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1.
Nat Commun ; 10(1): 2548, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186427

RESUMO

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.


Assuntos
Metilação de DNA/genética , DNA/sangue , Interação Gene-Ambiente , Estudos de Coortes , Epigênese Genética , Feminino , Sangue Fetal , Genótipo , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
2.
Artigo em Inglês | MEDLINE | ID: mdl-30396212

RESUMO

AIMS AND METHODS: Glucose homeostasis and energy balance are under control by peripheral and brain processes. Especially insulin signaling in the brain seems to impact whole body glucose homeostasis and interacts with fatty acid signaling. In humans circulating saturated fatty acids are negatively associated with brain insulin action while animal studies suggest both positive and negative interactions of fatty acids and insulin brain action. This apparent discrepancy might reflect a difference between acute and chronic fatty acid signaling. To address this question we investigated the acute effect of an intracerebroventricular palmitic acid administration on peripheral glucose homeostasis. We developed and implemented a method for simultaneous monitoring of brain activity and peripheral insulin action in freely moving mice by combining radiotelemetry electrocorticography (ECoG) and euglycemic-hyperinsulinemic clamps. This method allowed gaining insight in the early kinetics of brain fatty acid signaling and its contemporaneous effect on liver function in vivo, which, to our knowledge, has not been assessed so far in mice. RESULTS: Insulin-induced brain activity in the theta and beta band was decreased by acute intracerebroventricular application of palmitic acid. Peripherally it amplified insulin action as demonstrated by a significant inhibition of endogenous glucose production and increased glucose infusion rate. Moreover, our results further revealed that the brain effect of peripheral insulin is modulated by palmitic acid load in the brain. CONCLUSION: These findings suggest that insulin action is amplified in the periphery and attenuated in the brain by acute palmitic acid application. Thus, our results indicate that acute palmitic acid signaling in the brain may be different from chronic effects.

3.
Brief Bioinform ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30351397

RESUMO

Copy number aberrations (CNAs) are known to strongly affect oncogenes and tumour suppressor genes. Given the critical role CNAs play in cancer research, it is essential to accurately identify CNAs from tumour genomes. One particular challenge in finding CNAs is the effect of confounding variables. To address this issue, we assessed how commonly used CNA identification algorithms perform on SNP 6.0 genotyping data in the presence of confounding variables. We simulated realistic synthetic data with varying levels of three confounding variables-the tumour purity, the length of a copy number region and the CNA burden (the percentage of CNAs present in a profiled genome)-and evaluated the performance of OncoSNP, ASCAT, GenoCNA, GISTIC and CGHcall. Furthermore, we implemented and assessed CGHcall*, an adjusted version of CGHcall accounting for high CNA burden. Our analysis on synthetic data indicates that tumour purity and the CNA burden strongly influence the performance of all the algorithms. No algorithm can correctly find lost and gained genomic regions across all tumour purities. The length of CNA regions influenced the performance of ASCAT, CGHcall and GISTIC. OncoSNP, GenoCNA and CGHcall* showed little sensitivity. Overall, CGHcall* and OncoSNP showed reasonable performance, particularly in samples with high tumour purity. Our analysis on the HapMap data revealed a good overlap between CGHcall, CGHcall* and GenoCNA results and experimentally validated data. Our exploratory analysis on the TCGA HNSCC data revealed plausible results of CGHcall, CGHcall* and GISTIC in consensus HNSCC CNA regions. Code is available at https://github.com/adspit/PASCAL.

4.
IET Syst Biol ; 10(6): 210-218, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27879475

RESUMO

In systems biology, one is often interested in the communication patterns between several species, such as genes, enzymes or proteins. These patterns become more recognisable when temporal experiments are performed. This temporal communication can be structured by reaction networks such as gene regulatory networks or signalling pathways. Mathematical modelling of data arising from such networks can reveal important details, thus helping to understand the studied system. In many cases, however, corresponding models still deviate from the observed data. This may be due to unknown but present catalytic reactions. From a modelling perspective, the question of whether a certain reaction is catalysed leads to a large increase of model candidates. For large networks the calibration of all possible models becomes computationally infeasible. We propose a method which determines a substantially reduced set of appropriate model candidates and identifies the catalyst of each reaction at the same time. This is incorporated in a multiple-step procedure which first extends the network by additional latent variables and subsequently identifies catalyst candidates using similarity analysis methods. Results from synthetic data examples suggest a good performance even for non-informative data with few observations. Applied on CD95 apoptotic pathway our method provides new insights into apoptosis regulation.


