Medicine and Health Sciences Commons^™

Distinct Mechanisms Mediate Naïve And Memory Cd8 T-Cell Tolerance, Evan R. Jellison, Elizabeth G. Lingenheld, Li Zu, Lynn Puddington, Leo Lefrancois

UCHC Articles - Research

Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific …

Logic Modeling And The Ridiculome Under The Rug, Michael L. Blinov, Ion I. Moraru

UCHC Articles - Research

Logic-derived modeling has been used to map biological networks and to study arbitrary functional interactions, and fine-grained kinetic modeling can accurately predict the detailed behavior of well-characterized molecular systems; at present, however, neither approach comes close to unraveling the full complexity of a cell. The current data revolution offers significant promises and challenges to both approaches - and could bring them together as it has spurred the development of new methods and tools that may help to bridge the many gaps between data, models, and mechanistic understanding.

Have you used logic modeling in your research? It would not be surprising …

Herpes Simplex Viruses: Mechanisms Of Dna Replication, Sandra K. Weller

UCHC Articles - Research

Herpes simplex virus (HSV) encodes seven proteins necessary for viral DNA synthesis—UL9 (origin-binding protein), ICP8 (single-strand DNA [ssDNA]-binding protein), UL30/UL42 (polymerase), and UL5/UL8/UL52 (helicase/primase). It is our intention to provide an up-to-date analysis of our understanding of the structures of these replication proteins and how they function during HSV replication. The potential roles of host repair and recombination proteins will also be discussed.

Nf-Κb Contributes To The Detrimental Effects Of Social Isolation After Experimental Stroke, Venugopal Reddy Venna, Gillian Weston, Sharon E. Benashski, Sami Tarabishy, Fudong Liu, Jun Li, Lisa H. Conti, Louise D. Mccullough

UCHC Articles - Research

Social isolation (SI) is increasingly recognized as a risk factor for stroke. Individuals with lack of social support systems have an increased incidence of stroke, poorer recovery, and greater functional decline after injury compared to individuals with social support. Attesting to the importance of social factors in stroke outcome is that these same effects can be reproducibly demonstrated in animals; social interaction improves behavioral deficits and reduces damage after experimental stroke, whereas SI enhances injury. The mechanism by which SI exacerbates injury is unclear. We investigated the role of nuclear factor-kappaB (NF-κB) signaling in male mice that were pair housed …

Fast Rebinding Increases Dwell Time Of Src Homology 2 (Sh2)-Containing Proteins Near The Plasma Membrane, Dongmyung Oh, Mari Ogiue-Ikeda, Joshua A. Jadwin, Kazuya Machida, Bruce J. Mayer, Ji Yu

UCHC Articles - Research

Receptor tyrosine kinases (RTKs) control a host of biological functions by phosphorylating tyrosine residues of intracellular proteins upon extracellular ligand binding. The phosphotyrosines (p-Tyr) then recruit a subset of ∼100 Src homology 2 (SH2) domain-containing proteins to the cell membrane. The in vivo kinetics of this process are not well understood. Here we use total internal reflection (TIR) microscopy and single-molecule imaging to monitor interactions between SH2 modules and p-Tyr sites near the cell membrane. We found that the dwell time of SH2 modules within the TIR illumination field is significantly longer than predictions based on chemical dissociation rate constants, …

Interleukin-1Β In Central Nervous System Injury And Repair, Nicole A. Jackman, Sandra J. Hewett, Robert J. Claycomb

UCHC Articles - Research

Acute inflammation is a self-limiting, complex biological response mounted to combat pathogen invasion, to protect against tissue damage, and to promote tissue repair should it occur. However, unabated inflammation can be deleterious and contribute to injury and pathology. Interleukin-1β (IL-1β), a prototypical “pro-inflammatory” cytokine, is essential to cellular defense and tissue repair in nearly all tissues. With respect to brain, however, studies suggest that IL-1β has pleiotrophic effects. It acts as a neuromodulator in the healthy central nervous system (CNS), has been implicated in the pathogenic processes associated with a number of CNS maladies, but may also provide protection to …

Global Approaches To The Role Of Mirnas In Drug-Induced Changes In Gene Expression, Jodi E. Eipper-Mains, Betty A. Eipper, Richard E. Mains

UCHC Articles - Research

Neurons modulate gene expression with subcellular precision through excitation-coupled local protein synthesis, a process that is regulated in part through the involvement of microRNAs (miRNAs), a class of small non-coding RNAs. The biosynthesis of miRNAs is reviewed, with special emphasis on miRNA families, the subcellular localization of specific miRNAs in neurons, and their potential roles in the response to drugs of abuse. For over a decade, DNA microarrays have dominated genome-wide gene expression studies, revealing widespread effects of drug exposure on neuronal gene expression. We review a number of recent studies that explore the emerging role of miRNAs in the …

Deciphering Phosphotyrosine-Dependent Signaling Networks In Cancer By Sh2 Profiling, Kazuya Machida

UCHC Articles - Research

It has been a decade since the introduction of SH2 profiling, a modular domain-based molecular diagnostics tool. This review covers the original concept of SH2 profiling, different analytical platforms, and their applications, from the detailed analysis of single proteins to broad screening in translational research. Illustrated by practical examples, we discuss the uniqueness and advantages of the approach as well as its limitations and challenges. We provide guidance for basic researchers and oncologists who may consider SH2 profiling in their respective cancer research, especially for those focusing on tyrosine phosphoproteomics. SH2 profiling can serve as an alternative phosphoproteomics tool to …

