Differential modulation of GABAA receptor function by Mel1a and Mel1b receptors.
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Animals↗
Biomedical subjects
G M Brown
Publications and source records attributed to G M Brown.
600 MHz NMR studies of human articular cartilage keratan sulfates.
The use of high-field two-dimensional 1H-correlation data is described for the detailed comparison of intact keratan sulfate polymer chains derived from human articular cartilage sources as a function of age. For fetal material the nonreducing chain termini are shown to be sparsely capped by sialyl groups which, if present, are exclusively (alpha2-3)-linked to an unsulfated galactose residue. The asialo capping segment has the structure: Gal-GlcNAc6S-Gal-GlcNAc6S-. Examination of keratan sulfate from 10-year-old cartilage shows that capping by sialyl groups is complete, with (alpha2-3)-linkages predominant; for both this and the 38-year-old cartilage the three capping structures: NeuAc(alpha2-3)-Gal-GlcNAc6S-Gal-GlcNAc6S-, NeuAc(alpha2-3)-Gal-GlcNAc6S-Gal6S-GlcNAc6S-, and NeuAc(alpha2-3)-Gal6S-GlcNAc6S-Gal6S-GlcNAc6S- are clearly recognizable. The level of (alpha2-6)-linked chain capping sialyl groups is significant for 38-year-old cartilage keratan sulfate. Structural information concerning the linkage region to protein and the distribution of galactose environments is readily obtained from the spectra. Signal complexities severely limit the usefulness of two-dimensional correlation spectroscopy at 600 MHz for the examination of N-acetylglucosamine residues within the poly(N-acetyllactosamine) repeat sequence and signals representing fucose placements remain undifferentiated. This nondestructive approach complements current degradative methods for the structural examination of keratan sulfates.
Adult↗
Environmental imperatives reconsidered: demographic crises in western North America during the medieval climatic anomaly.
Review of late Holocene paleoenvironmental and cultural sequences from four regions of western North America show striking correlations between drought and changes in subsistence, population, exchange, health, and interpersonal violence during the Medieval Climatic Anomaly (A.D. 800-1350). While ultimate causality is difficult to identify in the archaeological record, synchrony of the environmental and cultural changes and the negative character of many human responses--increased interpersonal violence, deterioration of long-distance exchange relationships, and regional abandonments--suggest widespread demographic crises caused by decreased environmental productivity. The medieval droughts occurred at a unique juncture in the demographic history of western North America when unusually large populations of both hunter-gathers and agriculturalists had evolved highly intensified economies that put them in unprecedented ecological jeopardy. Long-term patterns in the archaeological record are inconsistent with the predicted outcomes of simple adaptation or continuous economic intensification, suggesting that in this instance environmental dynamics played a major role in cultural transformations across a wide expanse of western North America among groups with diverse subsistence strategies. These events suggest that environment should not be overlooked as a potential cause of prehistoric culture change.
Climate↗
An improved method for the structural profiling of keratan sulfates: analysis of keratan sulfates from brain and ovarian tumors.
A previously developed method for the structural fingerprinting of keratan sulfates (Brown et al., Glycobiology, 5, 311-317, 1995) has been adapted for use with oligosaccharides fluorescently labeled with 2-aminobenzoic acid following keratanase II digestion. The oligosaccharides are separated by high-pH anion-exchange chromatography on a Dionex AS4A-SC column. This methodology permits quantitative analysis of labeled oligosaccharides which can be detected at the sub-nanogram ( approximately 100 fmol) level. Satisfactory calibration of this method can be achieved using commercial keratan sulfate standards. Keratan sulfates from porcine brain phosphocan and human ovarian tumors have been examined using this methodology, and their structural features are discussed.
Acetylglucosaminidase↗
Melatonin concentrations in the luminal fluid, mucosa, and muscularis of the bovine and porcine gastrointestinal tract.
