DNA demethylation and histone deacetylation inhibition co-operate to re-express estrogen receptor beta and induce apoptosis in prostate cancer cell-lines

Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative anti-proliferative agent oestrogen receptor beta

Defining language impairments in a subgroup of children with autism spectrum disorder

Autism spectrum disorder (ASD) is diagnosed on the basis of core impairments in pragmatic language skills, which are found across all ages and subtypes. In contrast, there is significant heterogeneity in language phenotypes, ranging from nonverbal to superior linguistic abilities, as defined on standardized tests of vocabulary and grammatical knowledge. The majority of children are verbal but impaired in language, relative to age-matched peers. One hypothesis is that this subgroup has ASD and co-morbid specific language impairment (SLI). An experiment was conducted comparing children with ASD to children with SLI and typically developing controls on aspects of language processing that have been shown to be impaired in children with SLI: repetition of nonsense words. Patterns of performance among the children with ASD and language impairment were similar to those with SLI, and contrasted with the children with ASD and no language impairment and typical controls, providing further evidence for the hypothesis that a subgroup of children with ASD has co-morbid SLI. The findings are discussed in the context of brain imaging studies that have explored the neural bases of language impairment in ASD and SLI, and overlap in the genes associated with elevated risk for these disorders.M01 RR00533 - NCRR NIH HHS; R01 DC10290 - NIDCD NIH HHS; U19 DC03610 - NIDCD NIH HH

Fast Ensemble Smoothing

Smoothing is essential to many oceanographic, meteorological and hydrological applications. The interval smoothing problem updates all desired states within a time interval using all available observations. The fixed-lag smoothing problem updates only a fixed number of states prior to the observation at current time. The fixed-lag smoothing problem is, in general, thought to be computationally faster than a fixed-interval smoother, and can be an appropriate approximation for long interval-smoothing problems. In this paper, we use an ensemble-based approach to fixed-interval and fixed-lag smoothing, and synthesize two algorithms. The first algorithm produces a linear time solution to the interval smoothing problem with a fixed factor, and the second one produces a fixed-lag solution that is independent of the lag length. Identical-twin experiments conducted with the Lorenz-95 model show that for lag lengths approximately equal to the error doubling time, or for long intervals the proposed methods can provide significant computational savings. These results suggest that ensemble methods yield both fixed-interval and fixed-lag smoothing solutions that cost little additional effort over filtering and model propagation, in the sense that in practical ensemble application the additional increment is a small fraction of either filtering or model propagation costs. We also show that fixed-interval smoothing can perform as fast as fixed-lag smoothing and may be advantageous when memory is not an issue

Overlaps Between Autism and Language Impairment: Phenomimicry or Shared Etiology?

Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies. Yet these disorders co-occur at above chance levels, suggesting shared etiology. Simulations, however, show that additive pleiotropic genes cannot account for observed rates of language impairment in relatives, which are higher for probands with SLI than for those with ASD + language impairment. An alternative account is in terms of ‘phenomimicry’, i.e., language impairment in comorbid cases may be a consequence of ASD risk factors, and different from that seen in SLI. However, this cannot explain why molecular genetic studies have found a common risk genotype for ASD and SLI. This paper explores whether nonadditive genetic influences could account for both family and molecular findings. A modified simulation involving G × G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values. The simulations further suggest that the shape of distributions of phenotypic trait scores for different genotypes may provide evidence of whether a gene is involved in epistasis

OpenEP: A Cross-Platform Electroanatomic Mapping Data Format and Analysis Platform for Electrophysiology Research.

BACKGROUND: Electroanatomic mapping systems are used to support electrophysiology research. Data exported from these systems is stored in proprietary formats which are challenging to access and storage-space inefficient. No previous work has made available an open-source platform for parsing and interrogating this data in a standardized format. We therefore sought to develop a standardized, open-source data structure and associated computer code to store electroanatomic mapping data in a space-efficient and easily accessible manner. METHODS: A data structure was defined capturing the available anatomic and electrical data. OpenEP, implemented in MATLAB, was developed to parse and interrogate this data. Functions are provided for analysis of chamber geometry, activation mapping, conduction velocity mapping, voltage mapping, ablation sites, and electrograms as well as visualization and input/output functions. Performance benchmarking for data import and storage was performed. Data import and analysis validation was performed for chamber geometry, activation mapping, voltage mapping and ablation representation. Finally, systematic analysis of electrophysiology literature was performed to determine the suitability of OpenEP for contemporary electrophysiology research. RESULTS: The average time to parse clinical datasets was 400 ± 162 s per patient. OpenEP data was two orders of magnitude smaller than compressed clinical data (OpenEP: 20.5 ± 8.7 Mb, vs clinical: 1.46 ± 0.77 Gb). OpenEP-derived geometry metrics were correlated with the same clinical metrics (Area: R 2 = 0.7726, P < 0.0001; Volume: R 2 = 0.5179, P < 0.0001). Investigating the cause of systematic bias in these correlations revealed OpenEP to outperform the clinical platform in recovering accurate values. Both activation and voltage mapping data created with OpenEP were correlated with clinical values (mean voltage R 2 = 0.8708, P < 0.001; local activation time R 2 = 0.8892, P < 0.0001). OpenEP provides the processing necessary for 87 of 92 qualitatively assessed analysis techniques (95%) and 119 of 136 quantitatively assessed analysis techniques (88%) in a contemporary cohort of mapping studies. CONCLUSIONS: We present the OpenEP framework for evaluating electroanatomic mapping data. OpenEP provides the core functionality necessary to conduct electroanatomic mapping research. We demonstrate that OpenEP is both space-efficient and accurately representative of the original data. We show that OpenEP captures the majority of data required for contemporary electroanatomic mapping-based electrophysiology research and propose a roadmap for future development

