Medulloblastoma and ependymoma cells display levels of 5-carboxylcytosine and elevated TET1 expression

Background Alteration of DNA methylation (5-methylcytosine, 5mC) patterns represents one of the causes of tumorigenesis and cancer progression. Tet proteins can oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine (5caC). Although the roles of these oxidised forms of 5mC (oxi-mCs) in cancer pathogenesis are still largely unknown, there are indications that they may be involved in the mechanisms of malignant transformation. Thus, reduction of 5hmC content represents an epigenetic hallmark of human tumours and, according to our recent report; 5caC is enriched in a proportion of breast cancers and gliomas. Nevertheless, the distribution of oxi-mCs in paediatric brain tumours has not been assessed. Findings Here we analyse the global levels and spatial distribution of 5hmC and 5caC in 4 brain tumour cell lines derived from paediatric sonic hedgehog (SHH) pathway activated medulloblastomas (Daoy and UW228-3) and ependymomas (BXD-1425EPN and DKFZEP1NS). We show that, unlike HeLa cells, the paediatric tumour cell lines possess both 5hmC and 5caC at immunochemically detectable levels, and demonstrate that both modifications display high degrees of spatial overlap in the nuclei of medulloblastomas and ependymomas. Moreover, although 5hmC levels are comparable in the 4 brain tumour cell lines, 5caC staining intensities differ dramatically between them with highest levels of this mark in a subpopulation of DKFZ-EP1NS cells. Remarkably, the 5caC enrichment does not correlate with 5hmC levels and is not associated with alterations in Thymine DNA Glycosylase (TDG) expression in SHH medulloblastoma and ependymoma cell lines, but corresponds to elevated levels of TET1 transcript in UW228-3 and DKFZ-EP1NS cells. Conclusions We demonstrate that both 5caC enrichment and elevated TET1 expression are observed in SHH medulloblastomas and ependymomas. Our results suggest that increased Tet-dependent 5mC oxidation may represent one of the epigenetic signatures of cancers with neural stem cell origin and, thus, may contribute to development of novel approaches for diagnosis and therapy of the brain tumours

Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsy cohorts with evaluation of ApoE genotype

BACKGROUND AND PURPOSE: The impact of traumatic brain injury (TBI) on the pathogenesis of Alzheimer disease (AD) is still controversial. The aim of our retrospective autopsy study was to assess the impact of TBE and ApoE allele frequency on the development of AD. MATERIAL AND METHODS: We examined 1. the incidence of AD pathology (Braak stageing, CERAD, NIA-Reagan Institute criteria) in 58 consecutive patients (mean age ± SD 77.0 ± 6.8 years) with residual closed TBI lesions, and 2. the frequency of TBI residuals in 57 age-matched autopsy proven AD cases. In both series, ApoE was evaluated from archival paraffin-embedded brain material. RESULTS: 1. TBE series: 12.1 % showed definite and 10.3% probable AD (mean age 77.6 and 75.2 years), only 2/13 with ApoEε3/4. From 45 (77.6%) non-AD cases (mean age 78.2 years), 3 had ApoEε3/4. The prevalence of 22.4% AD in this small autopsy cohort was significantly higher than 3.3% in a recent large clinical series and 14% in the general population over age 70. 2. In the AD cohort with ApoEε4 allele frequency of 30% similar to other AD series, residuals of closed TBI were seen in 4 brains (7%) (mean age ± SD 78.2 ± 6.4), all lacking the ApoEε4 allele. TBI incidence was slightly lower than 8.5% in the clinical MIRAGE study. CONCLUSIONS: The results of this first retrospective autopsy study of TBI, ApoEε allele frequency, and AD confirm clinical studies suggesting severe TBI to be a risk factor for the development AD higher in subjects lacking ApoEε4 alleles. Further studies in larger autopsy series are needed to elucidate the relationship between TBI, genetic predisposition, and AD

Lineage diversification and historical demography of a montane bird Garrulax elliotii - implications for the Pleistocene evolutionary history of the eastern Himalayas

<p>Abstract</p> <p>Background</p> <p>Pleistocene climate fluctuations have shaped the patterns of genetic diversity observed in many extant species. In montane habitats, species' ranges may have expanded and contracted along an altitudinal gradient in response to environmental fluctuations leading to alternating periods of genetic isolation and connectivity. Because species' responses to climate change are influenced by interactions between species-specific characteristics and local topography, diversification pattern differs between species and locations. The eastern Himalayas is one of the world's most prominent mountain ranges. Its complex topography and environmental heterogeneity present an ideal system in which to study how climatic changes during Pleistocene have influenced species distributions, genetic diversification, and demography. The Elliot's laughing thrush (<it>Garrulax elliotii</it>) is largely restricted to high-elevation shrublands in eastern Himalayas. We used mitochondrial DNA and microsatellites to investigate how genetic diversity in this species was affected by Pleistocene glaciations.</p> <p>Results</p> <p>Mitochondrial data detected two partially sympatric north-eastern and southern lineages. Microsatellite data, however, identified three distinct lineages congruent with the geographically separated southern, northern and eastern eco-subregions of the eastern Himalayas. Geographic breaks occur in steep mountains and deep valleys of the Kangding-Muli-Baoxin Divide. Divergence time estimates and coalescent simulations indicate that lineage diversification occurred on two different geographic and temporal scales; recent divergence, associated with geographic isolation into individual subregions, and historical divergence, associated with displacement into multiple refugia. Despite long-term isolation, genetic admixture among these subregional populations was observed, indicating historic periods of connectivity. The demographic history of <it>Garrulax elliotii </it>shows continuous population growth since late Pleistocene (about 0.125 mya).</p> <p>Conclusion</p> <p>While altitude-associated isolation is typical of many species in other montane regions, our results suggest that eco-subregions in the eastern Himalayas exhibiting island-like characteristics appear to have determined the diversification of <it>Garrulax elliotii</it>. During the Pleistocene, these populations became isolated on subregions during interglacial periods but were connected when these expanded to low altitude during cooler periods. The resultant genetic admixture of lineages might obscure pattern of genetic variation. Our results provide new insights into sky island diversification in a previously unstudied region, and further demonstrate that Pleistocene climatic changes can have profound effects on lineage diversification and demography in montane species.</p

Vigilance in a Cooperatively Breeding Primate

Collective vigilance is considered a major advantage of group living in animals. We investigated vigilance behavior in wild mustached tamarins (Saguinus mystax), small, arboreal, cooperatively breeding New World primates that form stable mixed-species groups with saddleback tamarins (Saguinus fuscicollis). We aimed 1) to investigate whether vigilance patterns change according to individual activity and 2) to examine whether there is a social component of vigilance in their cooperative and nonaggressive society. We studied 11 factors that may influence vigilance and used this data to interpret the possible functions of vigilance. We observed 44 individuals in 3 mixed-species and 2 single-species groups of 2 populations that differed in population density and home range sizes. Vigilance changed greatly when individuals were engaged in different activities and individual vigilance was affected by different sets of factors depending on the activity. As vigilance decreased in proximity of conspecifics and heterospecifics when feeding, and in larger mixed-species groups when resting, we conclude that the predominant function of vigilance in mustached tamarins is predator related. However, the absence of the group size effect in very large single-species groups suggests that it may also function to maintain group cohesion. In the population with higher density and smaller home ranges individuals also increased their vigilance in home range overlap areas. We found no evidence that mustached tamarins monitor group mates to avoid food stealing or aggression. The effect of heterospecifics on individual vigilance suggests that collective vigilance might have been an important incentive in the evolution of tamarin mixed-species groups

Elevational Patterns of Species Richness, Range and Body Size for Spiny Frogs

Quantifying spatial patterns of species richness is a core problem in biodiversity theory. Spiny frogs of the subfamily Painae (Anura: Dicroglossidae) are widespread, but endemic to Asia. Using spiny frog distribution and body size data, and a digital elevation model data set we explored altitudinal patterns of spiny frog richness and quantified the effect of area on the richness pattern over a large altitudinal gradient from 0–5000 m a.s.l. We also tested two hypotheses: (i) the Rapoport's altitudinal effect is valid for the Painae, and (ii) Bergmann's clines are present in spiny frogs. The species richness of Painae across four different altitudinal band widths (100 m, 200 m, 300 m and 400 m) all showed hump-shaped patterns along altitudinal gradient. The altitudinal changes in species richness of the Paini and Quasipaini tribes further confirmed this finding, while the peak of Quasipaini species richness occurred at lower elevations than the maxima of Paini. The area did not explain a significant amount of variation in total, nor Paini species richness, but it did explain variation in Quasipaini. Five distinct groups across altitudinal gradient were found. Species altitudinal ranges did not expand with an increase in the midpoints of altitudinal ranges. A significant negative correlation between body size and elevation was exhibited. Our findings demonstrate that Rapoport's altitudinal rule is not a compulsory attribute of spiny frogs and also suggest that Bergmann's rule is not generally applicable to amphibians. The study highlights a need to explore the underlying mechanisms of species richness patterns, particularly for amphibians in macroecology

The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle

Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the “furnace” that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430–435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels

The epigenetic landscape of renal cancer

This is an accepted manuscript of an article published by Nature in Nature Reviews: Nephrology on 28/11/2016, available online: https://doi.org/10.1038/nrneph.2016.168 The accepted version of the publication may differ from the final published version.The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers