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Theories of general anaesthetic action

A general anaesthetic (or anesthetic) is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

General anaesthetics have been widely used in surgery since 1842 when Crawford Long for the first time administered diethyl ether to a patient and performed a painless operation. It has long been believed that general anaesthetics exert their effects (analgesia, unconsciousness, immobility) through a membrane mediated mechanism or by directly modulating the activity of membrane proteins in the neuronal membrane. In general, different anaesthetics exhibit different mechanisms of action such that there are numerous non-exclusionary molecular targets at all levels of integration within the central nervous system. However, for certain intravenous anaesthetics, such as propofol and etomidate, the main molecular target is believed to be GABAA receptor, with particular β subunits playing a crucial role.

The concept of specific interactions between receptors and drugs first introduced by Paul Ehrlich in 1897 states that drugs act only when they are bound to their targets (receptors). The identification of concrete molecular targets for general anaesthetics was made possible only with the modern development of molecular biology techniques for single amino acid mutations in proteins of genetically engineered mice.

Lipid solubility-anaesthetic potency correlation (the Meyer-Overton correlation)
A nonspecific mechanism of general anaesthetic action was first proposed by Emil Harless and Ernst von Bibra in 1847. They suggested that general anaesthetics may act by dissolving in the fatty fraction of brain cells and removing fatty constituents from them, thus changing activity of brain cells and inducing anaesthesia. In 1899 Hans Horst Meyer published the first experimental evidence of the fact that anaesthetic potency is related to lipid solubility. Two years later a similar theory was published independently by Charles Ernest Overton.

Meyer compared the potency of many agents, defined as the reciprocal of the molar concentration required to induce anaesthesia in tadpoles, with their olive oil/water partition coefficient. He found a nearly linear relationship between potency and the partition coefficient for many types of anaesthetic molecules such as alcohols, aldehydes, ketones, ethers, and esters. The anaesthetic concentration required to induce anaesthesia in 50% of a population of animals (the EC50) was independent of the means by which the anaesthetic was delivered, i.e., the gas or aqueous phase.

Meyer and Overton had discovered the striking correlation between the physical properties of general anaesthetic molecules and their potency: the greater the lipid solubility of a compound in olive oil, the greater its anaesthetic potency. This correlation is true for a wide range of anaesthetics with lipid solubilities ranging over 4-5 orders of magnitude if olive oil is used as the oil phase. This correlation can be improved considerably in terms of both the quality of the correlation and the increased range of anaesthetics if bulk octanol or a fully hydrated fluid lipid bilayer   is used as the "oil" phase. It was also noted that volatile anaesthetics are additive in their effects (a mixture of a half dose of two different volatile anaesthetics gave the same anaesthetic effect as a full dose of either drug alone).

The best characterized anesthetics site accounting for the Meyer-Overton correlation resides in ordered lipid domains. Anesthetics adhere non-specifically to the surface of a palmitate specific binding site within the lipid membrane displacing the palmitate from ordered GM1 lipids. The process gives rise to a component of membrane-mediated anesthesia. A similar mechanism was shown for luciferase. The anesthetics bound non-specifically to a hydrophobic surface and competed out the specific binding of luciferin. However luciferase is not physiologically relevant to vertebrates as it is not endogenously expressed in vertebrates.

Early lipid hypotheses of general anaesthetic action

From the correlation between lipid solubility and anaesthetic potency, both Meyer and Overton had surmised a unitary mechanism of general anaesthesia. They assumed that solubilization of lipophilic general anaesthetic in lipid bilayer of the neuron causes its malfunction and anaesthetic effect when critical concentration of anaesthetic is reached. Later in 1973 Miller and Smith suggested the critical volume hypothesis also called lipid bilayer expansion hypothesis. They assumed that bulky and hydrophobic anaesthetic molecules accumulate inside the hydrophobic (or lipophilic) regions of neuronal lipid membrane causing its distortion and expansion (thickening) due to volume displacement. Accumulation of critical amounts of anaesthetic causes membrane thickening sufficient to reversibly alter function of membrane ion channels thus providing anaesthetic effect. Actual chemical structure of the anaesthetic agent per se is not important, but its molecular volume plays the major role: the more space within membrane is occupied by anaesthetic - the greater is the anaesthetic effect. Based on this theory, in 1954 Mullins suggested that the Meyer-Overton correlation with potency can be improved if molecular volumes of anaesthetic molecules are taken into account. This theory existed for over 60 years and was supported by experimental fact that increases in atmospheric pressure reverse anaesthetic effect (pressure reversal effect).

Then other, physicochemical theories of anaesthetic action emerged that took into account the diverse chemical nature of general anaesthetics and suggested that anaesthetic effect is exerted through some perturbation of the lipid bilayer. Several types of bilayer perturbations were proposed to cause anaesthetic effect, including (1) changes in phase separation, (2) changes in bilayer thickness, (3) changes in order parameters, or (4) changes in curvature elasticity.

According to the lateral phase separation theory anaesthetics exert their action by fluidizing nerve membranes to a point when phase separations in the critical lipid regions disappear. This anaesthetic-induced fluidization makes membranes less able to facilitate the conformational changes in proteins that may be the basis for such membrane events as ion gating, synaptic transmitter release, and transmitter binding to receptors. More recent techniques with super resolution imaging show that the anesthetics do not overcome phase separation—the phase separation persists. Rather saturated lipids within the phase separation can undergo a transition from ordered to disordered which is dramatically affected by anesthetics. Nonetheless the concept of proteins moving between phase separated lipids in response to anesthetic has now been shown to be correct.

All these early lipid theories were generally thought to suffer from four weaknesses (full description with rebuttals see in sections below):
 * Stereoisomers of an anaesthetic drug have very different anaesthetic potency whereas their oil/gas partition coefficients are similar.
 * Certain drugs that are highly soluble in lipids, therefore expected to act as anaesthetics, exert convulsive effect instead (and therefore were called nonimmobilizers).
 * A small increase in body temperature affects membrane density and fluidity as much as general anaesthetics, yet it does not cause anaesthesia.
 * Increasing the chain length in a homologous series of straight-chain alcohols or alkanes increases their lipid solubility, but their anaesthetic potency stops increasing beyond a certain cutoff length.

The correlation between lipid solubility and potency of general anaesthetics was thought to be a necessary but insufficient condition for inferring a lipid target site. General anaesthetics could equally well be binding to hydrophobic target sites on proteins in the brain, but given the chemical diversity of anesthetics this would likely need to include more than one site and those sites would not inherently preclude a site in the membrane. For proteins, one reason that more polar general anaesthetics could be less potent is that they have to cross the blood–brain barrier to exert their effect on neurons in the brain.

Modern lipid hypothesis
There are two modern lipid hypotheses which are non-exclusionary with direct protein binding. The most recent hypothesis postulates that ordered lipids in the plasma membrane contain a structured binding site for the lipid palmitate. It is a lipid binding site within a lipid structure, not a protein structure. Proteins that contain a covalently attached palmitate (palmitoylation) are targeted to the ordered lipids through a specific lipid-lipid interaction. The binding of palmitate to the lipid domain is cholesterol dependent and the cell regulates the protein by nanoscopic localization. The anesthetics work by binding non-specifically to the palmitate binding site, which disrupts the ability of the cholesterol to bind to and sequester the protein into an inactive state. This membrane mediated mechanism was demonstrated experimentally by Pavel and colleagues in 2020. They showed the enzyme phospholipase D2 (PLD2) is anesthetic sensitive and activates the potassium channel TREK-1 through a membrane mediated mechanism. The anesthetics displaced PLD2 from ordered lipid domains allowing the enzyme to be activated by substrate presentation and activate the channel.

The second lipid hypothesis states that anaesthetic effect happens if solubilization of general anaesthetic in the bilayer causes a redistribution of membrane lateral pressures.

Each bilayer membrane has a distinct profile of how lateral pressures are distributed within it. Most membrane proteins (especially ion channels) are sensitive to changes in this lateral pressure distribution profile. These lateral stresses are rather large and vary with depth within the membrane. According to the modern lipid hypothesis a change in the membrane lateral pressure profile shifts the conformational equilibrium of certain membrane proteins known to be affected by clinical concentrations of anaesthetics such as ligand-gated ion channels. This mechanism is also nonspecific because the potency of the anaesthetic is determined not by its actual chemical structure, but by the positional and orientational distribution of its segments and bonds within the bilayer.

In 1997, Cantor suggested a detailed mechanism of general anesthesia based on lattice statistical thermodynamics. It was proposed that incorporation of amphiphilic and other interfacially active solutes (e.g. general anaesthetics) into the bilayer increases the lateral pressure selectively near the aqueous interfaces, which is compensated by a decrease in lateral pressure toward the centre of the bilayer. Calculations showed that general anaesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein by the following mechanism:
 * A channel tries to open in response to a nerve impulse thus increasing the cross-sectional area of the protein more near the aqueous interface than in the middle of the bilayer;
 * Then the anaesthetic-induced increase in lateral pressure near the interface shifts the protein conformational equilibrium back to the closed state, since channel opening will require greater work against the higher pressure at interface. This is the first hypothesis that provided not just correlations of potency with structural or thermodynamic properties, but a detailed mechanistic and thermodynamic understanding of anaesthesia.

