Distinctive cellular response to aluminum based adjuvants.

Aluminum-based adjuvants (ABAs) are used in human vaccines to enhance the magnitude of protective immune responses elicited against specific pathogens. One hypothesis is that stress signals released by aluminum-exposed necrotic cells play a role in modulating an immune response that contributes to the adjuvant's effectiveness. We hypothesized that aluminum adjuvant-induced necrosis would be similar irrespective of cellular origin or composition of the adjuvant. To test this hypothesis, human macrophages derived from peripheral monocytic cell line (THP-1) and cells derived from the human brain (primary astrocytes) were evaluated. Three commercially available formulations of ABAs (Alhydrogel, Imject alum, and Adju-Phos) were examined. Alum was also used as a reference. Cell viability, reactive oxygen species formation, and production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were quantified. Cells were exposed to different concentrations (10-100 μg/mL) of the adjuvants for 24 h or 72 h. The two FDA approved adjuvants (Alhydrogel and Adju-Phos) decreased cell viability in both cell types. At the 72 h time point, the decrease in viability was accompanied with increased ROS formation. The size of the aluminum agglomerates was not relatable to the changes observed. After exposure to ABAs, astrocytes and macrophages presented a distinct profile of cytokine secretion which may relate to the function and unique characteristics of each cell type. These variations indicate that aluminum adjuvants may have differing capability of activating cells of different origin and thus their utility in specific vaccine design should be carefully assessed for optimum efficacy

Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host

The cellular adaptive immune response plays a key role in resolving influenza infection. Experiments where individuals are successively infected with different strains within a short timeframe provide insight into the underlying viral dynamics and the role of a cross-reactive immune response in resolving an acute infection. We construct a mathematical model of within-host influenza viral dynamics including three possible factors which determine the strength of the cross-reactive cellular adaptive immune response: the initial naive T cell number, the avidity of the interaction between T cells and the epitopes presented by infected cells, and the epitope abundance per infected cell. Our model explains the experimentally observed shortening of a second infection when cross-reactivity is present, and shows that memory in the cellular adaptive immune response is necessary to protect against a second infection.Comment: 35 pages, 12 figure

Transcriptional Regulator TonEBP Mediates Oxidative Damages in Ischemic Kidney Injury

TonEBP (tonicity-responsive enhancer binding protein) is a transcriptional regulator whose expression is elevated in response to various forms of stress including hyperglycemia, inflammation, and hypoxia. Here we investigated the role of TonEBP in acute kidney injury (AKI) using a line of TonEBP haplo-deficient mice subjected to bilateral renal ischemia followed by reperfusion (I/R). In the TonEBP haplo-deficient animals, induction of TonEBP, oxidative stress, inflammation, cell death, and functional injury in the kidney in response to I/R were all reduced. Analyses of renal transcriptome revealed that genes in several cellular pathways including peroxisome and mitochondrial inner membrane were suppressed in response to I/R, and the suppression was relieved in the TonEBP deficiency. Production of reactive oxygen species (ROS) and the cellular injury was reproduced in a renal epithelial cell line in response to hypoxia, ATP depletion, or hydrogen peroxide. The knockdown of TonEBP reduced ROS production and cellular injury in correlation with increased expression of the suppressed genes. The cellular injury was also blocked by inhibitors of necrosis. These results demonstrate that ischemic insult suppresses many genes involved in cellular metabolism leading to local oxidative stress by way of TonEBP induction. Thus, TonEBP is a promising target to prevent AKI

Analysis of DNA-Damage Response to ionizing radiation in serum-shock synchronized human fibroblasts.

Many aspects of cellular physiology, including cellular response to genotoxic stress, are related to the circadian rhythmicity induced by the molecular clock. The current study investigated if the cellular response to DNA damage is in relation to endogenous expression levels of the PER2 protein, a key component of the molecular regulatory system that confers rhythmicity in mammalian cells. Human normal fibroblasts (CCD-34Lu) were subjected to serum shock to induce circadian oscillations of the PER2 protein and then irradiated with \u3b3- rays at times corresponding to the trough and peak expression of the PER2 protein. To better examine cellular response to DNA damage, the experiments performed in this study were carried out in non-proliferating CCD-34Lu fibroblasts in order to maintain the cell and circadian cycles separated while they were being exposed to genotoxic stress. Study results demonstrated that clonogenic cell survival, double-strand break repair kinetics, and TP53 protein levels were affected in the cells irradiated at the trough than in those irradiated at peak expression of the PER2 protein

