Graphical models for high dimensional genomic data

Graphical models study the relations among a set of random variables. In a graph, vertices represent variables and edges capture relations among the variables. We have developed three statistical methods for graphical model construction using high dimensional genomic data. We first focus on estimating a high-dimensional partial correlation matrix. It is estimated by ridge penalty followed by hypothesis testing. The null distribution of the test statistics derived from penalized partial correlation estimates has not been established. We address this challenge by estimating the null distribution from the empirical distribution of the test statistics of all the penalized partial correlation estimates. The performance of our method is systematically evaluated in simulation and application studies. Next, we consider estimating Directed Acyclic Graph (DAG) models for multivariate Gaussian random variables. The skeleton of a DAG is an undirected graphical model, which is constructed by removing the directions of all the edges in the DAG. Given observational data, not all the directions of the edges of a DAG are identifiable; however the skeleton of the DAG is identifiable. We propose a novel method named PenPC to estimate the skeleton of a high dimensional DAG by a two-step approach. We first estimate an undirected graph by selecting the non-zero entries of the partial correlation matrix, then remove false connections in this undirected graph to obtain the skeleton. We systematically study the asymptotic property of PenPC on high dimensional problems. Both simulations and real data analysis suggest that our method have substantially higher sensitivity and specificity to estimate network skeleton than existing methods. To orient the edges in the skeleton of a DAG, we exploit interventional data on an additional set of variables. The variables are direct causes of some vertices in the DAG and enable estimating directions of the edges in the skeleton. More specifically, given the skeleton of a DAG, we calculate the posterior probabilities of edge directions using the additional set of variables. We evaluate our method by simulations and an application where variables modeled by a DAG are gene expression and the additional set variables are DNA polymorphisms.Doctor of Philosoph

Partial correlation matrix estimation using ridge penalty followed by thresholding and re-estimation

Motivated by the problem of construction gene co-expression network, we propose a statistical framework for estimating high-dimensional partial correlation matrix by a three-step approach. We first obtain a penalized estimate of a partial correlation matrix using ridge penalty. Next we select the non-zero entries of the partial correlation matrix by hypothesis testing. Finally we reestimate the partial correlation coefficients at these non-zero entries. In the second step, the null distribution of the test statistics derived from penalized partial correlation estimates has not been established. We address this challenge by estimating the null distribution from the empirical distribution of the test statistics of all the penalized partial correlation estimates. Extensive simulation studies demonstrate the good performance of our method. Application on a yeast cell cycle gene expression data shows that our method delivers better predictions of the protein-protein interactions than the Graphic Lasso

The Proposal for Personalized Service and Exhibition Model based on Audience Tendency in Virtual museum

The Internet and the development of technology influence many people’s lives in a comprehensive way. The museum is not an exception to this. Online virtual museums let audience watch the exhibits any time they want, showing high accessibility. On the other hand, no matter how much technology develops, some limitations exist. For example, copying the original museum into a digital form cannot recreate the liveliness of the physical space and represent the aura that an art piece has. This paper focuses on the flexibility that the virtual space has compared to the physical space and decided that organization based on the audience is possible. First, an analysis of the present conditions about virtual museums’ services was done. Then, 7 types of classification of the audience based on interaction models of virtual museums. Based on the patterns of the present conditions of virtual museums and classifications of the audience, a suggestion about what kinds of customized services can be given based on the preferences of the audience was made. In addition, a user centered exhibition model that includes the audience’s preferences and a customized process of viewing the art works in the virtual museum based on those preferences was created. Hopefully, this paper will become a manual that focuses on user driven development and not on the service designs of the exhibits or the perspectives of the developer

Human microglial cells synthesize albumin in brain

Albumin has been implicated in Alzheimer's disease since it can bind to and transport amyloid beta, the causative agent; albumin is also a potent inhibitor of amyloid beta polymerization. In a pilot phase study of Human Brain Proteome Project, we found evidence that albumin may be synthesized in immortalized human microglial cells, human primary microglial cells, and human fetal and adult brain tissues. We also found the synthesis and secretion is enhanced upon microglial activation by Amyloid [beta]~1-42~, lipopolysaccharide treatment or human Alzheimer's brain

17β-estradiol reduces inflammation and modulates antioxidant enzymes in colonic epithelial cells

Background/Aims: Estrogen is known to have protective effect in colorectal cancer development. The aims of this study are to investigate whether estradiol treatment reduces inflammation in CCD841CoN, a female human colonic epithelial cell line and to uncover underlying mechanisms of estradiol effects. Methods: 17 beta-Estradiol (E2) effect was measured by Western blot after inducing inflammation of CCD841CoN by tumor necrosis factor alpha (TNF-alpha). Expression levels of estrogen receptor alpha (ER alpha) and beta (ER beta), cyclooxygenase-2 (COX-2), nuclear factor-kappa B (NF-kappa B), heme oxygenase-1 (HO-1), and NAD(P)H-quinone oxidoreductase-1 (NQO-1) were also evaluated. Results: E2 treatment induced expression of ERO but did not increase that of ER alpha. E2 treatment for 48 hours significantly elevated the expression of anti-oxidant enzymes, HO-1 and NQO-1. TNF-alpha treatment significantly increased the level of activated NF-kappa B (p < 0.05), and this increase was significantly suppressed by treatment of to nM of E2 (p < 0.05). E2 treatment ameliorated TNF-alpha-induced COX-2 expression and decrease of HO-1 expression. 4-(2-phenyl-5,7-bis(trifluoromethyl) pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP), antagonist of ER beta, removed the inhibitory effect of E2 in the TNF-alpha-induced COX-2 expression (p = 0.05). Conclusions: Estrogen seems to inhibit inflammation in female human colonic epithelial cell lines, through down-regulation of NF-kappa B and COX-2 expression and induction of anti-oxidant enzymes such as HO-1 and NQO-1.

Outer membrane protein a of Salmonella enterica serovar Typhimurium activates dendritic cells and enhances Th1 polarization

<p>Abstract</p> <p>Background</p> <p>Typhoid, which is caused by <it>Salmonella enterica </it>serovar Typhimurium, remains a major health concern worldwide. Multidrug-resistant strains of <it>Salmonella </it>have emerged which exhibit increased survivability and virulence, thus leading to increased morbidity. However, little is known about the protective immune response against this microorganism. The outer membrane protein (Omp)A of bacteria plays an important role in pathogenesis.</p> <p>Results</p> <p>We purified OmpA from <it>S. enterica </it>serovar Typhimurium (OmpA-sal) and characterized the role of OmpA-sal in promoting adaptive and innate immune responses. OmpA-sal functionally activated bone marrow-derived dendritic cells by augmenting expression of CD80, CD86, and major histocompatibility complex classes I and II. Interestingly, OmpA-sal induced production of interferon-γ from T cells in mixed lymphocyte reactions, thus indicating Th1-polarizing capacity. The expression of surface markers and cytokine production in dendritic cells was mediated by the TLR4 signaling pathway in a TLR4 Knock-out system.</p> <p>Conclusions</p> <p>Our findings suggest that OmpA-sal modulates the adaptive immune responses to <it>S. enterica </it>serovar Typhimurium by activating dendritic cells and driving Th1 polarization, which are important properties to consider in the development of effective <it>S. enterica </it>serovar Typhimurium vaccines and immunotherapy adjuvant.</p