Melatonin concentrations were measured in serum, luminal fluid, and tissues of the mucosa and muscularis of the entire bovine and porcine gastrointestinal tract (GIT). In both species, GIT levels profoundly exceeded serum levels. In pigs, melatonin was lowest in the luminal fluid and highest in the mucosa. No difference was found in various layers of bovine GIT. Compared to pigs, cows had higher melatonin levels in the stomach and ileum, but lower in the cecum and colon. There was no difference in melatonin levels between anterior and posterior segments of bovine GIT, whereas pigs exhibited several fold higher concentration of melatonin in the posterior segment (cecum and colon). Conversely, melatonin values in the anterior segment were significantly higher in cows, but in the posterior segments porcine values were higher. In cows, concentrations in the mucosa correlated with levels in the muscularis. Melatonin levels in the mucosa and muscularis were higher in the rumen and reticulum than in the omasum and abomasum. The species-specific levels and a distinct distribution of melatonin in the layers of the digestive tube indicates that this indole may be involved in the modulation of gastrointestinal function of monogastric as well as polygastric ungulates, albeit in a different capacity.
Animals↗
Low doses of melatonin and diurnal effects on thermoregulation and tolerance to uncompensable heat stress.
This study examined whether the reported hypothermic effect of melatonin ingestion increased tolerance to exercise at 40 degrees C, for trials conducted either in the morning or afternoon, while subjects were wearing protective clothing. Nine men performed four randomly ordered trials; two each in the morning (0930) and afternoon (1330) after the double-blind ingestion of either two placebo capsules or two 1-mg capsules of melatonin. Despite significant elevations in plasma melatonin to over 1,000 ng/ml 1 h after the ingestion of the first 1-mg dose, rectal temperature (T(re)) was unchanged before or during the heat-stress exposure. Also, all other indexes of temperature regulation and the heart rate response during the uncompensable heat stress were unaffected by the ingestion of melatonin. Initial T(re) was increased during the afternoon (37.1 +/- 0.2 degrees C), compared with the morning (36.8 +/- 0.2 degrees C) exposures, and these differences remained throughout the uncompensable heat stress, such that final T(re) was also increased for the afternoon (39.2 +/- 0.2 degrees C) vs. the morning (39.0 +/- 0.3 degrees C) trials. Tolerance times and heat storage were not different among the exposures at approximately 110 min and 16 kJ/kg, respectively. It was concluded that this low dose of melatonin had no impact on tolerance to uncompensable heat stress and that trials conducted in the early afternoon were associated with an increased T(re) tolerated at exhaustion that offset the circadian influence on resting T(re) and thus maintained tolerance times similar to those of trials conducted in the morning.
Adult↗
Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects.
OBJECTIVE: Several postmortem studies have reported a decreased density of serotonin 5-HT2 receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [18F]setoperone and positron emission tomography (PET) imaging. METHOD: Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT2 receptors was assessed with the use of [18F]setoperone and PET in standardized cortical regions of interest. RESULTS: Increasing age was associated with similar declines in 5-HT2 receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT2 receptor density in any of the cortical regions. CONCLUSIONS: This study failed to find the decrease in 5-HT2 receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT2 receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT2 receptors. This finding does not rule out a therapeutic role for 5-HT2 antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.
Antipsychotic Agents↗
Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.
OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.
Adolescent↗
Human aggrecan keratan sulfate undergoes structural changes during adolescent development.
Alkaline borohydride-reduced keratan sulfate chains were isolated from human articular cartilage aggrecan from individuals of various ages (0-85 years old). The chains were structurally characterized using 1H NMR spectroscopy, gel permeation chromatography, and oligosaccharide profiling (after digestion with the enzymes keratanase and keratanase II). The results show that from birth to early adolescence (0-9 years) the levels of alpha(1-3)-fucosylation, alpha(2-3)-sialylation, and galactose sulfation increase. Also, the weight-average molecular weight of the chains increases. During maturation (9-18 years) the levels of fucosylation and galactose sulfation continue to increase and alpha(2-6)-sialylation of the chains occurs. In adult life (18-85 years) there is little change in the weight-average molecular weight of the chains, and the levels of fucosylation, sialylation, and sulfation remain fairly constant.
