The constellation of dietary factors in adolescent acne: a semantic connectivity map approach.

BACKGROUND: Different lifestyle and dietetic factors have been linked with the onset and severity of acne. OBJECTIVE: To assess the complex interconnection between dietetic variables and acne. METHODS: This was a reanalysis of data from a case-control study by using a semantic connectivity map approach. 563 subjects, aged 10-24 years, involved in a case-control study of acne between March 2009 and February 2010, were considered in this study. The analysis evaluated the link between a moderate to severe acne and anthropometric variables, family history and dietetic factors. Analyses were conducted by relying on an artificial adaptive system, the Auto Semantic Connectivity Map (AutoCM). RESULTS: The AutoCM map showed that moderate-severe acne was closely associated with family history of acne in first degree relatives, obesity (BMI ≥ 30), and high consumption of milk, in particular skim milk, cheese/yogurt, sweets/cakes, chocolate, and a low consumption of fish, and limited intake of fruits/vegetables. CONCLUSION: Our analyses confirm the link between several dietetic items and acne. When providing care, dermatologists should also be aware of the complex interconnection between dietetic factors and acne.

Fentanyl vapor self-administration model in mice to study opioid addiction.

Intravenous drug self-administration is considered the "gold standard" model to investigate the neurobiology of drug addiction in rodents. However, its use in mice is limited by frequent complications of intravenous catheterization. Given the many advantages of using mice in biomedical research, we developed a noninvasive mouse model of opioid self-administration using vaporized fentanyl. Mice readily self-administered fentanyl vapor, titrated their drug intake, and exhibited addiction-like behaviors, including escalation of drug intake, somatic signs of withdrawal, drug intake despite punishment, and reinstatement of drug seeking. Electrophysiological recordings from ventral tegmental area dopamine neurons showed a lower amplitude of GABAB receptor-dependent currents during protracted abstinence from fentanyl vapor self-administration. This mouse model of fentanyl self-administration recapitulates key features of opioid addiction, overcomes limitations of the intravenous model, and allows investigation of the neurobiology of opioid addiction in unprecedented ways.

A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine.

The mesolimbic system is known to play a role in self-administration of opioids and psychostimulants. Although morphine and cocaine act by separate cellular mechanisms initially, the present study describes a common change in synaptic regulation of dopamine cells in the ventral tegmental area 1 week after termination of chronic treatment with either drug. Normally, D1 receptor activation augmented the amplitude of a gamma-aminobutyric acid type B (GABA(B)) inhibitory postsynaptic potential (IPSP), but in drug-experienced animals, D1 receptor activation caused an inhibition of the GABA(B) IPSP. The inhibition was blocked by adenosine A1 receptor antagonists and by agents that disrupted the metabolism of cAMP. This long-lasting dopamine-adenosine interaction may be one mechanism involved in dopamine-mediated craving and relapse to drug-seeking behaviors.

Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih.

Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine levels in brain regions receiving dense VTA input. Therefore, stress may activate the mesolimbic dopamine system in part through the actions of CRF in the VTA. Here, we explored the mechanism by which CRF affects VTA dopamine neuron firing. Using patch-clamp recordings from brain slices we first determined that the presence of I(h) is an excellent predictor of dopamine content in mice. We next showed that CRF dose-dependently increased VTA dopamine neuron firing, which was prevented by antagonism of the CRF receptor-1 (CRF-R1), and was mimicked by CRF-R1 agonists. Inhibition of the phospholipase C (PLC)-protein kinase C (PKC) signalling pathway, but not the cAMP-protein kinase A (PKA) signalling pathway, prevented the increase in dopamine neuron firing by CRF. Furthermore, the effect of CRF on VTA dopamine neurons was not attenuated by blockade of I(A), I(K(Ca)) or I(Kir), but was completely eliminated by inhibition of I(h). Although cAMP-dependent modulation of I(h) through changes in the voltage dependence of activation is well established, we surprisingly found that CRF, through a PKC-dependent mechanism, enhanced I(h) independent of changes in the voltage dependence of activation. Thus, our results demonstrated that CRF acted on the CRF-R1 to stimulate the PLC-PKC signalling pathway, which in turn enhanced I(h) to increase VTA dopamine neuron firing. These findings provide a cellular mechanism of the interaction between CRF and dopamine, which can be involved in promoting the avoidance of threatening stimuli, the pursuit of appetitive behaviours, as well as various psychiatric conditions.

Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons.

The orexins (hypocretins) play a crucial role in arousal, feeding and reward. Highly relevant to these functions, orexin-containing neurons from the lateral hypothalamus project densely to the ventral tegmental area (VTA), which is the origin of dopamine projections implicated in motivation and reward. Orexin A/hypocretin 1 (oxA/hcrt-1) can enable long-term changes associated with drugs of abuse; however, the effects of orexin B/hypocretin 2 (oxB/hcrt-2) on excitatory synaptic transmission in the VTA are unknown. We used whole-cell patch-clamp electrophysiology in rat horizontal midbrain slices to examine the effects of oxB/hcrt-2 on excitatory synaptic transmission. We observed that oxB/hcrt-2 has distinct effects from oxA/hcrt-1 in the VTA. oxB/Hcrt-2 (100 nM) increased presynaptic glutamate release in addition to a postsynaptic potentiation of NMDA receptors (NMDARs). The oxB/hcrt-2-mediated postsynaptic potentiation of NMDARs was mediated via activation of orexin/hypocretin 2 (OX2/Hcrt-2) receptors and protein kinase C (PKC). Furthermore, the increase in transmitter release probability was also PKC-dependent, but not through activation of orexin/hypocretin 1 (OX1/Hcrt-1) or OX2/Hcrt-2 receptors. Finally, oxB/hcrt-2 or the selective OX2/Hcrt-2 receptor agonist ala(11)-D-leu(15)-orexin B, significantly reduced spike-timing-induced long-term potentiation. Taken together, these results support a dual role for oxB/hcrt-2 in mediating enhanced glutamatergic transmission in the VTA, and suggest that oxA/hcrt-1 and oxB/hcrt-2 exert different functional roles in modulating the enhancement of the motivational components of arousal and feeding.

Dose-dependent changes in the synaptic strength on dopamine neurons and locomotor activity after cocaine exposure.

Changes in synaptic strength on ventral tegmental area (VTA) dopamine neurons are thought to play a critical role in the development of addiction-related behaviors. However, it is unknown how a single injection of cocaine at different doses affects locomotor activity, behavioral sensitization, and glutamatergic synaptic strength on VTA dopamine neurons in mice. We observed that behavioral sensitization to a challenge cocaine injection scaled with the dose of cocaine received 1 day prior. Interestingly, the locomotor activity after the initial exposure to different doses of cocaine corresponded to the changes in glutamatergic strength on VTA dopamine neurons. These results in mice suggest that a single exposure to cocaine dose-dependently affects excitatory synapses on VTA dopamine neurons, and that this acute synaptic alteration is directly associated with the locomotor responses to cocaine and not to behavioral sensitization.

Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine.

A compelling model of experience-dependent plasticity is the long-lasting sensitization to the locomotor stimulatory effects of drugs of abuse. Adaptations in the nucleus accumbens (NAc), a component of the mesolimbic dopamine system, are thought to contribute to this behavioral change. Here we examine excitatory synaptic transmission in NAc slices prepared from animals displaying sensitization 10-14 days after repeated in vivo cocaine exposure. The ratio of AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) receptor- to NMDA (N-methyl-d-aspartate) receptor-mediated excitatory postsynaptic currents (EPSCs) was decreased at synapses made by prefrontal cortical afferents onto medium spiny neurons in the shell of the NAc. The amplitude of miniature EPSCs at these synapses also was decreased, as was the magnitude of long-term depression. These data suggest that chronic in vivo administration of cocaine elicits a long-lasting depression of excitatory synaptic transmission in the NAc, a change that may contribute to behavioral sensitization and addiction.

Defining the role of corticotropin releasing factor binding protein in alcohol consumption.

The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD.

Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area.

Excitatory inputs to the ventral tegmental area (VTA) influence the activity of both dopaminergic (DA) and GABAergic (GABA) cells, yet little is known about the basic properties of excitatory synapses on these two cell types. Using a midbrain slice preparation and whole-cell recording techniques, we found that excitatory synapses on DA and GABA cells display several differences. Synapses on DA cells exhibit a depression in response to repetitive activation, are minimally affected by the GABAB receptor agonist baclofen, and express NMDA receptor-dependent long-term potentiation (LTP). In contrast, synapses on GABA cells exhibit a facilitation in response to repetitive activation, are depressed significantly by baclofen, and do not express LTP. The relative contribution of NMDA and non-NMDA receptors to the synaptic currents recorded from the two cell types is the same as is the depression of synaptic transmission elicited by the application of adenosine, serotonin, or methionine enkephalin (met-enkephalin). The significant differences in the manner in which excitatory synaptic inputs to DA and GABA cells in the VTA can be modulated have potentially important implications for understanding the behavior of VTA neurons during normal behavior and during pathological states such as addiction.