Thus, according to the modern lipid hypothesis anaesthetics do not act directly on their membrane protein targets, but rather perturb specialized lipid matrices at the protein-lipid interface, which act as mediators. This is a new kind of transduction mechanism, different from the usual key-lock interaction of ligand and receptor, where the anaesthetic (ligand) affects the function of membrane proteins by binding to the specific site on the protein. Thus, some membrane proteins are proposed to be sensitive to their lipid environment. A slightly different detailed molecular mechanism of how bilayer perturbation can influence the ion-channel was proposed in the same year. Oleamide (fatty acid amide of oleic acid) is an endogenous anaesthetic found in vivo (in the cat's brain) and it is known to potentiate sleep and lower the temperature of the body by closing the gap junction channel connexion. The detailed mechanism is shown on the picture: the well-ordered lipid(green)/cholesterol(yellow) ring that exists around connexon (magenta) becomes disordered on treatment with anaesthetic (red triangles), promoting a closure of connexon ion channel. This decreases brain activity and induces lethargy and anaesthetic effect. Recently super resolution imaging showed direct experimental evidence that volatile anesthetics disrupt the ordered lipid domains as predicted. In the same study, a related mechanism emerged where the anesthetics released the enzyme phospholipase D (PLD) from lipid domains and the enzyme bound to and activated TREK-1 channels by the production of phosphatidic acid. These results showed experimentally that the membrane is a physiologically relevant target of general anesthetics.

Membrane protein hypothesis of general anaesthetic action

In the early 1980s, Nicholas P. Franks and William R. Lieb demonstrated that the Meyer-Overton correlation can be reproduced using a soluble protein. They found that two classes of proteins are inactivated by clinical doses of anaesthetic in the total absence of lipids. These are luciferases, which are used by bioluminescent animals and bacteria to produce light, and cytochrome P450, which is a group of heme proteins that hydroxylate a diverse group of compounds, including fatty acids, steroids, and xenobiotics such as phenobarbital. Remarkably, inhibition of these proteins by general anaesthetics was directly correlated with their anaesthetic potencies. Luciferase inhibition also exhibits a long-chain alcohol cutoff, which is related to the size of the anaesthetic-binding pocket.

These observations were important because they demonstrated that general anaesthetics exert their effect non-specifically including when binding to proteins. This also opened up the possibility that anesthetics could work through direct binding to proteins, rather than affect membrane proteins indirectly through nonspecific interactions with lipid bilayer as mediator. It was shown that anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C.

However, the proteins considered the most likely molecular targets of anaesthetics are ion channels. According to this theory general anaesthetics are much more selective than in the lipid hypotheses, and they bind directly only to a small number of targets in the central nervous system, mostly ligand-gated ion channels in synapses and G-protein coupled receptors, altering their ion flux. Particularly Cys-loop receptors are plausible targets for general anaesthetics that bind at the interface between the subunits. The Cys-loop receptor superfamily includes inhibitory receptors (GABAA receptors, GABAC receptors, glycine receptors) and excitatory receptors (nicotinic acetylcholine receptor and 5-HT3 serotonin receptor). General anaesthetics can inhibit the channel functions of excitatory receptors or potentiate functions of inhibitory receptors, respectively.

The location of non-specific binding sites in ion channels is still a major question in the field. In particular, how does a compound that follows Overton-Meyer directly cause a conformational change in the protein? Typically, allosteric regulation involves a change in protein shape that accommodates the binding of the ligand. This mechanism is distinct from the luciferase mechanism. A second important question, how are the non-specific protein binding sites conserved across species and why do they generally inhibit excitatory receptors and potentiate inhibitory receptors? A number of experimental and computational studies have shown that general anaesthetics could alter the dynamics in the flexible loops that connect α-helices in a bundle and are exposed to the membrane-water interface of Cys-loop receptors. The main binding pockets of general anaesthetics, however, are located within transmembrane four-α-helix bundles of Cys-loop receptors.

GABAA receptor is a major target of general anesthetics
The GABAA receptor (GABAAR) is an ionotropic receptor activated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Activation of the GABAA receptor leads to an influx of chloride ions, which causes hyperpolarization of the neuronal membranes. The GABAA receptor has been identified as the main target of intravenous anesthetics such as propofol and etomidate. The binding site of propofol on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative. Strong activation of tonic GABAA receptor conductance by clinical concentrations of propofol has been confirmed with electrophysiological recordings from hippocampal CA1 neurons in adult rat brain slices. GABAA receptors that contain β3-subunits are the main molecular targets for the anesthetic actions of etomidate, whereas the β2-containing GABAA receptors are involved in the sedation elicited by this drug. Electrophysiological experiments with amnestic concentrations of etomidate have also shown enhancement of tonic GABAA conductance of CA1 pyramidal neurons in hippocampal slices. Potent activation of GABAA receptor-mediated inhibition with resulting strong depression of firing rates of neocortical neurons has also been demonstrated for clinical concentrations of volatile anesthetics such as isoflurane, enflurane and halothane.

Other molecular targets
The enhancement of GABAA receptor activity is unlikely to be the only mechanism to account for the wide range of behavioural effects of general anaesthetics. Accumulating experimental data suggests that modulation of two-pore domain potassium channels, or voltage-gated sodium channels may also account for some of the actions of volatile anaesthetic agents. Alternatively, inhibition of glutamate-gated N-methyl-D-aspartate receptors by ketamine, xenon, and nitrous oxide provides a mechanism of action in keeping with a predominant analgesic profile.

1. Stereoisomers of an anaesthetic drug
Stereoisomers that represent mirror images of each other are termed enantiomers or optical isomers (for example, the isomers of R-(+)- and S-(−)-etomidate). Physicochemical effects of enantiomers are always identical in an achiral environment (for example in the lipid bilayer). However, in vivo enantiomers of many general anaesthetics (e.g. isoflurane, thiopental, etomidate) can differ greatly in their anaesthetic potency despite the similar oil/gas partition coefficients. For example, the R-(+) isomer of etomidate is 10 times more potent anaesthetic than its S-(-) isomer. This means that optical isomers partition identically into lipid, but have differential effects on ion channels and synaptic transmission. This objection provides a compelling evidence that the primary target for anaesthetics is not the achiral lipid bilayer itself but rather stereoselective binding sites on membrane proteins that provide a chiral environment for specific anaesthetic-protein docking interactions.

Rebuttal to the objection: 1) Stereo selective transport of the anesthetic was never considered. Anesthetics are hydrophobic and transported bound to proteins in the blood. Any stereo selective binding to the transport protein would change the concentration at the site of action. Furthermore a protein sink in the membrane could bind one of the isomers slightly better and reduce the effective concentration the membrane experiences. All stereo isomers are effective anesthetics, they only shifted the sensitivity, suggesting selective transport and selective protein sinks need to be considered. 2) Lipids are chiral, the same as proteins. And like proteins, lipids have ordered and disordered regions. The field failed to investigate the chirality of ordered lipids due to a lack of knowledge of their existence.

2. Nonimmobilizers
All general anaesthetics induce immobilization (absence of movement in response to noxious stimuli) through depression of spinal cord functions, whereas their amnesic actions are exerted within the brain. According to the Meyer-Overton correlation the anaesthetic potency of the drug is directly proportional to its lipid solubility, however, there are many compounds that do not satisfy this rule. These drugs are strikingly similar to potent general anaesthetics and are predicted to be potent anaesthetics based on their lipid solubility, but they exert only one constituent of the anaesthetic action (amnesia) and do not suppress movement (i.e. do not depress spinal cord functions) as all anaesthetics do. These drugs are referred to as nonimmobilizers. The existence of nonimmobilizers suggests that anaesthetics induce different components of anaesthetic effect (amnesia and immobility) by affecting different molecular targets and not just the one target (neuronal bilayer) as it was believed earlier. Good example of non-immobilizers are halogenated alkanes that are very hydrophobic, but fail to suppress movement in response to noxious stimulation at appropriate concentrations. See also: flurothyl.

Rebuttal to the objection: This is a logical fallacy. The hypothesis does not require that every molecule ever tested obeys the hypothesis for the hypothesis to be true. The existence of less than 10-20 related compounds that are known to disobey the Meyer-Overton hypothesis in no way negates the hundreds if not thousands of chemically diverse compounds that do obey the Overton-Meyer hypothesis. Exceptions can exists for reasons unrelated to the mechanism underlying the Meyer-Overton hypothesis.

3. Temperature increases do not have anaesthetic effect
Experimental studies have shown that general anaesthetics including ethanol are potent fluidizers of natural and artificial membranes. However, changes in membrane density and fluidity in the presence of clinical concentrations of general anaesthetics are so small that relatively small increases in temperature (~1 °C) can mimic them without causing anaesthesia. The change in body temperature of approximately 1 °C is within the physiological range and clearly it is not sufficient to induce loss of consciousness per se. Thus membranes are fluidized only by large quantities of anaesthetics, but there are no changes in membrane fluidity when concentrations of anaesthetics are small and restricted to pharmacologically relevant.

