Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

Background

A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment.

Results

Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP.

Conclusions

We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.     

The fossil record of Glypturus Stimpson, 1866 (Crustacea,Decapoda, Axiidea,Callianassidae) revisited,with notes on palaeoecology and palaeobiogeography

Abstract: The fossil record of the callianassid genus Glypturus (Decapoda, Axiidea) is re‐evaluated. Our systematic revision, both of extant and fossil taxa, is based on major cheliped morphology only, thus providing an important impetus for palaeontological studies. Both spination and tuberculation of chelipeds are herein considered of great taxonomic importance. Presence of spines on the upper margins of the merus and propodus and the lower margin of the carpus are significant for generic assignment, whereas the extent of tuberculation on lateral surfaces of the propodus is important for assignment at the species level. Altogether, four extant and six exclusively fossil species of Glypturus are recognized. Several extinct callianassid taxa are now transferred to the genus, namely Callianassa berryi, Callianassa fraasi, Callianassa munieri, Callianassa pugnax and Callianassaspinosa; Callianassa pseudofraasi is considered a junior synonym of C. fraasi. Based on a comparison of ecological preferences of extant representatives, the presence of Glypturus in the fossil record is considered to be linked with tropical to subtropical, nearshore carbonate environments of normal salinity. We argue that Glypturus is of Tethyan origin, with a stratigraphical range going as far back as the Eocene. Since then, the genus migrated both westwards and eastwards, establishing present‐day communities in the western Atlantic and Indo‐West Pacific which both comprise several distinct species. In the presumed area of origin, the genus does no longer occur today. The exlusively fossil (middle Eocene) genus Eoglypturus from Italy is considered closely related to Glypturus and is thus assigned to the subfamily Callichirinae as well.     

Antimalarial iron chelator, FBS0701, shows asexual and gametocyte Plasmodium falciparum activity and single oral dose cure in a murine malaria model

Iron chelators for the treatment of malaria have proven therapeutic activity in vitro and in vivo in both humans and mice, but their clinical use is limited by the unsuitable absorption and pharmacokinetic properties of the few available iron chelators. FBS0701, (S)3"-(HO)-desazadesferrithiocin-polyether [DADFT-PE], is an oral iron chelator currently in Phase 2 human studies for the treatment of transfusional iron overload. The drug has very favorable absorption and pharmacokinetic properties allowing for once-daily use to deplete circulating free iron with human plasma concentrations in the high μM range. Here we show that FBS0701 has inhibition concentration 50% (IC(50)) of 6 μM for Plasmodium falciparum in contrast to the IC(50) for deferiprone and deferoxamine at 15 and 30 μM respectively. In combination, FBS0701 interfered with artemisinin parasite inhibition and was additive with chloroquine or quinine parasite inhibition. FBS0701 killed early stage P. falciparum gametocytes. In the P. berghei Thompson suppression test, a single dose of 100 mg/kg reduced day three parasitemia and prolonged survival, but did not cure mice. Treatment with a single oral dose of 100 mg/kg one day after infection with 10 million lethal P. yoelii 17XL cured all the mice. Pretreatment of mice with a single oral dose of FBS0701 seven days or one day before resulted in the cure of some mice. Plasma exposures and other pharmacokinetics parameters in mice of the 100 mg/kg dose are similar to a 3 mg/kg dose in humans. In conclusion, FBS0701 demonstrates a single oral dose cure of the lethal P. yoelii model. Significantly, this effect persists after the chelator has cleared from plasma. FBS0701 was demonstrated to remove labile iron from erythrocytes as well as enter erythrocytes to chelate iron. FBS0701 may find clinically utility as monotherapy, a malarial prophylactic or, more likely, in combination with other antimalarials.     

Foveal and Peripheral Fields of Vision Influences Perceptual Skill in Anticipating Opponents’ Attacking Position in Volleyball

The importance of perceptual-cognitive expertise in sport has been repeatedly demonstrated. In this study we examined the role of different sources of visual information (i.e., foveal versus peripheral) in anticipating volleyball attack positions. Expert (n = 11), advanced (n = 13) and novice (n = 16) players completed an anticipation task that involved predicting the location of volleyball attacks. Video clips of volleyball attacks (n = 72) were spatially and temporally occluded to provide varying amounts of information to the participant. In addition, participants viewed the attacks under three visual conditions: full vision, foveal vision only, and peripheral vision only. Analysis of variance revealed significant between group differences in prediction accuracy with higher skilled players performing better than lower skilled players. Additionally, we found significant differences between temporal and spatial occlusion conditions. Both of those factors interacted separately, but not combined with expertise. Importantly, for experts the sum of both fields of vision was superior to either source in isolation. Our results suggest different sources of visual information work collectively to facilitate expert anticipation in time-constrained sports and reinforce the complexity of expert perception.     

Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma

Background

The low toxicity of perfluorocarbons (PFCs), their high affinity for respiratory gases and their compatibility with lung surfactant have made them useful candidates for treating respiratory diseases such as adult respiratory distress syndrome. We report results for treating acute allergic and non-allergic bronchoconstriction in sheep using S-1226 (a gas mixture containing carbon dioxide and small volumes of nebulized perflubron). The carbon dioxide, which is highly soluble in perflubron, was used to relax airway smooth muscle.

Methods

Sheep previously sensitized to house dust mite (HDM) were challenged with HDM aerosols to induce early asthmatic responses. At the maximal responses (characterised by an increase in lung resistance), the sheep were either not treated or treated with one of the following; nebulized S-1226 (perflubron + 12% CO₂), nebulized perflubron + medical air, 12% CO₂, salbutamol or medical air. Lung resistance was monitored for up to 20 minutes after cessation of treatment.In additional naïve sheep, a segmental bronchus was pre-contracted with methacholine (MCh) and treated with nebulized S-1226 administered via a bronchoscope catheter. Subsequent bronchodilatation was monitored by real time digital video recording.

Results

Treatment with S-1226 for 2 minutes following HDM challenge resulted in a more rapid, more profound and more prolonged decline in lung resistance compared with the other treatment interventions. Video bronchoscopy showed an immediate and complete (within 5 seconds) re-opening of MCh-constricted airways following treatment with S-1226.

Conclusions

S-1226 is a potent and rapid formulation for re-opening constricted airways. Its mechanism(s) of action are unknown. The formulation has potential as a rescue treatment for acute severe asthma.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0098-x) contains supplementary material, which is available to authorized users.