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Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, and energy formation. H2Sn, which have additional sulfur atoms to H2S, and other S-sulfurated molecules such as cysteine persulfide and S-sulfurated cysteine residues of proteins, are produced by enzymes including 3-mercaptopyruvate sulfurtransferase (3MST). H2Sn are also generated by the chemical interaction of H2S with NO, or to a lesser extent with H2O2. S-sulfuration (S-sulfhydration) has been proposed as a mode of action of H2S and H2Sn to regulate the activity of target molecules. Recently, we found that H2S/H2S2 regulate the release of neurotransmitters, such as GABA, glutamate, and D-serine, a co-agonist of N-methyl-D-aspartate (NMDA) receptors. H2S facilitates the induction of hippocampal long-term potentiation, a synaptic model of memory formation, by enhancing the activity of NMDA receptors, while H2S2 achieves this by activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading to the activation of nearby neurons. The recent findings show the other aspects of TRPA1 channels—that is, the regulation of the levels of sulfur-containing molecules and their metabolizing enzymes. Disturbance of the signalling by H2S/H2Sn has been demonstrated to be involved in various diseases, including cognitive and psychiatric diseases. The physiological and pathophysiological roles of these molecules will be discussed. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) are signaling molecules produced by 3-mercaptopyruvate sulfurtransferase (3MST) that play various physiological roles, including the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory formation, by enhancing N-methyl-d-aspartate (NMDA) receptor activity. However, the presynaptic action of H2S/H2Sn on neurotransmitter release, regulation of LTP induction, and animal behavior are poorly understood. Here, we showed that H2S/H2S2 applied to the rat hippocampus by in vivo microdialysis induces the release of GABA, glutamate, and d-serine, a co-agonist of NMDA receptors. Animals with genetically knocked-out 3MST and the target of H2S2, transient receptor potential ankyrin 1 (TRPA1) channels, revealed that H2S/H2S2, 3MST, and TRPA1 activation play a critical role in LTP induction, and the lack of 3MST causes behavioral hypersensitivity to NMDA receptor antagonism, as in schizophrenia. H2S/H2Sn, 3MST, and TRPA1 channels have therapeutic potential for psychiatric diseases and cognitive deficits. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) together with polysulfides (H2Sn, n > 2) are signalling molecules like NO with various physiological roles including regulation of neuronal transmission, vascular tone, inflammation and oxygen sensing. H2S and H2Sn diffuse to the target proteins for S‐sulfurating their cysteine residues that induces the conformational changes to alter the activity. On the other hand, 3‐mercaptopyruvate sulfurtransferase transfers sulfur from a substrate 3‐mercaptopyruvate to the cysteine residues of acceptor proteins. A similar mechanism has also been identified in S‐nitrosylation. S‐sulfuration and S‐nitrosylation by enzymes proceed only inside the cell, while reactions induced by H2S, H2Sn and NO even extend to the surrounding cells. Disturbance of signalling by these molecules as well as S‐sulfuration and S‐nitrosylation causes many nervous system diseases. This review focuses on the signalling by H2S and H2Sn with S‐sulfuration comparing to that of NO with S‐nitrosylation and discusses on their roles in physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2 S) is a signalling molecule that regulates neuronal transmission, vascular tone, cytoprotection, inflammatory responses, angiogenesis, and oxygen sensing. Some of these functions have recently been ascribed to its oxidized form polysulfides (H2 Sn ), which can be produced by 3-mercaptopyruvate sulfurtransferase (MPST), also known as a H2 S-producing enzyme. H2 Sn activate ion channels, tumour suppressors, transcription factors, and protein kinases. H2 Sn S-sulfurate (S-sulfhydrate) cysteine residues of these target proteins to modify their activity by inducing conformational changes through the formation of a disulfide bridge between the two cysteine residues involved. The chemical interaction between H2 S and NO also generates H2 Sn , which may be a chemical entity that exerts the synergistic effect of H2 S and NO. MPST also produces redox regulators cysteine persulfide (CysSSH), GSH persulfide (GSSH), and persulfurated proteins. In addition to MPST, haemoproteins such as haemoglobin, myoglobin, neuroglobin, and catalase as well as SOD can produce H2 Sn , and sulfide quinone oxidoreductase and cysteinyl tRNA synthetase can make GSSH and CysSSH. This review focuses on the recent progress in the study of the production and physiological roles of these persulfurated and polysulfurated molecules. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is an endogenous gaseous transmitter synthesized in various cell types. It is well established that H2S functions in many physiological processes, including the relaxation of vascular smooth muscle, mediation of neurotransmission, regulation of inflammation, and modulation of insulin signaling. In recent years, it has been revealed that polysulfides, substances with a varying number of sulfur atoms (H2Sn), are generated endogenously from H2S in the presence of oxygen. A series of studies describes that sulfane sulfur has the unique ability to bind reversibly to other sulfur atoms to form hydropersulfides and polysulfides, and that polysulfides activate ion channels and promote calcium influx. Furthermore, polysulfides regulate tumor suppressor activity, promote the activation of transcription factors targeting antioxidant genes and regulate blood pressure by vascular smooth muscle relaxation. Insulin secretion from pancreatic β cells plays a critical role in response to increased blood glucose concentration. H2S has emerged as an important regulator of glycemic control and exhibits characteristic regulation of glucose homeostasis. However, the effects of polysulfides on glucose-stimulated insulin secretion (GSIS) are largely unknown. In this study, we demonstrated that pharmacological polysulfide salts including Na2S2, Na2S3, and Na2S4 considerably inhibit GSIS in mouse and rat pancreatic β-cell-derived MIN6 and INS-1 cell lines, and that the effect is dependent on the activation of ATP-sensitive potassium channels. In addition, we demonstrated that a mixture of Na2S and diethylamine NONOate inhibits GSIS in a similar way to the pharmacological administration of polysulfide salts. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) is a signaling molecule used to modify neuronal transmission, regulate vascular tone, protect tissues from oxidative stress, sense oxygen, and generate ATP. Hydrogen polysulfides (H 2 S n) have recently been identified as signaling molecules that mediate the activation of ion channels, regulation of tumor growth, and the transcriptional regulation of oxidative stress; some of which were previously ascribed to H 2 S. Cystathionine β-synthetase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) are known as H 2 S-producing enzymes. 3MST also produces H 2 S n and other persulfurated molecules such as cysteine persulfide, glutathione persulfide, and persulfurated proteins. The chemical interaction of H 2 S and nitric oxide (NO) also produces H 2 S n , which may be the mechanism underlying the synergistic effect of H 2 S and NO that was initially reported on vascular relaxation. H 2 S n and other persulfurated molecules elicit their effect via S-sulfuration (S-sulfhydration) of specific cysteine residues of the target proteins. This review article focuses on the production and roles of H 2 S n as well as H 2 S in the central nervous system. • Hydrogen sulfide (H 2 S) is a signaling molecule with various physiological roles. • Some functions previously reported by H 2 S have recently been ascribed to polysulfides (H 2 S n). • H 2 S n S-sulfurate (S-sulfhydrate) cysteine residues of the target proteins. • The disturbance of the signaling by H 2 S and H 2 S n may be involved in various neuronal diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hydrogen sulfide (H2 S) and polysulfides (H2 Sn ) are signalling molecules that mediate various physiological responses including cytoprotection. Their oxidized metabolite sulfite (SO32- ) is found in blood and tissues. However, its physiological role remains unclear. In this study, we investigated the cytoprotective effect of sulfite on neurons exposed to oxidative stress caused by high concentrations of the neurotransmitter glutamate, known as oxytosis.Experimental Approach: Concentrations of sulfite as well as those of cysteine and GSH in rats were measured by HPLC. Cytoprotective effects of sulfite on primary cultures of rat neurons against oxytosis was examined by WST-8 cytoprotective and LDH cytotoxicity assays and compared with that of H2 S, H2 Sn and thiosulfate.Key Results: Free sulfite, present at approximately 2 μM in the rat brain, converts cystine to cysteine more efficiently than H2 S and H2 Sn and facilitates transport of cysteine into cells. Physiological concentrations of sulfite protected neurons from oxytosis and were accompanied by increased intracellular concentrations of cysteine and GSH probably due to converting extracellular cystine to cysteine, more efficiently than H2 S and H2 Sn . In contrast, thiosulfate only slightly protected neurons from oxytosis.Conclusions and Implications: Our present data have shown sulfite to be a novel cytoprotective molecule against oxytosis, through maintaining cysteine levels in the extracellular milieu, leading to increased intracellular cysteine and GSH. Although there may be adverse clinical effects in sensitive individuals, our results provide a new insight into the therapeutic application of sulfite to neuronal diseases caused by oxidative stress.Linked Articles: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (HS) is a physiological mediator with various roles, including neuro-modulation, vascular tone regulation, and cytoprotection against ischemia-reperfusion injury, angiogenesis, and oxygen sensing. Hydrogen polysulfide (HS), which possesses a higher number of sulfur atoms than HS, recently emerged as a potential signaling molecule that regulates the activity of ion channels, a tumor suppressor, transcription factors, and protein kinases. Some of the previously reported effects of HS are now attributed to the more potent HS. HS is produced by 3-mercaptopyruvate sulfurtransferase (3MST) from 3-mercaptopyruvate (3MP) and is generated by the chemical interaction of HS with nitric oxide (NO). HS sulfhydrates (sulfurates) cysteine residues of target proteins and modifies their activity, whereas HS sulfurates oxidized cysteine residues as well as reduces cysteine disulfide bonds. This review focuses on the recent progress made in studies concerning the production and physiological roles of HS and HS. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) has been demonstrated to have physiological roles such as neuromodulation, vascular tone regulation, cytoprotection, oxygen sensing, inflammatory regulation, and cell growth. Recently, hydrogen polysulfides (H2Sn) have been found to be produced by 3-mercaptopyruvate sulfurtransferase and to regulate the activity of ion channels, tumor suppressers, and protein kinases. Furthermore, some of the effects previously reported to be mediated by H2S are now ascribed to H2Sn. Cysteine persulfide and cysteine polysulfide may also be involved in cellular redox regulation. The chemical interaction between H2S and nitric oxide (NO) can also produce H2Sn, nitroxyl, and nitrosopersulfide, suggesting their involvement in the reactions previously thought to be mediated by NO alone. This Forum focuses on and critically discusses the recent progress in the study of H2Sn, H2S, and NO as well as other per- or polysulfide species. Antioxid. Redox Signal. 00, 000-000. [ABSTRACT FROM AUTHOR]