Rebuttal to the objection: Early studies only considered the fluidity of the bulk lipid membrane. Recent work has shown that temperature changes can occur over several degrees in ordered nanoscopic lipid domains. Furthermore, fluidity is actively regulated by fatty acid desaturases. And lastly, competition of anesthetics with palmitoylated proteins occurs independent of temperature and despite increased ordered lipids.

4. Effect vanishes beyond a certain chain length
According to the Meyer-Overton correlation, in a homologous series of any general anaesthetic (e.g. n-alcohols, or alkanes), increasing the chain length increases the lipid solubility, and thereby should produce a corresponding increase in anaesthetic potency. However, beyond a certain chain length the anaesthetic effect disappears. For the n-alcohols, this cutoff occurs at a carbon chain length of about 13 and for the n-alkanes at a chain length of between 6 and 10, depending on the species.

If general anaesthetics disrupt ion channels by partitioning into and perturbing the lipid bilayer, then one would expect that their solubility in lipid bilayers would also display the cutoff effect. However, partitioning of alcohols into lipid bilayers does not display a cutoff for long-chain alcohols from n-decanol to n-pentadecanol. A plot of chain length vs. the logarithm of the lipid bilayer/buffer partition coefficient K is linear, with the addition of each methylene group causing a change in the Gibbs free energy of -3.63 kJ/mol.

The cutoff effect was first interpreted as evidence that anaesthetics exert their effect not by acting globally on membrane lipids but rather by binding directly to hydrophobic pockets of well-defined volumes in proteins. As the alkyl chain grows, the anaesthetic fills more of the hydrophobic pocket and binds with greater affinity. When the molecule is too large to be entirely accommodated by the hydrophobic pocket, the binding affinity no longer increases with increasing chain length. Thus the volume of the n-alkanol chain at the cutoff length provides an estimate of the binding site volume. This objection provided the basis for protein hypothesis of anaesthetic effect (see below).

However, cutoff effect can still be explained in the frame of lipid hypothesis. In short-chain alkanols (A) segments of the chain are rather rigid (in terms of conformational enthropy) and very close to hydroxyl group tethered to aqueous interfacial region ("buoy"). Consequently, these segments efficiently redistribute lateral stresses from the bilayer interior toward the interface. In long-chain alkanols (B) hydrocarbon chain segments are located further from hydroxyl group and are more flexible than in short-chain alkanols. Efficiency of pressure redistribution decreases as the length of hydrocarbon chain increases until anaesthetic potency is lost at some point. It was proposed that polyalkanols (C) will have anaesthetic effect similar to short-chain 1-alkanols if the chain length between two neighbouring hydroxyl groups is smaller than the cutoff. This idea was supported by the experimental evidence because polyhydroxyalkanes 1,6,11,16-hexadecanetetraol and 2,7,12,17-octadecanetetraol exhibited significant anaesthetic potency as was originally proposed.

Rebuttal to the objection: The argument assumes that all classes of anaesthetics must work the same on the membrane. It is quite possible that one or two classes of molecules could work through a non-membrane mediated mechanism. For example, the alcohols were shown to incorporate into the lipid membrane via an enzymatic transphosphatidylation reaction. The ethanol metabolite bound to and inhibited an anesthetic channel. And while this mechanism may contradict a single unitary mechanism of anaesthesia, it does not preclude a membrane mediated one.

title: Theories of general anaesthetic action


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Restaurants du Cœur

The Restaurants du Cœur (literally Restaurants of the Heart but meaning Restaurants of Love), commonly known as the Restos du Cœur, is a French charity founded by comedian Coluche (1944–1986) and its main activity is to distribute food packages and hot meals to those in need.

The association targets the homeless and those with of low income (single families, elderly people with a low pension, young adults, etc.). The association also helps people to find housing and supports other projects. This not-for-profit association has the "reconnu d'utilité publique" (recognised as being of public interest) status which exempts it from specific taxes. The association, highly respected in France, is known for its huge number of volunteers (66,000 in 2015) and its original fund-raising method, particularly through its yearly Les Enfoirés concert.

History
Comedian and actor Coluche launched the idea of the Restos du Cœur on 26 September 1985: "I have a little idea, a bit like this... If there are people who would be interested in sponsoring a free soup kitchen, we'd start first in Paris and then spread to France's big cities." The first Resto du Cœur opened on 21 December ahead of Christmas and soon multiplied all over the country. The goal of the founders was to give away 2,000 to 3,000 meals per day; 8.5 million meals were distributed in the first winter alone. In 2018, 130 million meals were served.

The initiative was supported by a song written by the songwriter and singer Jean-Jacques Goldman called les Restos du cœur, which included some of the lyrics being sung or read out by other celebrities. A televised show allowed the organisation to collect several million francs.

Coluche pleaded for the Restos' cause at the European Parliament in February 1986 after learning that surplus products cost more to store than to distribute free to the poor; his plea was heard and in 1987 the surplus was made available to four organisations.

Structure and Organisation
The Restos du Cœur consists of one national organisation and 119 departmental organisations.

The National Organisation
Founded by the comedian and actor Coluche in 1985, "Les Restos du Cœur - Relais du Cœur" is a voluntary association as defined by the French association law of 1901. Recognised as being of public interest, its goal is to help the neediest and to fight social marginalisation.

It is a founding member of the Committee of the Charter of Deontology of Social and Humanitarian Organisations, a group of associations committed to financial transparency. It owns the name and logo of the Restos du Cœur.

Every year, the general assembly elects its governing body, which in turn chooses the president and the board from its members. The board enacts the policy of the Restos, as defined by the general assembly, at weekly meetings. The national organisation's goals are:
 * to centralise purchases of food and to supply it to the departments;
 * to encourage the departmental organisations to be involved in the reintegration of their beneficiaries into society, and to support them in their endeavours using technical and financial support;
 * to ensure the training of volunteers;
 * to oversee, using policy officers, the consistency of their messages;
 * to control and consolidate the accounts of the departmental organisations, to look after their well-being, and to ensure their respect for the rules;
 * and to maintain communication between the Restos.

The Departmental Branches
The 113 departmental organisations can be found throughout 96 departments. Although they are legally autonomous, they operate using the same principles as the national organisation (general assemblies, governing bodies, boards), and are bound to them by a contractual agreement.

The departmental organisations manage, activate and coordinate activities on the ground with 40,000 volunteers in almost 2,500 Restos, which together welcome 600,000 beneficiaries a day. Their aims are to provide food aid, lodging, workshops (such as the Jardins du Cœur - "Gardens of the Heart") and cultural activities.

All these reintegration programmes exist to help beneficiaries to become normal citizens. Under the heading of "reinsertion into society" are several different kinds of activities:
 * from workshops to gardens;
 * from trucks doing nightly rounds in the big cities to long-term lodging solutions;
 * and from cultural activities to picnics.

Though the soup kitchens remain the most visible face of the Restos, they alone cannot ease the exclusion of those benefiting from their existence. Reinsertion is therefore considered top priority.

The "Les Restos demain" ("The Restos Tomorrow") survey, which polled more than 13,000 beneficiaries and volunteers in 1998 and 1999, confirmed the need to evolve and reinforced the will to extend the beneficiary-volunteer partnership.

A Need for Clarity
The Restos du Cœur are attentive to the good use of the funds. As an organisation essentially financed by private donors, public funds and public organisations, and with its activities carried out by volunteers, its overheads are generally very low (around 8% of resources) and unnecessary expenses are eliminated. Invitations to tender ensure that best value for money is obtained. Consequently, 90% of financial resources are devoted to activities.

In line with the organisation's legislation, the accounts of the organisation are inspected by auditors. Occasional discrepancies by some local groups are sanctioned and transmitted to the courts.

Voted on and passed in 1988, the loi Coluche ("Coluche law") permits small donors (the largest segment of funders) to benefit from the same tax breaks as big donors. A later amendment permits donors to get a tax break of 75% for donations up to €470. Above that, and within a limit of 20% of income, the tax break is 66%. Each donor receives a tax form on which an accountant confirms all the necessary calculations for the tax break, and a document stating how the money donated will be used by the Restos.

Since 1987, the Restos du Cœur have benefited financially from the European Plan to Help the Neediest (Plan européen d'aide aux plus démunis, or PEAD).

Donors
There are many different kinds of donors:
 * From children to the elderly, from artisans to multinationals, from housewives to stars, individuals are, in various ways, the most reliable supporters.
 * Those who generously give their services (loan of buildings, transport, printing...) or participate in authorised protests, which are strictly regulated financially and legally.
 * Those who give money by buying an Enfoirés CD (les Enfoirés - "The Tossers" or "The Bastards" in English - is the name of an annual concert to raise money for the cause), by bequeathing their goods or money, or by giving up their copyright over a work.
 * Those who give goods (books, clothes, food, hygiene products...).

However, the following are all forbidden:
 * fundraising or garage sales;
 * commercial operations without the consent of the Restos du Cœur;
 * and direct mailing canvassing financial donations, apart from those from the organisation itself.

Volunteers
The first campaign for the Restos du Cœur in 1985 netted 5,000 volunteers. Today, there are more than 63,000 of all backgrounds with one point in common: generosity devoid of political or religious points of view. Their actions are based on the Volunteers' Charter, whose six guiding points guarantee the good working order of the organisation. To fulfil their mission well, each volunteer undergoes a training period enabling them to learn the techniques necessary for their mission. Two professional trainers and some experienced volunteers give seminars where volunteers from all around France gather. Classes about the following subjects are held:
 * managing a Resto;
 * welcoming people who no longer try for or want to get help;
 * accompanying those who ask for moral support;
 * helping those who have trouble paying rent on the homes they have finally found;
 * and teaching at a workshop or a garden.

