Modelling the influence of RKIP on the ERK signalling pathway using the stochastic process algebra PEPA

This paper examines the influence of the Raf Kinase Inhibitor Protein (RKIP) on the Extracellular signal Regulated Kinase (ERK) signalling pathway [5] through modelling in a Markovian process algebra, PEPA [11]. Two models of the system are presented, a reagent-centric view and a pathway-centric view. The models capture functionality at the level of subpathway, rather than at a molecular level. Each model affords a different perspective of the pathway and analysis. We demonstrate the two models to be formally equivalent using the timing-aware bisimulation defined over PEPA models and discuss the biological significance

Deterministic mechanical model of T-killer cell polarization reproduces the wandering of aim between simultaneously engaged targets

T-killer cells of the immune system eliminate virus-infected and tumorous cells through direct cell-cell interactions. Reorientation of the killing apparatus inside the T cell to the T-cell interface with the target cell ensures specificity of the immune response. The killing apparatus can also oscillate next to the cell-cell interface. When two target cells are engaged by the T cell simultaneously, the killing apparatus can oscillate between the two interface areas. This oscillation is one of the most striking examples of cell movements that give the microscopist an unmechanistic impression of the cell's fidgety indecision. We have constructed a three-dimensional, numerical biomechanical model of the molecular-motor-driven microtubule cytoskeleton that positions the killing apparatus. The model demonstrates that the cortical pulling mechanism is indeed capable of orienting the killing apparatus into the functional position under a range of conditions. The model also predicts experimentally testable limitations of this commonly hypothesized mechanism of T-cell polarization. After the reorientation, the numerical solution exhibits complex, multidirectional, multiperiodic, and sustained oscillations in the absence of any external guidance or stochasticity. These computational results demonstrate that the strikingly animate wandering of aim in T-killer cells has a purely mechanical and deterministic explanation. © 2009 Kim, Maly

Na+/Ca(2+ )Exchanger a Druggable Target to Promote beta -Cell Proliferation and Function

An important feature of type 2 diabetes is a decrease in <i>β</i> -cell mass. Therefore, it is essential to find new approaches to stimulate <i>β</i> -cell proliferation. We have previously shown that heterozygous inactivation of the Na <sup>+</sup> /Ca <sup>2+</sup> exchanger (isoform 1; NCX1), a protein responsible for Ca <sup>2+</sup> extrusion from cells, increases <i>β</i> -cell proliferation, mass, and function in mice. Here, we show that <i>Ncx</i> 1 inactivation also increases <i>β</i> -cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates <i>β</i> -cell proliferation both <i>in vitro</i> and <i>in vivo</i> . NCX1 inhibition by small interfering RNA or small molecules activates the calcineurin/nuclear factor of activated T cells (NFAT) pathway and inhibits apoptosis induced by the immunosuppressors cyclosporine A (CsA) and tacrolimus in insulin-producing cell. Moreover, NCX1 inhibition increases the expression of <i>β</i> -cell-specific genes, such as <i>Ins1, Ins2,</i> and <i>Pdx</i> 1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na <sup>+</sup> /Ca <sup>2+</sup> exchange is a druggable target to stimulate <i>β</i> -cell function and proliferation. Specific <i>β</i> -cell inhibition of Na <sup>+</sup> /Ca <sup>2+</sup> exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote <i>β</i> -cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease

The NASA Exoplanet Archive: Data and Tools for Exoplanet Research

We describe the contents and functionality of the NASA Exoplanet Archive, a database and tool set funded by NASA to support astronomers in the exoplanet community. The current content of the database includes interactive tables containing properties of all published exoplanets, Kepler planet candidates, threshold-crossing events, data validation reports and target stellar parameters, light curves from the Kepler and CoRoT missions and from several ground-based surveys, and spectra and radial velocity measurements from the literature. Tools provided to work with these data include a transit ephemeris predictor, both for single planets and for observing locations, light curve viewing and normalization utilities, and a periodogram and phased light curve service. The archive can be accessed at http://exoplanetarchive.ipac.caltech.edu.Comment: Accepted for publication in the Publications of the Astronomical Society of the Pacific, 4 figure

Initial Performance of the NEOWISE Reactivation Mission

NASA's Wide-field Infrared Survey Explorer (WISE) spacecraft has been brought out of hibernation and has resumed surveying the sky at 3.4 and 4.6 μm. The scientific objectives of the NEOWISE reactivation mission are to detect, track, and characterize near-Earth asteroids and comets. The search for minor planets resumed on 2013 December 23, and the first new near-Earth object (NEO) was discovered 6 days later. As an infrared survey, NEOWISE detects asteroids based on their thermal emission and is equally sensitive to high and low albedo objects; consequently, NEOWISE-discovered NEOs tend to be large and dark. Over the course of its three-year mission, NEOWISE will determine radiometrically derived diameters and albedos for ~2000 NEOs and tens of thousands of Main Belt asteroids. The 32 months of hibernation have had no significant effect on the mission's performance. Image quality, sensitivity, photometric and astrometric accuracy, completeness, and the rate of minor planet detections are all essentially unchanged from the prime mission's post-cryogenic phase

