An arrhythmogenic metabolite in atrial fibrillation

Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF

What does literature tell us about the relationship between forest structural attributes and species richness in temperate forests? – A review

The effects of forest management on species richness and diversity have become important research interests. The need to maintain biodiversity for forest ecosystem functioning has led to the question of how strongly and in what ways forest management modifies the diversity and abundance of different species groups. It is well known that many forest species rely on specific structures that may be modified by forest management. Assessing the impact of forest management on species richness may therefore require identification of structural properties. For this literature review we identified a large set of structural attributes that can serve as potential drivers of the richness of different species groups. Most studies included here focused on only one or a few structural attributes as explanatory variables and a limited number of species groups as dependent variables; we therefore analyzed the available publications across species and structural properties. We gathered 410 relationships of structure and species richness out of 85 studies from the temperate region in Europe. Positive, negative, and neutral (non-existent) correlations between species richness and the presence of specific structural properties in European temperate forests were then compiled. Canopy gaps and structural attributes related to old-growth successional stage such as stand age and the share of large old trees were mostly positively correlated with species richness of the different taxa. Especially old-growth structures were ranked high in the reviewed literature. The structural attributes that were mainly positively correlated with species richness or the richness of groups of species may be used for further development of biodiversity monitoring concepts and forest management

Measured daily precipitation sums over Central Sulawesi for the period 1981-1999

Data compiled within the IMPENSO project. The Impact of ENSO on Sustainable Water Management and the Decision-Making Community at a Rainforest Margin in Indonesia (IMPENSO), http://www.gwdg.de/~impenso, was a German-Indonesian research project (2003-2007) that has studied the impact of ENSO (El Nino-Southern Oscillation) on the water resources and the agricultural production in the PALU RIVER watershed in Central Sulawesi. ENSO is a climate variability that causes serious droughts in Indonesia and other countries of South-East Asia. The last ENSO event occurred in 1997. As in other regions, many farmers in Central Sulawesi suffered from reduced crop yields and lost their livestock. A better prediction of ENSO and the development of coping strategies would help local communities mitigate the impact of ENSO on rural livelihoods and food security. The IMPENSO project deals with the impact of the climate variability ENSO (El Niño Southern Oscillation) on water resource management and the local communities in the Palu River watershed of Central Sulawesi, Indonesia. The project consists of three interrelated sub-projects, which study the local and regional manifestation of ENSO using the Regional Climate Models REMO and GESIMA (Sub-project A), quantify the impact of ENSO on the availability of water for agriculture and other uses, using the distributed hydrological model WaSiM-ETH (Sub-project B), and analyze the socio-economic impact and the policy implications of ENSO on the basis of a production function analysis, a household vulnerability analysis, and a linear programming model (Sub-project C). The models used in the three sub-projects will be integrated to simulate joint scenarios that are defined in collaboration with local stakeholders and are relevant for the design of coping strategies

Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer

Purpose: We aimed to identify DNA methylation biomarkers of progression-free survival (PFS) to platinum-based chemotherapy in high-grade serous ovarian cancer (HGSOC) within biologically relevant ovarian cancer-associated pathways.<p></p> Experimental Design: Association with PFS of CpG island (CGI) promoter DNA methylation at genes in the pathways Akt/mTOR, p53, redox, and homologous recombination DNA repair was sought with PFS as the primary objective in a prospectively collected ovarian cancer cohort (n = 150). Significant loci were validated for associations between PFS, methylation, and gene expression in an independent The Cancer Genome Atlas (TCGA) data set of HGSOC (n = 311).<p></p> Results: DNA methylation at 29 CGI loci linked to 28 genes was significantly associated with PFS, independent from conventional clinical prognostic factors (adjusted P < 0.05). Of 17 out of the 28 genes represented in the TCGA data set, methylation of VEGFB, VEGFA, HDAC11, FANCA, E2F1, GPX4, PRDX2, RAD54L, and RECQL4 was prognostic in this independent patient cohort (one-sided P < 0.05, false discovery rate < 10%). A multivariate Cox model was constructed, with clinical parameters (age, stage, grade, and histologic type) and significant loci. The final model included NKD1, VEGFB, and PRDX2 as the three best predictors of PFS (P = 6.62 × 10−6, permutation test P < 0.05). Focussing only on known VEGFs in the TCGA cohort showed that methylation at promoters of VEGFA, VEGFB, and VEGFC was significantly associated with PFS.<p></p> Conclusions: A three loci model of DNA methylation could identify two distinct prognostic groups of patients with ovarian cancer (PFS: HR = 2.29, P = 3.34 × 10−5; overall survival: HR = 1.87, P = 0.007) and patients more likely to have poor response to chemotherapy (OR = 3.45, P = 0.012).<p></p&gt

Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer

Epigenetic changes in tumours are associated not only with cancer development and progression, but also with resistance to chemotherapy. Aberrant DNA methylation at CpG islands and associated epigenetic silencing are observed during the acquisition of drug resistance. However, it remains unclear whether all of the observed changes are drivers of drug resistance, causally associated with response of tumours to chemotherapy, or are passenger events representing chance DNA methylation changes. Systematic approaches that link DNA methylation and expression with chemosensitivity will be required to identify key drivers. Such drivers will be important prognostic or predicitive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance

Index of biodiversity potential (IBP) versus direct species monitoring in temperate forests

International audienceEffects of forest management on forest biodiversity have received increasing attention in both research and forestry practice. Despite advances in technology, monitoring of biodiversity remains time and cost-intensive and requires specific taxonomic expertise. In forest management, however, there is increasing interest and need to integrate biodiversity monitoring into forest inventories efficiently to estimate the potential effects of forest management on biodiversity. Forest management systems can differ greatly depending on management goals and the intensity and frequency of the applied silvicultural interventions. To identify management effects on biodiversity, an estimation of biodiversity using forest structural attributes may be a reasonable approach. Forest structure can – compared to conventional species-based monitoring - easily be captured during forest inventories and does not require specific taxonomic expertise. The IBP (Index of Biodiversity Potential) is a composite index aiming to provide practitioners with an efficient tool for estimating biodiversity at the local level. We recorded the IBP on 147 plots in three regions of Germany, where detailed biodiversity monitoring had been conducted. This study quantified the relationship between changes in the IBP scores and changes in species richness for 13 taxonomic groups. To determine this, we analyzed estimated relationships between the IBP and species richness using a count regression model. We found positive estimated relationships with species richness of birds, fungi, true bugs, lichens, and moths in at least 3 of 5 examined forest types. However, for spiders, bats, carabids, necrophagous and saproxylic beetles, either no relationship with the IBP or estimated relationships with only one forest type were found. Changes in scores for the IBP's factors number of vertical layers, large living trees, tree-related microhabitats, and proportion of gaps correlated with changes in the measured species richness in many cases. Even though the IBP is generally not adequate to predict actual presence or precise number of species, it can be utilized to depict a forest stand's potential in terms of species richness. Due to its easy and time-efficient application, it could be a useful proxy used in combination with species-based monitoring approaches

Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival

Purpose: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS). Experimental Design: Epithelial ovarian tumors (screening study n = 120, validation study n = 61), prospectively collected through a cohort study, were analyzed by differential methylation hybridization at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and PFS was examined by Cox proportional hazards model. Results: DNA methylation is associated with PFS at 20 of 302 loci (P < 0.05, n = 111), with 5 loci significant at false discovery rate (FDR) less than 10%. A total of 11 of 20 loci retain significance in an independent validation cohort (n = 48, P <= 0.05, FDR <= 10%), and 7 of these loci, at FZD4, DVL1, NFATC3, ROCK1, LRP5, AXIN1, and NKD1 genes, are independent from clinical parameters (adjusted P < 0.05). Increased methylation at these loci associates with increased hazard of disease progression. A multivariate Cox model incorporates only NKD1 and DVL1, identifying two groups differing in PFS [HR = 2.09; 95% CI (1.39-3.15); permutation test P < 0.005]. Methylation at DVL1 and NFATC3 show significant association with response. Consistent with their epigenetic regulation, reduced expression of FZD4, DVL1, and ROCK1 is an indicator of early-disease relapse in an independent ovarian tumor cohort (n = 311, adjusted P < 0.05). Conclusion: The data highlight the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identify methylation at NKD1 and DVL1 as independent predictors of PFS

Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands-4

Sed on the fitted model (dashed smooth line in red). The red and blue solid line are the positive and negative cut-offs, respectively. b: Scatter plot of sensitive scores against resistant scores in A2780 series cell lines. The hypermethylated loci are colored in red and hypomethylated loci are in blue. The robust regression model is Y = 0.9956X + 0.0019.<p><b>Copyright information:</b></p><p>Taken from "Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands"</p><p>http://www.biomedcentral.com/1471-2105/9/337</p><p>BMC Bioinformatics 2008;9():337-337.</p><p>Published online 8 Aug 2008</p><p>PMCID:PMC2529322.</p><p></p

Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands-3

He increase of CR slowly, but starts to increase dramatically when the CR goes above 140%, at which point the inconsistency rate is generally about 1%. Not all cell lines could reach this point e.g. MCP3.<p><b>Copyright information:</b></p><p>Taken from "Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands"</p><p>http://www.biomedcentral.com/1471-2105/9/337</p><p>BMC Bioinformatics 2008;9():337-337.</p><p>Published online 8 Aug 2008</p><p>PMCID:PMC2529322.</p><p></p