Metabolic Pathways Enhancement Confers Poor Prognosis in p53 Exon Mutant Hepatocellular Carcinoma.

RNA-Sequencing (RNA-Seq), the most commonly used sequencing application tool, is not only a method for measuring gene expression but also an excellent media to detect important structural variants such as single nucleotide variants (SNVs), insertion/deletion (Indels), or fusion transcripts. The Cancer Genome Atlas (TCGA) contains genomic data from a variety of cancer types and also provides the raw data generated by TCGA consortium. p53 is among the top 10 somatic mutations associated with hepatocellular carcinoma (HCC). The aim of the present study was to analyze concordant different gene profiles and the priori defined set of genes based on p53 mutation status in HCC using RNA-Seq data. In the study, expression profile of 11 799 genes on 42 paired tumor and adjacent normal tissues was collected, processed, and further stratified by the mutated versus normal p53 expression. Furthermore, we used a knowledge-based approach Gene Set Enrichment Analysis (GSEA) to compare between normal and p53 mutation gene expression profiles. The statistical significance (nominal P value) of the enrichment score (ES) genes was calculated. The ranked gene list that reflects differential expression between p53 wild-type and mutant genotypes was then mapped to metabolic process by KEGG, an encyclopedia of genes and genomes to assign functional meanings. These approaches enable us to identify pathways and potential target gene/pathways that are highly expressed in p53 mutated HCC. Our analysis revealed 2 genes, the hexokinase 2 (HK2) and Enolase 1 (ENO1), were conspicuous of red pixel in the heatmap. To further explore the role of these genes in HCC, the overall survival plots by Kaplan-Meier method were performed for HK2 and ENO1 that revealed high HK2 and ENO1 expression in patients with HCC have poor prognosis. These results suggested that these glycolysis genes are associated with mutated-p53 in HCC that may contribute to poor prognosis. In this proof-of-concept study, we proposed an approach for identifying novel potential therapeutic targets in human HCC with mutated p53. These approaches can take advantage of the massive next-generation sequencing (NGS) data generated worldwide and make more out of it by exploring new potential therapeutic targets

Topological surface electronic states in candidate nodal-line semimetal CaAgAs

We investigate systematically the bulk and surface electronic structure of the candidate nodal-line semimetal CaAgAs by angle resolved photoemission spectroscopy and density functional calculations. We observed a metallic, linear, non-$k_z$-dispersive surface band that coincides with the high-binding-energy part of the theoretical topological surface state, proving the topological nontriviality of the system. An overall downshift of the experimental Fermi level points to a rigid-band-like $p$-doping of the samples, due possibly to Ag vacancies in the as-grown crystals.Comment: 6 pages, 5 figure

Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells

BACKGROUND: The microtubule associated protein tau is the principle component of neurofibrillar tangles, which are a characteristic marker in the pathology of Alzheimer's disease; similar lesions are also observed after chronic alcohol abuse. Formaldehyde is a common environmental contaminant and also a metabolite of methanol. Although many studies have been done on methanol and formaldehyde intoxication, none of these address the contribution of protein misfolding to the pathological mechanism, in particular the effect of formaldehyde on protein conformation and polymerization. RESULTS: We found that unlike the typical globular protein BSA, the natively-unfolded structure of human neuronal tau was induced to misfold and aggregate in the presence of ~0.01% formaldehyde, leading to formation of amyloid-like deposits that appeared as densely staining granules by electron microscopy and atomic force microscopy, and bound the amyloid-specific dyes thioflavin T and Congo Red. The amyloid-like aggregates of tau were found to induce apoptosis in the neurotypic cell line SH-SY5Y and in rat hippocampal cells, as observed by Hoechst 33258 staining, assay of caspase-3 activity, and flow cytometry using Annexin V and Propidium Iodide staining. Further experiments showed that Congo Red specifically attenuated the caspase-3 activity induced by amyloid-like deposits of tau. CONCLUSION: The results suggest that low concentrations of formaldehyde can induce human tau protein to form neurotoxic aggregates, which could play a role in the induction of tauopathies

Identification of metabolites of kurarinone from Sophora flavescens Ait in rat urine by ultra-performance liquid chromatography with linear ion trap orbitrap mass spectrometry

Purpose: To study the in vivo metabolism of kurarinone, a lavandulyl flavanone which is a major constituent of Kushen and a marker compound with many biological activities, using ultra-performance liquid chromatography coupled with linear ion trap Orbitrap mass spectrometry (UPLC-LTQ-Orbitrap-MS).Methods: Six male Sprague-Dawley rats were randomly divided into two groups. First, kurarinone was suspended in 0.5 % carboxymethylcellulose sodium  (CMC-Na) aqueous solution, and was given to rats (n = 3, 2 mL for each rat) orally at 50 mg/kg. A 2 mL aliquot of 0.5 % CMC-Na aqueous solution was administered to the rats in the control group. Next, urine samples were collected over 0-24 h after the oral administrations and all urine samples were pretreated by a solid phase extraction (SPE) method. Finally, all samples were analyzed by a UPLC-LTQ-Orbitrap mass spectrometry coupled with an electrospray ionization source (ESI) that was operated in the negative ionization mode.Results: A total of 11 metabolites, including the parent drug and 10 phase II metabolites in rat urine, were first detected and interpreted based on accurate mass measurement, fragment ions, and chromatographic retention times. The results were based on the assumption that kurarinone glucuronidation was the dominant  metabolite that was excreted in rat urine.Conclusion: The results from this work indicate that kurarinone in vivo is typically transformed to nontoxic glucuronidation metabolites, and these findings may help to characterize the metabolic profile of kurarinone.Keywords: Kurarinone, Metabolites, Sophora flavescens Ait., Glucuronidation metabolite

Density-driven higher-order topological phase transitions in amorphous solids

Amorphous topological states, which are independent of the specific spatial distribution of microscopic constructions, have gained much attention. Recently, higher-order topological insulators, which are a new class of topological phases of matter, have been proposed in amorphous systems. Here, we propose a density-driven higher-order topological phase transition in a two-dimensional amorphous system. We demonstrate that the amorphous system hosts a topological trivial phase at low density. With an increase in the density of lattice sites, the topological trivial phase converts to a higher-order topological phase characterized by a quantized quadrupole moment and the existence of topological corner states. Furthermore, we confirm that the density-driven higher-order topological phase transition is size dependent. In addition, our results should be general and equally applicable to three-dimensional amorphous systems. Our findings may greatly enrich the study of higher-order topological states in amorphous systems