GScluster: Network-weighted gene-set clustering analysis

Background: Gene-set analysis (GSA) has been commonly used to identify significantly altered pathways or functions from omics data. However, GSA often yields a long list of gene-sets, necessitating efficient post-processing for improved interpretation. Existing methods cluster the gene-sets based on the extent of their overlap to summarize the GSA results without considering interactions between gene-sets. Results: Here, we presented a novel network-weighted gene-set clustering that incorporates both the gene-set overlap and protein-protein interaction (PPI) networks. Three examples were demonstrated for microarray gene expression, GWAS summary, and RNA-sequencing data to which different GSA methods were applied. These examples as well as a global analysis show that the proposed method increases PPI densities and functional relevance of the resulting clusters. Additionally, distinct properties of gene-set distance measures were compared. The methods are implemented as an R/Shiny package GScluster that provides gene-set clustering and diverse functions for visualization of gene-sets and PPI networks. Conclusions: Network-weighted gene-set clustering provides functionally more relevant gene-set clusters and related network analysis

REGNET: Mining context-specific human transcription networks using composite genomic information

Background: Genome-wide expression profiles reflect the transcriptional networks specific to the given cell context. However, most statistical models try to estimate the average connectivity of the networks from a collection of gene expression data, and are unable to characterize the context-specific transcriptional regulations. We propose an approach for mining context-specific transcription networks from a large collection of gene expression fold-change profiles and composite gene-set information.Results: Using a composite gene-set analysis method, we combine the information of transcription factor binding sites, Gene Ontology or pathway gene sets and gene expression fold-change profiles for a variety of cell conditions. We then collected all the significant patterns and constructed a database of context-specific transcription networks for human (REGNET). As a result, context-specific roles of transcription factors as well as their functional targets are readily explored. To validate the approach, nine predicted targets of E2F1 in HeLa cells were tested using chromatin immunoprecipitation assay. Among them, five (Gadd45b, Dusp6, Mll5, Bmp2 and E2f3) were successfully bound by E2F1. c-JUN and the EMT transcription networks were also validated from literature.Conclusions: REGNET is a useful tool for exploring the ternary relationships among the transcription factors, their functional targets and the corresponding cell conditions. It is able to provide useful clues for novel cell-specific transcriptional regulations. The REGNET database is available at http://mgrc.kribb.re.kr/regnet.open0

Genomic Signature of the Standardized Uptake Value in 18F-Fluorodeoxyglucose Positron Emission Tomography in Breast Cancer

The standardized uptake value (SUV), an indicator of the degree of glucose uptake in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10−4). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53–FOXM1 and its downstream effectors in glycolysis–gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools

Prof. Tütengil'i Anlamak ve tamamlamak

Taha Toros Arşivi, Dosya No: 200-Cavit Orhan Tütengil. Not: Gazetenin "Düşünenlerin Düşünceleri" köşesinde yayımlanmıştır.Unutma İstanbul projesi İstanbul Kalkınma Ajansı'nın 2016 yılı "Yenilikçi ve Yaratıcı İstanbul Mali Destek Programı" kapsamında desteklenmiştir. Proje No: TR10/16/YNY/010

Dual effect of fetal bovine serum on early development depends on stage-specific reactive oxygen species demands in pigs

<div><p>Despite the application of numerous supplements to improve <i>in vitro</i> culture (IVC) conditions of mammalian cells, studies regarding the effect of fetal bovine serum (FBS) on mammalian early embryogenesis, particularly in relation to redox homeostasis, are lacking. Herein, we demonstrated that early development of <i>in vitro</i>-produced (IVP) porcine embryos highly depends on the combination of FBS supplementation timing and embryonic reactive oxygen species (ROS) requirements. Interestingly, FBS significantly reduced intracellular ROS levels in parthenogenetically activated (PA) embryos regardless of the developmental stage. However, the beneficial effect of FBS on early embryogenesis was found only during the late phase (IVC 4–6 days) treatment group. In particular, developmental competence parameters, such as blastocyst formation rate, cellular survival, total cell number and trophectoderm proportion, were markedly increased by FBS supplementation during the late IVC phase. In addition, treatment with FBS elevated antioxidant transcript levels during the late IVC phase. In contrast, supplementation with FBS during the entire period (1–6 days) or during the early IVC phase (1–2 days) greatly impaired the developmental parameters. Consistent with the results from PA embryos, the developmental competence of <i>in vitro</i> fertilization (IVF) or somatic cell nuclear transfer (SCNT) embryos were markedly improved by treatment with FBS during the late IVC phase. Moreover, the embryonic stage-specific effects of FBS were reversed by the addition of an oxidant and were mimicked by treatment with an antioxidant. These findings may increase our understanding of redox-dependent early embryogenesis and contribute to the large-scale production of high-quality IVP embryos.</p></div

Molecularly dispersed nickel-containing species on the carbon nitride network as electrocatalysts for the oxygen evolution reaction

Hybrid materials containing single atoms or molecule-based active species immobilized on nanomaterials have been suggested as new, efficient catalytic systems for various reactions. In this study, novel hybrid materials consisting of molecularly dispersed Ni-based species on a graphitic carbon nitride (g-C3N4) framework are prepared, and their excellent electrocatalytic performance for the oxygen evolution reaction (OER) is discussed. Extensive chemical and structural characterizations confirm that the Ni-based species are attached and well-dispersed on the C3N4 network without agglomeration. In addition, results obtained from electrochemical characterization suggest that Ni-containing molecular entities dispersed on the C3N4 network are active species for the OER

Involvement of p-p38 MAPK and p-AKT cascades in FBS-associated phenotypes during late IVC phase.

<p>(A) Western blot analysis of p-p38 MAPK and p-AKT in control and FBS supplementation during late phase in porcine PA embryos. (B) Representative photographs of the developed blastocysts (white asterisks; left panel) and quantification of blastocyst developmental rate (right panel) in the indicated groups. Bar = 100 μm. The data are from three independent experiments, and values represent the means ± SE (*P < 0.05). (C) Immunocytochemical analysis of Cdx2/DAPI. Merged images (light green) between Cdx2 (green) and DAPI (blue) signals are shown (top panel) and quantification of the total cell number (bottom left panel) and ICM/TE proportion (bottom right panel) in the indicated groups. Bar = 50 μm. (D) Apoptosis detection analysis in blastocysts from the indicated groups. Merged images (light green) between TUNEL (green, white arrow) and DAPI (blue) signals are shown (top panel) and quantification of apoptotic cells (bottom panel). Bar = 50 μm. The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05).</p

Effect of FBS supplementation timing on the developmental competence of porcine PA embryos.

<p>(A) Representative photographs of blastocysts (white asterisks) developed in the presence or absence of FBS during the entire culture period (0–6 days), early phase (0–1 and 0–2 days) and late phase (4–6 and 5–6 days) of IVC. Bar = 50 μm. (B) Quantification of the blastocyst developmental rate in the indicated groups. The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05). (C and D) DAPI staining for scoring the number of cells in blastocysts of the indicated groups (C) and quantification of the total cell number (D). Bar = 50 μm (C). The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05; D).</p

Beneficial effect of FBS during late IVC phase on developmental competence of porcine IVF embryos.

<p>(A) Bright field (top panel) and fluorescence (bottom panel) images of blastocysts treated with CM-H₂DCFDA after cultivation in the presence or absence of FBS for 4–6 days of IVC (left panel) and quantification of ROS levels in the indicated groups (right panel). Bar = 100 μm. The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05). (B) Representative photographs of the blastocysts (white asterisks; left panel) developed in the presence or absence of FBS for 4–6 days of IVC after IVF and quantification of blastocyst developmental (center panel) and hatching (right panel) rates in the indicated groups. The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05). (C) qRT-PCR analysis of the relative abundances of antioxidant genes <i>SOD1</i>, <i>GPx1</i>, <i>Catalase</i> and <i>Prdx2</i> in blastocysts from the indicated groups. The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05). (D) Immunocytochemistry of Cdx2 (top panel) and TUNEL staining (bottom panel) in blastocysts from the indicated groups. Bar = 50 μm. Merged images (light green color) between green (Cdx2, top panel; TUNEL, bottom panel) and blue (DAPI; both panels) signals are shown. (E and F) Quantification of ICM/TE (E) and apoptotic cell (F) number and proportion in the indicated groups. The data are from three independent experiments, and values represent the means ± SE (^*<i>P</i> < 0.05).</p