Noise-induced divisive gain control in neuron models

A recent computational study of gain control via shunting inhibition has shown that the slope of the frequency-versus-input (f-I) characteristic of a neuron can be decreased by increasing the noise associated with the inhibitory input (Neural Comput. 13, 227-248). This novel noise-induced divisive gain control relies on the concommittant increase of the noise variance with the mean of the total inhibitory conductance. Here we investigate this effect using different neuronal models. The effect is shown to occur in the standard leaky integrate-and-fire (LIF) model with additive Gaussian white noise, and in the LIF with multiplicative noise acting on the inhibitory conductance. The noisy scaling of input currents is also shown to occur in the one-dimensional theta-neuron model, which has firing dynamics, as well as a large scale compartmental model of a pyramidal cell in the electrosensory lateral line lobe of a weakly electric fish. In this latter case, both the inhibition and the excitatory input have Poisson statistics; noise-induced divisive inhibition is thus seen in f-I curves for which the noise increases along with the input I. We discuss how the variation of the noise intensity along with inputs is constrained by the physiological context and the class of model used, and further provide a comparison of the divisive effect across models.     

Sheared Aanti.Aanti base pairs in a destabilizing 2 x 2 internal loop: the NMR structure of 5'(rGGCAAGCCU)2

The 5'(rGGCAAGCCU)(2) duplex contains tandem A.A pairs. The three-dimensional structure of the 5'(rGGCAAGCCU)(2) duplex was modeled by molecular dynamics and energy minimization with NMR-derived distance and dihedral angle restraints. Although the 5'(rCAAG)(2) loop is thermodynamically destabilizing by 1.1 kcal/mol, the tandem A.A pairs adopt a predominant conformation: a sheared anti-anti (A.A trans Hoogsteen/Sugar-edge) alignment similar to that observed in the crystal structure of the P4-P6 domain of the Tetrahymena thermophila intron [Cate, J. H., Gooding, A. R., Podell, E., Zhou, K., Golden, B. L., Kundrot, C. E., Cech, T. R., and Doudna, J. A. (1996) Science 273, 1678-1685]. The NMR-derived structure of the 5'(rGGCAAGCCU)(2) duplex exhibits cross-strand hydrogen bonds from N3 of A4 to an amino hydrogen of A5 and from the 2' oxygen of the A4 sugar to the other amino hydrogen of A5. An intrastrand hydrogen bond is formed from the 2' OH hydrogen of A4 to O5' of A5. The cross-strand A5 bases are stacked. The Watson-Crick G-C regions are essentially A-form. The sheared anti-anti (A.A trans Hoogsteen/Sugar-edge) alignment provides potential contact sites for tertiary interactions and, therefore, is a possible target site for therapeutics. Thus, thermodynamically destabilizing internal loops can be preorganized for tertiary interactions or ligand binding.     

Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells

Probiotic bacteria are microorganisms that benefit the host by preventing or ameliorating disease. However, little information is known regarding the scientific rationale for using probiotics as alternative medicine. The purpose of this paper is to investigate the mechanisms of probiotic beneficial effects on intestinal cell homeostasis. We now report that one such probiotic, Lactobacillus rhamnosus GG (LGG), prevents cytokine-induced apoptosis in two different intestinal epithelial cell models. Culture of LGG with either mouse or human colon cells activates the anti-apoptotic Akt/protein kinase B. This model probiotic also inhibits activation of the pro-apoptotic p38/mitogen-activated protein kinase by tumor necrosis factor, interleukin-1alpha, or gamma-interferon. Furthermore, products recovered from LGG culture broth supernatant show concentration-dependent activation of Akt and inhibition of cytokine-induced apoptosis. These observations suggest a novel mechanism of communication between probiotic microorganisms and epithelia that increases survival of intestinal cells normally found in an environment of pro-apoptotic cytokines.     

Clinically validated benchmarking of normalisation techniques for two-colour oligonucleotide spotted microarray slides

Acquisition of microarray data is prone to systematic errors. A correction, called normalisation, must be applied to the data before further analysis is performed. With many normalisation techniques published and in use, the best way of executing this correction remains an open question. In this study, a variety of single-slide normalisation techniques, and different parameter settings for these techniques, were compared over many replicated microarray experiments. Different normalisation techniques were assessed through the distribution of the standard deviation of replicates from one biological sample across different slides. It is shown that local normalisation outperformed global normalisation, and intensity-based 'LOWESS' outperformed trimmed mean and median normalisation techniques. Overall, the top performing normalisation technique was a print-tip-based LOWESS with zero robust iterations. Lastly, we validated this evaluation methodology by examining the ability to predict oestrogen receptor-positive and -negative breast cancer samples with data that had been normalised using different techniques.     