Assuntos
Catálise , Redes Reguladoras de Genes , Transdução de Sinais/fisiologia , Biologia de Sistemas , Algoritmos , Apoptose , Biologia Computacional , Simulação por Computador , Células HeLa , Humanos , Funções Verossimilhança , Modelos Biológicos , Modelos Estatísticos , Redes Neurais (Computação) , Probabilidade , Receptor fas/metabolismo
5.
IET Syst Biol ; 9(5): 193-203, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26405143

RESUMO

In computational systems biology, the general aim is to derive regulatory models from multivariate readouts, thereby generating predictions for novel experiments. In the past, many such models have been formulated for different biological applications. The authors consider the scenario where a given model fails to predict a set of observations with acceptable accuracy and ask the question whether this is because of the model lacking important external regulations. Real-world examples for such entities range from microRNAs to metabolic fluxes. To improve the prediction, they propose an algorithm to systematically extend the network by an additional latent dynamic variable which has an exogenous effect on the considered network. This variable's time course and influence on the other species is estimated in a two-step procedure involving spline approximation, maximum-likelihood estimation and model selection. Simulation studies show that such a hidden influence can successfully be inferred. The method is also applied to a signalling pathway model where they analyse real data and obtain promising results. Furthermore, the technique can be employed to detect incomplete network structures.


Assuntos
Modelos Biológicos , Modelos Estatísticos , Biologia de Sistemas/métodos , Algoritmos , Janus Quinase 2 , Fator de Transcrição STAT5 , Transdução de Sinais
6.
EMBO Rep ; 16(7): 836-50, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26012739

RESUMO

More than 50% of mammalian genomes consist of retrotransposon sequences. Silencing of retrotransposons by heterochromatin is essential to ensure genomic stability and transcriptional integrity. Here, we identified a short sequence element in intracisternal A particle (IAP) retrotransposons that is sufficient to trigger heterochromatin formation. We used this sequence in a genome-wide shRNA screen and identified the chromatin remodeler Atrx as a novel regulator of IAP silencing. Atrx binds to IAP elements and is necessary for efficient heterochromatin formation. In addition, Atrx facilitates a robust and largely inaccessible heterochromatin structure as Atrx knockout cells display increased chromatin accessibility at retrotransposons and non-repetitive heterochromatic loci. In summary, we demonstrate a direct role of Atrx in the establishment and robust maintenance of heterochromatin.


Assuntos
DNA Helicases/genética , DNA Helicases/metabolismo , Genes de Partícula A Intracisternal , Heterocromatina/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Montagem e Desmontagem da Cromatina , Instabilidade Genômica , Heterocromatina/genética , Interferência de RNA , RNA Interferente Pequeno , Proteína Nuclear Ligada ao X
7.
Health Econ ; 23(6): 653-69, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23696223

RESUMO

In this paper, we propose a methodological approach to measure the relationship between hospital costs and health outcomes. We propose to investigate the relationship for each condition or disease area by using patient-level data. We examine health outcomes as a function of costs and other patient-level variables by using the following: (1) two-stage residual inclusion with Murphy-Topel adjustment to address costs being endogenous to health outcomes, (2) random-effects models in both stages to correct for correlation between observation, and (3) Cox proportional hazard models in the second stage to ensure that the available information is exploited. To demonstrate its application, data on mortality following hospital treatment for acute myocardial infarction (AMI) from a large German sickness fund were used. Provider reimbursement was used as a proxy for treatment costs. We relied on the Ontario Acute Myocardial Infarction Mortality Prediction Rules as a disease-specific risk-adjustment instrument. A total of 12,284 patients with treatment for AMI in 2004-2006 were included. The results showed a reduction in hospital costs by €100 to increase the hazard of dying, that is, mortality, by 0.43%. The negative association between costs and mortality confirms that decreased resource input leads to worse outcomes for treatment after AMI.


Assuntos
Custos Hospitalares/estatística & dados numéricos , Infarto do Miocárdio/economia , Idoso , Comorbidade , Feminino , Alemanha/epidemiologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Readmissão do Paciente/estatística & dados numéricos , Resultado do Tratamento
8.
RNA Biol ; 9(10): 1266-74, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22995831

RESUMO

For decades, cold-adapted, temperature-sensitive (ca/ts) strains of influenza A virus have been used as live attenuated vaccines. Due to their great public health importance it is crucial to understand the molecular mechanism(s) of cold adaptation and temperature sensitivity that are currently unknown. For instance, secondary RNA structures play important roles in influenza biology. Thus, we hypothesized that a relatively minor change in temperature (32-39°C) can lead to perturbations in influenza RNA structures and, that these structural perturbations may be different for mRNAs of the wild type (wt) and ca/ts strains. To test this hypothesis, we developed a novel in silico method that enables assessing whether two related RNA molecules would undergo (dis)similar structural perturbations upon temperature change. The proposed method allows identifying those areas within an RNA chain where dissimilarities of RNA secondary structures at two different temperatures are particularly pronounced, without knowing particular RNA shapes at either temperature. We identified such areas in the NS2, PA, PB2 and NP mRNAs. However, these areas are not identical for the wt and ca/ts mutants. Differences in temperature-induced structural changes of wt and ca/ts mRNA structures may constitute a yet unappreciated molecular mechanism of the cold adaptation/temperature sensitivity phenomena.


Assuntos
Adaptação Fisiológica , Vírus da Influenza A/genética , Modelos Moleculares , Conformação de Ácido Nucleico , RNA Mensageiro/química , Proteínas Virais/genética , Sequência de Bases , Temperatura Baixa , Simulação por Computador , Vírus da Influenza A/metabolismo , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo
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