Assessing cellular response to functionalized α-helical peptide hydrogels

α-Helical peptide hydrogels are decorated with a cell-binding peptide motif (RGDS), which is shown to promote adhesion, proliferation, and differentiation of PC12 cells. Gel structure and integrity are maintained after functionalization. This opens possibilities for the bottom-up design and engineering of complex functional scaffolds for 2D and 3D cell cultures.</p

Best Response Games on Regular Graphs

With the growth of the internet it is becoming increasingly important to understand how the behaviour of players is affected by the topology of the network interconnecting them. Many models which involve networks of interacting players have been proposed and best response games are amongst the simplest. In best response games each vertex simultaneously updates to employ the best response to their current surroundings. We concentrate upon trying to understand the dynamics of best response games on regular graphs with many strategies. When more than two strategies are present highly complex dynamics can ensue. We focus upon trying to understand exactly how best response games on regular graphs sample from the space of possible cellular automata. To understand this issue we investigate convex divisions in high dimensional space and we prove that almost every division of $k-1$ dimensional space into $k$ convex regions includes a single point where all regions meet. We then find connections between the convex geometry of best response games and the theory of alternating circuits on graphs. Exploiting these unexpected connections allows us to gain an interesting answer to our question of when cellular automata are best response games

Heat shock proteins and the cellular response to osmotic stress

In antidiuresis, the intrarenal distribution of HSP25/27, alpha beta -crystallin, HSP72, OSP94 and HSP110 corresponds to the osmotic gradient between cortex and papilla: low amounts in the cortex and high values in the inner medulla and papilla. In addition, medullary HSP72 levels change appropriately with the diuretic state. Studies on MUCK cells suggest that, in the renal medulla in vivo, stressors, such as NaCl and low pH, may act in concert to induce HSP72 expression. Urea, added to the medium at high concentrations (600 mM), causes the majority of MUCK cells to die. Prior exposure of these cells to hypertonic media (NaCl addition), a maneuver that induces HSP72, protects the cells against the deleterious effects of high urea concentrations. Inhibition of HSP72 expression by stable antisense transfection or SB203580 treatment abolishes the beneficial effects of prior hypertonic stress. Conversely, overexpression of HSP72 under isotonic conditions by a dexamethasone-driven vector confers substantial resistance against subsequent exposure to high urea concentrations. Taken together these results suggest that also in the renal inner medulla, NaCl-induced enhancement of HSP72 expression may help counteract the detrimental effects of high urea concentrations. Copyright (C) 2000 S. Karger AG Basel

Murine terminal deoxynucleotidyl transferase: cellular distribution and response to cortisone

The mouse thymus contains two forms of terminal deoxynucleotidyl transferase (TdT) which are distinguishable by the salt concentration necessary to elute them from a phosphocellulose column, by their distrubtion among the thymocyte subpopulations, and by their sensitivity to cortisone treatment. In the whole thymus the later eluting peak (peak II) is the predominant one with about 3-10% of the total activity appearing in peak I. Both peak I and peak II activities are most sensitively assayed by the polymerization of dGMP onto an oligo(dA) primer. The minor population of thymocytes which is less dense and cortisone-resistant contains a higher specific activity of peak I TdT. The majority of TdT activity is, however, found in the major population of thymocytes which occurs in the center region of a bovine serum albumin gradient and is cortisone-sensitive. A very low level of an activity indistinguishable from peak II TdT activity is also detected in the mouse bone marrow. Other tissues, such as spleen, liver, heart, and brain lack detectable amounts of TdT activity

How Push-To-Talk Makes Talk Less Pushy

This paper presents an exploratory study of college-age students using two-way, push-to-talk cellular radios. We describe the observed and reported use of cellular radio by the participants. We discuss how the half-duplex, lightweight cellular radio communication was associated with reduced interactional commitment, which meant the cellular radios could be used for a wide range of conversation styles. One such style, intermittent conversation, is characterized by response delays. Intermittent conversation is surprising in an audio medium, since it is typically associated with textual media such as instant messaging. We present design implications of our findings.Comment: 10 page