Cyclic AMP modulation and its effects on chemo-resistant colon cancer cell proliferation and survival

One of the major problems associated with colorectal cancer is resistance to cytotoxic chemotherapeutic agents. New strategies are therefore required to inhibit colon cancer proliferation and survival. Here I use modulators of cAMP pathways, including inhibitors of phosphodiesterase 4 (PDE4) enzymes, which are under clinical development for other disease states, to inhibit the breakdown of cAMP and to assess the effects of raising intracellular cAMP on colon cancer proliferation and survival. I found that some chemo-resistant cancer cells are addicted to keeping low cAMP in PDE4 regulated compartments, and modulation of this pool causes G1/S-phase arrest and apoptosis. I also show that PDE4 controlled cAMP negatively regulates the PI 3-Kinase/Akt pathway, which some cells are addicted to for survival. Furthermore, I investigated the expression and role of PDE4 enzymes in metastatic colon cancer cells and assessed the effects of modulating their expression on survival. Also, I used a clinically relevant analogue of forskolin, an agonist of adenylyl cyclase, to examine the general effect on growth of epithelial cancer cell lines. This work might provide new strategies for the treatment of advanced colon cancer

A globally accurate theory for a class of binary mixture models

Using the self-consistent Ornstein-Zernike approximation (SCOZA) results for the 3D Ising model, we obtain phase diagrams for binary mixtures described by decorated models. We obtain the plait point, binodals, and closed-loop coexistence curves for the models proposed by Widom, Clark, Neece, and Wheeler. The results are in good agreement with series expansions and experiments.Comment: 16 pages, 10 figure

Magneto-seismology: effect of inhomogeneous magnetic field on transversal coronal loop oscillations

The extreme-ultraviolet (EUV) imagers onboard the planned Solar Dynamics Observatory (SDO) and Solar Orbiter (SO) will offer us the best chance yet of using observations of post-flare loop oscillations to probe the fine structure of the corona. Recently developed magnetohydrodynamic (MHD) wave theory has shown that the properties of loop oscillations depend on their plasma fine structure. Up to this point, many studies have concentrated solely on the effect of plasma density stratification on coronal loop oscillations. In this paper we develop MHD wave theory which models the effect of an inhomogeneous magnetic field on coronal loop oscillations. The results have the potential to be used in testing the efficacy of photospheric magnetic field extrapolations and have important implications regarding magneto-seismology of the corona

Sulfite: Cytochrome \u3cem\u3ec\u3c/em\u3e Oxidoreductase from \u3cem\u3eThiobacillus novellus\u3c/em\u3e

Direct oxidation of sulfite to sulfate occurs in various photo- and chemotrophic sulfur oxidizing microorganisms as the final step in the oxidation of reduced sulfur compounds and is catalyzed by sulfite:cytochrome c oxidoreductase (EC1.8.2.1). Here we show that the enzyme from Thiobacillus novellus is a periplasmically located αβ heterodimer, consisting of a 40.6-kDa subunit containing a molybdenum cofactor and an 8.8-kDa mono-heme cytochrome c 552 subunit (midpoint redox potential, E m8.0 = +280 mV). The organic component of the molybdenum cofactor was identified as molybdopterin contained in a 1:1 ratio to the Mo content of the enzyme. Electron paramagnetic resonance spectroscopy revealed the presence of a sulfite-inducible Mo(V) signal characteristic of sulfite:acceptor oxidoreductases. However, pH-dependent changes in the electron paramagnetic resonance signal were not detected. Kinetic studies showed that the enzyme exhibits a ping-pong mechanism involving two reactive sites. K m values for sulfite and cytochrome c 550 were determined to be 27 and 4 μm, respectively; the enzyme was found to be reversibly inhibited by sulfate and various buffer ions. The sorABgenes, which encode the enzyme, appear to form an operon, which is preceded by a putative extracytoplasmic function-type promoter and contains a hairpin loop termination structure downstream ofsorB. While SorA exhibits significant similarities to known sequences of eukaryotic and bacterial sulfite:acceptor oxidoreductases, SorB does not appear to be closely related to any knownc-type cytochromes

Ion-Molecule Reactions in Unsaturated Hydrocarbons: Allene, Propyne, Diacetylene, and Vinylacetylene

Ion-molecule reactions in allene, propyne, diacetylene, and vinylacetylene (1-buten-3-yne) have been studied at near-thermal energies by the technique of ion cyclotron resonance mass spectrometry. Rate coefficients and branching ratios are reported for the reactions of C_3H^+_n (n = 1-4) with allene and propyne and for the reactions of C_4H^+_n (n = 0-5) with diacetylene and vinylacetylene. Branching ratios are also given for the reactions of C_4H^+_n, C_5H_n, and C_6H^+_n with propyne and for reactions of C_6H^+_n with diacetylene and vinylacetylene. More than 90% of the reactive channels lead to product ions having a larger carbon skeleton than the reactant ion. Evidence for ions with the same m/e ratio having differing reactivities was obtained for C_3H^+_3, C_6H^+_7, and C_7H^+_7. Ion reaction sequences in allene and propyne were followed at higher pressures (l0^(-4) torr) to investigate secondary, tertiary, and higher order processes

Investigation of prediction methods for the loads and stresses of Apollo type spacecraft parachutes. Volume 1: Loads

An analysis was conducted with the objective of upgrading and improving the loads, stress, and performance prediction methods for Apollo spacecraft parachutes. The subjects considered were: (1) methods for a new theoretical approach to the parachute opening process, (2) new experimental-analytical techniques to improve the measurement of pressures, stresses, and strains in inflight parachutes, and (3) a numerical method for analyzing the dynamical behavior of rapidly loaded pilot chute risers

Zinc disrupts central carbon metabolism and capsule biosynthesis in Streptococcus pyogenes.

Neutrophils release free zinc to eliminate the phagocytosed bacterial pathogen Streptococcus pyogenes (Group A Streptococcus; GAS). In this study, we investigated the mechanisms underpinning zinc toxicity towards this human pathogen, responsible for diseases ranging from pharyngitis and impetigo, to severe invasive infections. Using the globally-disseminated M1T1 GAS strain, we demonstrate that zinc stress impairs glucose metabolism through the inhibition of the glycolytic enzymes phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase. In the presence of zinc, a metabolic shift to the tagatose-6-phosphate pathway allows conversion of D-galactose to dihydroxyacetone phosphate and glyceraldehyde phosphate, partially bypassing impaired glycolytic enzymes to generate pyruvate. Additionally, zinc inhibition of phosphoglucomutase results in decreased capsule biosynthesis. These data indicate that zinc exerts it toxicity via mechanisms that inhibit both GAS central carbon metabolism and virulence pathways

Stability of Ca-montmorillonite hydrates: A computer simulation study

Classic simulations are used to study interlayer structure, swelling curves, and stability of Ca-montmorillonite hydrates. For this purpose, NPzzT$ and MuPzzT ensembles are sampled for ground level and given burial conditions. For ground level conditions, a double layer hydrate having 15.0 A of basal spacing is the predominant state for relative vapor pressures (p/po) ranging in 0.6-1.0. A triple hydrate counting on 17.9 A of interlaminar distance was also found stable for p/po=1.0. For low vapor pressures, the system may produce a less hydrated but still double layer state with 13.5 A or even a single layer hydrate with 12.2 A of interlaminar distance. This depends on the established initial conditions. On the other hand, the effect of burial conditions is two sided. It was found that it enhances dehydration for all vapor pressures except for saturation, where swelling is promoted.Comment: 8 pages, 9 figure