Artists
Coluche knew that the best way he could help the Restos was to present his own image and those of his friends. In one winter, he created the Enfoirés around this idea.

On 26 January 1986, Coluche presented a show on national television that lasted all afternoon. An exceptional group of people gathered together: politicians of all stripes, presenters from all the TV channels and radio stations, and all kinds of artists and sports stars.

Since then, every year an Enfoirés concert has been held to encourage people to donate to the Restos du Cœur. It has become a very popular event. Each year, the media explain the goals of the organisation and remind people of where they can donate or volunteer. The Enfoirés themselves support the Restos by giving up the profits from the concerts and albums of these concerts.

There was also a charity song about it on TF1 (2012 appel aux dons spot), beautifully accompanied with the music of the Spanish band PLOU.

Belgium: 1986
There are 16 Restos in Belgium: 12 in Wallonia, two in Flanders and two in Brussels. Coluche inaugurated the first one, at Liège, on 22 February 1986. It was immediately decided to leave it open all year long, and as elsewhere, the services provided were quickly swamped.

The Belgian Federation of Restos currently offers many services (social, legal, reinsertion...), and help (administrative, financial, medical, lodging...).

Germany: 1997
One can also find Restaurant des Herzens in Germany, specifically in Erfurt and Leipzig.

In Erfurt, there is a cultural programme with theatre and music, and even a Father Christmas for the children. In 2004, however, dwindling donations resulted in reduced opening hours.

In Leipzig, the beneficiaries have to pay 50 euro cents per meal, otherwise the distribution of food would be impossible to finance. Nevertheless, a free minibus service operates between the central railway station and the restaurant.

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

title: Restaurants du Cœur


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User:Scott&Nigel

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title: User:Scott&Nigel


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SAFER

In cryptography, SAFER (Secure And Fast Encryption Routine) is the name of a family of block ciphers designed primarily by James Massey (one of the designers of IDEA) on behalf of Cylink Corporation. The early SAFER K and SAFER SK designs share the same encryption function, but differ in the number of rounds and the key schedule. More recent versions — SAFER+ and SAFER++ — were submitted as candidates to the AES process and the NESSIE project respectively. All of the algorithms in the SAFER family are unpatented and available for unrestricted use.

SAFER K and SAFER SK
The first SAFER cipher was SAFER K-64, published by Massey in 1993, with a 64-bit block size. The "K-64" denotes a key size of 64 bits. There was some demand for a version with a larger 128-bit key, and the following year Massey published such a variant incorporating new key schedule designed by the Singapore Ministry for Home affairs: SAFER K-128. However, both Lars Knudsen and Sean Murphy found minor weaknesses in this version, prompting a redesign of the key schedule to one suggested by Knudsen; these variants were named SAFER SK-64 and SAFER SK-128 respectively — the "SK" standing for "Strengthened Key schedule", though the RSA FAQ reports that, "one joke has it that SK really stands for 'Stop Knudsen', a wise precaution in the design of any block cipher". Another variant with a reduced key size was published, SAFER SK-40, to comply with 40-bit export restrictions.

All of these ciphers use the same round function consisting of four stages, as shown in the diagram: a key-mixing stage, a substitution layer, another key-mixing stage, and finally a diffusion layer. In the first key-mixing stage, the plaintext block is divided into eight 8-bit segments, and subkeys are added using either addition modulo 256 (denoted by a "+" in a square) or XOR (denoted by a "+" in a circle). The substitution layer consists of two S-boxes, each the inverse of each other, derived from discrete exponentiation (45x) and logarithm (log45x) functions. After a second key-mixing stage there is the diffusion layer: a novel cryptographic component termed a pseudo-Hadamard transform (PHT). (The PHT was also later used in the Twofish cipher.)

SAFER+ and SAFER++
There are two more-recent members of the SAFER family that have made changes to the main encryption routine, designed by the Armenian cryptographers Gurgen Khachatrian (American University of Armenia) and Melsik Kuregian in conjunction with Massey.

 * SAFER+ (Massey et al., 1998) was submitted as a candidate for the Advanced Encryption Standard and has a block size of 128 bits. The cipher was not selected as a finalist. Bluetooth uses custom algorithms based on SAFER+ for key derivation (called E21 and E22) and authentication as message authentication codes (called E1). Encryption in Bluetooth does not use SAFER+.
 * SAFER++ (Massey et al., 2000) was submitted to the NESSIE project in two versions, one with 64 bits, and the other with 128 bits.

title: SAFER


text:
Milton Brown

Milton Brown (September 8, 1903 – April 18, 1936) was an American band leader and vocalist who co-founded the genre of Western swing. His band was the first to fuse hillbilly hokum, jazz, and pop together into a unique, distinctly American hybrid, thus giving him the nickname, "Father of Western Swing". The birthplace of Brown's upbeat "hot-jazz hillbilly" string band sound was developed at the Crystal Springs Dance Hall in Fort Worth, Texas, from 1931 to 1936. Along with Bob Wills, with whom he performed at the beginning of his career, Brown developed the sound and style of Western swing in the early 1930s. For a while, he and his band, the Musical Brownies, were more popular than Bob Wills and his Texas Playboys. Brown's career was cut short in 1936 when he died following a car accident.

Early years
Born in Stephenville, Texas, in 1903, Brown moved to Fort Worth, Texas, in 1918. After graduating from Fort Worth's Arlington Heights High School in 1925, he worked as a cigar salesman, but he lost his job when the Great Depression hit in the late '20s.

Brown began his musical career in 1930, when he met Bob Wills and guitarist Herman Arnspiger. They were performing at a local Fort Worth dance and Brown joined the duo on a chorus of "St. Louis Blues". The trio decided to team up to play medicine shows around Texas and Brown landed a regular radio spot on WBAP for the group, where they played a show sponsored by Aladdin Lamp Company, which had the band change its name to the Aladdin Laddies.

Light Crust Doughboys
In early 1931, the group was hired by the Light Crust Flour Company—which was run by Burrus Mill and Elevator Company—to appear daily on the radio station KFJZ. The company, which was managed by W. Lee O'Daniel (also known as "Pappy" O'Daniel) who hosted the radio  shows, had the group rename themselves the Light Crust Doughboys. The Doughboys were an instant success, and soon O'Daniel moved them to another radio station, then syndicated the program statewide.

The Doughboys were playing cowboy songs, jazz, blues, and popular songs—a repertoire so diverse that the band's audience continued to expand. In February 1932, they recorded a single for Victor under the name the Fort Worth Doughboys. The band was playing dance music and wanted to play at dances, but O'Daniel was reluctant to let the group play outside of their radio shows. He also was hesitant to pay them much money, which angered Brown. In September 1932, in need of additional money to support his aging parents, Brown left the band after he had an argument about money with O'Daniel.

Musical Brownies
After leaving the Light Crust Doughboys, Brown formed the world's first Western swing band in Fort Worth, Texas, the Musical Brownies. The first incarnation of the Brownies featured Brown, guitarist Derwood Brown, bassist Wanna Coffman, Ocie Stockard on tenor banjo, and fiddle player Jesse Ashlock. Shortly afterward, pianist Fred "Papa" Calhoun and fiddle player Cecil Brower (who replaced Ashlock) joined the group. Like the Light Crust Doughboys, the Musical Brownies played a mixture of country, pop, and jazz, but the Brownies had a harder rhythm & blues dance edge than their predecessors.

Almost immediately, Brown and His Musical Brownies were a huge success. The group had a regular spot on the radio station KTAT and drew large crowds to various Texas and Oklahoma dance halls. Their home venue, Crystal Springs Dance Hall in Fort Worth, was sold out nearly every Saturday night from 1933 to 1936. Brown and Wills remained friends.

In April 1934, the band recorded eight songs for Bluebird Records; and then another ten recordings for the label in August. Brown and his talented group of musicians were responsible for numerous innovations, notably in late 1934, the Brownies added the true pioneer of the world's first electrically amplified steel guitar—Bob Dunn. Dunn was a jazz guitarist who first heard electric steel guitar played by a down and out blues performer on the Coney Island Boardwalk—Dunn's innovative steel guitar solo riffs single-handedly created country & western's most recognized solo instrumental sound. His upbeat "Taking Off" instrumental is an example of his inspired solos; a towering inspiration to many Western swing, country and even rock guitarists in the years to follow.

In January 1935, Brown's band signed with Decca records and recorded 36 songs for the label with Brown singing lead vocals on most all of the tracks. Released as singles over the course of 1935, the songs helped establish the band as the most popular Western swing band in the entire southwest United States. In March 1936, Brown and his Musical Brownies travelled to New Orleans to record their second set of sessions for Decca. By this time, fiddler Brower had been replaced by Cliff Bruner. At these sessions, the Brownies cut about 50 songs, which were issued throughout 1936 and 1937.