Electrophysiological pharmacology of the autoreceptor-mediated responses of dopaminergic cells to antiparkinsonian drugs.

It is generally accepted that the dopamine receptor ligands currently used in the treatment of parkinsonian symptoms mainly stimulate dopamine (DA) receptors of the D2 family to produce beneficial effects. Although several animal models can provide useful indications on the activity of the antiparkinsonian drugs in the brain, the specific cellular sites and the mechanism of action of these therapeutic agents are not completely known. In this article, Nicola Mercuri, Antonello Bonci and Giorgio Bernardi suggest that the electrophysiological effects of antiparkinsonian drugs on nigral dopaminergic cells are related to their clinical efficacy. In addition, they report that the stimulation of the D2 'autoreceptors' located on the residual dopamine-containing cells is implicated in the therapeutic response elicited by dopamine receptor agonists in parkinsonism. Thus, an electrophysiological approach, which can give basic information regarding the actions of direct and indirect DA receptor agonists on the dopaminergic neurones, might be relevant for the evolution of the pharmacological strategies in Parkinson's disease.

Activation of metabotropic glutamate receptors induces an inward current in rat dopamine mesencephalic neurons.

To investigate the electrophysiological effects of the stimulation of the metabotropic excitatory amino acid receptors, we applied trans-1-amino-cyclopentane-1,3-dicarboxylate, an agonist of this type of receptors, on presumed rat dopamine cells intracellularly recorded in vitro. Trans-1-amino-cyclopentane-1,3-dicarboxylate (3-30 microM, t-ACPD) caused a sustained increase of the spontaneous firing rate and a depolarization. When the membrane potential was held at about the resting level (-50, -60 mV), by the single-electrode voltage-clamp technique, t-ACPD induced an inward current. In 57% of the tested cells the inward current was associated with a decrease of the apparent input conductance. In the remaining cells no obvious changes in membrane conductance were observed. The active form of t-ACPD, (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylate [3-50 microM, (1S,3R)-ACPD] also produced a reversible inward current on the dopaminergic cells and this was antagonized by (S)-4-carboxy-3-hydroxyphenylglycine (300 microM), a selective antagonist of the (1S,3R)-ACPD-induced depolarization on central neurons. The (1S,3R)-ACPD-induced inward current was not antagonized by L-2-amino-3-phosphonopropionic acid (100 microM), an antagonist of the t-ACPD-induced activation of inositide synthesis. 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM), an alfa-amino-3-hydroxy-5- methyl-isoxazole propionic acid/kainate antagonist, DL-amino-5-phosphonopentanoic acid (30 microM), an N-methyl-D-aspartate antagonist, and scopolamine (10 microM), a muscarinic antagonist, did not significantly affect the actions of t-ACPD. A block of synaptic transmission obtained by applying tetrodotoxin failed to prevent the action of t-ACPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses of rat mesencephalic dopaminergic neurons to a prolonged period of oxygen deprivation.

We employed intracellular electrophysiological techniques to examine the effects of a prolonged anoxia (more than 7 min superfusion with artificial cerebrospinal fluid saturated with 95% N2-5% O2) on dopaminergic neurons of the rat ventral mesencephalon maintained in vitro. A prolonged anoxia caused an inhibition of the spontaneous firing and a sustained (mean 16 min) and slowing declining hyperpolarization of the membrane in 30 dopaminergic cells. This was associated with a decrease of the apparent input resistance at 5, 10, 15 and 20 min of O2 deprivation by 38% (n = 18), 42% (n = 8), 48% (n = 18) and 54% (n = 8) of control, respectively. The continuation of anoxia, 1-4 min after the hyperpolarizing period, induced an irreversible depolarization (n = 8). More than 50% of the cells (17 of 30) fully recovered their electrophysiological properties after 15 min of O2 deprivation. Since the intracellular diffusion of cesium (a potassium channel blocker) was able to block the hyperpolarization and to reveal a depolarization caused by anoxia, we tested whether the blockade of the hyperpolarization modified the resistance of the cells to O2 deprivation. We observed that the cells loaded with cesium were depolarized and damaged in a period of O2 deprivation less than 10 min. The apparent input resistance of these neurons was irreversibly reduced by 36% of the control at 5 min of anoxia (n = 6). Furthermore, in order to ascertain whether an impairment of the sodium/potassium pump due to energy failure is involved in the anoxia-induced depolarization, we blocked the Na+/K+ ATPase pump with the inhibitor ouabain.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice.

