1,889 research outputs found

    Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b

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    Pseudohypoparathyroidism (PHP) is caused by reduced expression of genes within the GNAS cluster, resulting in parathormone resistance. The cluster contains multiple imprinted transcripts, including the stimulatory G protein α subunit (Gs-α) and NESP55 transcript preferentially expressed from the maternal allele, and the paternally expressed XLas, A/B and antisense transcripts. PHP1b can be caused by loss of imprinting affecting GNAS A/B alone (associated with STX16 deletion), or the entire GNAS cluster (associated with deletions of NESP55 in a minority of cases). We performed targeted genomic next-generation sequencing (NGS) of the GNAS cluster to seek variants and indels underlying PHP1b. Seven patients were sequenced by hybridisation-based capture and fourteen more by long-range PCR and transposon-mediated insertion and sequencing. A bioinformatic pipeline was developed for variant and indel detection. In one family with two affected siblings, and in a second family with a single affected individual, we detected maternally inherited deletions of 40 and 33 bp, respectively, within the deletion previously reported in rare families with PHP1b. All three affected individuals presented with atypically severe PHP1b; interestingly, the unaffected mother in one family had the detected deletion on her maternally inherited allele. Targeted NGS can reveal sequence changes undetectable by current diagnostic methods. Identification of genetic mutations underlying epigenetic changes can facilitate accurate diagnosis and counselling, and potentially highlight genetic elements critical for normal imprint settin

    Role of renal prostaglandins during antidiuresis and water diuresis in man

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    Role of renal prostaglandins during antidiuresis and water diuresis in man. The relationship of renal prostaglandins to antidiuretic hormone action and water diuresis was examined in 13 normal subjects and 2 subjects with diabetes insipidus. Following overnight water deprivation, an oral water load caused a prompt and sustained rise in the rate of urinary PGE2 excretion from 7.7 ± 1.2 to 81.6 ± 26.4 ng/hr (P < 0.0001) in 7 normal subjects. Because the simultaneous increase in urinary excretion of urea was only 17% of the rise in urinary PGE2, passive wash-out of renal PGE2 probably accounts for only a small fraction of the increment in PGE2 excretion. Administration of the antidiuretic hormone analogue DDAVP to 6 normal subjects during sustained water diuresis resulted in a decrease in PGE2 excretion and urine flow rate comparable to that of dehydrated subjects. Thus, PGE2 excretion varied directly with urine flow rate over a wide range of states of hydration in all 13 normal subjects. One patient with central diabetes insipidus and one with nephrogenic diabetes insipidus demonstrated a similar positive correlation of PGE2 excretion rate and urinary flow rate in states of hydration, dehydration, and after administration of DDAVP. In the patient with nephrogenic diabetes insipidus, this relationship of PGE2 excretion rate to urine flow rate was unaffected by DDAVP over a broad range of urine flow rates. Inhibition of prostaglandin synthesis with indomethacin in 6 normal subjects resulted in a significant decline in free water clearance (7.7 ± 1.0 to 4.7 ± 0.9 ml/min, P < 0.001) and an increase in the minimal UOSM (61 ± 4 to 93 ± 19 mOsm/kg, P < 0.01) achieved during water diuresis without a change in creatinine or osmolar clearances. Furthermore, the tightly linked relationship of PGE2 excretion rate to urine flow rate was reduced in 5 of 6 subjects during indomethacin treatment. We conclude that urinary PGE2 excretion varies directly with urine flow rate and is not directly dependent on ADH activity or state of hydration in man. The rise in PGE2 excretion during water diuresis may enhance the excretion of free water since indomethacin treatment blunted free water clearance while suppressing the rise in PGE2 excretion.Rôle des prostaglandines rénales au cours de l'antidiurèse et de la diurèse aqueuse chez l'homme. La relation entre les prostaglandines rénales et l'action de l'hormone antidiurétique et la diurèse aqueuse a été étudiée chez 13 sujets normaux et 2 sujets atteints de diabète insipide. A la suite d'une restriction d'eau pendant la nuit précédant l'étude, une charge d'eau par voie orale a déterminé une augmentation rapide et prolongée du débit urinaire de PGE2 de 7,7 ± 1,2 à 81,6 ± 26,4 ng/hr (P < 0,001) chez 7 sujets normaux. Puisque l'augmentation simultanée de l'excrétion urinaire d'urée était seulement de 17% de l'augmentation de la PGE2 urinaire, un lavage passif de la PGE2 rénale explique probablement une partie seulement de l'augmentation de l'excrétion de PGE2. L'administration d'un analogue de l'hormone antidiurétique, DDAVP, à 6 sujets normaux au cours d'une diurèse aqueuse prolongée a eu pour conséquence une diminution de l'excrétion de PGE2 et du débit urinaire comparable à celle des sujets déshydratés. Ainsi l'excrétion de PGE2 varie directement avec le débit urinaire sur un large éventail d'états d'hydratation chez tous les 13 sujets normaux. Un malade atteint de diabète insipide central et un malade atteint de diabète insipide néphrogénique ont eu une corrélation positive semblable du débit d'excrétion de PGE et du débit urinaire dans les états d'hydratation, de déshydratation, et après l'administration de DDAVP. Chez le malade atteint de diabète insipide néphrogénique, cette relation de l'excrétion de PGE2 au débit urinaire n'a pas été affectée par DDAVP sur un large éventail de valeurs du débit urinaire. L'inhibition de la synthèse de prostaglandine par l'indométhacine chez 6 sujets normaux a eu pour conséquence une diminution significative de la clairance de l'eau libre (7,7 ± 1,0 à 4,7 ± 0,9 ml/mn, P < 0,001) et une augmentation de la valeur minimale de UOSM (61 ± 4 à 93 ± 19 mOsm/kg, P < 0,01) obtenues au cours d'une diurèse aqueuse sans modification de la clairance de la créatinine ou de la clairance osmolaire. De plus, la relation étroite entre l'excrétion de PGE2 et le débit urinaire a été réduite chez 5 des 6 sujets au cours du traitement par l'indométhacine. Nous concluons que l'excrétion urinaire de PGE2 varie directement avec le débit urinaire et n'est pas directement dépendante de l'activité de l'ADH ou de l'état d'hydratation chez l'homme. L'augmentation de l'excrétion de PGE2 au cours de la diurèse aqueuse peut accroître l'excrétion d'eau libre puisque le traitement par l'indométhacine atténue la clairance de l'eau libre en même temps qu'il supprime l'augmentation de l'excrétion de PGE2

