text:
5-Hydroxytryptamine or
Other names
5-Hydroxytryptamine, 5-HT, Enteramine; Thrombocytin, 3-(β-Aminoethyl)-5-hydroxyindole, Thrombotonin
|CAS number
|IUPHAR ligand
|Jmol-3D images
|Image 1
|Molecular formula
|Molar mass
|176.215 g/mol
|White powder
|Melting point
|167.7 °C (333.9 °F; 440.8 K) 121–122 °C (ligroin)[1]
|Boiling point
|416 ± 30 °C (at 760 Torr)[2]
|Solubility in water
|slightly soluble
|Acidity (pKa)
|10.16 in water at 23.5 °C[3]
|Dipole moment
|External MSDS
|750 mg/kg (subcutaneous, rat),[4] 4500 mg/kg (intraperitoneal, rat),[5] 60 mg/kg (oral, rat)
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.[6]
Approximately 90% of the [7][8] The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.
Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors.
Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing (serotonin itself does not cause flushing. Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine), diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes,[9] a serotonin-secreting carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes onto the valve.
In addition to animals, serotonin is found in fungi and plants.[10] Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection. Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.
Functions 1
- Receptors 1.1
Gauge of food availability (appetite) 1.2
- Effects of food content 1.2.1
- In the digestive tract (emetic) 1.2.2
- Gauge of social situation 1.2.3
- Growth and reproduction 1.3
- Aging and age-related phenotypes 1.4
- Bone metabolism 1.5
- Organ development 1.6
- Cardiovascular growth factor 1.7
- Deficiency 1.8
In the brain 2
- Gross anatomy 2.1
Microanatomy 2.2
- Receptors 2.2.1
- Termination 2.2.2
- Serotonylation 2.2.3
- Biosynthesis 3
Drugs targeting the 5-HT system 4
- Psychedelic drugs 4.1
Antidepressants 4.2
- Serotonin syndrome 4.2.1
- Antiemetics 4.3
- In unicellular organisms 5
In plants 6
- Methyl-tryptamines and hallucinogens 6.1
- Insect venom 7
- History 8
- Notes 9
- References 10
- External links 11
Serotonin is a neurotransmitter and is found in all
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- Commons category template with no category set
- Commons category with page title same as on Wikidata
- Serotonin
- Tryptamine alkaloids
- Biogenic amines
- Neurotransmitters
- TAAR1 agonists
- Serotonin receptor agonists
- Serotonin releasing agents
- 5-Hydroxytryptamine MS Spectrum
- Serotonin bound to proteins in the PDB
- PsychoTropicalResearch Extensive reviews on serotonergic drugs and Serotonin Syndrome.
- Molecule of the Month: Serotonin at University of Bristol
- 60-Second Psych: No Fair! My Serotonin Level Is Low, Scientific American
- Serotonin Test Interpretation on ClinLab Navigator.
- Gutknecht L, Jacob C, Strobel A et al. (June 2007). "Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation". The International Journal of Neuropsychopharmacology 10 (3): 309–20.
- The Psychobiology of Serotonin Deficiency Syndrome
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- ^ Banu N, Zaidi KR, Mehdi G, Mansoor T; Zaidi; Mehdi; Mansoor (2005). "Neurohumoral alterations and their role in amoebiasis" (PDF). Indian J. Clin Biochem 20 (2): 142–5.
- ^ Acharya DP, Sen MR, Sen PC; Sen; Sen (1989). "Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals". Indian J. Exp. Biol. 27 (8): 718–20.
- ^ Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W.; Abele; Gohr; Stuhlfauth-Roisch; Grosse (1999). "Latest on enzymology of serotonin biosynthesis in walnut seeds". Adv Exp Med Biol. Advances in Experimental Medicine and Biology 467: 637–644.
- ^ Feldman JM, Lee EM; Lee (October 1985). "Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid". The American Journal of Clinical Nutrition 42 (4): 639–43.