Significance: Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury. H2S is produced from l-cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase. Recent Advances: In addition to these enzymes, we recently identified a novel pathway to produce H2S from d-cysteine, which involves d-amino acid oxidase (DAO) along with 3MST. These enzymes are localized in the cytoplasm, mitochondria, and peroxisomes. However, some enzymes translocate to organelles under specific conditions. Moreover, H2S-derived potential signaling molecules such as polysulfides and HSNO have been identified. Critical Issues: The physiological stimulations, which trigger the production of H2S and its derivatives and maintain their local levels, remain unclear. Future Directions: Understanding the regulation of the H2S production and H2S-derived signaling molecules and the specific stimuli that induce their release will provide new insights into the biology of H2S and therapeutic development in diseases involving these substances. Antioxid. Redox Signal. 22, 362-376. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) has been considered to be a physiological mediator since the identification of endogenous sulfides in the mammalian brain. H 2 S is produced from l -cysteine by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST), and cysteine aminotransferase (CAT). CSE and CAT are regulated by Ca 2+ . At steady-state low intracellular concentrations of Ca 2+ , CSE and the 3MST/CAT pathway produce H 2 S. However, after intracellular concentrations of Ca 2+ increase in stimulated cells, the production of H 2 S by these enzymes decreases. We recently identified a fourth pathway, by which H 2 S is produced from d -cysteine by the enzymes d -amino acid oxidase (DAO) and 3MST. This pathway is mainly localized in the cerebellum and the kidney. The production of H 2 S from d -cysteine is 80 times more efficient than that from l -cysteine in the kidney, and the administration of d -cysteine to mice ameliorates renal ischemia-reperfusion injury more effectively than l -cysteine. These results suggest that d -cysteine might be used to treat renal diseases or even increase the success of kidney transplantation. We found that H 2 S-derived polysulfides exist in the brain and activate transient receptor potential ankyrin-1 (TRPA1) channels 300 times more potently than H 2 S. Although TRPA1 channels mediate sensory transduction and respond to a variety of stimuli, including cold temperature, pungent compounds and environmental irritants, their endogenous ligand(s) has not been identified. The sulfane sulfur of polysulfides is a reactive electrophile that is readily transferred to a nucleophilic protein thiolate to generate the protein persulfide or bound sulfane sulfur by sulfhydration (as referred to as sulfuration). The bound sulfane sulfur-producing activity of polysulfides is much greater than that of H 2 S. This review focuses on the physiological roles of H 2 S and H 2 S-derived polysulfides as signaling molecules. [ABSTRACT FROM AUTHOR]

