Understanding false positives in reporter gene assays: in silico chemogenomics approaches to prioritize cell-based HTS data

High throughput screening (HTS) data is often noisy, containing both false positives and negatives. Thus, careful triaging and prioritization of the primary hit list can save time and money by identifying potential false positives before incurring the expense of followup. Of particular concern are cell-based reporter gene assays (RGAs) where the number of hits may be prohibitively high to be scrutinized manually for weeding out erroneous data. Based on statistical models built from chemical structures of 650 000 compounds tested in RGAs, we created "frequent hitter" models that make it possible to prioritize potential false positives. Furthermore, we followed up the frequent hitter evaluation with chemical structure based in silico target predictions to hypothesize a mechanism for the observed "off target" response. It was observed that the predicted cellular targets for the frequent hitters were known to be associated with undesirable effects such as cytotoxicity. More specifically, the most frequently predicted targets relate to apoptosis and cell differentiation, including kinases, topoisomerases, and protein phosphatases. The mechanism-based frequent hitter hypothesis was tested using 160 additional druglike compounds predicted by the model to be nonspecific actives in RGAs. This validation was successful (showing a 50% hit rate compared to a normal hit rate as low as 2%), and it demonstrates the power of computational models toward understanding complex relations between chemical structure and biological function.     

Experimental study of transient forced turbulent separation and reattachment on a bevelled trailing edge

The purpose of this experimental study is to analyze the transient processes of the separation and reattachment of a turbulent boundary layer at the trailing edge of a splitter plate. The separation is driven by a steady pneumatic injection, considered here as an actuator controlling the mixing layer. Particle image velocimetry and hot-film measurements are performed at various stages of the processes. The results highlight the behavior of each transient. Analysis of the time scale of the processes is realized by means of bi-orthogonal decomposition. This gives essential information (e.g., time scale, qualitative features) for future applications using duty cycle mode to excite instabilities of the mixing layer.     

Linking Phase-Field and Atomistic Simulations to Model Dendritic Solidification in Highly Undercooled Melts

Even though our theoretical understanding of dendritic solidification is relatively well developed, our current ability to model this process quantitatively remains extremely limited. This is due to the fact that the morphological development of dendrites depends sensitively on the degree of anisotropy of capillary and/or kinetic properties of the solid-liquid interface, which is not precisely known for materials of metallurgical interest. Here we simulate the crystallization of highly undercooled nickel melts using a computationally efficient phase-field model together with anisotropic properties recently predicted by molecular dynamics simulations. The results are compared to experimental data and to the predictions of a linearized solvability theory that includes both capillary and kinetic effects at the interface.     

In vitro 4 MHz NMR proton relaxation times and in vitro mechanical behavior at low extension of human common carotid arterial wall

We investigated the influence of the biomechanical behavior of human common carotid arterial wall on the NMR proton relaxation times using a Bruker Minispec at 4 MHz. The study was limited to low extension in simple longitudinal elongation of the carotid wall (the maximum loading stretch ratio being 40%). Twenty-five carotid samples divided into 2 longitudinal strips were tested. The first strip was used to determine the nondimensional elastic parameter alpha according to the mechanical model of Fung. The second strip was used to measure the proton relaxation times. T1 value was 316.8 ms +/- 27.6 and T2 value was 59.9 ms +/- 6.8. A significant linear correlation was found between T1 and Ln alpha (p = 0.02). T1 and T2 were not correlated to the age but linearly correlated to the tissue water content (p less than 0.0001), however the age and alpha were not correlated to the tissue water content. These results may reflect the differences in the amount of water binding sites of the elastin which is involved in the elasticity of the carotid wall at low extension.     

Adaptive shape functions and internal mesh adaptation for modeling progressive failure in adhesively bonded joints

Macroscopic finite elements are elements with an embedded analytical solution that can capture detailed local fields, enabling more efficient, mesh independent finite element analysis. The shape functions are determined based on the analytical model rather than prescribed. This method was applied to adhesively bonded joints to model joint behavior with one element through the thickness. This study demonstrates two methods of maintaining the fidelity of such elements during adhesive non-linearity and cracking without increasing the mesh needed for an accurate solution. The first method uses adaptive shape functions, where the shape functions are recalculated at each load step based on the softening of the adhesive. The second method is internal mesh adaption, where cracking of the adhesive within an element is captured by further discretizing the element internally to represent the partially cracked geometry. By keeping mesh adaptations within an element, a finer mesh can be used during the analysis without affecting the global finite element model mesh. Examples are shown which highlight when each method is most effective in reducing the number of elements needed to capture adhesive nonlinearity and cracking. These methods are validated against analogous finite element models utilizing cohesive zone elements.     

Undoped Trans - (CH)X : Magnetic Resonance and Structure

Arguments are given that soliton conditions might be best realized at the surfaces of the fibrils constituting the Shirakawa polyacetylene. The implications of this hypothesis on the interpretation of magnetic resonance and other experiments are discussed.     

Generating a random cyclic permutation

We prove correct an algorithm that, givenn>0, stores in arrayb[0..n–1] a random cyclic permutation of the integers in 0..n–1, with each cyclic permutation having equal probability of being stored inb. The algorithm was developed by Sattolo; our contribution is to present a more convincing proof using standard program-proving methods.Dedicated to Peter Naur on the occasion of his 60th birthdayThis research was supported by the NSF under grant DCR-8320274.Visiting Cornell from the Computer Science Department, Jiangxi Normal University, Nanchang, People's Republic of China.