Rapid method for measuring ScFv thermal stability by yeast surface display

We have characterized a simplified method to determine the relative thermal stability of single-chain antibodies by following the irreversible denaturation of scFv fusions on the surface of yeast by flow cytometry. The method was highly reproducible and correlated well with other methods used to monitor thermal denaturation of the soluble proteins. We found a range of thermal stabilities for wild-type single-chain antibodies with half-maximum denaturation temperatures between 43 and 61 degrees C. The ability to quantitate thermal stability of antibodies or other proteins that are immobilized on the surface of yeast allows rapid comparisons of primary structural information with stability. Thermal denaturation could be a useful parameter to consider in the choice of scFv fragments for various applications.     

Control for confounding in the presence of measurement error in hierarchical models

Hierarchical modeling is becoming increasingly popular in epidemiology, particularly in air pollution studies. When potential confounding exists, a multilevel model yields better power to assess the independent effects of each predictor by gathering evidence across many sub-studies. If the predictors are measured with unknown error, bias can be expected in the individual substudies, and in the combined estimates of the second-stage model. We consider two alternative methods for estimating the independent effects of two predictors in a hierarchical model. We show both analytically and via simulation that one of these gives essentially unbiased estimates even in the presence of measurement error, at the price of a moderate reduction in power. The second avoids the potential for upward bias, at the price of a smaller reduction in power. Since measurement error is endemic in epidemiology, these approaches hold considerable potential. We illustrate the two methods by applying them to two air pollution studies. In the first, we re-analyze published data to show that the estimated effect of fine particles on daily deaths, independent of coarse particles, was downwardly biased by measurement error in the original analysis. The estimated effect of coarse particles becomes more protective using the new estimates. In the second example, we use published data on the association between airborne particles and daily deaths in 10 US cities to estimate the effect of gaseous air pollutants on daily deaths. The resulting effect size estimates were very small and the confidence intervals included zero.     

Management of vesicoureteral reflux

Four cases of vesicoureteral reflux are discussed by prominent pediatric urologists. The condition can range from minimal reflux into the distal ureter to massive reflux causing tortuosity of the ureter and hydronephrosis. Treatment options range from medical management to tapering of the ureter with reimplantation. The cross-trigonal technique is popular among pediatric urologists, and the Politano-Leadbetter technique is a very successful technique that has stood the test of time. The extravesical approach to ureteral reimplantation reduces morbidity, shortens hospital stays, reduces medical costs, and maintains the high success rates of the intravesical techniques. Subureteric injection of bulking agents to correct the reflux holds promise as an alternative to open surgery, but presents the challenge of identifying the ideal bulking agent.     

Substituted 4-[4-(dimethylamino)styryl]pyridinium salt as a fluorescent probe for cell microviscosity

In aqueous solution, 4-[4-(dimethylamino)styryl]pyridine (DMASP) derivatives displayed dual fluorescence, in which excitation at either 469 or 360 nm produced an emission band near 600 nm. Increasing the viscosity of the environment intensified the fluorescence emission obtained at the longer wavelength of excitation, whereas the emission at the lower wavelength of excitation showed little change in intensity. Thus, using the ratio of the 600 nm emission obtained by exciting at 469 nm to that obtained with 360 nm excitation, it is possible to obtain a value related to the local viscosity that does not depend on the system parameters. The fluorescence emission of the dye in aqueous solution, as well as in living cells, is well suited for use with visible fluorescence spectroscopy. The N-carboxymethyl butyl ester DMASP derivative (1) was found to be irreversibly loaded into living smooth muscle cells, presumably because it is hydrolyzed by cellular esterases, transforming it into a membrane-impermeable fluorescent carboxylate DMASP derivative. (2) After calibrating 2 against glycerol/water and sucrose/water mixtures of known viscosity, the fluorescence ratio generated from cultured smooth muscle cells in dual-excitation mode gave an average intracellular viscosity of 4.5 cP. This value corresponds to those reported in the literature.