Highlights: [•] H2S is produced by four enzymatic pathways. [•] H2S regulates synaptic transmission. [•] H2S protects neurons from oxidative stress. [•] H2S-derived polysulfides activate TRPA1 channels. [Copyright &y& Elsevier]

Highlights: [•] Polysulfide uptake induces acceleration of GSH synthesis and HO-1 expression. [•] Polysulfide possesses cytoprotective function against ROS toxicity in the cell. [•] Polysulfide-induced disulfide formation of Keap1 causes Nrf2 activation. [•] The PI3K/Akt phosphorylation pathway is activated by polysulfide. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that hydrogen sulfide (H2S) has a variety of physiological functions. H2S is produced from cysteine by 3 sulfur-transferases. H2S, in turn, generates polysulfides, the functions of which are not well understood. H2S induces Ca2+ influx in astrocytes, a type of glia. However, the receptor that mediates the response has not been identified. Here, we have shown that polysulfides induce Ca2+ influx by activating transient receptor potential (TRP)A1 channels in rat astrocytes (EC50 91 nM, Hill coefficient value 1.77±0.26) and that the maximum response was induced at 0.5 wM, which is 1/320 of the concentration of H2S required to achieve a response of similar magnitude (160 µM, EC50 116 µM). TRPA1-selective agonists, allyl isothiocyanate and cinnamaldehyde, induced Ca2+ influx, and responses to polysulfides were suppressed by TRPAl-selective inhibitors, HC-030031 and AP-18, as well as by siRNAs selective to TRPA1. The present study suggests that polysulfides are possible H2S-derived signaling molecules that stimulate TRP channels in the brain. [ABSTRACT FROM AUTHOR]

It has been almost two decades since the first demonstration of hydrogen sulfide (H2S) as a physiological mediator of cognitive function and vascular tone. H2S is physiologically important because it protects various organs from ischemia-reperfusion injury besides regulating inflammation, oxygen sensing, cell growth, and senescence. The production, metabolism, and regulation of H2S have been studied extensively. H2S modulates target proteins through sulfhydration (or sulfuration) or by the reduction of cysteine disulfide bonds. A large number of novel H2S-donating compounds are being developed owing to the therapeutic potential of H2S. Recently, polysulfides, rather than H2S, have been identified as molecules that sulfhydrate (or sulfurate) their target proteins. Antioxid. Redox Signal. 22, 347-349. [ABSTRACT FROM AUTHOR]

Since the first description of hydrogen sulfide (H2S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H2S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H2S in the brain, suggesting that H2S may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (H2S) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that H2S relaxes vascular smooth muscle in synergy with nitric oxide (NO) and that cystathionine γ-lyase (CSE) is another producing enzyme. This study also opened up a new research area of a crosstalk between H2S and NO. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by H2S have been subsequently demonstrated. Two additional pathways for the production of H2S with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (H2Sn, n ≥ 2) are potential signaling molecules produced by 3MST. H2Sn regulate the activity of ion channels and enzymes, as well as even the growth of tumors. S-Sulfuration (S-sulfhydration) proposed by Snyder is the main mechanism for H2S/H2Sn underlying regulation of the activity of target proteins. This mini review focuses on the key findings on H2S/H2Sn signaling during the first 25 years. [ABSTRACT FROM AUTHOR]

Polysulfides are a typical type of bound sulfur, which is physiologically stable form of sulfur species, derived from the hydrogen sulfide (H 2 S) that is generated endogenously in cells. We previously reported that bound sulfur protects neuronal cells from oxidative injury. In the present study, we demonstrated that polysulfides inhibited cell growth and promoted neurite outgrowth in mouse neuroblastoma Neuro2A (N2A) cells. However, Na 2 S showed no effect on neurite outgrowth in N2A cells. Furthermore, 2-APB and SKF96365, which are typical transient receptor potential (TRP) channel inhibitors, suppressed the neurite outgrowth induced by Na 2 S 4 . These new findings suggest that bound sulfur could induce neurite outgrowth and cell differentiation of N2A cells by accelerating calcium influx. [ABSTRACT FROM AUTHOR]