- ^ Pénez N, Culioli G, Pérez T, Briand JF, Thomas OP, Blache Y; Culioli; Pérez; Briand; Thomas; Blache (October 2011). "Antifouling properties of simple indole and purine alkaloids from the Mediterranean gorgonian Paramuricea clavata". Journal of Natural Products 74 (10): 2304–8.
- ^ Guillén-Casla V, Rosales-Conrado N, León-González ME, Pérez-Arribas LV, Polo-Díez LM; Rosales-Conrado; León-González; Pérez-Arribas; Polo-Díez (April 2012). "Determination of serotonin and its precursors in chocolate samples by capillary liquid chromatography with mass spectrometry detection". Journal of Chromatography A 1232: 158–65.
- ^ Tyler VE (September 1958). "Occurrence of serotonin in a hallucinogenic mushroom". Science 128 (3326): 718.
- ^ Stanley E. Manahan, Toxicological Chemistry and Biochemistry, Third Edition. CRC Press, 2002. ISBN 9781420032123
- ^ Michael R. Dobbs Clinical Neurotoxicology: Syndromes, Substances, Environments, Expert Consult. Elsevier Health Sciences, 2009. ISBN 9780323070997
- ^ Negri L (2006). "[Vittorio Erspamer (1909–1999)]". Med Secoli (in Italian) 18 (1): 97–113.
- ^ Rapport MM, Green AA, Page IH; Green; Page (December 1948). "Serum vasoconstrictor, serotonin; isolation and characterization". The Journal of Biological Chemistry 176 (3): 1243–51.
- ^ FELDBERG W, TOH CC; Toh (February 1953). "Distribution of 5-hydroxytryptamine (serotonin, enteramine) in the wall of the digestive tract". The Journal of Physiology 119 (2–3): 352–62.
- ^ SciFinder – Serotonin Substance Detail. Accessed (4 November 2012).
- ^ Twarog BM, Page IH; Page (October 1953). "Serotonin content of some mammalian tissues and urine and a method for its determination". The American Journal of Physiology 175 (1): 157–61.
- ^ References are ignored for the functions of these receptors due to the fact they appear on the WorldHeritage pages for the specific receptor in question
In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.[114] Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(β-Aminoethyl)-5-hydroxyindole.[115] In 1953, Betty Twarog and Page discovered serotonin in the central nervous system.[116]
In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine".[112] In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin.[113]
Wasps and hornets have serotonin in their venom,[110]:393-394 as do scorpions.[111]:468
Insect venom
Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by monoamine oxidase enzymes (mainly MAO-A) in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus Panaeolus.[109]
Methyl-tryptamines and hallucinogens
Unlike its precursors, 5-HTP and tryptophan, serotonin does not cross the blood–brain barrier, which means ingesting serotonin in the diet has no immediate effect on brain serotonin levels.
Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 µg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 µg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.[108]
Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see above). It is also naturally found in Paramuricea clavata, or the Red Sea Fan.[107]
However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits as a way of speeding the passage of seeds through the digestive tract, in the same way as many well-known seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.[106]
In drying seeds, serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.[105]
In plants
Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae.[100] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[101][102] Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection.[103] E. histolytica also responds to the presence of serotonin by becoming more virulent.[104] This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside a host, the density of entoamoebas is low, hence also the serotonin concentration. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the serotonin concentration increases.
In unicellular organisms
Some 5-HT3 antagonists, such as ondansetron, granisetron, and tropisetron, are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of postoperative nausea and vomiting.
Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.[98] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.[99]
Serotonin syndrome
Although phobias and depression might be attenuated by serotonin-altering drugs, this does not mean the individual's situation has been improved, but only the individual's perception of the environment. Sometimes, a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.[97]
Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. This has been connected to the observation that the benefit of SSRIs may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time).[93] The antidepressants mirtazapine and mianserin (5HT2 and 5HT3 receptors antagonists) have mood-elevating effects. This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods, rather than level directly correlating with mood. In fact, the 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling.[94] The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.[95][96] Therefore, increasing levels of extracellular serotonin may be associated with increased affect, for good or for worse.
Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder and social phobia. Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content, and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. The side-effects that have become apparent recently include a decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain.[63] There is investigation into whether SSRIs benefits to mood are somehow related to dopamine receptor sensitivity indirectly influenced by antidepressant mechanisms. In one study, patients with depression taking an SSRI were given low dose D2 receptor antagonist administration, and reported negative effect on mood.[92]
The psychedelic drugs psilocin/psilocybin, DMT, mescaline, phencyclidine and LSD are agonists, primarily at 5HT2A/2C receptors.[88][89][90] The empathogen-entactogen MDMA releases serotonin from synaptic vesicles of neurons.[91]
Psychedelic drugs
Several classes of drugs target the 5-HT system, including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.
Drugs targeting the 5-HT system
Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood–brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood–brain barrier. These agents are available as dietary supplements, and may be effective serotonergic agents. One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.
Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Asperigillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction.[87]
In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform.[75]
Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins.[58] This process underlies serotonin effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis.[85] A similar process underlies the pancreatic release of insulin.[58] The effects of serotonin upon vascular smooth muscle tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.[86]
Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km of 114 micromoles/l for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport 'capacity' than SERT, "..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems." The study also suggests some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitude; therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine, albeit at Km values even higher than that of 5-HT (330–15,000 μmoles/L).
Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). A 2006 study conducted by the University of Washington suggested a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance".[64]
The 5-HT receptors, the receptors for serotonin, are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G protein-coupled, seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.[84]
Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[82] There are 7 or 8 raphe nuclei (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which located along the midline of the brainstem, and centered around the reticular formation.[83] Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.
Gross anatomy
In the brain
Consumption of an average amount of alcohol (.8g/kg of body weight) shows to decrease tryptophan by about 25%, leading to a similar decrease in serotonin. The sexual and impulsive behavior resulting from an intoxicated state is at least partially an effect of the decrease in serotonin because serotonin regulates these behaviors.[81]
Depletion of serotonin is common between disorders such as obsessive-compulsive disorder, depression, and anxiety. However, Dr. Marazziti and his researchers at the University of Pisa in Italy, found that depletion of serotonin also occurs in people who have recently fallen in love. This leads to the obsessive component associated with early stages of love.[81]
Recent research conducted at Rockefeller University shows, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.[80]
In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy[78] genetically modified lab mice to produce low levels of the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age. Researchers now believe low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death.[60] If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[79]
Genetically altered mice that lack TPH2 are normal when they are born. However, after three days, they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain, 50% of the mutants died during the first four weeks, but in a mixed strain, 90% survived. Normally, the mother weans the litter after three weeks, but the mutant animals needed five weeks. After that, they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young.[76] Despite the blood–brain barrier, the loss of serotonin production in the brain is partially compensated by intestinal serotonin. The behavioural changes become greatly enhanced if one crosses TPH1- with TPH2-lacking mice and gets animals that lack TPH entirely.[77]
Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice lacking TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure.[75]
Genetically altered C. elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.[73][74]
Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide, along with cabergoline, in causing valvular heart disease.[69][70] As a result of this, the FDA removed pergolide from the U.S. market in March 2007.[71] (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).[72]
Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.[66] In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. They are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and methysergide),[66] the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.[67] As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since reported in 2003 to be associated with cardiac fibrosis.[68]
Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.[64] In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.[65]
Cardiovascular growth factor
In the fruitfly, where insulin both regulates blood sugar and acts as a growth factor, serotonergic neurons regulate the adult body size by affecting insulin secretion.[55][56] Serotonin has also been identified as the trigger for swarm behavior in locusts.[57] In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, so serotonin suppresses insulin release from the beta cells in the pancreas,[58] and exposure to SSRIs reduces fetal growth.[59] Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.[60] Serotonin present in the blood then stimulates cellular growth to repair liver damage.[61] 5HT2B receptors also activate osteocytes, which build up bone[62] However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.[63]
Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning and longevity.[47][48][49] Rodent experiments shows that early life exposure to SSRI:s makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,[50][51] which are reversed by treatment with antidepressants.[52] By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.[53][54]
Organ development
In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.[41][42][43][44] Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1B receptors, it negatively regulates bone mass, while it does so positively through 5-HT2B receptors and 5-HT2C receptors. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.[45] These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders.[46]
Bone metabolism
Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in C. elegans.[39] During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory.[40] The effect is restored by mutations and drugs (including mianserin and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early phase of aging.
