Melatonin and Its Metabolites Protect Human Melanocytes Against UVB-Induced Damage: Involvement of NRF2-Mediated Pathways

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing of NRF2 using siRNA diminished the protective effects of melatonin, while the membrane melatonin receptors (MT1 or MT2) did not change the activities of either melatonin or its derivatives. Melatonin and its metabolites enhanced the DNA repair in melanocytes exposed to UVB and stimulated expression of p53 phosphorylated at Ser-15. In conclusion, melatonin and its metabolites protect melanocytes from UVB-induced DNA damage and oxidative stress through activation of NRF2-dependent pathways; these actions are independent of an effect on the classic membrane melatonin receptors. Thus, melatonin and its derivatives can serve as excellent protectors of melanocytes against UVB-induced pathology

Non-Equilibrium in Adsorbed Polymer Layers

High molecular weight polymer solutions have a powerful tendency to deposit adsorbed layers when exposed to even mildly attractive surfaces. The equilibrium properties of these dense interfacial layers have been extensively studied theoretically. A large body of experimental evidence, however, indicates that non-equilibrium effects are dominant whenever monomer-surface sticking energies are somewhat larger than kT, a common case. Polymer relaxation kinetics within the layer are then severely retarded, leading to non-equilibrium layers whose structure and dynamics depend on adsorption kinetics and layer ageing. Here we review experimental and theoretical work exploring these non-equilibrium effects, with emphasis on recent developments. The discussion addresses the structure and dynamics in non-equilibrium polymer layers adsorbed from dilute polymer solutions and from polymer melts and more concentrated solutions. Two distinct classes of behaviour arise, depending on whether physisorption or chemisorption is involved. A given adsorbed chain belonging to the layer has a certain fraction of its monomers bound to the surface, f, and the remainder belonging to loops making bulk excursions. A natural classification scheme for layers adsorbed from solution is the distribution of single chain f values, P(f), which may hold the key to quantifying the degree of irreversibility in adsorbed polymer layers. Here we calculate P(f) for equilibrium layers; we find its form is very different to the theoretical P(f) for non-equilibrium layers which are predicted to have infinitely many statistical classes of chain. Experimental measurements of P(f) are compared to these theoretical predictions.Comment: 29 pages, Submitted to J. Phys.: Condens. Matte

Chemical data evaluation: General considerations and approaches for IUPAC projects and the chemistry community (IUPAC Technical Report)

The International Union of Pure and Applied Chemistry has a long tradition of supporting the compilation of chemical data and their evaluation through direct projects, nomenclature and terminology work, and partnerships with international scientific bodies, government agencies, and other organizations. The IUPAC Interdivisional Subcommittee on Critical Evaluation of Data has been established to provide guidance on issues related to the evaluation of chemical data. In this first report, we define the general principles of the evaluation of scientific data and describe best practices and approaches to data evaluation in chemistryinfo:eu-repo/semantics/publishedVersio

Confrontational Behavior and Escalation to War 1816-1980: A Research Plan

The understanding of international war, like many complex social events, may be - and has been - ap proached from a range of theoretical perspectives and via a variety of research strategies. Outside of the work of Bloch (1898), Sorokin (1936), Richardson (1941), and Wright (1942), however, there was little re search of a scientific nature until the mid-1960s. And while these past fifteen years have certainly not given us a compelling theory of international war, they have seen a steady growth in cumulative knowledge regar ding the correlates of war. These results, despite the expected mix of inconsistencies and anomalies, provide us with some sense of the factors that are most consistently associated with war over the last century and a half, along with some tentative insights into the rising and declining potency of these factors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68556/2/10.1177_002234338201900104.pd

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Effect Of Cardiac Motion On Body Surface Electrocardiographic Potentials: An MRI-Based Simulation Study

This paper describes an electrical model of cardiac ventricles incorporating real geometry and motion. The heart anatomy and its motion through the cardiac cycle are obtained from segmentations of multiple-slice MRI time sequences; the special conduction system is constructed using an automated mapping procedure from an existing static heart model. The heart model is mounted in an anatomically realistic voxel model of the human body. The cardiac electrical source and surface potentials are determined numerically using both a finite-difference scheme and a boundary-element method with the incorporation of the motion of the heart. The electrocardiograms (ECG) and body surface potential maps are calculated and compared to the static simulation in the resting heart. The simulations demonstrate that introducing motion into the cardiac model modifies the ECG signals, with the most obvious change occurring during the T-wave at peak contraction of the ventricles. Body surface potential maps differ in some local positions during the T-wave, which may be of importance to a number of cardiac models, including those incorporating inverse methods