Immunomodulatory Properties of Dental-Derived Mesenchymal Stem Cells

Mesenchymal stem cells are considered as an attractive tool for tissue regeneration. Almost all dental tissues contain a population of MSC-like cells, which were extensively studied within the last few years. Besides their ability to differentiate into different cell types, dental MSCs also possess strong immunomodulatory properties. Dental MSCs modulate both innate and adaptive immune response and influence the activity of almost all components of the immune system. The interaction between dental MSCs and the immune system is reciprocal because immunomodulatory activity of MSCs is strongly regulated by cytokines produced by immune cells. MSCs isolated from inflamed tissues might exhibit impaired immunomodulatory capacity, suggesting a potential role of these cells in inflammatory diseases and particularly periodontitis. Recent studies suggest that immunomodulatory properties of MSCs can also play an important role in their tissue regenerative capacity. The therapeutic effects of MSCs, including their immunomodulatory capacity, are largely explained by their tropic activity, including production of immunomodulatory proteins and growth factors. Summarizing, dental MSCs play an important role in tissue homeostasis under healthy and diseased conditions

An improved parameter estimation and comparison for soft tissue constitutive models containing an exponential function

Motivated by the well-known result that stiffness of soft tissue is proportional to the stress, many of the constitutive laws for soft tissues contain an exponential function. In this work, we analyze properties of the exponential function and how it affects the estimation and comparison of elastic parameters for soft tissues. In particular, we find that as a consequence of the exponential function there are lines of high covariance in the elastic parameter space. As a result, one can have widely varying mechanical parameters defining the tissue stiffness but similar effective stress–strain responses. Drawing from elementary algebra, we propose simple changes in the norm and the parameter space, which significantly improve the convergence of parameter estimation and robustness in the presence of noise. More importantly, we demonstrate that these changes improve the conditioning of the problem and provide a more robust solution in the case of heterogeneous material by reducing the chances of getting trapped in a local minima. Based upon the new insight, we also propose a transformed parameter space which will allow for rational parameter comparison and avoid misleading conclusions regarding soft tissue mechanics

Cordycepin Suppresses Expression of Diabetes Regulating Genes by Inhibition of Lipopolysaccharide-induced Inflammation in Macrophages

Background: It has been recently noticed that type 2 dia-betes (T2D), one of the most common metabolic diseases, causes a chronic low-grade inflammation and activation of the innate immune system that are closely involved in the pathogenesis of T2D. Cordyceps militaris, a traditional me-dicinal mushroom, produces a component compound, cordy-cepin (3’-deoxyadenosine). Cordycepin has been known to have many pharmacological activities including immuno-logical stimulating, anti-cancer, and anti-infection activities. The molecular mechanisms of cordycepin in T2D are not clear. In the present study, we tested the role of cordycepin on the anti-diabetic effect and anti-inflammatory cascades in LPS-stimulated RAW 264.7 cells. Methods: We confirmed the levels of diabetes regulating genes mRNA and protein of cytokines through RT-PCR and western blot analysis and fol

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Molecular Halogens Above the Arctic Snowpack: Emissions, Diurnal Variations, and Recycling Mechanisms

Elevated levels of reactive bromine and chlorine species in the springtime Arctic boundary layer contribute to ozone depletion and mercury oxidation, as well as reactions with volatile organic compounds. Recent laboratory and field studies have revealed that snowpack photochemistry leads to Br2 and Cl2 production, the mechanisms of which remain poorly understood. In this work, we use a photochemical box model, with a simplified snow module, to examine the halogen chemistry occurring during the March 2012 Bromine, Ozone, and Mercury Experiment (BROMEX) near Utqiaġvik (Barrow), Alaska. Elevated daytime Br2 levels (e.g., 6–30 parts per trillion (ppt) at around local noon) reported in previous studies and in this work may be explained by Br + BrNO2/BrONO2 reactions under conditions of depleted O3 (<~10 ppb) and background NO2 (10–100 ppt). Even at low background NOx levels at Utqiaġvik, ClONO2 is predicted to be important in the production of Cl2 via multiphase reaction with Cl−. In the late afternoon, photolysis alone cannot explain the rapid decrease of Cl2 observed in the Arctic boundary layer. Heterogeneous reactions of Cl2 on aerosol particles and surface snowpack are suggested to play a key role in atmospheric Cl2 removal and possible BrCl production. Given the importance of the snowpack in the multiphase chemistry of the Arctic boundary layer, future measurements should focus on vertically resolved measurements of NOx and reactive halogens, as well as simultaneous particulate and snow halide measurements, to further evaluate and isolate the halogen production and vertical propagation mechanisms through one‐dimensional modeling.Key PointsHeterogeneous uptake of Cl2 is an important missing sink of Cl2 and source of BrCl in Arctic modelsThe multiphase reaction of ClONO2 is suggested to play a key role in Arctic snowpack Cl2 productionBr + BrNO2/BrONO2 may lead to elevated daytime Br2 under low O3 conditions, even for “background” NOxPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141542/1/jgrd54213.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141542/2/jgrd54213_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141542/3/jgrd54213-sup-0001-Data_S1.pd

An integrated map of structural variation in 2,504 human genomes

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. © 2015 Macmillan Publishers Limited. All rights reserved

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe