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.     

Validation of Fecal Glucocorticoid Metabolite Assays for South African Herbivores

ABSTRACT Fecal glucocorticoid metabolite (FGM) assays are a popular means of monitoring adrenocortical activity (i.e., physiological stress response) in wildlife. Species-specific differences in glucocorticoid metabolism and excretion require assay validation, including both laboratory and biological components, before assay use in new species. We validated a commercially available radioimmunoassay (MP ¹²⁵I corticosterone RIA kit [MP Biomedicals, Solon, OH]) for measuring FGMs of several South African herbivores, including giraffe (Giraffa camelopardalis), impala (Aepyceros melampus), nyala (Tragelaphus buxtoni), kudu (Tragelaphus strepsiceros), wildebeest (Connochaetes taurinus), and zebra (Equus burchelli). These herbivores are important in South African parks and reserves for ecotourism and as a prey base for predators and serve an integral role in ecosystem processes. Standard biochemical validations (e.g., recovery of exogenous corticosterone, intra- and interassay variation, and parallelism) demonstrated that the assay accurately and precisely measured FGMs of all 6 herbivore species. Our biological validations demonstrated that the assay was sensitive enough to detect changes in FGM production associated with season. Samples collected during the dry season (Jun-Aug) contained higher FGM concentrations than those from the wet season (Dec-Feb) in all species. We established optimal sample dilutions and reference FGM levels for these 6 herbivores, which can now be used to monitor the effects of management and ecotourism activities on the stress responses of these herbivores.     

A Study of Two Morphological Variants of the Diatom Fragilaria crotonensis Kitton using Electron Microscopy

Two forms of Fragilaria crotonensis Kitton, one with flaredends to the cells, the other with ends that taper to a narrowrod-like tip, were previously distinguished by light microscopyand by their contrasting relationships with the parasitic chytridsRhizophydium fragilariae Canter and one referred to as species3. Examples of the above diatom types, taken from a number ofgeographically widely separated lakes, have been examined byelectron microscopy. Additional morphological differences aredescribed. The ocellus in flared-type cells consists of 4–5rows of pores while in rod-type cells fewer (2–3) rowsof pores are present. Valve thickenings on the mantle at theapex of rod-type cells are rarely visible whereas in flared-typecells they are usually very prominent. A rimoportula was presentin both cell types. In flared cells its external aperture liesimmediately behind the apex usually in line with the striaeand the internal aperture is often orientated with its longaxis oblique to that of the diatom cell. The rimoportula inrod-type cells opens at the centre of the valve face and theinternal aperture is orientated at 90° to the apical axisof the valve. Comparison made with type material suggests thatthe rod-form should be recognized as F. crotonensis var. crotonensisand the flared-form as var. prolongata Grunow ex van Heurck. Fragilaria crotonensis, diatom, systematics, chytrid infection, rimoportula     

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.