Death
On the morning of April 13, 1936, Brown suffered a car accident, which may have been attributed to his habitual falling asleep at inopportune times, possibly narcolepsy. Although he survived the impact and was expected to recover, he died five days later from pneumonia. Brown's single-car accident occurred on Fort Worth's Jacksboro Highway after the car he was driving hit a telephone pole. A 16-year-old girl, Katy Prehoditch, was killed in the crash. She had slipped away from her house without her parents' knowledge to go to Crystal Springs Dance Hall with friends. Brown had agreed to give the girl a ride home.

Brown was taken to Fort Worth's Methodist Hospital where his injuries were initially believed to not be life-threatening. However, one of his broken ribs had punctured a lung. Pneumonia set in and he died five days later. The site of the crash was in the southbound lane of Jacksboro Highway directly across the street from the "Avalon Motel" which still stands today... and quite eerily, Brown had recorded the song "Avalon" two months prior to his accident.

Following Brown's death, Derwood Brown kept the Musical Brownies together for two years, recording a dozen sides for Decca in 1937.

title: Milton Brown


text:
1999 European Parliament election in the United Kingdom

The 1999 European Parliament election was the United Kingdom's part of the European Parliament election 1999. It was held on 10 June 1999. Following the European Parliamentary Elections Act 1999, it was the first European election to be held in the United Kingdom where the whole country used a system of proportional representation. In total, 87 Members of the European Parliament were elected from the United Kingdom across twelve new regional constituencies.

The change in voting system resulted in significant changes in seats. The Conservatives won double the number of seats they had won in the previous European election, in 1994, while the Labour Party saw its seats reduced from 62 to 29. The Liberal Democrats saw their number of seats increase to 10 from just 2 in the previous election. The UK Independence Party (UKIP), Green Party and Plaid Cymru gained their first seats in the European Parliament.

A by-election to the British Parliament also took place on the same day in the Leeds Central constituency - Labour held the seat but with significantly reduced turnout.

The House of Commons Library calculated notional seat changes based on what the result would have been if the 1994 European elections had been held under proportional representation. The notional results and seat changes are shown in the results box for this article.

It was the first European Parliament election to be held since the 1997 general election which resulted in a change of government from Conservative to Labour.

Turnout was 24%, the lowest of any member state in the 1999 election where the EU average was 49.51%. It was also the lowest of any European election in the United Kingdom, and the lowest of any member state until the 2009 election and to date is the lowest turnout for any national election in the history of the United Kingdom.

Electoral system
The European Parliamentary Elections Act 1999 introduced a closed-list party list system method of proportional representation, calculated using the D'Hondt method into Great Britain. In Northern Ireland, the Single Transferable Vote, which is also a form of proportional representation, which had been used since the first European election in 1979 was retained. The Act also created twelve new electoral regions, which were based on the British government's nine administrative Regions of England, Northern Ireland, Scotland and Wales. The effect of the introduction of proportional representation was that many small parties won seats to the European Parliament for the first time.

United Kingdom
The Conservatives doubled the number of seats from the last European election. Labour saw their 62 seats reduced to just 29. It was the first European Parliament election to be held since the change of United Kingdom government from Conservative to Labour two years earlier. The Liberal Democrats saw their number of seats increase to 10 from just 2 in the previous election. The UK Independence Party, Green Party and Plaid Cymru won their first seats in the European Parliament.

These changes were largely due to the move to proportional representation from first-past-the-post. The House of Commons Library calculated that if the 1994 European elections had been held under proportional representation, Labour would have won 43 MEPs, the Conservatives 26, the Lib Dems 11, the SNP 3 and Plaid Cymru 1.

Great Britain
Summary of the election results for Great Britain

Northern Ireland
Summary of the election results for Northern Ireland

MEPs defeated
Labour
 * Angela Billingham (East Midlands)
 * Sue Waddington (East Midlands)
 * Veronica Hardstaff (East Midlands)
 * Clive Needle (East of England)
 * Peter Truscott (East of England)
 * David Thomas (East of England)
 * Carole Tongue (London)
 * Shaun Spiers (London)
 * Mary Honeyball (London)
 * Michael Elliot (London)
 * Dr Gordon Adam (North East)
 * Tony Cunningham (North West)
 * Mark Hendrick (North West)
 * Hugh McMahon (Scotland)
 * Anita Pollack (South East England)
 * Ian White (South West England)
 * Joe Wilson (Wales)
 * David Morris (Wales)
 * Michael Tappin (West Midlands)
 * David Hallam (West Midlands)
 * Roger Barton (Yorkshire and the Humber)
 * Barry Seal (Yorkshire and the Humber)

Liberal Democrat
 * Robin Teverson (South West England)

Conservative
 * Edward Kellett-Bowman (South East England)
 * Bryan Cassidy (South West England)

Pro-Euro Conservative Party
 * John Stevens, former Conservative MEP (South East England)
 * Brendan Donnelly, former Conservative MEP (West Midlands)

Independent Labour
 * Christine Oddy, former Labour MEP (West Midlands)

Scottish Socialist Party
 * Hugh Kerr, former Labour MEP (Essex West and Hertfordshire East)

Leeds Left Alliance
 * Ken Coates, former Labour MEP (East Midlands)

Aftermath
Labour's results brought about a debate within the party about the introduction of proportional representation. In September 1998, a poll of 150 MPs had found that 58% backed the introduction of proportional representation. A follow-up poll ran on the Sunday after the election found that this had decreased to 43%, with the majority wanting a return to the first-past-the-post system. It has also been argued, however, that the introduction of proportional representation actually reduced Labour's losses, as first-past-the-post is more sensitive to swings in public opinion.


text:
Algebraic geometry and analytic geometry

In mathematics, algebraic geometry and analytic geometry are two closely related subjects. While algebraic geometry studies algebraic varieties, analytic geometry deals with complex manifolds and the more general analytic spaces defined locally by the vanishing of analytic functions of several complex variables. The deep relation between these subjects has numerous applications in which algebraic techniques are applied to analytic spaces and analytic techniques to algebraic varieties.

Main statement
Let X be a projective complex algebraic variety. Because X is a complex variety, its set of complex points X(C) can be given the structure of a compact complex analytic space. This analytic space is denoted Xan. Similarly, if $$\mathcal{F}$$ is a sheaf on X, then there is a corresponding sheaf $$\mathcal{F}^\text{an}$$ on Xan. This association of an analytic object to an algebraic one is a functor. The prototypical theorem relating X and Xan says that for any two coherent sheaves $$\mathcal{F}$$ and $$\mathcal{G}$$ on X, the natural homomorphism:
 * $$\text{Hom}_{\mathcal{O}_X}(\mathcal{F},\mathcal{G})\rightarrow\text{Hom}_{\mathcal{O}^{\text{an}}_X}(\mathcal{F}^{\text{an}},\mathcal{G}^{\text{an}})$$

is an isomorphism. Here $$\mathcal{O}_X$$ is the structure sheaf of the algebraic variety X and $$\mathcal{O}_X^{\text{an}}$$ is the structure sheaf of the analytic variety Xan. More precisely, the category of coherent sheaves on the algebraic variety X is equivalent to the category of analytic coherent sheaves on the analytic variety Xan, and the equivalence is given on objects by mapping $$\mathcal{F}$$ to $$\mathcal{F}^\text{an}$$. (Note in particular that $$\mathcal{O}^{\text{an}}_X$$ itself is coherent, a result known as the Oka coherence theorem, and also, it was proved in “Faisceaux Algebriques Coherents” that the structure sheaf of the algebraic variety $$\mathcal{O}_X$$ is coherent.

Another important statement is as follows: For any coherent sheaf $$\mathcal{F}$$ on an algebraic variety X the homomorphisms
 * $$\varepsilon_q\ :\ H^q(X,\mathcal{F}) \rightarrow H^q(X^{an},\mathcal{F}^{an})$$

are isomorphisms for all q's. This means that the q-th cohomology group on X is isomorphic to the cohomology group on Xan.

The theorem applies much more generally than stated above (see the formal statement below). It and its proof have many consequences, such as Chow's theorem, the Lefschetz principle and Kodaira vanishing theorem.

Background
Algebraic varieties are locally defined as the common zero sets of polynomials and since polynomials over the complex numbers are holomorphic functions, algebraic varieties over C can be interpreted as analytic spaces. Similarly, regular morphisms between varieties are interpreted as holomorphic mappings between analytic spaces. Somewhat surprisingly, it is often possible to go the other way, to interpret analytic objects in an algebraic way.

For example, it is easy to prove that the analytic functions from the Riemann sphere to itself are either the rational functions or the identically infinity function (an extension of Liouville's theorem). For if such a function f is nonconstant, then since the set of z where f(z) is infinity is isolated and the Riemann sphere is compact, there are finitely many z with f(z) equal to infinity. Consider the Laurent expansion at all such z and subtract off the singular part: we are left with a function on the Riemann sphere with values in C, which by Liouville's theorem is constant. Thus f is a rational function. This fact shows there is no essential difference between the complex projective line as an algebraic variety, or as the Riemann sphere.

Important results
There is a long history of comparison results between algebraic geometry and analytic geometry, beginning in the nineteenth century. Some of the more important advances are listed here in chronological order.

