,3 BPG at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen in the tissues. Conversely, a high pH, low CO2, or low 2,3 BPG favors the relaxed form, which can better bind oxygen.[44] The partial pressure of the system also affects O2 affinity where, at high partial pressures of oxygen (such as those present in the alveoli), the relaxed (high affinity, R) state is favoured. Inversely, at low partial pressures (such as those present in respiring tissues), the (low affinity, T) tense state is favoured.[45] Additionally, the binding of oxygen to the iron(II) heme pulls the iron into the plane of the porphyrin ring, causing a slight conformational shift. The shift encourages oxygen to bind to the three remaining heme units within hemoglobin (thus, oxygen binding is cooperative).

text: Deoxygenated hemoglobin[edit]

text: Deoxygenated hemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for the measurement of the amount of oxygen in a patient's blood by an instrument called a pulse oximeter. This difference also accounts for the presentation of cyanosis, the blue to purplish color that tissues develop during hypoxia.[46]

text: Deoxygenated hemoglobin is paramagnetic; it is weakly attracted to magnetic fields.[47][48] In contrast, oxygenated hemoglobin exhibits diamagnetism, a weak repulsion from a magnetic field.[48]

text: Evolution of vertebrate hemoglobin[edit]

text: Scientists agree that the event that separated myoglobin from hemoglobin occurred after lampreys diverged from jawed vertebrates.[49] This separation of myoglobin and hemoglobin allowed for the different functions of the two molecules to arise and develop: myoglobin has more to do with oxygen storage while hemoglobin is tasked with oxygen transport.[50] The α- and β-like globin genes encode the individual subunits of the protein.[22] The predecessors of these genes arose through another duplication event also after the gnathosome common ancestor derived from jawless fish, approximately 450–500 million years ago.[49] The development of α and β genes created the potential for hemoglobin to be composed of multiple subunits, a physical composition central to hemoglobin's ability to transport oxygen. Having multiple subunits contributes to hemoglobin's ability to bind oxygen cooperatively as well as be regulated allosterically.[50] Subsequently, the α gene also underwent a duplication event to form the HBA1 and HBA2 genes.[51] These further duplications and divergences have created a diverse range of α- and β-like globin genes that are regulated so that certain forms occur at different stages of development.[50]

text: Most ice fish of the family Channichthyidae have lost their hemoglobin genes as an adaptation to cold water.[5]

text: Iron's oxidation state in oxyhemoglobin[edit]

text: Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin (Hb-O2), by experimental measurement, is diamagnetic (no net unpaired electrons), yet the lowest-energy (ground-state) electron configurations in both oxygen and iron are paramagnetic (suggesting at least one unpaired electron in the complex). The lowest-energy form of oxygen, and the lowest energy forms of the relevant oxidation states of iron, are these:

text:
Triplet oxygen, the lowest-energy molecular oxygen species, has two unpaired electrons in antibonding π* molecular orbitals.
Iron(II) tends to exist in a high-spin 3d6 configuration with four unpaired electrons.
Iron(III) (3d5) has an odd number of electrons, and thus must have one or more unpaired electrons, in any energy state.

text: All of these structures are paramagnetic (have unpaired electrons), not diamagnetic. Thus, a non-intuitive (e.g., a higher-energy for at least one species) distribution of electrons in the combination of iron and oxygen must exist, in order to explain the observed diamagnetism and no unpaired electrons.

text: The two logical possibilities to produce diamagnetic (no net spin) Hb-O2 are:

text:
Low-spin Fe2+ binds to singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. However, the singlet form of oxygen is the higher-energy form of the molecule.
Low-spin Fe3+ binds to O2•− (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving observed diamagnetic properties. Here, the iron has been oxidized (has lost one electron), and the oxygen has been reduced (has gained one electron).

tag: ol

text: Another possible model in which low-spin Fe4+ binds to peroxide, O22−, can be ruled out by itself, because the iron is paramagnetic (although the peroxide ion is diamagnetic). Here, the iron has been oxidized by two electrons, and the oxygen reduced by two electrons.

