Maximal information component analysis: a novel non-linear network analysis method.

BackgroundNetwork construction and analysis algorithms provide scientists with the ability to sift through high-throughput biological outputs, such as transcription microarrays, for small groups of genes (modules) that are relevant for further research. Most of these algorithms ignore the important role of non-linear interactions in the data, and the ability for genes to operate in multiple functional groups at once, despite clear evidence for both of these phenomena in observed biological systems.ResultsWe have created a novel co-expression network analysis algorithm that incorporates both of these principles by combining the information-theoretic association measure of the maximal information coefficient (MIC) with an Interaction Component Model. We evaluate the performance of this approach on two datasets collected from a large panel of mice, one from macrophages and the other from liver by comparing the two measures based on a measure of module entropy, Gene Ontology (GO) enrichment, and scale-free topology (SFT) fit. Our algorithm outperforms a widely used co-expression analysis method, weighted gene co-expression network analysis (WGCNA), in the macrophage data, while returning comparable results in the liver dataset when using these criteria. We demonstrate that the macrophage data has more non-linear interactions than the liver dataset, which may explain the increased performance of our method, termed Maximal Information Component Analysis (MICA) in that case.ConclusionsIn making our network algorithm more accurately reflect known biological principles, we are able to generate modules with improved relevance, particularly in networks with confounding factors such as gene by environment interactions

High-Density Genotypes of Inbred Mouse Strains: Improved Power and Precision of Association Mapping.

Human genome-wide association studies have identified thousands of loci associated with disease phenotypes. Genome-wide association studies also have become feasible using rodent models and these have some important advantages over human studies, including controlled environment, access to tissues for molecular profiling, reproducible genotypes, and a wide array of techniques for experimental validation. Association mapping with common mouse inbred strains generally requires 100 or more strains to achieve sufficient power and mapping resolution; in contrast, sample sizes for human studies typically are one or more orders of magnitude greater than this. To enable well-powered studies in mice, we have generated high-density genotypes for ∼175 inbred strains of mice using the Mouse Diversity Array. These new data increase marker density by 1.9-fold, have reduced missing data rates, and provide more accurate identification of heterozygous regions compared with previous genotype data. We report the discovery of new loci from previously reported association mapping studies using the new genotype data. The data are freely available for download, and Web-based tools provide easy access for association mapping and viewing of the underlying intensity data for individual loci

Editorial: Epigenetic Regulation in Cardiovascular Diseases

Cardiovascular disease (CVD) is the leading cause of death globally. Progress in the diagnosis, prevention, and treatment of CVD is contingent on the advancement of our knowledge to explain the complex pathophysiology underlying CVD in which gene expression re-programming plays a fundamental role. Emerging evidence highlights the impact of epigenetic regulation on the transition of gene expression patterns from physiological to pathological states. Epigenetics, originally defined as stably heritable phenotypes resulting from changes in a chromosome without alterations in the DNA sequence, is now more broadly understood to encompass any modification to DNA structure or function that influences phenotypes related to development or disease other than an actual change to the sequence. The epigenetic environment of a gene is mostly determined by DNA methylation, histone modifications, and chromatin remodeling. Various writers, readers, and erasers for different epigenetic marks have been discovered, and their dysfunction tightly correlates with the development of CVD. Research elucidating epigenetic regulations in this field have, in turn, promoted novel drug discoveries to treat CVD. The identification of novel epigenetic players in CVD and how they act to fine-tune molecular processes would help expand our understanding of the complexity of cardiovascular pathophysiology. In the current Research Topic, we have collected 16 high-quality studies that cover promising, recent, and novel research trends in the epigenetic regulation of CVD

Time resolved in-situ multi-contrast X-ray imaging of melting in metals

In this work, the application of a time resolved multi-contrast beam tracking technique to the investigation of the melting and solidification process in metals is presented. The use of such a technique allows retrieval of three contrast channels, transmission, refraction and dark-field, with millisecond time resolution. We investigated different melting conditions to characterize, at a proof-of-concept level, the features visible in each of the contrast channels. We found that the phase contrast channel provides a superior visibility of the density variations, allowing the liquid metal pool to be clearly distinguished. Refraction and dark-field were found to highlight surface roughness formed during solidification. This work demonstrates that the availability of the additional contrast channels provided by multi-contrast X-ray imaging delivers additional information, also when imaging high atomic number specimens with a significant absorption

Liver resection or combined chemoembolization and radiofrequency ablation improve survival in patients with hepatocellular carcinoma

Background/ Aims: To evaluate the long-term outcome of surgical and non-surgical local treatments of patients with hepatocellular carcinoma (HCC). Methods: We stratified a cohort of 278 HCC patients using six independent predictors of survival according to the Vienna survival model for HCC (VISUM- HCC). Results: Prior to therapy, 224 HCC patients presented with VISUM stage 1 (median survival 18 months) while 29 patients were classified as VISUM stage 2 (median survival 4 months) and 25 patients as VISUM stage 3 (median survival 3 months). A highly significant (p < 0.001) improved survival time was observed in VISUM stage 1 patients treated with liver resection ( n = 52; median survival 37 months) or chemoembolization (TACE) and subsequent radiofrequency ablation ( RFA) ( n = 44; median survival 45 months) as compared to patients receiving chemoembolization alone (n = 107; median survival 13 months) or patients treated by tamoxifen only (n = 21; median survival 6 months). Chemoembolization alone significantly (p <= 0.004) improved survival time in VISUM stage 1 - 2 patients but not (p = 0.341) in VISUM stage 3 patients in comparison to those treated by tamoxifen. Conclusion: Both liver resection or combined chemoembolization and RFA improve markedly the survival of patients with HCC

A method for phase reconstruction from measurements obtained using a configured detector with a scanning transmission X-ray microscope

Abstract We developed a technique for performing quantitative phase reconstructions from differential phase contrast images obtained using a configured detector in a scanning transmission X-ray microscope geometry. The technique uses geometric optics to describe the interaction of the X-ray beam with the specimen, which allows interpretation of the measured intensities in terms of the derivative of the phase thickness. Integration of the resulting directional derivatives is performed using a Fourier integration technique. We demonstrate the approach by reconstructing simulated measurements of a 0:5Àmm-diameter gold sphere at 7-keV photon energy. Published by Elsevier B.V

Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure

Cardiometabolic disorders encompass a broad range of cardiovascular complications associated with metabolic dysfunction. These conditions have an increasing share in the health burden worldwide due to worsening endemic of hypertension, obesity, and diabetes. Previous studies have identified Tumor Protein p53-inducible Nuclear Protein 2 (Trp53inp2) as a molecular link between hyperglycemia and cardiac hypertrophy. However, its role in cardiac pathology has never been determined in vivo. In this study, we generated a cardiac specific knockout model of Trp53inp2 (Trp53inp2-cKO) and investigated the impact of Trp53inp2 inactivation on the pathogenesis of heart failure under mechanic or/and metabolic stresses. Based on echocardiography assessment, inactivation of Trp53inp2 in heart led to accelerated onset of HFrEF in response to pressure-overload, with significantly reduced ejection fraction and elevated heart failure marker genes comparing to the control mice. In contrast, inactivation of Trp53inp2 ameliorated cardiac dysfunction induced by combined stresses of high fat diet and moderate pressure overload (Cardiometabolic Disorder Model). Moreover, Trp53inp2 inactivation led to reduced expression of glucose metabolism genes in lean, pressure-overloaded hearts. However, the same set of genes were significantly induced in the Trp53inp2-cKO hearts under both mechanical and metabolic stresses. In summary, we have demonstrated for the first time that cardiomyocyte Trp53inp2 has diametrically differential roles in the pathogenesis of heart failure and glucose regulation under mechanical vs. mechanical plus metabolic stresses. This insight suggests that Trp53inp2 may exacerbate the cardiac dysfunction during pressure overload injury but have a protective effect in cardiac diastolic function in cardiometabolic disease

Solidification of Al alloys under electromagnetic pulses and characterization of the 3D microstructures under synchrotron x-ray tomography

A novel programmable electromagnetic pulse device was developed and used to study the solidification of Al-15 pct Cu and Al-35 pct Cu alloys. The pulsed magnetic fluxes and Lorentz forces generated inside the solidifying melts were simulated using finite element methods, and their effects on the solidification microstructures were characterized using electron microscopy and synchrotron X-ray tomography. Using a discharging voltage of 120 V, a pulsed magnetic field with the peak Lorentz force of ~1.6 N was generated inside the solidifying Al-Cu melts which were showed sufficiently enough to disrupt the growth of the primary Al dendrites and the Al2Cu intermetallic phases. The microstructures exhibit a strong correlation to the characteristics of the applied pulse, forming a periodical pattern that resonates the frequency of the applied electromagnetic field