Riemann's existence theorem
Riemann surface theory shows that a compact Riemann surface has enough meromorphic functions on it, making it an (smooth projective) algebraic curve. Under the name Riemann's existence theorem a deeper result on ramified coverings of a compact Riemann surface was known: such finite coverings as topological spaces are classified by permutation representations of the fundamental group of the complement of the ramification points. Since the Riemann surface property is local, such coverings are quite easily seen to be coverings in the complex-analytic sense. It is then possible to conclude that they come from covering maps of algebraic curves—that is, such coverings all come from finite extensions of the function field.

The Lefschetz principle
In the twentieth century, the Lefschetz principle, named for Solomon Lefschetz, was cited in algebraic geometry to justify the use of topological techniques for algebraic geometry over any algebraically closed field K of characteristic 0, by treating K as if it were the complex number field. An elementary form of it asserts that true statements of the first order theory of fields about C are true for any algebraically closed field K of characteristic zero. A precise principle and its proof are due to Alfred Tarski and are based in mathematical logic.

This principle permits the carrying over of some results obtained using analytic or topological methods for algebraic varieties over C to other algebraically closed ground fields of characteristic 0. (e.g. Kodaira type vanishing theorem.)

Chow's theorem
, proved by Wei-Liang Chow, is an example of the most immediately useful kind of comparison available. It states that an analytic subspace of complex projective space that is closed (in the ordinary topological sense) is an algebraic subvariety. This can be rephrased as "any analytic subspace of complex projective space that is closed in the strong topology is closed in the Zariski topology." This allows quite a free use of complex-analytic methods within the classical parts of algebraic geometry.

GAGA
Foundations for the many relations between the two theories were put in place during the early part of the 1950s, as part of the business of laying the foundations of algebraic geometry to include, for example, techniques from Hodge theory. The major paper consolidating the theory was Géometrie Algébrique et Géométrie Analytique by Jean-Pierre Serre, now usually referred to as GAGA. It proves general results that relate classes of algebraic varieties, regular morphisms and sheaves with classes of analytic spaces, holomorphic mappings and sheaves. It reduces all of these to the comparison of categories of sheaves.

Nowadays the phrase GAGA-style result is used for any theorem of comparison, allowing passage between a category of objects from algebraic geometry, and their morphisms, to a well-defined subcategory of analytic geometry objects and holomorphic mappings.

Formal statement of GAGA
f =\varphi^\mathrm{an} $$. If $$ \mathcal R $$ is a coherent analytic sheaf of $$ \mathcal O_X^\mathrm{an} $$-modules over Xan then there exists a coherent algebraic sheaf $$ \mathcal F $$ of $$ \mathcal O_X $$-modules and an isomorphism $$ \mathcal F^\mathrm{an} \cong \mathcal R $$.
 * 1) Let $$ (X,\mathcal O_X) $$ be a scheme of finite type over C. Then there is a topological space Xan that as a set consists of the closed points of X with a continuous inclusion map λX: Xan → X. The topology on Xan is called the "complex topology" (and is very different from the subspace topology).
 * 2) Suppose φ: X → Y is a morphism of schemes of locally finite type over C. Then there exists a continuous map φan: Xan → Yan such that λY ∘ φan = φ ∘ λX.
 * 3) There is a sheaf $$ \mathcal O_X^\mathrm{an} $$ on Xan such that $$ (X^\mathrm{an}, \mathcal O_X^\mathrm{an}) $$ is a ringed space and λX: Xan → X becomes a map of ringed spaces. The space $$ (X^\mathrm{an}, \mathcal O_X^\mathrm{an}) $$ is called the "analytification" of $$ (X,\mathcal O_X) $$ and is an analytic space. For every φ: X → Y the map φan defined above is a mapping of analytic spaces. Furthermore, the map φ ↦ φan maps open immersions into open immersions. If X = Spec(C[x1,...,xn]) then Xan = Cn and $$ \mathcal O_X^\mathrm{an}(U) $$ for every polydisc U is a suitable quotient of the space of holomorphic functions on U.
 * 4) For every sheaf $$ \mathcal F $$ on X (called algebraic sheaf) there is a sheaf $$ \mathcal F^\mathrm{an} $$ on Xan (called analytic sheaf) and a map of sheaves of $$ \mathcal O_X $$-modules $$ \lambda_X^*: \mathcal F\rightarrow (\lambda_X)_* \mathcal F^\mathrm{an} $$. The sheaf $$ \mathcal F^\mathrm{an} $$ is defined as $$ \lambda_X^{-1} \mathcal F \otimes_{\lambda_X^{-1} \mathcal O_X} \mathcal O_X^\mathrm{an} $$. The correspondence $$ \mathcal F \mapsto \mathcal F^\mathrm{an} $$ defines an exact functor from the category of sheaves over $$ (X, \mathcal O_X) $$ to the category of sheaves of $$ (X^\mathrm{an}, \mathcal O_X^\mathrm{an}) $$. The following two statements are the heart of Serre's GAGA theorem (as extended by Alexander Grothendieck, Amnon Neeman, and others).
 * 5) If f: X → Y is an arbitrary morphism of schemes of finite type over C and $$ \mathcal F $$ is coherent then the natural map $$ (f_* \mathcal F)^\mathrm{an}\rightarrow f_*^\mathrm{an} \mathcal F^\mathrm{an} $$ is injective. If f is proper then this map is an isomorphism. One also has isomorphisms of all higher direct image sheaves $$ (R^i f_* \mathcal F)^\mathrm{an} \cong R^i f_*^\mathrm{an} \mathcal F^\mathrm{an} $$ in this case.
 * 6) Now assume that Xan is Hausdorff and compact. If $$ \mathcal F, \mathcal G $$ are two coherent algebraic sheaves on $$ (X, \mathcal O_X) $$ and if $$ f\colon \mathcal F^\mathrm{an} \rightarrow \mathcal G^\mathrm{an} $$ is a map of sheaves of $$ \mathcal O_X^\mathrm{an} $$-modules then there exists a unique map of sheaves of $$ \mathcal O_X $$-modules $$ \varphi: \mathcal F\rightarrow \mathcal G $$ with $$

In slightly lesser generality, the GAGA theorem asserts that the category of coherent algebraic sheaves on a complex projective variety X and the category of coherent analytic sheaves on the corresponding analytic space Xan are equivalent. The analytic space Xan is obtained roughly by pulling back to X the complex structure from Cn through the coordinate charts. Indeed, phrasing the theorem in this manner is closer in spirit to Serre's paper, seeing how the full scheme-theoretic language that the above formal statement uses heavily had not yet been invented by the time of GAGA's publication.