Abstract It has been known that hydrogen sulfide and/or polysulfides are produced from a (poly)sulfurated sulfur-acceptor substrate of 3-mercaptopyruvate sulfurtransferase (MST) via thioredoxin (Trx) reduction in vitro. In this study, we used thiosulfate as the donor substrate and the catalytic reaction was terminated on the formation of a persulfide or polysulfides. We can present alternative pathway of production of hydrogen sulfide and/or polysulfides from (poly)sulfurated catalytic-site cysteine of reaction intermediates of MST via Trx reduction. Matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometric analysis revealed that after prolonged incubation of MST with thiosulfate, a trisulfide adduct becomes predominant at the sulfurated catalytic-site cysteine. When these adducts were reduced by Trx with reducing system (MST: Escherichia coli Trx: E. coli Trx reductase:NADPH = 1:5:0.02:12.5 molar ratio), liquid chromatography with tandem mass spectrometric analysis for monobromobimane-derivatized H 2 S n revealed that H 2 S 2 first appeared, and then H 2 S and H 2 S 3 did later. The results were confirmed by high-performance liquid chromatography-fluorescence analysis. Highlights • Thiosulfate forms (poly)sulfurated catalytic-site cysteine of reaction intermediate of 3-mercaptopyruvate sulfurtransferase and the catalytic reaction was terminated on the formation of a persulfide or polysulfide. • (Poly)sulfurated catalytic-site cysteine can be reduced by thioredoxin with reducing system. • Hydrogen sulfide and/or polysulfides are alternatively produced from a (poly)sulfurated reaction intermediate. [ABSTRACT FROM AUTHOR]

Previous studies indicated that bound sulfur species (BSS), including hydrogen polysulfide (H 2 S n ), have various physiological functions in mammalian cells. Although H 2 S n molecules have been considered as secondary metabolites derived from hydrogen sulfide (H 2 S) based on in vitro studies or predetermined reaction formula, the physiological form of BSS and their endogenous concentration remain unclear. In the present study, we aimed to improve the usual method using monobromobimane (mBB) followed by high performance liquid chromatographic (HPLC) analysis for HS － for simultaneous determination of H 2 S, H 2 S 2 , H 2 S 3 and cysteine persulfide in biological samples. We demonstrated that mBB derivatization of H 2 S and H 2 S n standards under alkaline conditions (pH 9.5) induced significant decreases in H 2 S 2 and H 2 S 3 levels and a significant increase in the H 2 S level in an incubation time-dependent manner. Conversely, the derivatization of mBB adducts of H 2 S 2 and H 2 S 3 were stable under neutral conditions (pH 7.0), which is physiologically relevant. Therefore, we re-examined the method using mBB and applied an improved method for the evaluation of H 2 S, H 2 S 2 , and H 2 S 3 in mouse brain under physiological pH conditions. The concentrations of H 2 S and H 2 S 2 were 0.030 ± 0.004 μmol/g protein and 0.026 ± 0.002 μmol/g protein, respectively. Although the level of H 2 S 3 was below the quantification limit of this method, H 2 S 3 was detected in mouse brain. Using the method established here, we reveal for the first time the existence of endogenous H 2 S 2 and H 2 S 3 in mammalian brain tissues. H 2 S 2 and H 2 S 3 exert anti-oxidant activity and anti-carbonyl stress effects through the regulation of redox balance in neuronal cells. Thus, our observations provide novel insights into the physiological functions of BSS in the brain and into neuronal diseases involved in redox imbalance. [ABSTRACT FROM AUTHOR]

Polysulfide is a bound sulfur species derived from endogenous H2S. When mouse neuroblastoma, Neuro2A cells were exposed to tert-butyl hydroperoxide after treatment with polysulfide, a significant decline in cell toxicity was observed. Rapid uptake of polysulfides induced translocation of Nrf2 into the nucleus, resulting in acceleration of GSH synthesis and HO-1 expression. We demonstrated that polysulfide reversibly modified Keap1 to form oxidized dimers and induced the translocation of Nrf2. Moreover, polysulfide treatment accelerated Akt phosphorylation, which is a known pathway of Nrf2 phosphorylation. Thus, polysulfide may mediate the activation of Nrf2 signaling, thereby exerting protective effects against oxidative damage in Neuro2A cells. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that hydrogen sulfide (H2S) has a variety of physiological functions. H2S is produced from cysteine by 3 sulfurtransferases. H2S, in turn, generates polysulfides, the functions of which are not well understood. H2S induces Ca2+ influx in astrocytes, a type of glia. However, the receptor that mediates the response has not been identified. Here, we have shown that polysulfides induce Ca2+ influx by activating transient receptor potential (TRP) A1 channels in rat astrocytes (EC50 91nM, Hill coefficient value 1.77±0.26) and that the maximum response was induced at 0.5microM, which is 1/320 of the concentration of H2S required to achieve a response of similar magnitude (160 microM, EC50 116microM). TRPA1-selective agonists, allyl isothiocyanate and cinnamaldehyde, induced Ca2+ influx, and responses to polysulfides were suppressed by TRPA1-selective inhibitors, HC-030031 and AP-18, as well as by siRNAs selective to TRPA1. The present study suggests that polysulfides are possible H2S -derived signaling molecules that stimulate TRP channels in the brain. [ABSTRACT FROM AUTHOR]