In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.[35] Serotonin is necessary for normal nematode male mating behavior,[36] and the inclination to leave food to search for a mate.[37] The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway,[38] which control long-term adaption.
Growth and reproduction
In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression,[32] and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[33] Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.[34]
With Macaque monkeys, it has been found that alpha males have twice the level of serotonin released in the brain, as measured by the levels of 5-Hydoxyindolacetic acid (5-HIAA) in the cerebro-spinal fluid, than that found in subordinate males and females. Dominance and high levels of cerebro-serotonon levels seem to go hand in hand. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established serotonin levels of the new dominant individuals also rose to double that found in subdominant males and females. The reason why serotonin levels are only high in dominant males but not dominant females has not yet been established.[31]
If a lobster is injected with serotonin, it behaves as if it were alpha, while octopamine causes subordinate behavior.[29] A crayfish that is frightened may flip its tail to flee, and the effect of serotonin on this behavior depends largely on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.[30]
How much food an animal gets not only depends on food availability but also depends on the animal's ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker (this is not to say anti-social animals do not concern themselves with the needs of others and do not steal food from others). Thus, serotonin is not only involved in the perception of food availability but also involved in social rank.
If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.[27] The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.[28]
The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.
In the digestive tract (emetic)
Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan do not.[22] This is because the transport system which brings tryptophan across the blood-brain barrier is also selective for the other amino acids which are contained in protein food sources.[23] High plasma levels of other large neutral amino acids prevents the plasma concentration of tryptophan from increasing brain concentration levels.[23] Research also suggests eating a diet rich in carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.[23] However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels.[24][25] Muscles use 12 of the 13 amino acid groups (not using tryptophan), allowing more muscular individuals to produce more serotonin.[26]
Effects of food content
When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with increased weight gain,[18] especially in people with a low number of receptors.[19] The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm,[20] just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.[21]
Serotonin functions as a neurotransmitter in the nervous systems of simple, as well as complex, animals. For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new source of food or in male animals finding a female with which to mate.[15] When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food.[16] The released serotonin activates the muscles used for feeding, while octopamine suppresses them.[17] Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability.
Gauge of food availability (appetite)
|Ki (nM)[12]
|Receptor function[Note 1]
|5-HT1 receptor family signals via Gi/o inhibition of adenylyl cyclase.
|Memory (agonists ↓); learning (agonists ↓); anxiety (agonists ↓); depression (agonists ↓); positive, negative, and cognitive symptoms of schizophrenia (partial agonists ↓); analgesia (agonists ↑); aggression (agonists ↓); dopamine release in the prefrontal cortex (agonists ↑); serotonin release and synthesis (agonists ↓)
|Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor.
|Vasoconstriction (agonists ↑)
|5-HT2 receptor family signals via Gq activation of phospholipase C.
|Psychedelia (agonists ↑; antagonists ↑); depression (agonists & antagonists ↓); anxiety (antagonists ↓); positive and negative symptoms of schizophrenia (antagonists ↓); norepinephrine release from the locus coeruleus (antagonists ↑); glutamate release in the prefrontal cortex
|Cardiovascular functioning (agonists increase risk of pulmonary hypertension), empathy (via the spindle neurons or Von Economo neurons[13])
|Dopamine release into the mesocorticolimbic pathway (agonists ↓); acetylcholine release in the prefrontal cortex (agonists ↑); appetite (agonists ↓); antipsychotic effects (agonists ↑); antidepressant effects (agonists & antagonists ↑)
|Other 5-HT receptors
|Emesis (agonists ↑); anxiolysis (antagonists ↑)
|Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via Gαq activation of adenylyl cyclase.
|Memory consolidation.[14] Signals via Gi/o inhibition of adenylyl cyclase
|Cognition (antagonists ↑); antidepressant effects (agonists & antagonists ↑). Gs signalling via activating adenylyl cyclase.
|Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by Gs signalling via activating adenylyl cyclase.