text: User talk:212.76.33.74

title: User talk:212.76.33.74


text:
User:Rbrwr/companies

 * 3i Group -- 3i Group plc
 * Abbey National -- Abbey National plc
 * Alliance & Leicester -- Alliance & Leicester plc -- Alliance and Leicester
 * Alliance Unichem -- Alliance Unichem plc
 * Allied Domecq -- Allied Domecq plc
 * Amvescap -- Amvescap plc
 * Anglo American -- Anglo American plc -- Anglo-American
 * Antofagasta -- Antofagasta plc
 * Associated British Foods -- Associated British Foods plc
 * Astrazeneca -- Astrazeneca plc
 * Aviva -- Aviva plc
 * BAA -- BAA plc
 * BAE Systems -- BAE Systems plc -- BAE SYSTEMS
 * BG Group -- BG Group plc -- British Gas
 * BHP Billiton -- BHP Billiton plc -- BHP
 * BOC Group -- BOC Group plc -- BOC
 * BP -- BP plc
 * BT Group -- BT Group plc -- BT -- British Telecom
 * Barclays -- Barclays plc -- Barclays Bank -- Barclay's Bank
 * Boots Co -- Boots Co plc -- Boots the Chemist
 * Bradford & Bingley -- Bradford & Bingley plc -- Bradford and Bingley
 * British Airways -- British Airways plc
 * British American Tobacco -- British American Tobacco plc -- BAT
 * British Land Co -- British Land Co plc -- British Land
 * British Sky Broadcasting Group -- British Sky Broadcasting Group plc -- BSkyB
 * Bunzl -- Bunzl plc
 * Cable & Wireless -- Cable & Wireless plc -- Cable and Wireless
 * Cadbury Schweppes -- Cadbury Schweppes plc -- Cadbury/s/'s -- Schweppes
 * Carnival -- Carnival plc
 * Centrica -- Centrica plc -- British Gas
 * Compass Group -- Compass Group plc
 * Daily Mail & General Trust (A Shs) -- Daily Mail & General Trust -- Daily Mail & General Trust plc
 * Diageo -- Diageo plc
 * Dixons Group -- Dixons Group plc -- Dixons
 * EMAP -- EMAP plc
 * Enterprise Inns -- Enterprise Inns plc
 * Exel -- Exel plc
 * Friends Provident -- Friends Provident plc
 * GKN -- GKN plc
 * GUS -- GUS plc
 * Gallaher Group -- Gallaher Group plc
 * GlaxoSmithKline -- GlaxoSmithKline plc
 * HBOS -- HBOS plc
 * HSBC Hldgs -- HSBC Hldgs plc -- HSBC
 * Hanson -- Hanson plc
 * Hays -- Hays plc
 * Hilton Group -- Hilton Group plc
 * Imperial Chemical Industries -- Imperial Chemical Industries plc -- ICI
 * Imperial Tobacco Group -- Imperial Tobacco Group plc -- Imperial Tobacco
 * Intercontinental Hotels -- Intercontinental Hotels Group plc -- Intercontinental Hotels Group -- Intercontinental Hotels Group plc -- InterContinental Hotels -- InterContinental Hotels Group plc -- InterContinental Hotels Group -- InterContinental Hotels Group plc
 * ITV -- ITV plc
 * Johnson Matthey -- Johnson Matthey plc
 * Kingfisher -- Kingfisher plc
 * Land Securities -- Land Securities plc
 * Legal & General Group -- Legal & General Group plc
 * Liberty Intl -- Liberty Intl plc
 * Lloyds TSB Group -- Lloyds TSB Group plc -- Lloyds TSB -- Lloyds Bank
 * MAN Group -- MAN Group plc -- MAN
 * Marks & Spencer Group -- Marks & Spencer Group plc -- Marks & Spencer
 * MM02 PLC -- MM02
 * Morrison (Wm) Supermarkets -- Morrison (Wm) Supermarkets plc -- Morrisons -- Morrison (Wm) -- Wm Morrison
 * National Grid Group -- National Grid Group plc -- National Grid
 * Next -- Next plc
 * Northern Rock -- Northern Rock plc
 * Old Mutual -- Old Mutual plc
 * Pearson -- Pearson plc
 * Prudential -- Prudential plc
 * Reckitt Benckiser -- Reckitt Benckiser plc
 * Reed Elsevier -- Reed Elsevier plc
 * Rentokil Initial -- Rentokil Initial plc
 * Reuters Group -- Reuters Group plc -- Reuters
 * Rexam -- Rexam plc
 * Rio Tinto Group -- Rio Tinto plc -- RTZ -- Rio Tinto Zinc
 * Rolls-Royce -- Rolls-Royce plc
 * Royal Bank Of Scotland Group -- Royal Bank Of Scotland Group plc
 * Royal & Sun Alliance -- Royal & Sun Alliance plc
 * SABMiller -- SABMiller plc
 * Sage Group -- Sage Group plc -- Sage -- SageSoft
 * Sainsbury (J) -- Sainsbury (J) plc -- Sansburys -- Sainsbury's
 * Schroders PLC -- Schroders
 * Schroders PLC-NV -- Schroders-NV
 * Scottish & Newcastle -- Scottish & Newcastle plc -- ScottishCourage
 * Scottish & Southern Energy -- Scottish & Southern Energy plc
 * Scottish Power -- Scottish Power plc
 * Severn Trent -- Severn Trent plc -- Severn Trent Water
 * Shell Transport & Trading Co -- Shell Transport & Trading Co plc -- Shell -- Shell Oil
 * Shire Pharmaceuticals Group -- Shire Pharmaceuticals Group plc
 * Smith & Nephew -- Smith & Nephew plc -- Smith and Nephew -- Smith and Nephew plc
 * Smiths Group -- Smiths Group plc
 * Standard Chartered -- Standard Chartered plc
 * Tesco -- Tesco plc
 * Tomkins -- Tomkins plc
 * Unilever -- Unilever plc
 * United Utilities -- United Utilities plc
 * Vodafone Group -- Vodafone Group plc
 * Whitbread -- Whitbread plc
 * William Hill -- William Hill plc
 * Wolseley -- Wolseley plc
 * WPP Group -- WPP Group plc -- WPP
 * Xstrata -- Xstrata plc
 * Yell Group -- Yell Group plc

title: User:Rbrwr/companies


text:
Bootleg Series Volume 1: The Quine Tapes

Bootleg Series Volume 1: The Quine Tapes is a triple live album by The Velvet Underground. It was released on October 16, 2001, by Polydor, the record label overseeing the band's UMG back catalogue. It was recorded by Robert Quine, a fan of the band who would later become an influential guitarist, playing with Richard Hell, Lou Reed, and Lloyd Cole.

The Quine Tapes
During 1969, the Velvet Underground toured the United States and Canada, playing well over 70 dates. By this time, the band had picked up a sizeable fan base and every now and then a fan would bring along, with consent of the band, recording equipment to record a set. Most of the time, this would mean relatively simple hand-held recorders resulting in lo-fi mono audience recordings, as with this set and the live album Live at Max's Kansas City (1972) (1969: The Velvet Underground Live was the notable exception, using stereo soundboard recordings).

Robert Quine, an avid Velvet Underground fan, used to travel to as many concerts as possible. He became friends with the band and they allowed him to record sets from the audience, occasionally asking for playbacks. Quine recorded many concerts, but as his original musicassette tapes began to wear out, he compiled four reels of what he considered the best material. These "best-of" reels were ultimately released in 2001 as the present The Quine Tapes set. The original musicassettes from which the reels were compiled no longer exist.

Musically, The Quine Tapes finds the band in the same phase in their history as documented on 1969—the two sets even share a performance of "Rock and Roll", recorded at the same concert by both Quine and the Matrix sound personnel. Quine's tapes, although lo-fi audience recordings, capture much more of the music's ambience, especially in the larger venues, such as Washington University in St. Louis. Additionally, The Quine Tapes contains songs that the band only rarely performed by this time, such as "Sunday Morning", "Venus in Furs" and "The Black Angel's Death Song", along with other obscurities such as "Over You", "Ride into the Sun", and "Follow the Leader", which had never even been bootlegged in its original form.

The Bootleg Series
The Quine Tapes is, to date, the only entry in the Bootleg Series. The second volume was to be a recording of an April 1967 show at The Gymnasium in New York City, which marked the live debut of "Sister Ray". Two songs from the show, "Guess I'm Falling in Love" and "Booker T", appeared on the box set Peel Slowly and See (1995), and the full show was released in December 2013 as part of the "Super Deluxe" reissue of White Light/White Heat. It contains the only known recorded performance of "I'm Not a Young Man Anymore".

Monetary disputes between the band and Universal have apparently put a hold on future entries in the series. This same dispute over a revised contract also kept "Miss Joanie Lee," recorded during a rehearsal at Andy Warhol's Factory, from appearing on the deluxe two-disc reissue of The Velvet Underground & Nico.

Personnel

 * The Velvet Underground
 * Sterling Morrison – lead and rhythm guitar, backing vocals, bass
 * Lou Reed – vocals, rhythm and lead guitar
 * Maureen Tucker – percussion, lead vocals on "After Hours" and "I'm Sticking with You"
 * Doug Yule – bass guitar, organ, backing vocals, lead vocal on "Ride into the Sun"

 * Technical staff
 * Robert Quine – recording engineer
 * The Velvet Underground – producers


text:
Chow's theorem

In mathematics, Chow's theorem may refer to a number of theorems due to Wei-Liang Chow:
 * Chow's theorem: The theorem that asserts that any analytic subvariety in projective space is actually algebraic.
 * Chow–Rashevskii theorem: In sub-Riemannian geometry, the theorem that asserts that any two points are connected by a horizontal curve.

title: Chow's theorem


text:
HP-IL

The HP-IL (Hewlett-Packard Interface Loop), was a short-range interconnection bus or network introduced by Hewlett-Packard in the early 1980s. It enabled many devices such as printers, plotters, displays, storage devices (floppy disk drives and tape drives), test equipment, etc. to be connected to programmable calculators such as the HP-41C, HP-71B and HP-75C/D, the Series 80 and HP-110 computers, as well as generic ISA bus based PCs.

Principles
As its name implies, an HP-IL network formed a loop (i.e. it was a Ring network): each device in the loop had a pair of two-wire connections, one designated in, which received messages from the previous device in the loop; and one designated out, which delivered messages to the next device in the loop. One device on the loop is designated the controller, and manages all other devices on the loop. HP-IL cables utilize a unique two-pin connector design with polarizing D-shaped shells, and can be connected together without further adapters to extend their length.

HP-IL uses a token passing protocol for media access control: messages are passed from one device to the next until they return to the originator. When the loop is initialized, the controller sends an "Auto Address 1" message to the first device; that device (and each subsequent device) takes the number in the message it receives as its own address, and then forwards the message with the address incremented to the next device. When the "Auto Address n" message finally returns to the controller, it can tell how many devices are on the loop (n-1). Up to 31 devices can be addressed using this method. Once addresses are assigned, the controller can then assign "talker" or "listener" roles to any device on the loop. By addressing each device in turn, and using the "Send Accessory ID" message, the controller can determine the role and capability of each device on the loop.

When the controller assigns listener role to a device, that device accepts and processes data received from the loop. The role of talker allows a device to originate data on the loop. Multiple devices can be assigned the role of listener at once, but the role of talker can only be assigned to a single device at a time. Data transfer between loop devices is accomplished by the controller designating a talker and one or more listeners and then sourcing a "Send Data" message.

Most devices that were designed to be used as controllers were fixed in that role, but the HP-71B was capable of assuming either controller or device mode; and with the HP 82402 Dual HP-IL Adapter, the HP-71B could even be configured with multiple loops.