A Bayesian Approach To Pathway Analysis By Integrating Gene–Gene Functional Directions And Microarray Data, David W. Rowe, Yifang Zhao, Ming-Hui Chen, Dong-Guk Shin, Lynn Kuo

UCHC Articles - Research

Many statistical methods have been developed to screen for differentially expressed genes associated with specific phenotypes in the microarray data. However, it remains a major challenge to synthesize the observed expression patterns with abundant biological knowledge for more complete understanding of the biological functions among genes. Various methods including clustering analysis on genes, neural network, Bayesian network and pathway analysis have been developed toward this goal. In most of these procedures, the activation and inhibition relationships among genes have hardly been utilized in the modeling steps. We propose two novel Bayesian models to integrate the microarray data with the putative …

The Role Of Ifnar And Myd88 Signaling In Induction Of Il-15 Expression In Vivo, Leo Lefrancois, Sara L. Colpitts, Thomas A. Stoklasek, Courtney R. Plumlee, Joshua J. Obar

UCHC Articles - Research

Interleukin-15 (IL-15) plays a multifaceted role in immune homeostasis, but the unreliability of IL-15 detection has stymied exploration of IL-15 regulation in vivo. To visualize IL-15 expression, we created a transgenic mouse expressing emerald-GFP (EmGFP) under IL-15 promoter control. EmGFP/IL-15 was prevalent in innate cells including dendritic cells (DCs), macrophages, and monocytes. However, DC subsets expressed varying levels of EmGFP/IL-15 with CD8⁺ DCs constitutively expressing EmGFP/IL-15 and CD8⁻ DCs expressing low EmGFP/IL-15 levels. Virus infection resulted in IL-15 upregulation in both subsets. By crossing the transgenic mice to mice deficient in specific elements of innate signaling, we …

B Cells, Not Just For Antibody Anymore: The Latest Regulators Of Innate Immunity, Kamal M. Khanna, Leo Lefrancois

UCHC Articles - Research

B cell antibody production is thought to be crucial for protection against virus infection. In this issue of Immunity, Moseman et al. (2012) illustrate an antibody-independent role for B cells in macrophage activation that prevents virus dissemination after subcutaneous infection.

Borrelia Burgdorferi Requires The Alternative Sigma Factor Rpos For Dissemination Within The Vector During Tick-To-Mammal Transmission, Star M. Dunham-Ems, Melissa J. Caimano, Justin D. Radolf

UCHC Articles - Research

While the roles of rpoSBb and RpoS-dependent genes have been studied extensively within the mammal, the contribution of the RpoS regulon to the tick-phase of the Borrelia burgdorferi enzootic cycle has not been examined. Herein, we demonstrate that RpoS-dependent gene expression is prerequisite for the transmission of spirochetes by feeding nymphs. RpoS-deficient organisms are confined to the midgut lumen where they transform into an unusual morphotype (round bodies) during the later stages of the blood meal. We show that round body formation is rapidly reversible, and in vitro appears to be attributable, in part, to reduced levels of Coenzyme A …

In Vivo Fate Mapping Identifies Mesenchymal Progenitor Cells, Slavica Pejda, Brya G. Matthews, Dario Repic, Liping Wang, Haitao Li, Mark S. Kronenberg, Xi Jiang, Peter Maye, Douglas J. Adams, David W. Rowe, Hector L. Aguila, Ivo Kalajzic

UCHC Articles - Research

Adult mesenchymal progenitor cells have enormous potential for use in regenerative medicine. However, the true identity of the progenitors in vivo and their progeny has not been precisely defined. We hypothesize that cells expressing a smooth muscle α-actin promoter (αSMA) directed Cre transgene represent mesenchymal progenitors of adult bone tissue. By combining complementary colors in combination with transgenes activating at mature stages of the lineage we characterized the phenotype and confirmed the ability of isolated αSMA+ cells to progress from a progenitor to fully mature state. In vivo lineage tracing experiments using a new bone formation model confirmed the osteogenic …

Bone Tissue Engineering: Recent Advances And Challenges, Ami R. Amini, Cato T. Laurencin, Syam P. Nukavarapu

UCHC Articles - Research

The worldwide incidence of bone disorders and conditions has trended steeply upward and is expected to double by 2020, especially in populations where aging is coupled with increased obesity and poor physical activity. Engineered bone tissue has been viewed as a potential alternative to the conventional use of bone grafts, due to their limitless supply and no disease transmission. However, bone tissue engineering practices have not proceeded to clinical practice due to several limitations or challenges. Bone tissue engineering aims to induce new functional bone regeneration via the synergistic combination of biomaterials, cells, and factor therapy. In this review, we …

An Open-Source Sandbox For Increasing The Accessibility Of Functional Programming To The Bioinformatics And Scientific Communities, Matthew Fenwick, Colbert Sesanker, Jay Vyas, Michael R. Gryk

UCHC Articles - Research

Scientists are continually faced with the need to express complex mathematical notions in code. The renaissance of functional languages such as LISP and Haskell is often credited to their ability to implement complex data operations and mathematical constructs in an expressive and natural idiom. The slow adoption of functional computing in the scientific community does not, however, reflect the congeniality of these fields. Unfortunately, the learning curve for adoption of functional programming techniques is steeper than that for more traditional languages in the scientific community, such as Python and Java, and this is partially due to the relative sparseness of …