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• Premium: 350 gsm for glossy and kraft, 360 gsm for matte.
• Standard: The traditional look, with clean 90 degree corners.
How to create an eye-catching design
• Have a quick, direct headline and no more than 2 different fonts.
• Keep your design simple – too many elements can be overwhelming.
•Stand out by using colorful photography, or making your logo big and bold.
Tips to put your postcards to work
• Create a consistent look by using the same paper and design as your business cards.
• Include a special offer or coupon so that you can track customer response.
• Create bag inserts to thank customers and highlight other products or services you offer.

subset: commoncrawl


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Young fast-food and retail workers demonstrate on the streets of Milwaukee
This is the second installment of a four-part series on Millennials and the new economy, based on the author's monthlong road trip with stops in the Rust Belt, Omaha, and Texas. Read the first.
This past May, I visited Milwaukee and spent the day with a few young startup founders. You know the types: college-educated twenty-somethings who, upon graduating into a terrible job market, decided to create their own jobs instead. Bright, organized, and creative, they are the kind of Millennials often held up as the scrappy saviors of our brave new economic world. They told me how affordable Milwaukee was, especially compared to the city's pricier neighbor, Chicago. Angela Damiani, director of NEWaukee, a networking organization for young professionals, and a homeowner at 27, observed that "if you want to start a business or follow a pipe dream, Milwaukee is the type of place you can do that, because it's so small and cheap and so interconnected."
But after leaving NEWaukee's cozy basement space—complete with a basketball hoop, a PBR longboard, and afternoon mimosas—and stepping out into the street, I encountered a strikingly different scene. A large group of workers, most young and of color, were protesting outside the Grand Avenue mall. The demonstration was the latest in a series of strikes by fast-food and retail workers demanding $15 an hour and the right to form a union. I asked everyone I met the same questions I'd asked the startup kids earlier: Is Milwaukee chock full of opportunities? Is Milwaukee cheap?
"Haha, that's cute. No," said 18-year-old Amir Graham, who works at McDonald's to help out his mother, a bartender and single parent. It's not hard to imagine Graham at a small liberal-arts school—"I put my head in the books and do a lot of studies on my own time on economics, sociology, stuff like that"—but with his schedule, going to school full-time would be a struggle.
I chatted with Jevon Walker, who is 20 and works at Old Country Buffet, a national chain restaurant. He goes to community college for audio engineering and hopes to start a local studio, but he's not sure that's realistic. "I've never been anywhere else besides Milwaukee, and opportunities are not available here in this city," he said. No matter how "affordable" Milwaukee is, "you can't support a family on $7.25 an hour." He's right, of course: Workers clocking 40 hours a week at that wage only earn $15,080 a year—just below the poverty line in Wisconsin for a family of two.
Most of the striking workers greeted my questions with a laugh. They described abandoned playgrounds and pregnant middle-schoolers and unpaid bills after 60-hour weeks at Domino's. That PBR longboard rolling on the startup floor seemed a million miles away.
Reporters and pundits are always worrying about Millennials, but other than a racially tinged mention of poor, "ghetto-fabulous" young people, stories like Time magazine's May 20 cover piece on the "me me me generation" rarely acknowledge people like Walker and Graham. "Millennials" usually describes boomerang kids staring at fading Obama posters or optimistic entrepreneurs-by-necessity. Walker and Graham, on the other hand, are just "poor." There's a major disconnect, in the media and in life, between recession-addled twenty-somethings whose bright futures have been bruised, and the ones who always assumed their futures would be that way.