Applications
Hewlett-Packard developed a range of devices to be connected to the HP-IL, mostly peripherals such as printers and storage devices for calculators. Through the 82169A HP-IL/HP-IB Interface, HP-IL controllers could be connected to instruments with an HP-IB (aka GPIB or IEEE-488) interface, or vice versa. There were also plans to make test equipment with IL interfaces, but apart from the somewhat popular 3468A multimeter, only a few devices were introduced before HP-IL itself became obsolete.

In addition to the HP-IB interface, HP also sold RS-232 and general-purpose parallel I/O interfaces as well as a prototype kit to create custom interfaces.

HP Calculator Applications
Several HP calculators were offered with HP-IL interfaces. In the HP-75C/D it was built in, in others such as the HP-71 and HP-41, plug in interface modules were available (such as the HP82160A for the HP-41). Popular uses for the HP-IL on the calculators included printing (using the HP 82162A thermal printer) and cassette file storage (through the HP 82161A digital cassette drive). For ease of use, the calculators supported automatic I/O address assignment ("AUTOIO"), where printer or mass storage commands are directed to the first available device of the appropriate type. Where multiple devices per type were present, a manual ("MANIO") assignment mode could be used.

HP-IL to HP-IB interfacing
Through the 82169A interface converter, even small calculators could be used to control a number of devices on a standard HP-IB (GPIB, IEEE-488) bus, an interface in wide use for test and measurement equipment. The converter can operate in either of two modes, Translator or Mailbox. Translator mode is adequate for systems where only one controller is present (typically a calculator on HP-IL), while Mailbox mode applies when there are separate controllers present on both buses.

In Translator mode with an HP-IL controller, the default addressing mode is to connect the converter as the last device in the HP-IL loop, to set its own HP-IB address higher than the number of devices on the HP-IL loop, and to set the addresses of devices to be addressed on the HP-IB side must be higher than the converter's address. Deviating from this scheme requires manual control of addressing.

In Mailbox mode, the controllers on either side can place a message into the converter's buffer memory, for the other side to retrieve from that memory.

Controllers

 * HP 82160A HP-IL HP-41 extension module (for the HP-41C)
 * HP 82973A HP-IL interface for IBM PC and compatibles with ISA bus
 * HP 82938A Interface for Series 80 desktop computers/controllers
 * HP 82401A HP-IL module for HP-71B
 * HP-75C/D
 * HP 110 aka HP Portable
 * HP 110 Plus aka HP Portable Plus (HP 45711A)
 * HP 45643A HP-IL/Parallel Interface for the HP-150
 * HP Integral PC
 * HP-3392A

Interfaces

 * HP 82164A HP-IL/RS-232C Interface (serial port)
 * HP 82165A HP-IL/GPIO Interface (generic parallel port)
 * HP 82166A HP-IL Converter (smaller version of GPIO interface intended for embedded use)
 * HP 82166C HP-IL Converter Prototyping Kit
 * HP 82169A HP-IL/HPIB Interface (bidirectional)
 * HP 5061-3166 HP-IL/SCSI Interface
 * HP 82402 Dual HP-IL Adapter for the HP-71B

Peripherals

 * HP 9114A/B Disc Drives
 * HP 82161A Tape Drive
 * HP 82162A Thermal Printer (HP-IL version of HP 82143A printer for HP-41C)
 * HP 82163A/B Video Interface
 * HP 92198A 80-Column Video Interface (Mountain Computer)
 * HP 82168A, 92205M Acoustic Couplers (Modems)
 * HP 82905A/B Printers
 * HP 2225B ThinkJet Printer
 * HP 7470A Graphics Plotter (Opt. 003 HP-IL Interface)
 * HP 2671A/G Alphanumeric Graphics Thermal Printer

Test instruments

 * HP 1630A/D/G and HP1631 Logic analyzers (can be loop controller)
 * HP 3421A Data Acquisition/Control Unit
 * HP 3468A/B Digital Multimeters (HP-IL version of HP 3478A with GPIB)
 * HP 5384A and HP 5385A frequency counters with option 003 (HP-IL)
 * HP 8590A spectrum analyzer with option 022 (HP-IL)
 * HP 5890 Gas Chromatograph and companion Autosampler HP 7673 have an HP-IL interface option for instrument programming and data logging using the HP 19405A Sampler/Event Control Module (S/ECM) and the HP 3392A Gas Chromatograph Integrator as controller.
 * HP 4945A Transmission Impairment Measuring Set (Opt 103)
 * HP 5006A Signature Analyzer (Opt 030)

Software

 * HP-IL Development Module (plug-in Application ROM module for HP-41C)
 * HP 82183A Extended I/O Module

Third-party

 * FSI164A HP-IL/RS-232C Interface by Firmware Specialists
 * Leitz IL-41 Theodolite interface
 * CMT RAM Disc 128-512k RAM Disc; Optional RS-232
 * Ocean Scientific HP-IL A/D Interface
 * Direct Connect Modem 300 Plus Modem & Bar Code Reader
 * PAC Hardware GMBH (Germany) PAC-Screen 80-col/graphics video interface with parallel printer port and mouse port
 * Interloop #111 HP-IL Repeater
 * Interloop #130 HP-IL Twinax Terminator
 * Interloop #200 HP-IL Step Motor Driver
 * Interloop #210 HP-IL IO Interface
 * Steinmetz & Brown SB10161A/2A Single/Dual 5 1/4" Disc Drive
 * Interface Instruments ADC71A Analog to Digital Converter

title: HP-IL


text:
The Evolution of Melanism

The Evolution of Melanism: a study of recurring necessity; with special reference to industrial melanism in the Lepidoptera is a 1973 science book by the lepidopterist Bernard Kettlewell.

The book includes Kettlewell's original papers in the journal Heredity on his classic predation experiments on the peppered moth. It also covers Kettlewell's experiments in Shetland on other Lepidoptera (moths and butterflies).

The book is centered on the authors research of evolution of industrial melanism in peppered moths. It does not goes much in-depth about the evolution of melanism in other species as the title might suggest. The book introduces the reader with a 50-page long chapter about melanism. Then, the book goes in-depth about industrial melanism. Finally, the peppered moth Biston betularia is discussed in all its known details of that time. Knowledge of the genetics of the melanistic forms of the moths, the knowledge of the predation by birds and the knowledge of blackening of the environment in the English midlands is discussed and used for Kettlewell's most important experiments on natural selection. This is also the climax of the book, namely the details and outcomes of his own experiments on natural selection. Kettlewell also shows other cases, such as his experiments in the Shetland Islands with Lasiocampa quercus (‘Recessive melanic plymorphisms’) and Amanthes glareosa (‘Northern melanism’) (Kettlewell et al., 1969). However, these lack knowledge compared to the Biston experiments. Therefore, they are mostly seem as secondary importance. However, according to Carson (1974), “they play an important role in showing that manifold genetic melanisms can exist apart from those that have evolved as a genetic response to industrial pollution”. The conclusion of the book discusses several melanisms, such as polymorphism.

Importance of the book
The experiments with the peppered moths, as described in this book, are arguably the most dramatic and best known case of adaptive evolution. For many people at that time, this was the first evidence that they could see evolution taking place in the world around them, and could see how fast evolution can go since Darwin came up with the hypothesis (Kettlewell, 1959). In today's biology books on primary schools and even in university books, this is still one of the most common example of adaptive evolution according to Carson (1974). It also led to more studies to industrial melanism in other species and places at that time but also currently. After his papers were published in the late 1950s (from which his book mostly consists of), there was an increase in studies. These included two-spot ladybirds (Adalia bipuncta) in the U.K. (Creed, 1970) and some Lepidoptera from North America (Owen, 1961). More recent studies were conducted on seasnakes (Emydocephalus annulatus) in New Caledonia (Goiran et al., 2017).

Criticism
Most of the information depicted in the book was already published before and it followed the presentation of Kettlewell's papers. He has altered many figures and tables slightly compered to the originals which were mostly published in the journal Heredity. It was therefore criticised that this book was more a compilation of Kettlewell's work instead of a synthesis (Carson, 1974). Furthermore, some of the black-and-white photographs were of better quality in the journals than in the book.

The entomologist and geneticist Michael Majerus reviewed this in his 1998 book Melanism: Evolution in Action, and compared it with more recent studies which did not support some of Kettlewell's conclusions. He called for more research, and in 2001 began extended experiments. In 2002, Judith Hooper wrote a book about Kettlewell, Of Moths and Men, accusing Kettlewell of fraudulent data. Majerus concluded his research in 2007, with results which he described as a complete vindication of the natural selection theory of peppered moth evolution, answering the various questions which had been raised.

title: The Evolution of Melanism


text:
Venda Nova do Imigrante

Venda Nova do Imigrante is a municipality, with a capital of the same name, in east central Espírito Santo, Brazil. Created in 1989, by separating from Conceição do Castelo, it stands at a height of 630 meters above sea level. Its population was 25,745 (2020) and its area is 185.9 km2.

It was mainly colonised by northern Italian immigrants and still holds Italian-themed festivals such as the Polenta festival and wine festivals. Other such traditions still held on to are traditional Italian dancing and choral singing, often seen during such festivals.

Bordering municipalities include: (E) Domingos Martins, (N) Afonso Claudio, (W) Conceição do Castelo and Castelo in the south.

title: Venda Nova do Imigrante