Influence of chromophores on quarternary structure of phycobiliproteins from the cyanobacterium, Mastigocladus laminosus

Chromophores of C-phycocyanin and phycoerythrο-cyanin have been chemically modified by reduction to rubins , bleaching , photoisomerization , or perturbation with bulky substituents. Pigments containing modified chromophores, or hybrids containing modified and unmodified chromophores in individual protomers have been prepared. All modifications inhibit the association of the (aß)-protomers of these pigments to higher aggregates. The results demonstrate a pronounced effect of the state of the chromophores on biliprotein quaternary structure. It may be important in phycobi1isome assembly , and also in the dual function of biliproteins as (i) antenna pigments for photosynthesis and (ii) reaction centers for photomor-phogenesis

Genetic Covariance Structure of Reading, Intelligence and Memory in Children

This study investigates the genetic relationship among reading performance, IQ, verbal and visuospatial working memory (WM) and short-term memory (STM) in a sample of 112, 9-year-old twin pairs and their older siblings. The relationship between reading performance and the other traits was explained by a common genetic factor for reading performance, IQ, WM and STM and a genetic factor that only influenced reading performance and verbal memory. Genetic variation explained 83% of the variation in reading performance; most of this genetic variance was explained by variation in IQ and memory performance. We hypothesize, based on these results, that children with reading problems possibly can be divided into three groups: (1) children low in IQ and with reading problems; (2) children with average IQ but a STM deficit and with reading problems; (3) children with low IQ and STM deficits; this group may experience more reading problems than the other two

Cathepsin D SNP associated with increased risk of variant Creutzfeldt-Jakob disease

<p>Abstract</p> <p>Background</p> <p>Variant Creutzfeldt-Jakob disease (vCJD) originally resulted from the consumption of foodstuffs contaminated by bovine spongiform encephalopathy (BSE) material, with 163 confirmed cases in the UK to date. Many thousands are likely to have been exposed to dietary infection and so it is important (for surveillance, epidemic modelling, public health and understanding pathogenesis) to identify genetic factors that may affect individual susceptibility to infection. This study looked at a polymorphism in the cathepsin D gene (refSNP ID: rs17571) previously examined in Alzheimer's disease (AD).</p> <p>Methods</p> <p>Blood samples taken from 110 vCJD patients were tested for the C-T base change, and genotype data were compared with published frequencies for a control population using multiple logistic regression.</p> <p>Results</p> <p>There was a significant excess of the cathepsin D polymorphism TT genotype in the vCJD cohort compared to controls. The TT genotype was found to have a 9.75 fold increase in risk of vCJD compared to the CT genotype and a 10.92 fold increase compared to the CC genotype.</p> <p>Conclusion</p> <p>This mutation event has been observed to alter the protease activity of the cathepsin D protein and has been linked to an increase in amyloid beta plaque formation in AD. vCJD neuropathology is characterised by the presence of amyloid plaques, formed from the prion protein, and therefore alterations in the amyloid processing activity of cathepsin D may affect the neuropathogenesis of this disease.</p

Attribution of extreme events to climate change in the Australian region – A review

Extreme event attribution is a rapidly growing field of climate science with important implications for public and government understanding of human-induced climate change. However, there is substantial variation in how well events can be attributed to human-induced climate change, depending on the nature of the event. Focusing on Australia: at one end of the scale, large-scale heat events on both the land and in the ocean are well suited to attribution studies because climate models simulate them reasonably well, there are high-quality observations available and our understanding of the processes that lead to extreme heat events is reasonably well developed. At the other end of the scale, very important phenomenon such as changes in east coast lows, severe convective storms and long-term droughts are less well observed, are beyond our current capability to robustly simulate in climate models and the complex mechanisms that lead to intensification are not well understood. Thus, some important extreme events can be linked to human-induced climate change, with a high degree of confidence, while others cannot. We review the state of the science relevant to event attribution with a focus on Australia. We highlight where progress can be made, focusing on observations, physical understanding, and realistic climate modelling