The latter Millennials didn't need Occupy or an economic downturn to inject them with class consciousness. A couple of weeks before the Milwaukee protest, I had coffee with Josie Kenol, a 28-year-old CVS pharmacist and a single mom of three living in West Homestead, Pennsylvania. She told me the recession "really didn't bother me none … nothing's changing around me. I think the whole economy thing was for people who actually had it, then lost it. But if you don't have it, you can't miss something you never had." Of course, it's not technically true that the recession didn't impact the poor—it's just that the fall from the last rung to rock bottom isn't as dramatic.
Still, for some, witnessing and experiencing "rock bottom" can be radicalizing. "That period really shaped me and shaped my politics," said Siwatu Salama-Ra, a 21-year-old peer educator from a low-income family in Detroit. She agrees with Kenol that the recession "wasn't this big surprise, especially in Detroit" but it profoundly affected her family. Her mother lost the house she'd owned for 35 years to foreclosure in 2009 because the property taxes were too high. Neither she nor her neighbors knew anything about the foreclosure process. "We had no resources, no information about what could we do to keep it," she says. "[People down the block] … didn't know legal actions or legal things to fight back. I've watched my neighborhood deteriorate." Salama-Ra says her own experiences led her to want to be a political force in her community. "It's for myself. For us," she says.
For poor Millennials joining fast-food and retail strikes across the country, or becoming more active at the community level like Salama-Ra, it's less that they're finally getting a taste of poverty and more that they can't take it anymore. And this is fueling a general sense, at least in some crowds, that something needs to change. Even if young, low-income people don't experience the indignation—some would say entitlement—of disillusioned college kids, many can't help but notice a change in the national climate. It's not a coincidence that this slowly shifting mood comes at the heels of the very manifestation of young, (mostly) middle class outrage: the Occupy movement. Regardless of its tactical failures, it started a conversation that seeped beyond the confines of people who grew up financially comfortable.
"This stuff is in the air and it's more common than four years ago," says Sarah Jaffe, a labor journalist who reported on Occupy. "Out of the parks, [we] found ways to be involved in other things. This is a circle of people who have class consciousness," either because they "read the right books in college" or because the bad economy was affecting them directly. These organizers approached not the downwardly mobile workers of Whole Foods or Starbucks, but workers at McDonald's and Domino's—people who have always known the traps of poverty, but didn't necessarily know they had any other options. People like Josie Kenol in West Hempstead or Jevon Walker in Milwaukee.
Yet this tenuous alliance is just that: tenuous. Jaffe admits that "we're all screwed by this economy, but we're not equally screwed." There's a whole chunk of Millennials who have barely noticed this upheaval, who instead have responded to the bad economy by using their networks and resources to start businesses of their own in cheaper cities like Milwaukee. The ironic thing is, entrepreneurial college grads would benefit from the same changes low-income workers are demanding: a better minimum wage, access to health care, and stronger social-safety net. No matter who you are, a basic standard of living encourages risk-taking. Sure, one group is more screwed than the other. But it only hurts everyone if they keep talking past each other.
This is the second installment of a four-part series on Millennials and the new economy, based on the author's monthlong road trip with stops in the Rust Belt, Omaha, and Texas. Read the first.


text: Shop Local Tip #9: Find Local EntertainmentDinner and a movie can get a little boring after a while - and expensive. Why not find some other way to be entertained in your local Millbrae community? I'll bet there are many fun things to do in your neighborhood. Next time you want to have a little fun, go to a local Millbrae theater production, Millbrae sporting event or what's on exhibit at your nearby Millbrae museum. Maybe buy a sandwich from your local Millbrae deli and picnic at the Millbrae park, take a class at the Millbrae recreational center or catch a live local band. Local entertainment calendars can be found online or in your local paper and are often quite easy on the budget.


