Additional file 1 of Identifying genes associated with brain volumetric differences through tissue specific transcriptomic inference from GWAS summary data

Additional file 1: This file contains the following supplementary tables. Supplemental Table S1a. Gene findings from the UKB analysis, where TBV is the trait of interest. Shown in the table are the p-values. Supplemental Table S1b. Gene findings from the ENIGMA2 analysis, where ICV is the trait of interest. Of note, this is a targeted analysis which only examines the gene findings from the previous UKB analysis. In other words, we were looking for which TBV-associated genes were also significantly associated with ICV. Shown in the table are the p-values. Supplemental Table S2. Among 10 genes discovered in our study, 9 of them (except FAM215B) are significantly associated with TBV in the gene-based association analysis of the original UKB GWAS (Zhao et al.). Supplemental Table S3. Results of enrichment analysis of 10 discovered genes on Gene Ontology Biological Processes. Supplemental Table S4. Results of enrichment analysis of 10 discovered genes on Gene Ontology Molecular Functions

Additional file 1: of Identification of epigenetic interactions between miRNA and DNA methylation associated with gene expression as potential prognostic markers in bladder cancer

Supplementary information. Table S1. Significant epigenetic interactions between miRNA and methylation associated with target genes. Table S2. Significant epigenetic interactions between miRNA and methylation associated with target genes for papillary subtype. Table S3. Significant epigenetic interactions between miRNA and methylation associated with target genes for non-papillary subtype. Table S4. Summary of overall survival analysis results. Figure S1. Venn Diagram of Significant target genes for papillary, non-papillary subtypes. Figure S2. Survival analysis between two subgroups (LL and HH). Figure S3. Gene expression boxplot for two subgroups (LL and HH). Figure S4. Gene expression boxplot for four subgroups (LL, LH, HL, and HH). Figure S5. Survival analysis across four subgroups (LL, LH, HL, and HH). (DOCX 2368 kb

The effects of alternative splicing on miRNA binding sites in bladder cancer

<div><p>Eukaryotic organisms have developed a variety of mechanisms to regulate translation post-transcriptionally, including but not limited to the use of miRNA silencing in many species. One method of post-transcriptional regulation is through miRNAs that bind to the 3′ UTRs to regulate mRNA abundance and influence protein expression. Therefore, the diversity of mRNA 3′ UTRs mediating miRNA binding sites influence miRNA-mediated regulation. Alternative polyadenylation, by shortening mRNA isoforms, increases the diversity of 3′ UTRs; moreover, short mRNA isoforms elude miRNA-medicated repression. Because no current prediction methods for putative miRNA target sites consider whether or not 1) splicing-informed miRNA binding sites and/or 2) the use of 3′ UTRs provide higher resolution or functionality, we sought to identify not only the genome-wide impact of using exons in mRNA 3′ UTRs but also their functional connection to miRNA regulation and clinical outcomes in cancer. With a genome-wide expression of mRNA and miRNA quantified by 395 bladder cancer cases from The Cancer Genome Atlas (TCGA), we 1) demonstrate the diversity of 3′ UTRs affecting miRNA efficiency and 2) identify a set of genes clinically associated with mRNA expression in bladder cancer. Knowledge of 3′ UTR diversity will not only be a useful addition to current miRNA target prediction algorithms but also enhance the clinical utility of mRNA isoforms in the expression of mRNA in cancer. Thus, variability among cancer patient’s variability in molecular signatures based on these exon usage events in 3′ UTR along with miRNAs in bladder cancer may lead to better prognostic/treatment strategies for improved precision medicine.</p></div

Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer’s Disease

Mitochondrial oxidative stress is a key pathologic factor in neurodegenerative diseases, including Alzheimer’s disease. Abnormal generation of reactive oxygen species (ROS), resulting from mitochondrial dysfunction, can lead to neuronal cell death. Ceria (CeO₂) nanoparticles are known to function as strong and recyclable ROS scavengers by shuttling between Ce³⁺ and Ce⁴⁺ oxidation states. Consequently, targeting ceria nanoparticles selectively to mitochondria might be a promising therapeutic approach for neurodegenerative diseases. Here, we report the design and synthesis of triphenylphosphonium-conjugated ceria nanoparticles that localize to mitochondria and suppress neuronal death in a 5XFAD transgenic Alzheimer’s disease mouse model. The triphenylphosphonium-conjugated ceria nanoparticles mitigate reactive gliosis and morphological mitochondria damage observed in these mice. Altogether, our data indicate that the triphenylphosphonium-conjugated ceria nanoparticles are a potential therapeutic candidate for mitochondrial oxidative stress in Alzheimer’s disease

Case study of the <i>BACE1</i> gene, which shows statistically significant differential expression of miRNA-mediated transcript isoforms between stage status and histology status—but not survival outcome.

<p>For plots A and B, the x-axes represent miRNA expression, and the y-axes represent the relative ratio of miRNA-mediated transcript isoforms expression to overall transcript isoforms expression per single miRNA (i.e., hsa-miR-17-5p). The p-value was corrected with the Bonferroni method. (A) Red dots and blue dots represent stage 0 and stage 1 of bladder cancer, respectively. (B) Red dots and blue dots represent histology 0 and histology 1 of bladder cancer, respectively. (C) In the two groups of bladder cancer cases that expressed high PSI and low PSI, we observed no differences in survival outcome.</p

Continuous O₂‑Evolving MnFe₂O₄ Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer

Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O₂ concentration. Herein, we design biocompatible manganese ferrite nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O₂-evolving property of MnFe₂O₄ nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amount of nanoparticles and improve therapeutic outcomes of PDT for tumors <i>in vivo</i>. In addition, MFMSNs exhibit T₂ contrast effect in magnetic resonance imaging (MRI), allowing <i>in vivo</i> tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy

Highly Sensitive Diagnosis of Small Hepatocellular Carcinoma Using pH-Responsive Iron Oxide Nanocluster Assemblies

Iron oxide nanoparticle (IONP)-based magnetic resonance imaging (MRI) contrast agents have been widely used for the diagnosis of hepatic lesions. However, current IONP-based liver-specific MRI contrast agents rely on single-phase contrast enhancement of the normal liver, which is not sensitive enough to detect early stage small hepatocellular carcinomas (HCCs). We herein report i-motif DNA-assisted pH-responsive iron oxide nanocluster assemblies (termed RIAs), which provide an inverse contrast enhancemt effect to improve the distinction between normal liver and target HCC tissues. The acidic pH of the tumor microenvironment triggers the disassembly of the RIAs, which leads to a drastic decrease in their relaxivity ratio (<i>r</i>₂/<i>r</i>₁), thus converting the RIAs from a T2 to T1 contrast agent. This inverse contrast enhancement of normal liver darkening and HCC brightening under T1 imaging mode was validated on an orthotopic HCC model. Our design provides a novel strategy for the exploitation of the next-generation intelligent MRI contrast agents

Case study of the <i>VEGFA</i> gene, which shows statistically significant differential expression of miRNA-mediated transcript isoforms between stage status, histology status, and survival outcomes.

<p>For plots A and B, the x-axes represent miRNA expression, and the y-axes represent the relative ratio of miRNA-mediated transcript isoforms expression to overall transcript isoforms expression per a single miRNA (i.e., hsa-miR-361-5p). The p-value was corrected with the Bonferroni method (A) Red dots and blue dots represent stage 0 and stage 1 of bladder cancer, respectively. (B) Red dots and blue dots represent histology 0 and histology 1 of bladder cancer, respectively. (C) In the two groups of bladder cancer cases that expressed high PSI and low PSI, the later showed better survival outcomes, compared to the latter. As expected, more severe stage group 0 (i.e., purple plot in (D) and histology group 1 (i.e., green plot in E) exhibited a shorter expected survival time.</p

Study design overview.

<p>Step 1 involved constructing a comprehensive set of relationships between mRNA and miRNA by compiling three existing miRNA target databases: miTarBase, TargetScan, and miRanda. Step 2 involved searching for the miRNA-binding exons (MBEs) and identifying which transcript isoforms retain or do not retain MBEs. When a transcript isoform loses miRNA binding sites in the 3′ UTR due to one of these events—i.e., 1) exon skipping (miRNA 2 in mRNA2), 2) alternative splice 3′ or 5′ splice sites (miRNA 3 in mRNA1), 3) mutually exclusive 3′ UTR regions (i.e. mRNA3 vs. mRNA5 and mRNA5 vs. mRNA6), defining the case that miRNA binding sites in the genomic regions translated into the two mRNAs do not overlap each other at all, and 4) others in these three cases (i.e., retained introns, non-coding RNA, and alternative polyadenylation)—it was assigned to miRNA-binding Group A; otherwise, it was assigned to Group B. Steps 3, 4, and 5 were to not only identify alternative splicing isoforms and splicing events, but also calculate FPKM as a quantitative expression level using TopHat and Cufflinks. We used level 3 data for miRNA expression in the TCGA. Step 6 integrated comprehensive sets of MBEs status in 3′ UTRs with the expression of miRNA and mRNA and, therefore, estimated the relative expression ratio between Group A (i.e., transcript isoforms repressed by miRNA, defined by MBE-retaining mRNA) and all mRNA expression. This is a normalized measurement of the miRNA-mediated repression ratio to the overall transcript expressions per single gene. The multiplicity was corrected by the Bonferroni method. Step 7 first tested an association of differential expression of miRNA-mediated transcript isoforms in the two-stage and histology groups and then predicted overall survival time in the bladder cancer cases.</p

Electrochemical Synthesis of NH₃ at Low Temperature and Atmospheric Pressure Using a γ‑Fe₂O₃ Catalyst

The electrochemical synthesis of NH₃ by the nitrogen reduction reaction (NRR) at low temperature (<65 °C) and atmospheric pressure using nanosized γ-Fe₂O₃ electrocatalysts were demonstrated. The activity and selectivity of the catalyst was investigated both in a 0.1 M KOH electrolyte and when incorporated into an anion-exchange membrane electrode assembly (MEA). In a half-reaction experiment conducted in a KOH electrolyte, the γ-Fe₂O₃ electrode presented a faradaic efficiency of 1.9% and a weight-normalized activity of 12.5 nmol h^–1 mg^–1 at 0.0 V_RHE. However, the selectivity toward N₂ reduction decreased at more negative potentials owing to the competing proton reduction reaction. When the γ-Fe₂O₃ nanoparticles were coated onto porous carbon paper to form an electrode for a MEA, their weight-normalized activity for N₂ reduction was found to increase dramatically to 55.9 nmol h^–1 mg^–1. However, the weight- and area-normalized N₂ reduction activities of γ-Fe₂O₃ decreased progressively from 35.9 to 14.8 nmol h^–1 mg^–1 and from 0.105 to 0.043 nmol h^–1 cm^–2_act, respectively, during a 25 h MEA durability test. In summary, a study of the fundamental behavior and catalytic activity of γ-Fe₂O₃ nanoparticles in the electrochemical synthesis of NH₃ under low temperature and pressure is presented