Dopamine plays a key role in the control of motor and cognitive functions through the interaction with membrane receptors. Dopamine elicits its physiological effect by interacting with receptors that belong to the seven transmembrane domain G-protein-coupled receptors family. Pharmacological and structural analyses have allowed the division of these receptors into two classes: the D1- and D2-like receptors. The D1-like subfamily comprises D1 and D5 while the D2-like is formed by D2, D3 and D4. Dopaminergic neurons arise from the ventral tegmental area and the substantia nigra. These neurons give rise to four dopaminergic pathways: the nigrostriatal, the mesolimbic, the mesocortical and tuberoinfundibular pathways. These pathways are involved in the control of movement, learning, motivation reward and hormone synthesis and release. Dysfunction in these pathways leads to neurological, psychiatric and endocrine disorders. Indeed, degeneration of the nigrostriatal pathway leads to Parkinson's disease in humans, characterized by a strong reduction of released dopamine. Thus, a fine tuning of the firing discharge of dopaminergic neurons is a key function in the regulation of dopamine mediated activities in the central nervous system. Somatodendritic dopaminergic autoreceptors of the D2-like family are responsible for such a function. However, it is still controversial whether this function could be ascribed only to one or more members of this subfamily.

Presynaptic muscarinic (M3) receptors reduce excitatory transmission in dopamine neurons of the rat mesencephalon.

The effects of carbachol (0.01-30 microM) and muscarine (10-30 microM) on the excitatory synaptic potentials were studied using conventional intracellular recordings from dopaminergic neurons in rat mesencephalic slices. Both muscarinic agonists reversibly reduced the excitatory synaptic potentials, evoked by local electrical stimulation. The EC50 for carbachol was determined to be 4.5 microM. The maximal degree of the excitatory synaptic potentials suppression caused by carbachol and muscarine was around 40% of control. This suppression was completely blocked by the non-specific muscarinic antagonist atropine (1 microM) and the selective M3 antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (1 microM). Other antagonists, preferentially acting at M1, M2 and M4 receptors, were not effective. Furthermore, the acetylcholinesterase inhibitor, physostigmine (50 microM), decreased the amplitude of the excitatory synaptic potentials, indicating that ambient acetylcholine can depress this potential. Direct depolarizing responses to glutamate were not changed by muscarine. In addition, muscarine facilitated the second excitatory synaptic potentials during a paired-pulse protocol. Thus, the effect of the muscarinic agonists is attributable to a presynaptic locus of action. The action of muscarine was not mediated by an N-ethylmaleimide-sensitive G-protein since it was not modified by a treatment of the slices with this agent. The calcium channels blockers, omega-conotoxin GIVA, omega-agatoxin IVA and omega-conotoxin MVIIC did not affect the action of muscarine on the excitatory synaptic potentials. When the potassium currents were reduced by extracellular barium and 4-aminopyridine, the muscarinic agonists still depressed the excitatory synaptic potentials. Our data indicate that presynaptically located M3 receptors modulate the excitatory transmission to midbrain dopaminergic neurons via a N-ethylmaleimide-insensitive G-protein which activates mechanisms neither linked to N-, P-, Q-type calcium channels nor to barium- and 4-aminopyridine-sensitive potassium channels.

Effects of riluzole on rat cortical neurones: an in vitro electrophysiological study.