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Rectangle By Rokit Boost - Hybrid Bluetooth Speaker
Description: Perfect little thing • Rectangle is a Bluetooth speaker with a build in microphone for conference calls. • Rectangle design, fits perfectly on your desk, nightstand or anywhere else basically. • Equipped with a Bluetooth V3.0, class II chipset. • Support 3.5mm line-in for non Bluetooth devices. (Like an iPod shuffle) • product dimension: 145 x 66 x 33mm, weight: 215g Easy pairing, connection and control Auxiliary input lets you play other audio sources, like an MP3 or portable DVD/CD player, no Bluetooth needed. Rectangle has its own power and volume controls on top, as well as skip buttons, it controls everything else; playlists, streaming music stations, etc. No remote control needed.
Price: $34.99 to $49.99


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Oracle Team USA and high winds on San Francisco Bay on Thursday kept challenger Emirates Team New Zealand from the one victory needed to take home yachting's coveted trophy.
The US team rallied to win the race held before winds topped safety limits and caused the second match to be postponed until yesterday.
The defending champions shifted the blame for a fourth frustrating race delay onto the Kiwis, saying they want to raise the wind limit, but the New Zealand team will not agree.
"It just seems a little strange that halfway through a series you need to change a wind limit that has been agreed to [at the start]," New Zealand skipper Dean Barker said. "It doesn't seem right to change any rules halfway through a series."
Barker appeared suspect of the motive of the defending champions, whose catamaran has sailed better in higher winds.
Wind racing limits were lowered after the "huge shock" of the death of Artemis team member Andrew "Bart" Simpson while training on the Bay, but fierce on-water bouts have built the skills and confidence of the Cup finalists, who "are up for" racing in higher winds, Oracle skipper Jimmy Spithill reasoned.
The AC72 catamaran of Swedish team Artemis, one of three challenger hopefuls, capsized in May and Simpson, a British double Olympic medalist, drowned after being trapped under the overturned structure.
The sophisticated AC72 catamarans sailed by the teams reach speeds higher than cars crossing the Golden Gate Bridge bordering one side of the tight race course.
The postponement on Thursday was the fourth time racing was canceled due to high winds.
"We want to race," Spithill said. "I think both teams are up for it. You have a beautiful breeze like this in the afternoon and then you have to come ashore; you ask yourself why you are doing it."
Oracle are not being spared the stiff winds of a daunting deficit in the best-of-17 series. New Zealand have won eight races and needs just one more to wrest the prized trophy from the grip of Oracle Team USA owner Larry Ellison.
The defending champions have won four races, but still need seven victories to retain the Cup because they were penalized two points before the start for pre-regatta violations.
"We can win seven more races," Spithill said. "We are confident in our boat and believe we can do it; we almost have nothing to lose."
Oracle seized control of race 12 at the starting line, hooking the Kiwis and forcing them to tack away and slow while Oracle darted ahead.
The defending champions held the lead into the pivotal upwind third leg of the race, forcing a second split at the third gate and then controlling the downwind leg to the final gate.
Oracle crossed the finish line 31 seconds ahead of the Kiwis.
Oracle have scrambled to make changes to their yacht after being repeatedly outsailed by the Kiwis, markedly improving their performance, but not washing away doubts that they can deny New Zealand a single clinching triumph.
"We don't believe this is over until we win one more race," Barker said. "It is a battle. You have to fight hard for each point; there are no give-mes."
The America's Cup, first contested in 1851, has been held since 2010 by Ellison.
The technology industry titan, whose personal fortune is estimated at about US$40 billion beat Alinghi's giant Swiss catamaran 2-0 three years ago in Valencia, Spain, with a 30m long rigid wing trimaran.


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Major Ensembles
The Department of Music has many scholarship opportunities.
Several ensembles are developed for students that have outstanding skills in music. The members of these select ensembles all receive scholarships. Members are determined by special auditions that are held during the Summer before the school year.
For more information about these groups contact the Fresno State Music Department at (559) 278-2654.


