Genome-wide estimation of gender differences in the gene expression of human livers: Statistical design and analysis

BACKGROUND: Gender differences in gene expression were estimated in liver samples from 9 males and 9 females. The study tested 31,110 genes for a gender difference using a design that adjusted for sources of variation associated with cDNA arrays, normalization, hybridizations and processing conditions. RESULTS: The genes were split into 2,800 that were clearly expressed (expressed genes) and 28,310 that had expression levels in the background range (not expressed genes). The distribution of p-values from the 'not expressed' group was consistent with no gender differences. The distribution of p-values from the 'expressed' group suggested that 8 % of these genes differed by gender, but the estimated fold-changes (expression in males / expression in females) were small. The largest observed fold-change was 1.55. The 95 % confidence bounds on the estimated fold-changes were less than 1.4 fold for 79.3 %, and few (1.1%) exceed 2-fold. CONCLUSION: Observed gender differences in gene expression were small. When selecting genes with gender differences based upon their p-values, false discovery rates exceed 80 % for any set of genes, essentially making it impossible to identify any specific genes with a gender difference

A multi-gene signature predicts outcome in patients with pancreatic ductal adenocarcinoma.

© 2014 Haider et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Improved usage of the repertoires of pancreatic ductal adenocarcinoma (PDAC) profiles is crucially needed to guide the development of predictive and prognostic tools that could inform the selection of treatment options

Design principles for riboswitch function

Scientific and technological advances that enable the tuning of integrated regulatory components to match network and system requirements are critical to reliably control the function of biological systems. RNA provides a promising building block for the construction of tunable regulatory components based on its rich regulatory capacity and our current understanding of the sequence–function relationship. One prominent example of RNA-based regulatory components is riboswitches, genetic elements that mediate ligand control of gene expression through diverse regulatory mechanisms. While characterization of natural and synthetic riboswitches has revealed that riboswitch function can be modulated through sequence alteration, no quantitative frameworks exist to investigate or guide riboswitch tuning. Here, we combined mathematical modeling and experimental approaches to investigate the relationship between riboswitch function and performance. Model results demonstrated that the competition between reversible and irreversible rate constants dictates performance for different regulatory mechanisms. We also found that practical system restrictions, such as an upper limit on ligand concentration, can significantly alter the requirements for riboswitch performance, necessitating alternative tuning strategies. Previous experimental data for natural and synthetic riboswitches as well as experiments conducted in this work support model predictions. From our results, we developed a set of general design principles for synthetic riboswitches. Our results also provide a foundation from which to investigate how natural riboswitches are tuned to meet systems-level regulatory demands

Environmental Determinants of Infectious Disease: A Framework for Tracking Causal Links and Guiding Public Health Research

BACKGROUND: Discoveries that emerging and re-emerging pathogens have their origin in environmental change has created an urgent need to understand how these environmental changes impact disease burden. In this article we present a framework that provides a context from which to examine the relationship between environmental changes and disease transmission and a structure from which to unite disparate pieces of information from a variety of disciplines. METHODS: The framework integrates three interrelated characteristics of environment–disease relationships: a) Environmental change manifests in a complex web of ecologic and social factors that may ultimately impact disease; these factors are represented as those more distally related and those more proximally related to disease. b) Transmission dynamics of infectious pathogens mediate the effects that environmental changes have on disease. c) Disease burden is the outcome of the interplay between environmental change and the transmission cycle of a pathogen. RESULTS: To put this framework into operation, we present a matrix formulation as a means to define important elements of this system and to summarize what is known and unknown about the these elements and their relationships. The framework explicitly expresses the problem at a systems level that goes beyond the traditional risk factor analysis used in public health, and the matrix provide

Solvothermal synthesis and thermoelectric properties of indium telluride nanostring-cluster hierarchical structures

A simple solvothermal approach has been developed to successfully synthesize n-type α-In2Te3 thermoelectric nanomaterials. The nanostring-cluster hierarchical structures were prepared using In(NO3)3 and Na2TeO3 as the reactants in a mixed solvent of ethylenediamine and ethylene glycol at 200°C for 24 h. A diffusion-limited reaction mechanism was proposed to explain the formation of the hierarchical structures. The Seebeck coefficient of the bulk pellet pressed by the obtained samples exhibits 43% enhancement over that of the corresponding thin film at room temperature. The electrical conductivity of the bulk pellet is one to four orders of magnitude higher than that of the corresponding thin film or p-type bulk sample. The synthetic route can be applied to obtain other low-dimensional semiconducting telluride nanostructures

ATR Inhibition Potentiates the Radiation-induced Inflammatory Tumor Microenvironment.

Purpose ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these drugs on the tumor microenvironment.Experimental Design: We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed posttherapy.Results Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3+ and NK cells, but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II IFN response, with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5, and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5, and CXCL10 are produced from tumor cells after ATRi + RT.Conclusions We show that DNA damage by ATRi and RT leads to an IFN response through activation of nucleic acid-sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximize tumor control through antitumor immunity

Mathematical Model of a Cell Size Checkpoint

How cells regulate their size from one generation to the next has remained an enigma for decades. Recently, a molecular mechanism that links cell size and cell cycle was proposed in fission yeast. This mechanism involves changes in the spatial cellular distribution of two proteins, Pom1 and Cdr2, as the cell grows. Pom1 inhibits Cdr2 while Cdr2 promotes the G2 → M transition. Cdr2 is localized in the middle cell region (midcell) whereas the concentration of Pom1 is highest at the cell tips and declines towards the midcell. In short cells, Pom1 efficiently inhibits Cdr2. However, as cells grow, the Pom1 concentration at midcell decreases such that Cdr2 becomes activated at some critical size. In this study, the chemistry of Pom1 and Cdr2 was modeled using a deterministic reaction-diffusion-convection system interacting with a deterministic model describing microtubule dynamics. Simulations mimicked experimental data from wild-type (WT) fission yeast growing at normal and reduced rates; they also mimicked the behavior of a Pom1 overexpression mutant and WT yeast exposed to a microtubule depolymerizing drug. A mechanism linking cell size and cell cycle, involving the downstream action of Cdr2 on Wee1 phosphorylation, is proposed

Extracorporeal Shock Wave Therapy Reverses Ischemia-Related Left Ventricular Dysfunction and Remodeling: Molecular-Cellular and Functional Assessment

An optimal treatment for patients with diffuse obstructive arterial disease unsuitable for catheter-based or surgical intervention is still pending. This study tested the hypothesis that extracorporeal shock wave (ECSW) therapy may be a therapeutic alternative under such clinical situation. Myocardial ischemia was induced in male mini-pigs through applying an ameroid constrictor over mid-left anterior descending artery (LAD). Twelve mini-pigs were equally randomized into group 1 (Constrictor over LAD only) and group 2 (Constrictor over LAD plus ECSW [800 impulses at 0.09 mJ/mm2] once 3 months after the procedure). Results showed that the parameters measured by echocardiography did not differ between two groups on days 0 and 90. However, echocardiography and left ventricular (LV) angiography showed higher LV ejection fraction and lower LV end-systolic dimension and volume in group 2 on day 180 (p<0.035). Besides, mRNA and protein expressions of CXCR4 and SDF-1α were increased in group 2 (p<0.04). Immunofluorescence staining also showed higher number of vWF-, CD31-, SDF-1α-, and CXCR4-positive cells in group 2 (all p<0.04). Moreover, immunohistochemical staining showed notably higher vessel density but lower mean fibrosis area, number of CD40-positive cells and apoptotic nuclei in group 2 (all p<0.045). Mitochondrial protein expression of oxidative stress was lower, whereas cytochrome-C was higher in group 2 (all p<0.03). Furthermore, mRNA expressions of MMP-9, Bax and caspase-3 were lower, whereas Bcl-2, eNOS, VEGF and PGC-1α were higher in group 2 (all p<0.01). In conclusion, ECSW therapy effectively reversed ischemia-elicited LV dysfunction and remodeling through enhancing angiogenesis and attenuating inflammation and oxidative stress