1. The electrophysiological effects of riluzole on rat prefrontal and frontal cortical neurones were investigated by using both extracellular (field) and intracellular recording techniques in brain slices. 2. Bath applied riluzole (3-200 microM) depressed the cortico-cortical stimulus-evoked field potential in a concentration-related manner (EC50 = 29.5 microM). 3. Riluzole (3-100 microM) reduced the tonic firing of the neocortical neurones which was caused by intracellular current injection, while it did not have any effect on the resting membrane potential and apparent input resistance of these cells. 4. In the presence of tetrodotoxin (1 microM) and tetraethylammonium (30 mM), the injection of a depolarizing current step generated a calcium spike in the neocortical neurones. Riluzole (30 microM) abolished this calcium-dependent action potential. However, when the amount of the depolarizing current was increased the calcium-dependent regenerative potential was evoked again. 5. The depolarization of the membrane (10-20 mV) caused by brief (8-15 s) bath applications of glutamate (300 microM-1 mM) were not changed in the presence of riluzole (30 microM). 6. It is concluded that riluzole has direct actions on rat neocortical neurones: (a) it blocks the repetitive discharge of sodium action potentials and (b) it increases the threshold for the generation of the calcium spike. These two cellular mechanisms might at least in part account for the depression of the cortico-cortical field potential caused by this drug.

Effects of dihydropyridine calcium antagonists on rat midbrain dopaminergic neurones.

1. The effects of the dihydropyridine calcium channel antagonists, nifedepine and nimodipine (300 nM-30 microM) were tested in vitro on intracellularly recorded dopaminergic neurones in the rat ventral mesencephalon. 2. Bath applied nifedipine and nimodipine inhibited in a concentration-dependent manner the spontaneous firing discharge of the action potentials, whereas, the dihydropyridine calcium channel agonist, Bay K 8644 increased the firing rate. 3. Pacemaker oscillations and bursts of action potentials were produced by loading the cells with caesium. Nifedipine and nimodipine reduced the rate and the duration of the caesium-induced membrane oscillations and decreased the number of action potentials in a burst. During the blockade of potassium currents the dopaminergic neurones often developed a prolonged (100-800 ms) afterdepolarization that was also inhibited by dihydropyridines. 4. The spontaneous discharge of calcium spikes was also inhibited by both dihydropyridine calcium antagonists. The apparent input resistance and the level of membrane potential were not affected by the dihydropyridine calcium antagonists. 5. If the action potential duration was less than 150 ms the shape of the spike was not clearly influenced by both calcium antagonists. However, when the duration of the action potential was longer than 150-200 ms due to the intracellular injection of caesium ions plus the extracellular application of tetraethylammonium (10-50 mM), both nifedipine and nimodipine reversibly shortened the plateau potential. 6. It is suggested that nifedipine and nimodipine depress the rhythmic and bursting activity of the dopaminergic cells and shorten the calcium action potential by blocking dihydropyridine-sensitive high-threshold calcium currents.

Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study.

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

Antigenicity of synthetic peptides derived from C100 protein of hepatitis C virus.

Synthetic octapeptides spanning the 119-147 region of the Hepatitis C Virus (HCV) C100 protein were tested on HCV positive sera. The 138-145 region proved to be antigenic and possibly able to avoid undesired cross-reactions.

Genetic rearrangements in the tyrB-uvrA region of the enterobacterial chromosome: a potential cause for different class B acid phosphatase regulation in Salmonella enterica and Escherichia coli.

Unlike in Escherichia coli, in Salmonella enterica production of class B acid phosphatase (AphA) was detectable also in cells growing in the presence of glucose. Characterization of the aphA locus from a S. enterica ser. typhi strain showed that the aphA determinant is very similar to the E. coli homolog, and that its chromosomal location between the highly conserved tyrB and uvrA genes is retained. However, the aphA flanking regions were found to be markedly different in the two species, either between tyrB and aphA or between aphA and uvrA. The differences in the aphA 5'-flanking region, which in S. enterica is considerably shorter than in E. coli (183 vs. 1121 bp) and includes potential promoter sequences not present in E. coli, could be responsible for the different regulation of class B acid phosphatase observed in the two species.

Identification of the gene (aphA) encoding the class B acid phosphatase/phosphotransferase of Escherichia coli MG1655 and characterization of its product.

An open reading frame located in the tyrB-uvrA intergenic region of the Escherichia coli MG1655 chromosome was identified as encoding the class B acid phosphatase of this species on the basis of cloning and expression experiments. A protocol for purification of the enzyme (named AphA) was developed, and its properties were analyzed. The enzyme is a 100-kDa homotetrameric protein which apparently requires a metal co-factor for activity. Similarly to other bacterial class B acid phosphatases, it is able to dephosphorylate several organic phosphomonoesters as well as to catalyze the transfer of low-energy phosphate groups from phosphomonoesters to hydroxyl groups of various organic compounds.