text: Direct experimental data:

text:
X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2.
Infrared vibrational frequencies of the O-O bond suggests a bond length fitting with superoxide (a bond order of about 1.6, with superoxide being 1.5).
X-ray Absorption Near Edge Structures at the iron K-edge. The energy shift of 5 eV between deoxyhemoglobin and oxyhemoglobin, as for all the methemoglobin species, strongly suggests an actual local charge closer to Fe3+ than Fe2+.[52][53][54]

text: Thus, the nearest formal oxidation state of iron in Hb-O2 is the +3 state, with oxygen in the −1 state (as superoxide .O2−). The diamagnetism in this configuration arises from the single unpaired electron on superoxide aligning antiferromagnetically with the single unpaired electron on iron (in a low-spin d5 state), to give no net spin to the entire configuration, in accordance with diamagnetic oxyhemoglobin from experiment.[55][56]

text: The second choice of the logical possibilities above for diamagnetic oxyhemoglobin being found correct by experiment, is not surprising: singlet oxygen (possibility #1) is an unrealistically high energy state. Model 3 leads to unfavorable separation of charge (and does not agree with the magnetic data), although it could make a minor contribution as a resonance form. Iron's shift to a higher oxidation state in Hb-O2 decreases the atom's size, and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins.

text: Early postulates by bio-inorganic chemists claimed that possibility #1 (above) was correct and that iron should exist in oxidation state II. This conclusion seemed likely, since the iron oxidation state III as methemoglobin, when not accompanied by superoxide .O2− to "hold" the oxidation electron, was known to render hemoglobin incapable of binding normal triplet O2 as it occurs in the air. It was thus assumed that iron remained as Fe(II) when oxygen gas was bound in the lungs. The iron chemistry in this previous classical model was elegant, but the required presence of the diamagnetic, high-energy, singlet oxygen molecule was never explained. It was classically argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the low-spin configuration, which would be diamagnetic in Fe(II). This forced low-spin pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron's change in size. Extraction of an additional electron from iron by oxygen is required to explain both iron's smaller size and observed increased oxidation state, and oxygen's weaker bond.

text: The assignment of a whole-number oxidation state is a formalism, as the covalent bonds are not required to have perfect bond orders involving whole electron transfer. Thus, all three models for paramagnetic Hb-O2 may contribute to some small degree (by resonance) to the actual electronic configuration of Hb-O2. However, the model of iron in Hb-O2 being Fe(III) is more correct than the classical idea that it remains Fe(II).

text: Cooperativity[edit]

text: When oxygen binds to the iron complex, it causes the iron atom to move back toward the center of the plane of the porphyrin ring (see moving diagram). At the same time, the imidazole side-chain of the histidine residue interacting at the other pole of the iron is pulled toward the porphyrin ring. This interaction forces the plane of the ring sideways toward the outside of the tetramer, and also induces a strain in the protein helix containing the histidine as it moves nearer to the iron atom. This strain is transmitted to the remaining three monomers in the tetramer, where it induces a similar conformational change in the other heme sites such that binding of oxygen to these sites becomes easier.

text: As oxygen binds to one monomer of hemoglobin, the tetramer's conformation shifts from the T (tense) state to the R (relaxed) state. This shift promotes the binding of oxygen to the remaining three monomer's heme groups, thus saturating the hemoglobin molecule with oxygen.[57]

text: In the tetrameric form of normal adult hemoglobin, the binding of oxygen is, thus, a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first molecules of oxygen bound influencing the shape of the binding sites for the next ones, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above; i.e., when one subunit protein in hemoglobin becomes oxygenated, a conformational or structural change in the whole complex is initiated, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.