Acetylglucosaminidase↗
Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors.
The pineal hormone, melatonin, inhibits proliferation of estrogen receptor (ER)-positive MCF-7 human breast cancer cells, modulates both ER mRNA and protein expression, and appears to be serum dependent, indicating interaction between melatonin and serum components. To examine the effects of melatonin on ER activity, ER transactivation assays were performed by transiently transfecting MCF-7 cells with an ERE-luciferase reporter construct. MCF-7 cells pre-treated with melatonin for as little as 5 min followed by either epidermal growth factor (EGF) or insulin resulted in the estrogen-independent transactivation of the ER. None of the compounds when used alone transactivated the ER. The ability of melatonin and EGF to transactivate the ER was abolished by the addition of the antiestrogen, ICI 164384, suggesting that melatonin and EGF co-operate to transactivate the ER. The modulation of ER transactivation was associated with changes in mitogen activated protein kinase activity and ER phosphorylation. This ER transactivation was blocked by pertussis toxin, a Galpha i-protein-coupled receptor inhibitor, suggesting cross talk between the G-protein-coupled melatonin receptor pathway and the EGF/insulin tyrosine kinase receptor pathways in modulating ER transactivation. Exactly how the ability of melatonin in combination with EGF to transactivate the ER relates to melatonin's observed growth suppressive effects is not clear. It is possible that, although melatonin and EGF transactivate the ER, this transactivation does not result in the full transcription of estrogen-responsive genes, but rather, makes the ER refractory to activation by estradiol, thus, blocking the mitogenic actions of estradiol.
Blotting, Western↗
13C-NMR spectroscopy of keratan sulphates--assignments for five sialylated pentasaccharides derived from the non-reducing chain termini of bovine articular cartilage keratan sulphate by keratanase II digestion.
Skeletal keratan sulphate has been fragmented using the enzyme keratanase II, and 13C chemical-shift data are reported for five reduced sialylated pentasaccharides that derived from the non-reducing chain terminal region. They have the structures: NeuAc(alpha2-6)Gal(beta1-4)GlcNAc6S(beta1-3)Gal(beta1-4)GlcNAc6 S-ol, NeuAc(alpha2-3)Gal(beta1-4)GlcNAc6S(beta1-3)Gal(beta1-4)GlcNAc6 S-ol, NeuAc(alpha2-6)Gal(beta1-4)GlcNAc6S(beta1-3)Gal6S(beta1-4)++ +GlcNAc6S-ol, NeuAc(alpha2-3)Gal(beta1-4)GlcNAc6S(beta1-3)Gal(6S)(beta1-4)Glc NAc6S-ol, and NeuAc(alpha2-3)Gal(6S)(beta1-4)GlcNAc6S(beta1-3)Gal(6S)(beta1-4)++ +GlcNAc6S-ol, where GlcNAc6S-ol represents N-acetyl-glucosaminitol 6-O-sulphate and NeuAc represents N-acetylneuraminic acid. The use of these 13C-NMR spectroscopy data for the recognition of specific chain-capping structures within native keratan sulphates is discussed. In addition, examination of the data derived from the NeuAc(alpha2-6) capping structures strongly suggests that sulphation three residues away from the neuraminic acid cap has a profound effect upon the conformation of the capping region.
Acetylglucosaminidase↗
Hormonal and subjective responses to intravenous m-chlorophenylpiperazine in women with seasonal affective disorder.