Matrix Rigidity Regulates Cancer Cell Growth by Modulating Cellular Metabolism and Protein Synthesis

Background: Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and at sites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect the biology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy. Methodology/Principal Findings: This study uses flexible polyacrylamide gels as substrates for cell growth in conjunction with a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to their differential growth on soft and rigid substrates. Compared to cells growing on more rigid/stiff substrates (>10,000 Pa), cells on soft substrates (150–300 Pa) exhibited a longer cell cycle, due predominantly to an extension of the G1 phase of the cell cycle, and were metabolically less active, showing decreased levels of intracellular ATP and a marked reduction in protein synthesis. Using stable isotope labeling of amino acids in culture (SILAC) and mass spectrometry, we measured the rates of protein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identified cellular proteins whose syntheses were either preferentially inhibited or preserved on soft matrices. The former category included proteins that regulate cytoskeletal structures (e.g., tubulins) and glycolysis (e.g., phosphofructokinase-1), whereas the latter category included proteins that regulate key metabolic pathways required for survival, e.g., nicotinamide phosphoribosyltransferase, a regulator of the NAD salvage pathway. Conclusions/Significance: The cellular properties of rigidity-dependent cancer cells growing on soft matrices are reminiscent of the properties of dormant cancer cells, e.g., slow growth rate and reduced metabolism. We suggest that the use of relatively soft gels as cell culture substrates would allow molecular pathways to be studied under conditions that reflect the different mechanical environments encountered by cancer cells upon metastasis to distant sites

Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery

Motivation: Signaling pathways control a large variety of cellular processes. However, currently, even within the same database signaling pathways are often curated at different levels of detail. This makes comparative and cross-talk analyses difficult. Results: We present SignaLink, a database containing 8 major signaling pathways from Caenorhabditis elegans, Drosophila melanogaster, and humans. Based on 170 review and approx. 800 research articles, we have compiled pathways with semi-automatic searches and uniform, well-documented curation rules. We found that in humans any two of the 8 pathways can cross-talk. We quantified the possible tissue- and cancer-specific activity of cross-talks and found pathway-specific expression profiles. In addition, we identified 327 proteins relevant for drug target discovery. Conclusions: We provide a novel resource for comparative and cross-talk analyses of signaling pathways. The identified multi-pathway and tissue-specific cross-talks contribute to the understanding of the signaling complexity in health and disease and underscore its importance in network-based drug target selection. Availability: http://SignaLink.orgComment: 9 pages, 4 figures, 2 tables and a supplementary info with 5 Figures and 13 Table

Complex networks theory for analyzing metabolic networks

One of the main tasks of post-genomic informatics is to systematically investigate all molecules and their interactions within a living cell so as to understand how these molecules and the interactions between them relate to the function of the organism, while networks are appropriate abstract description of all kinds of interactions. In the past few years, great achievement has been made in developing theory of complex networks for revealing the organizing principles that govern the formation and evolution of various complex biological, technological and social networks. This paper reviews the accomplishments in constructing genome-based metabolic networks and describes how the theory of complex networks is applied to analyze metabolic networks.Comment: 13 pages, 2 figure

Intercalated theophylline-smectite hybrid for pH-mediated delivery

On the basis of their large specific surface areas, high adsorption and cation exchange capacities, swelling potential and low toxicity, natural smectite clays are attractive substrates for the gastric protection of neutral and cationic drugs. Theophylline is an amphoteric xanthine derivative that is widely used as a bronchodilator in the treatment of asthma and chronic obstructive pulmonary disease. This study considers the in vitro uptake and release characteristics of the binary theophylline-smectite system. The cationic form of theophylline was readily ion exchanged into smectite clay at pH 1.2 with a maximum uptake of 67±2 mg g−1. Characterisation of the drug-clay hybrid system by powder X-ray diffraction analysis, Fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy confirmed that the theophylline had been exclusively intercalated into the clay system in an amorphous form. The drug remained bound within the clay under simulated gastric conditions at pH 1.2; and the prolonged release of approximately 40% of the drug was observed in simulated intestinal fluid at pH 6.8 and 7.4 within a 2-h timeframe. The incomplete reversibility of the intercalation process was attributed to chemisorption of the drug within the clay lattice. These findings indicate that smectite clay is a potentially suitable vehicle for the safe passage of theophylline into the duodenum. Protection from absorption in the stomach and subsequent prolonged release in the small intestine are advantageous in reducing fluctuations in serum concentration which may impact therapeutic effect and toxicit