text: The dynamic mechanism of the cooperativity in hemoglobin and its relation with the low-frequency resonance has been discussed.[58]

text: Binding for ligands other than oxygen[edit]

text: Besides the oxygen ligand, which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide (CO2) and nitric oxide (NO). The carbon dioxide is bound to amino groups of the globin proteins to form carbaminohemoglobin; this mechanism is thought to account for about 10% of carbon dioxide transport in mammals. Nitric oxide can also be transported by hemoglobin; it is bound to specific thiol groups in the globin protein to form an S-nitrosothiol, which dissociates into free nitric oxide and thiol again, as the hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.[59]

text: Competitive[edit]

text: The binding of oxygen is affected by molecules such as carbon monoxide (for example, from tobacco smoking, exhaust gas, and incomplete combustion in furnaces). CO competes with oxygen at the heme binding site. Hemoglobin's binding affinity for CO is 250 times greater than its affinity for oxygen,[60] meaning that small amounts of CO dramatically reduce hemoglobin's ability to transport oxygen. Since carbon monoxide is a colorless, odorless and tasteless gas, and poses a potentially fatal threat, carbon monoxide detectors have become commercially available to warn of dangerous levels in residences. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin, which may cause the skin of CO poisoning victims to appear pink in death, instead of white or blue. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.

text: In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN−), sulfur monoxide (SO), and sulfide (S2−), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.

text: The iron atom in the heme group must initially be in the ferrous (Fe2+) oxidation state to support oxygen and other gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as explained above). Initial oxidation to the ferric (Fe3+) state without oxygen converts hemoglobin into "hemiglobin" or methemoglobin, which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitric oxide is capable of converting a small fraction of hemoglobin to methemoglobin in red blood cells. The latter reaction is a remnant activity of the more ancient nitric oxide dioxygenase function of globins.

text: Allosteric[edit]

text: Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:

text: Hence, blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide, which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places on the protein, while carbon dioxide binds at the α-amino group.[61] Carbon dioxide binds to hemoglobin and forms carbaminohemoglobin.[62] This decrease in hemoglobin's affinity for oxygen by the binding of carbon dioxide and acid is known as the Bohr effect. The Bohr effect favors the T state rather than the R state. (shifts the O2-saturation curve to the right). Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the root effect. This is seen in bony fish.

text: It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal curve of hemoglobin makes it efficient in binding (taking up O2 in lungs), and efficient in unloading (unloading O2 in tissues).[63]

text: In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect. Hemoglobin in organisms at high altitudes has also adapted such that it has less of an affinity for 2,3-BPG and so the protein will be shifted more towards its R state. In its R state, hemoglobin will bind oxygen more readily, thus allowing organisms to perform the necessary metabolic processes when oxygen is present at low partial pressures.[64]

text: Animals other than humans use different molecules to bind to hemoglobin and change its O2 affinity under unfavorable conditions. Fish use both ATP and GTP. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.[65] GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra hydrogen bond formed that further stabilizes the tense state.[66] Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.[67]

text: A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.

text: Hemoglobin also carries nitric oxide (NO) in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not released in the cytoplasm of erythrocytes but transported by an anion exchanger called AE1 out of them.[68]

text: Types in humans[edit]

text: Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.[69][70]

text: In the embryo:

text:
Gower 1 (ζ2ε2)
Gower 2 (α2ε2) (PDB: 1A9W)
Hemoglobin Portland I (ζ2γ2)
Hemoglobin Portland II (ζ2β2).

text: In the fetus:

text: Hemoglobin F (α2γ2) (PDB: 1FDH).

text: After birth:

text:
Hemoglobin A (α2β2) (PDB: 1BZ0) – The most common with a normal amount over 95%
Hemoglobin A2 (α2δ2) – δ chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.5–3.5%
Hemoglobin F (α2γ2) – In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

text: Variant forms that cause disease:

text:
Hemoglobin D-Punjab – (α2βD2) – A variant form of hemoglobin.
Hemoglobin H (β4) – A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of α thalassemia.
Hemoglobin Barts (γ4) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.
Hemoglobin S (α2βS2) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.
Hemoglobin C (α2βC2) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
Hemoglobin E (α2βE2) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
Hemoglobin AS – A heterozygous form causing sickle cell trait with one adult gene and one sickle cell disease gene
Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding Hemoglobin C.
Hemoglobin Hopkins-2 - A variant form of hemoglobin that is sometimes viewed in combination with Hemoglobin S to produce sickle cell disease.

text: Degradation in vertebrate animals[edit]

text: When red cells reach the end of their life due to aging or defects, they are removed from the circulation by the phagocytic activity of macrophages in the spleen or the liver or hemolyze within the circulation. Free hemoglobin is then cleared from the circulation via the hemoglobin transporter CD163, which is exclusively expressed on monocytes or macrophages. Within these cells the hemoglobin molecule is broken up, and the iron gets recycled. This process also produces one molecule of carbon monoxide for every molecule of heme degraded.[71] Heme degradation is one of the few natural sources of carbon monoxide in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage. Iron is removed from heme and salvaged for later use, it is stored as hemosiderin or ferritin in tissues and transported in plasma by beta globulins as transferrins. When the porphyrin ring is broken up, the fragments are normally secreted as a yellow pigment called bilirubin, which is secreted into the intestines as bile. Intestines metabolise bilirubin into urobilinogen. Urobilinogen leaves the body in faeces, in a pigment called stercobilin. Globulin is metabolised into amino acids that are then released into circulation.

text: Role in disease[edit]

text: Hemoglobin deficiency can be caused either by a decreased amount of hemoglobin molecules, as in anemia, or by decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen. Hemoglobinopathies (genetic defects resulting in abnormal structure of the hemoglobin molecule)[72] may cause both. In any case, hemoglobin deficiency decreases blood oxygen-carrying capacity. Hemoglobin deficiency is, in general, strictly distinguished from hypoxemia, defined as decreased partial pressure of oxygen in blood,[73][74][75][76] although both are causes of hypoxia (insufficient oxygen supply to tissues).

text: Other common causes of low hemoglobin include loss of blood, nutritional deficiency, bone marrow problems, chemotherapy, kidney failure, or abnormal hemoglobin (such as that of sickle-cell disease).

text: The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO2, causing an altered oxygen–hemoglobin dissociation curve. However, it can also be pathologically altered in, e.g., carbon monoxide poisoning.

text: Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

text: Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants.

text: There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.

text: To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is typically 50–55 days).

text: Glycosylated hemoglobin is the form of hemoglobin to which glucose is bound. The binding of glucose to amino acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in many proteins, and is not known to serve a useful purpose. However, the binding to hemoglobin does serve as a record for average blood glucose levels over the lifetime of red cells, which is approximately 120 days. The levels of glycosylated hemoglobin are therefore measured in order to monitor the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM). Poor control of T2DM results in high levels of glycosylated hemoglobin in the red blood cells. The normal reference range is approximately 4–5.9%. Though difficult to obtain, values less than 7% are recommended for people with T2DM. Levels greater than 9% are associated with poor control of the glycosylated hemoglobin, and levels greater than 12% are associated with very poor control. Diabetics who keep their glycosylated hemoglobin levels close to 7% have a much better chance of avoiding the complications that may accompany diabetes (than those whose levels are 8% or higher).[77] In addition, increased glycosylation of hemoglobin increases its affinity for oxygen, therefore preventing its release at the tissue and inducing a level of hypoxia in extreme cases.[78]

text: Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called polycythemia. This elevation may be caused by congenital heart disease, cor pulmonale, pulmonary fibrosis, too much erythropoietin, or polycythemia vera.[79] High hemoglobin levels may also be caused by exposure to high altitudes, smoking, dehydration (artificially by concentrating Hb), advanced lung disease and certain tumors.[41]

text: A recent study done in Pondicherry, India, shows its importance in coronary artery disease.[80]

text: Diagnostic uses[edit]

