Dysregulated cePathways suggest NGF-induced cell proliferation.

<p><b>(a).</b> Growth factor pathways that gained cePathway relationship in tumors with NGF signaling pathways in the TCGA data (red) and in GSE57297[<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006074#pcbi.1006074.ref019" target="_blank">19</a>] (purple). <b>(b).</b> Behavior of running sum between Reactome “signaling by NGF” pathway and KEGG “TGFβ signaling” pathway. Gray lines represent running sum of 50 random trials (Actual p-values are estimated from 2,000 such random trials).</p

Model-based analysis of competing-endogenous pathways (MACPath) in human cancers - Fig 3

<p><b>Identifying gained/lost indirect cePathway relationships (a).</b> In normal when regulating miRNAs (R1 and R2) are active (in abundance relative to other competing molecules[<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006074#pcbi.1006074.ref021" target="_blank">21</a>]), down-regulation of x would direct more copies of R1 to repress y. In turn, repressed y would direct R2 to repress z. Overall, ceRNA relationship on (<i>x</i>, <i>y</i>) and (<i>y</i>, <i>z</i>) would yield indirect ceRNA relationship on (<i>x</i>, <i>z</i>). In tumor when (<i>x</i>, <i>y</i>) lost ceRNA relationship possibly in association to inactivation of the regulating miRNAs, down-regulation of x would not repress y and z, representing the loss of not only direct ceRNA relationship in (<i>x</i>, <i>y</i>) and (<i>y</i>, <i>z</i>) but also indirect ceRNA relationship in (<i>x</i>, <i>z</i>). From normal and tumor condition, (<i>x</i>, <i>z</i>) would lose co-expression in tumors (Δρ<0) altogether with (<i>y</i>, <i>z</i>) and (<i>x</i>, <i>z</i>). <b>(b).</b> Accumulative distribution of co-expression (ρ) in direct and indirect ceRNA relationships (found in direct and indirect cePathway relationships) in normal samples, compared to the same number of random pairs (n = 5,000).</p

Identifying direct cePathway relationship dysregulations in tumors.

<p><b>(a).</b> An illustration of ceRNA relationship change network. RNA A shares a significant number of miRNA binding sites with RNA C and D, where ρ_normal and ρ_tumor represent their co-expression in normal and tumor samples, respectively. Between normal and tumor samples, co-expression decrease in tumors (Δρ = ρ_tumor-ρ_normal<0) between A and C could represent their ceRNA relationship loss and co-expression increase (Δρ>0) between A and D represent their ceRNA relationship gain. <b>(b)</b>. An example of a cePathway relationship gain between pathway P and Q in the ceRNA relationship change network. CePathway relationship loss would be identified in the same fashion.<b>(c).</b> An illustration of MACPath to identify cePathway relationship dysregulation between pathway P and Q. Genes showing ceRNA relationship changes from pathway P are sorted by the magnitude of the changes (θ_P from <b>Def. 2</b>, blue for loss and red for gain in the left bar). On the genes ranked by θ_P, a running sum is calculated for genes in pathway <i>Q</i> (in the right bar). The maximum variation of the running sum from 0 is the ceRNA relationship change enrichment score (CES_P(Q)). <b>(d).</b> The number difference of ceRNAs between pathway pairs (normal vs. tumor) divided by P value MACPath estimated for the pairs. <b>(e).</b> Upper panel shows behavior of running sum between Reactome "lipid transport" pathway and PID "HIF1 TF" pathway. Gray lines represent running sum of 50 permutation trials. Lower panel shows θ of neighbor genes to Reactome "lipid transport" pathways ranked by their θ. Red lines indicate where genes in PID “HIF1 TF” are placed.</p

The lost indirect cePathway relationship between KEGG “DNA replication” and KEGG “WNT signaling”.

<p><b>(a).</b> Red nodes are ceRNA genes of KEGG “DNA replication” and blue nodes are those of KEGG “WNT signaling”. 1,132 genes (green and light blue nodes) mediate the ceRNA loss between the pathways, where green nodes are 615 minimally mediating gene set. Visualization is taken from Cytoscape[<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1006074#pcbi.1006074.ref027" target="_blank">27</a>]. <b>(b).</b> Enrichment of the minimally mediating genes to oncogenes (red) and tumor suppressors (blue) compared to the same number of random genes. Error bar represents standard variation values from 100 random trials. <b>(c).</b> Ratio of differentially expressed tumor suppressors in the set of the mediating genes compared to other genes in the set. EdgeR estimates differential expression with FDR-corrected P value < 0.05.</p

Model-based analysis of competing-endogenous pathways (MACPath) in human cancers

<div><p>Competing endogenous RNA (ceRNA) has emerged as an important post-transcriptional mechanism that simultaneously alters expressions of thousands genes in cancers. However, only a few ceRNA genes have been studied for their functions to date. To understand the major biological functions of thousands ceRNA genes as a whole, we designed Model-based Analysis of Competing-endogenous Pathways (MACPath) to infer pathways co-regulated through ceRNA mechanism (cePathways). Our analysis on breast tumors suggested that NGF (nerve growth factor)-induced tumor cell proliferation might be associated with tumor-related growth factor pathways through ceRNA. MACPath also identified indirect cePathways, whose ceRNA relationship is mediated by mediating ceRNAs. Finally, MACPath identified mediating ceRNAs that connect the indirect cePathways based on efficient <i>integer linear programming</i> technique. Mediating ceRNAs are unexpectedly enriched in tumor suppressor genes, whose down-regulation is suspected to disrupt indirect cePathways, such as between DNA replication and WNT signaling pathways. Altogether, MACPath is the first computational method to comprehensively understand functions of thousands ceRNA genes, both direct and indirect, at the pathway level.</p></div

Supplemental_Appendix - Sex Differences in the Association Between Cyberbullying Victimization and Mental Health, Substance Use, and Suicidal Ideation in Adolescents

<p>Supplemental_Appendix for Sex Differences in the Association Between Cyberbullying Victimization and Mental Health, Substance Use, and Suicidal Ideation in Adolescents by Soyeon Kim, Melissa Kimber, Michael H. Boyle, and Katholiki Georgiades in The Canadian Journal of Psychiatry</p

Positivity rate for atopic dermatitis symptom by study period.

<p>Periods 1 to 4 are described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119501#sec002" target="_blank">methods</a> section.</p><p>* <i>P</i><0.0001 by comparison between each period.</p><p>^†<i>P</i><0.05 by Duncan's post hoc multiple comparison.</p><p>Positivity rate for atopic dermatitis symptom by study period.</p

Levels of indoor air pollutants, temperature and humidity over the study period.

<p>Standard levels for indoor air quality control in public use facilities are set by the Ministry of Environment, Republic of Korea.</p><p>All levels are written as geometric mean ± geometric standard deviation.</p><p>Periods 1 to 4 are described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119501#sec002" target="_blank">methods</a> section.</p><p>PM₁₀, particles < 10 μm in diameter; PM_2.5, particles < 2.5 μm in diameter; PM_1.0, particles < 1.0 μm in diameter; NO, nitrogen oxide; NO₂, nitrogen dioxide; NO_X, nitrogen oxide compounds; TVOC, total volatile organic compound; ppb, parts per billion.</p><p>Levels of indoor air pollutants, temperature and humidity over the study period.</p

Indoor and outdoor air pollutant levels according to the study period.

<p>Circles and bars represent geometric mean ± geometric standard deviation. *<i>P</i> < 0.05, ** <i>P</i> < 0.01</p

Manganese Complex of Ethylene­diamine­tetraacetic Acid (EDTA)–Benzothiazole Aniline (BTA) Conjugate as a Potential Liver-Targeting MRI Contrast Agent

A novel manganese­(II) complex based on an ethylene­diamine­tetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn²⁺, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and <i>R</i>₁ relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent. The diagnostic utility of this new Mn complex in MRI was demonstrated by high-sensitivity tumor detection in an animal model of liver cancer