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About willbates
It would be very interesting if they actually tried this. Surely a large entertainment company would try this strategy on one of their smaller projects as an experiment. They need to get their merchandising and other revenue stream strategy right.
I'm usually one to be fairly liberal with information sharing but there has to be decent degree of privacy protection and sharing peoples searches with just anyone isn't really on in my book.
It is a really tough one because there is clearly a massive grey area with this. Sure, if someone copies something 'word-for-word' style that is clearly against copy-write but when it comes to infringements it gets very messy.
It is too easy for people to download music for free for them to focus on that as the main source of revenue generation. They need to develop other sides of the business, mainly around the musicians as 'starts', meaning massive gigs and merchandising etc.
This is really interesting stuff and makes complete sense. The notion of idea transfer fits in very well with the 'standing on shoulders' model of economic growth, have a look.
Or is it more of a case of lazy teachers who can't be bothered to do their preparation properly? In any case, if they created those lesson plans in work time whilst being paid by the school then it is act actually not theirs to sell, it is the schools!
It is really interesting when you start looking into shell companies, especially with regards to who they own and who owns them. It is often very difficult to track, clearly things to hide!
Sure, people should protect their networks but some of my friends think that if a network isn't protected they don't mind their neighbours using it! At the very most it should be a fine.
Haha, paying that bill would surely make him eat his words!!
Firstly, making a poster of a photo can't infringe copy right in my view. However, destroying evidence and lying isn't only stupid, it's an infringement of the law, silly!
This is the trick for entrepreneurs, having the vision for other ways to do things and monetising them. Stoll clearly made a big mistake, mainly through lack of vision.
Interesting points, obviously there are massive differences between unions and trade organisations but it would be interesting to see the analysis of similarities. Could there be cross-firm strikes? I doubt it but there is definitely an incentive to limit labor supply to drive up wage. The issue is that competition legislators should, if independent, maintain a level playing field and trade organisations shouldn't have enough power to significantly influence.
Very good points, they may very well make higher profits this way. It would be an interesting experiment anyhow. I particularly like your thoughts about a 'free' good feeding into paid goods. Just be careful when you try to get technical about economics because some of the finer points are not really true, for example, music downloads (even if free) are not strictly speaking infinite as it is a function of population, download speed, duration of popularity etc. I know this may seem picky in this example but an economic theory has to have multiple (if not universal) application. Just be careful rigidly arguing a good is infinite. very nice ideas though.
The definition of economics is the study into the efficient allocation of scarce resources, so if the resource isn't scarce it isn't economics. In any case, there can be a price of zero and scarcity if there are no clear ownership rights, which is economics. I don't think we have trouble with infinity, it just doesn't make logical sense because (as a planet) we have limited resources.
If Google doesn't was to create content then they needed to have tried harder to partner with cable providers. I think long-run this content will go online, it will turn out very much like the current situation in print media. As long as content providers have intellectual property they will still be able to generate add revenue, which is all they will get.
It definitely should be illegal but in any case I have no idea why companies would do it, it's just annoying and makes consumers hate their brand!!


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The rates listed below are the maximum rates that the Department will pay per day.
Group 1A includes Cook, DeKalb, DuPage, Kane, Kendall, Lake, and McHenry counties.
Group 1B includes Boone, Champaign, Kankakee, Madison, McLean, Monroe, Ogle, Peoria, Rock Island, Sangamon, St. Clair, Tazewell, Whiteside, Will, Winnebago, and Woodford counties.
Group 2 includes all counties not listed in Group 1A or 1B.
License-Exempt Day Care Home, Non-Relative in Child's Home or Relative 764, 765, 766, 767 includes all counties.
Providers cannot charge the State of Illinois rates that exceed the maximum allowed by the State and rates that are higher than those charged by the provider to the general public for similar services. This includes discounts such as multiple child discounts, staff discounts, full-week discounts, pre-pay discounts, and sliding fee scales.