text: Hemoglobin concentration measurement is among the most commonly performed blood tests, usually as part of a complete blood count. For example, it is typically tested before or after blood donation. Results are reported in g/L, g/dL or mol/L. 1 g/dL equals about 0.6206 mmol/L, although the latter units are not used as often due to uncertainty regarding the polymeric state of the molecule.[81] This conversion factor, using the single globin unit molecular weight of 16,000 Da, is more common for hemoglobin concentration in blood. For MCHC (mean corpuscular hemoglobin concentration) the conversion factor 0.155, which uses the tetramer weight of 64,500 Da, is more common.[82] Normal levels are:

text:
Men: 13.8 to 18.0 g/dL (138 to 180 g/L, or 8.56 to 11.17 mmol/L)
Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37 mmol/L)
Children: 11 to 16 g/dL (111 to 160 g/L, or 6.83 to 9.93 mmol/L)
Pregnant women: 11 to 14 g/dL (110 to 140 g/L, or 6.83 to 8.69 mmol/L) (9.5 to 15 usual value during pregnancy)[83][84]

text: Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women must be at least 11 g/dL and at least 10.5 g/dL during the 2nd trimester.[85]

text: Dehydration or hyperhydration can greatly influence measured hemoglobin levels. Albumin can indicate hydration status.

text: If the concentration is below normal, this is called anemia. Anemias are classified by the size of red blood cells, the cells that contain hemoglobin in vertebrates. The anemia is called "microcytic" if red cells are small, "macrocytic" if they are large, and "normocytic" otherwise.

text: Hematocrit, the proportion of blood volume occupied by red blood cells, is typically about three times the hemoglobin concentration measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares with a hematocrit of 51%.[86]

text: Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method called Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.[87]

text: Concentrations of oxy- and deoxyhemoglobin can be measured continuously, regionally and noninvasively using NIRS.[88][89][90][91][92] NIRS can be used both on the head and on muscles. This technique is often used for research in e.g. elite sports training, ergonomics, rehabilitation, patient monitoring, neonatal research, functional brain monitoring, brain computer interface, urology (bladder contraction), neurology (Neurovascular coupling) and more.

text: Long-term control of blood sugar concentration can be measured by the concentration of Hb A1c. Measuring it directly would require many samples because blood sugar levels vary widely through the day. Hb A1c is the product of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in more Hb A1c. Because the reaction is slow, the Hb A1c proportion represents glucose level in blood averaged over the half-life of red blood cells, is typically 50–55 days. An Hb A1c proportion of 6.0% or less show good long-term glucose control, while values above 7.0% are elevated. This test is especially useful for diabetics.[93]

text: The functional magnetic resonance imaging (fMRI) machine uses the signal from deoxyhemoglobin, which is sensitive to magnetic fields since it is paramagnetic. Combined measurement with NIRS shows good correlation with both the oxy- and deoxyhemoglobin signal compared to the BOLD signal.[94]

text: Athletic tracking and self tracking uses[edit]

text: Hemoglobin can be tracked noninvasively, to build an individual data set tracking the hemoconcentration and hemodilution effects of daily activities for better understanding of sports performance and training. Athletes are often concerned about endurance and intensity of exercise. The sensor uses light-emitting diodes that emit red and infrared light through the tissue to a light detector, which then sends a signal to a processor to calculate the absorption of light by the hemoglobin protein.[95] This sensor is similar to a pulse oximeter, which consists of a small sensing device that clips to the finger.

text: Analogues in non-vertebrate organisms[edit]

text: A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant kingdoms. Organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins and the heme moiety (iron in a flat porphyrin support), they are often called hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of "myoglobin" and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or, they may have a recognizable separate circulatory system but not one that deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin-containing molecules (even monomeric globin ones) that deal with gas-binding are referred to as oxyhemoglobins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments that must be anaerobic.[96] They may even deal with detoxification of chlorinated materials in a way analogous to heme-containing P450 enzymes and peroxidases.