    Eating with a Purpose:Consumer Response to Functional Food Health Claims in Conflicting Versus Complementary Information Environments

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    Marketers of food products have recently introduced a variety of “functional foods” that promise consumers improvements in targeted physiological functions. However, despite the proliferation of functional food health claims promising more than basic nutrition, little is known about consumer responses to these claims, particularly in information environments in which inconsistent information may be available about the efficacy of a particular functional ingredient

    RdgB2 is required for dim-light input into intrinsically photosensitive retinal ganglion cells.

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    A subset of retinal ganglion cells is intrinsically photosensitive (ipRGCs) and contributes directly to the pupillary light reflex and circadian photoentrainment under bright-light conditions. ipRGCs are also indirectly activated by light through cellular circuits initiated in rods and cones. A mammalian homologue (RdgB2) of a phosphoinositide transfer/exchange protein that functions in Drosophila phototransduction is expressed in the retinal ganglion cell layer. This raised the possibility that RdgB2 might function in the intrinsic light response in ipRGCs, which depends on a cascade reminiscent of Drosophila phototransduction. Here we found that under high light intensities, RdgB2(-/-) mutant mice showed normal pupillary light responses and circadian photoentrainment. Consistent with this behavioral phenotype, the intrinsic light responses of ipRGCs in RdgB2(-/-) were indistinguishable from wild-type. In contrast, under low-light conditions, RdgB2(-/-) mutants displayed defects in both circadian photoentrainment and the pupillary light response. The RdgB2 protein was not expressed in ipRGCs but was in GABAergic amacrine cells, which provided inhibitory feedback onto bipolar cells. We propose that RdgB2 is required in a cellular circuit that transduces light input from rods to bipolar cells that are coupled to GABAergic amacrine cells and ultimately to ipRGCs, thereby enabling ipRGCs to respond to dim light

    Self-reported pregnancy exposures and placental DNA methylation in the MARBLES prospective autism sibling study.

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    Human placenta is a fetal-derived tissue that offers a unique sample of epigenetic and environmental exposures present in utero. In the MARBLES prospective pregnancy study of high-risk younger siblings of children with autism spectrum disorder (ASD), pregnancy and environmental factors collected by maternal interviews were examined as predictors of placental DNA methylation, including partially methylated domains (PMDs), an embryonic feature of the placental methylome. DNA methylation data from MethylC-seq analysis of 47 placentas of children clinically diagnosed at 3 years with ASD or typical development using standardized assessments were examined in relation to: child's gestational age, birth-weight, and diagnosis; maternal pre-pregnancy body mass index, smoking, education, parity, height, prenatal vitamin and folate intake; home ownership; pesticides professionally applied to lawns or gardens or inside homes, pet flea/tick pouches, collars, or soaps/shampoos used in the 3 months prior to or during pregnancy. Sequencing run, order, and coverage, and child race and sex were considered as potential confounders. Akaike information criterion was used to select the most parsimonious among candidate models. Final prediction models used sandwich estimators to produce homoscadisticity-robust estimates of the 95% confidence interval (CI) and P-values controlled the false discovery rate at 5%. The strongest, most robust associations were between pesticides professionally applied outside the home and higher average methylation over PMDs [0.45 (95% CI 0.17, 0.72), P = 0.03] and a reduced proportion of the genome in PMDs [-0.42 (95% CI - 0.67 to -0.17), P = 0.03]. Pesticide exposures could alter placental DNA methylation more than other factors

    Anisotropies in the gamma-ray sky from millisecond pulsars

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    Pulsars emerge in the Fermi era as a sizable population of gamma-ray sources. Millisecond pulsars (MSPs) constitute an older subpopulation whose sky distribution extends to high Galactic latitudes, and it has been suggested that unresolved members of this class may contribute a significant fraction of the measured large-scale isotropic gamma-ray background (IGRB). We investigate the possible energy-dependent contribution of unresolved MSPs to the anisotropy of the Fermi-measured IGRB. For observationally motivated MSP population models, we show that the preliminary Fermi anisotropy measurement places an interesting constraint on the abundance of MSPs in the Galaxy and the typical MSP flux, about an order of magnitude stronger than constraints on this population derived from the intensity of the IGRB alone. We also examine the possibility of an MSP component in the IGRB mimicking a dark matter signal in anisotropy-based searches, and conclude that the energy dependence of an anisotropy signature would distinguish MSPs from all but very light dark matter candidates
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