BACKGROUND: There is emerging evidence of serotonergic dysfunction in patients with seasonal affective disorder (SAD). We examined central serotonergic function in female patients with SAD (fall-winter pattern) by means of neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist m-chlorophenylpiperazine. METHODS: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to m-chlorophenylpiperazine (0.1 mg/kg intravenously) and placebo in 14 unmedicated female patients with SAD in the depressed state and 15 female normal controls. All testing was done in the fall-winter months and during the follicular phase of the menstrual cycle. Plasma prolactin and cortisol levels were used as neuroendocrine measures, while subjective responses were assessed by means of visual analog scales of 10 mood states. RESULTS: On the basis of net responses to m-chlorophenylpiperazine (placebo effects subtracted from drug effects), patients with SAD exhibited blunted prolactin responses and less sadness than normal controls in response to the drug. When order of presentation of drug and placebo was taken into consideration, altered "calm" and "high" responses were also found in the patient group. CONCLUSION: Evidence of dysfunction at or downstream to central serotonergic receptors in female patients with SAD confirms and extends findings from previous research.
Adult↗
Genetic analysis of meiotic recombination in humans by use of sperm typing: reduced recombination within a heterozygous paracentric inversion of chromosome 9q32-q34.3.
To investigate patterns of genetic recombination within a heterozygous paracentric inversion of chromosome 9 (46XY inv[9] [q32q34.3]), we performed sperm typing using a series of polymorphic microsatellite markers spanning the inversion region. For comparison, two donors with cytogenetically normal chromosomes 9, one of whom was heterozygous for a pericentric chromosome 2 inversion (46XY inv[2] [p11q13]), were also tested. Linkage analysis was performed by use of the multilocus linkage-analysis program SPERM, and also CRI-MAP, which was adapted for sperm-typing data. Analysis of the controls generated a marker order in agreement with previously published data and revealed no significant interchromosomal effects of the inv(2) on recombination on chromosome 9. FISH employing cosmids containing appropriate chromosome 9 markers was used to localize the inversion breakpoint of inv(9). Analysis of inv(9) sperm was performed by use of a set of microsatellite markers that mapped centromeric to, telomeric to, and within the inversion breakpoints. Three distinct patterns of recombination across the region were observed. Proximal to the centromeric breakpoint, recombination was similar to normal levels. Distal to the telomeric breakpoint, there was an increase in recombination found in the inversion patient. Finally, within the inversion, recombination was dramatically reduced, but several apparent double recombinants were found. A putative model explaining these data is proposed.
Adult↗
Characterisation of the coding sequence and fine mapping of the human DFFRY gene and comparative expression analysis and mapping to the Sxrb interval of the mouse Y chromosome of the Dffry gene.
DFFRY (the Y-linked homologue of the DFFRX Drosophila fat-facets related X gene) maps to proximal Yq11.2 within the interval defining the AZFa spermatogenic phenotype. The complete coding region of DFFRY has been sequenced and shows 89% identity to the X-linked gene at the nucleotide level. In common with DFFRX , the potential amino acid sequence contains the conserved Cys and His domains characteristic of ubiquitin C-terminal hydrolases. The human DFFRY mRNA is expressed in a wide range of adult and embryonic tissues, including testis, whereas the homologous mouse Dffry gene is expressed specifically in the testis. Analysis of three azoospermic male patients has shown that DFFRY is deleted from the Y chromosome in these individuals. Two patients have a testicular phenotype which resembles Sertoli cell-only syndrome, and the third diminished spermatogenesis. In all three patients, the deletions extend from close to the 3' end into the gene, removing the entire coding sequence of DFFRY. The mouse Dffry gene maps to the Sxrb deletion interval on the short arm of the mouse Y chromosome and its expression in mouse testis can first be detected between 7.5 and 10.5 days after birth when type A and B spermatogonia and pre-leptotene and leptotene spermatocytes are present.
Adult↗
Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution.