text: The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Primitive species such as bacteria, protozoa, algae, and plants often have single-globin hemoglobins. Many nematode worms, molluscs, and crustaceans contain very large multisubunit molecules, much larger than those in vertebrates. In particular, chimeric hemoglobins found in fungi and giant annelids may contain both globin and other types of proteins.[12]

text: One of the most striking occurrences and uses of hemoglobin in organisms is in the giant tube worm (Riftia pachyptila, also called Vestimentifera), which can reach 2.4 meters length and populates ocean volcanic vents. Instead of a digestive tract, these worms contain a population of bacteria constituting half the organism's weight. The bacteria react with H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. The worms end with a deep-red fan-like structure ("plume"), which extends into the water and absorbs H2S and O2 for the bacteria, and CO2 for use as synthetic raw material similar to photosynthetic plants. The structures are bright-red due to their containing several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species are.[97][98]

text: Other oxygen-binding proteins[edit]

text: Presence in nonerythroid cells[edit]

text: Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include the A9 dopaminergic neurons in the substantia nigra, astrocytes in the cerebral cortex and hippocampus, and in all mature oligodendrocytes.[11] It has been suggested that brain hemoglobin in these cells may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy production".[11] It has been noted further that "A9 dopaminergic neurons may be at particular risk since in addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals".[11] This may explain the risk of these cells for degeneration in Parkinson's disease.[11] The hemoglobin-derived iron in these cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia nigra), but rather is due to neuromelanin.

text: Outside the brain, hemoglobin has non-oxygen-carrying functions as an antioxidant and a regulator of iron metabolism in macrophages,[99] alveolar cells,[100] and mesangial cells in the kidney.[101]

text: In history, art and music[edit]

text: Historically, an association between the color of blood and rust occurs in the association of the planet Mars, with the Roman god of war, since the planet is an orange-red, which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself,[102] although the ligation and redox state of the iron can influence the pi to pi* or n to pi* electronic transitions of the porphyrin and hence its optical characteristics.

text: Artist Julian Voss-Andreae created a sculpture called "Heart of Steel (Hemoglobin)" in 2005, based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron.[103][104]

text: Montreal artist Nicolas Baier created Lustre (Hémoglobine), a sculpture in stainless steel that shows the structure of the hemoglobin molecule. It is displayed in the atrium of McGill University Health Centre's research centre in Montreal. The sculpture measures about 10 metres × 10 metres × 10 metres.[105][106]


document_title: Esther Anderson (Sanford and Son)

question_text: who played aunt ethel on sanford and son

text: Esther Anderson (Sanford and Son)

text: This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2015) (Learn how and when to remove this template message)

tag: table

text:
Esther Anderson

Esther Winfield-Anderson

First appearance
"The Big Party"

Last appearance
"Here Comes the Bride: Part Two"

Created by
Norman Lear and Bud Yorkin, based on Albert Steptoe created by Galton and Simpson

Portrayed by
LaWanda Page

Information

Gender
Female

Occupation
Deaconess

Family
Elroy Winfield (father)
Essie Winfield (mother)

Spouse(s)
Woodrow "Woody" Anderson

Children
Clifford Daniel "Cliff" Anderson (son) (adopted)

Relatives
Elizabeth Winfield Sanford (sister; deceased)
Flossie Winfield (sister)
Ethel Winfield (sister)
Minnie Winfield (sister)
Ellen Winfield (sister)
Hazel Winfield (sister)
Rosetta Winfield (sister)
Elsie Winfield (sister)
Fred Sanford (brother-in-law)
Edgar (brother-in-law)
Jake (brother-in-law)
Paul (brother-in-law)
Lamont Sanford (nephew)
Elizabeth (niece)

text: Esther Winfield Anderson, known and feared as Aunt Esther, is a fictional character from the television series, Sanford and Son. She was played by actress LaWanda Page, an acquaintance of the series' star, Redd Foxx. Page was Foxx's first and only choice to play Esther.

text: Enemy for Foxx's character[edit]

text: At first, Fred's main enemy on the show was in his sister-in-law and Lamont's aunt, Ethel (Beah Richards). Ethel's involvement in the Sanfords' family squabbles lasted only midway through the second season, whereupon she was replaced with her more tart-tongued sister, Esther.

text: Fred and Esther's relationship as in-laws went on to become a major part of the series' legend, as each time Esther appeared, Fred would insult her and audiences were drawn to the show in greater numbers. Conversely, Esther's disdain for Fred stemmed back to when he and Elizabeth were dating; she had disapproved of Fred marrying her sister. He would often contort his face upon Esther's entrance and make disparaging remarks to her, comparing her with King Kong and Godzilla. Esther would refer to Fred as an "old heathen." Despite his stubbornness, Fred would sometimes redeem himself with acts of kindness toward Esther.

text: Character history[edit]

text: Esther Anderson is the Bible-toting sister-in-law of Fred Sanford. She is a staunchly religious Baptist who finds little use for humor and often criticizes Fred. Elizabeth, Esther's younger sister, was married to Fred, and Esther and the rest of the Winfield family were against the marriage from the outset. However, Esther often expressed that if anything good came out of the marriage it was her nephew, Fred's son, Lamont.

text: Lamont adored his aunt Esther, and would, against Fred's and Grady's wishes, allow her to stay in their house and often defended her against their insults. Since Esther and her family were the only real connection he had to his late mother, Lamont welcomed her often. She, in turn, was there to counsel Lamont on his life, and did her best to help him to get out of living in his father's junkyard house. She did so because she felt that Elizabeth would not have wanted Lamont, whom Esther felt was very intelligent, to remain in such a limited life.

text: Fred responded to Esther's entrances by making exaggerated grimaces. He would then proceed to insult her, likening her to animals and fictitious movie monsters. Fred often focused on Esther's looks, once telling her, "I could stick your face in some dough and make gorilla cookies!" He also often insulted her by calling her "ugly" and pronouncing it Ug-leee!.

text: Esther's usual reactions to Fred's antics were to scowl and say, "Watch it, sucka!" Sometimes, cracking from the constant barrage of insults, she would swing her purse wildly in Fred's direction while angrily calling him an "old fish-eyed fool" or "heathen", among other names. Once, during a public prayer, Esther made reference to Fred, calling him a "snaggle-toothed jackass." She also clashed with Fred's friend Grady Wilson, whom she disliked because he was Fred's friend.

text: Despite their constant arguments, some episodes reveal that Esther and Fred were capable of kindness towards each other, such as when Fred helped her adopt a child. In one episode, Fred gave Esther $100 he won gambling to help her church, leaving him 35 cents.

text: Esther's long-suffering but loving alcoholic husband Woodrow (played by Raymond Allen) appeared infrequently later in the series. Woodrow was constantly drunk and somewhat henpecked. He eventually became sober so he and Esther could adopt a young orphan, Daniel (Eric Laneuville) in "Aunt Esther Meets Her Son".

text: In the final two seasons of Sanford and Son, as well as its failed spin-off Sanford, Esther lived next door to Fred at the Sanford Arms, the boarding house owned and run by Fred, which was located next to his junk shop.

text: Esther also made a cameo appearance at the beginning of the movie Friday.

text: Religious conflicts[edit]

text: Esther was a devout churchgoer, always armed with the Bible, and whenever she went to do battle with Fred, which was often, she was usually aided by some women from her church, or by her drunken husband, Woodrow; or would simply show up at Fred's house quoting the Bible. Usually, at any random moment, even in mid-sentence, Esther would throw her hands up and exclaim, "Oh, Glory!" (though it came out as H'ah Glory), even during her most heated arguments with Fred.

text: Her upright image was deflated when it was revealed that she had sex with a man called "Big Money Grip" in her youth. Grip had mistaken Esther for the beautiful Elizabeth in the dark, which led Grip to claim he was Lamont's real father.

text: Page's convincing portrayal of the "church lady" image of Aunt Esther was in marked contrast to the "blue" material of her stand-up act and record albums.

text: Fictional characters introduced in 1973Sanford and Son charactersFictional African-American peopleFictional characters from Los Angeles

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