The Delta Sxrb interval of the mouse Y chromosome is critical for spermatogenesis and expression of the male-specific minor transplantation antigen H-Y. Several genes have been mapped to this interval and each has a homologue on the X chromosome. Four, Zfy1 , Zfy2 , Ube1y and Dffry , are expressed specifically in the testis and their X homologues are not transcribed from the inactive X chromosome. A further two, Smcy and Uty , are ubiquitously expressed and their X homologues escape X-inactivation. Here we report the identification of another gene from this region of the mouse Y chromosome. It encodes the highly conserved eukaryotic translation initiation factor eIF-2gamma. In the mouse this gene is ubiquitously expressed, has an X chromosome homologue which maps close to Dmd and escapes X-inactivation. The coding regions of the X and Y genes show 86% nucleotide identity and encode putative products with 98% amino acid identity. In humans, the eIF-2gamma structural gene is located on the X chromosome at Xp21 and this also escapes X-inactivation. However, there is no evidence of a Y copy of this gene in humans. We have identified autosomal retroposons of eIF-2gamma in both humans and mice and an additional retroposon on the X chromosome in some mouse strains. Ark blot analysis of eutherian and metatherian genomic DNA indicates that X-Y homologues are present in all species tested except simian primates and kangaroo and that retroposons are common to a wide range of mammals. These results shed light on the evolution of X-Y homologous genes.
Amino Acid Sequence↗
Relationship between melatonin levels in plasma and gastrointestinal tissues and the incidence and severity of gastric ulcers in pigs.
Four weeks of administration of melatonin mixed in the diet (5 mg/kg of food) significantly reduced the incidence of gastric ulcers in young pigs. In control and melatonin supplemented animals, significantly higher levels of melatonin were found in the stomach tissues as compared to jejunum, ileum, or colon. Pigs with the most severe ulcers exhibited significantly lower concentrations of melatonin in their stomach tissue and the blood plasma. Pigs fed coarsely ground diet exhibited higher tissue levels of melatonin in the stomach than animals fed a finely ground diet. Coarse diet was also associated with a lower score of gastric ulcers. No relationship between tissue levels of melatonin and the severity of gastric ulcers was found in other segments of the gastrointestinal tract. In the second experiment we determined that there was no significant difference between the gastro-protective effects of 2.5, 5.0, and 10.0 mg of melatonin mixed per 1 kg of food. A coarsely ground diet is hypothesized to have a gastro-protective effect by stimulating the production of melatonin in the stomach tissues. Dietary supplementation of food with melatonin, at threshold levels perhaps lower than 2.5 mg/kg/feed, may significantly reduce the incidence of gastric ulcers in pigs.
Animal Feed↗
No effect of depression on [(15)O]H2O PET response to intravenous d-fenfluramine.
OBJECTIVE: Subnormal prolactin responses to the serotonin-releasing agonist fenfluramine occur in depression. Since many measures of serotonin pathology occur in depression, abnormal responses to fenfluramine may occur in brain structures other than the hypothalamic-pituitary axis. One study compared six depressed and six healthy subjects' responses to oral d,l-fenfluramine by assessing [18F]fluorodeoxyglucose uptake as detected by positron emission tomography (PET). That study showed several abnormalities within the cortex, and the authors concluded that low responsivity to d,l-fenfluramine is widespread in depression. In this study abnormalities in regional neuromodulation by serotonin in major depression were assessed with intravenous d-fenfluramine and [(15)O]H2O PET. METHOD: Changes in regional cerebral blood flow (CBF) were detected by using [(15)O]H2O PET after administration of intravenous d-fenfluramine to 13 depressed and 18 healthy women. The PET scans were done 20 and 5 minutes before and 20 and 35 minutes after d-fenfluramine administration. Differences between the depressed and healthy groups in change in regional CBF (mean postfenfluramine minus mean prefenfluramine) were analyzed by using statistical parametric mapping. RESULTS: There were no significant differences between depressed and healthy subjects; in fact, changes in regional CBF after intravenous d-fenfluramine were remarkably similar. CONCLUSIONS: Degrees of neuronal responsivity to d-fenfluramine are similar in depressed and healthy subjects. Differences between the previous and current findings may be accounted for by greater specificity of intravenous d-fenfluramine to serotonin release, timing of scans, paucity of suicidal subjects in the current study, or greater variance in regional CBF from direct vascular effects of serotonin.
Administration, Oral↗
This porridge is too thin.
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Ethics, Medical↗