Predicting protein-ligand affinity with a random matrix framework

Rapid determination of whether a candidate compound will bind to a particular target receptor remains a stumbling block in drug discovery. We use an approach inspired by random matrix theory to decompose the known ligand set of a target in terms of orthogonal "signals" of salient chemical features, and distinguish these from the much larger set of ligand chemical features that are not relevant for binding to that particular target receptor. After removing the noise caused by finite sampling, we show that the similarity of an unknown ligand to the remaining, cleaned chemical features is a robust predictor of ligand-target affinity, performing as well or better than any algorithm in the published literature. We interpret our algorithm as deriving a model for the binding energy between a target receptor and the set of known ligands, where the underlying binding energy model is related to the classic Ising model in statistical physics.This research was funded by a grant from Roche Pharmaceuticals. A.A.L. acknowledges the support of a Fulbright Fellowship. L.J.C. was supported by a Next Generation Fellowship, and a Marie Curie Career Integration Grant (Evo-Couplings, Grant 631609). M.P.B. is an investigator of the Simons Foundation, and also acknowledges support from the National Science Foundation through DMS-1411694

Nonlinear hydrodynamic and thermoacoustic oscillations of a bluff-body stabilised turbulent premixed flame

Turbulent premixed flames often experience thermoacoustic instabilities when the combustion heat release rate is in phase with acoustic pressure fluctuations. Linear methods often assume a priori that oscillations are periodic and occur at a dominant frequency with a fixed amplitude. Such assumptions are not made when using nonlinear analysis. When an oscillation is fully saturated, nonlinear analysis can serve as a useful avenue to reveal flame behaviour far more elaborate than period-one limit cycles, including quasi-periodicity and chaos in hydrodynamically or thermoacoustically self-excited system. In this paper, the behaviour of a bluff-body stabilised turbulent premixed propane/air flame in a model jet-engine afterburner configuration is investigated using computational fluid dynamics. For the frequencies of interest in this investigation, an unsteady Reynolds-averaged Navier–Stokes approach is found to be appropriate. Combustion is represented using a modified laminar flamelet approach with an algebraic closure for the flame surface density. The results are validated by comparison with existing experimental data and with large eddy simulation, and the observed self-excited oscillations in pressure and heat release are studied using methods derived from dynamical systems theory. A systematic analysis is carried out by increasing the equivalence ratio of the reactant stream supplied to the premixed flame. A strong variation in the global flame structure is observed. The flame exhibits a self-excited hydrodynamic oscillation at low equivalence ratios, becomes steady as the equivalence ratio is increased to intermediate values, and again exhibits a self-excited thermoacoustic oscillation at higher equivalence ratios. Rich nonlinear behaviour is observed and the investigation demonstrates that turbulent premixed flames can exhibit complex dynamical behaviour including quasiperiodicity, limit cycles and period-two limit cycles due to the interactions of various physical mechanisms. This has implications in selecting the operating conditions for such flames and for devising proper control strategies for the avoidance of thermoacoustic instability.The authors would like to acknowledge financial support from the Dorothy Hodgkin Postgraduate Award and Rolls-Royce Plc.This is the author accepted manuscript. The final version is available from Taylor & Francis via http://dx.doi.org/10.1080/13647830.2015.111855

Metabolic Phenotype of Stage IV Lung Adenocarcinoma: relationship with epidermal growth factor receptor mutation

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Inferring Population Preferences via Mixtures of Spatial Voting Models

Understanding political phenomena requires measuring the political preferences of society. We introduce a model based on mixtures of spatial voting models that infers the underlying distribution of political preferences of voters with only voting records of the population and political positions of candidates in an election. Beyond offering a cost-effective alternative to surveys, this method projects the political preferences of voters and candidates into a shared latent preference space. This projection allows us to directly compare the preferences of the two groups, which is desirable for political science but difficult with traditional survey methods. After validating the aggregated-level inferences of this model against results of related work and on simple prediction tasks, we apply the model to better understand the phenomenon of political polarization in the Texas, New York, and Ohio electorates. Taken at face value, inferences drawn from our model indicate that the electorates in these states may be less bimodal than the distribution of candidates, but that the electorates are comparatively more extreme in their variance. We conclude with a discussion of limitations of our method and potential future directions for research.Comment: To be published in the 8th International Conference on Social Informatics (SocInfo) 201

Physical demand but not dexterity is associated with motor flexibility during rapid reaching in healthy young adults

Healthy humans are able to place light and heavy objects in small and large target locations with remarkable accuracy. Here we examine how dexterity demand and physical demand affect flexibility in joint coordination and end-effector kinematics when healthy young adults perform an upper extremity reaching task. We manipulated dexterity demand by changing target size and physical demand by increasing external resistance to reaching. Uncontrolled manifold analysis was used to decompose variability in joint coordination patterns into variability stabilizing the end-effector and variability de-stabilizing the end-effector during reaching. Our results demonstrate a proportional increase in stabilizing and de-stabilizing variability without a change in the ratio of the two variability components as physical demands increase. We interpret this finding in the context of previous studies showing that sensorimotor noise increases with increasing physical demands. We propose that the larger de-stabilizing variability as a function of physical demand originated from larger sensorimotor noise in the neuromuscular system. The larger stabilizing variability with larger physical demands is a strategy employed by the neuromuscular system to counter the de-stabilizing variability so that performance stability is maintained. Our findings have practical implications for improving the effectiveness of movement therapy in a wide range of patient groups, maintaining upper extremity function in old adults, and for maximizing athletic performance

Personalized prediction of EGFR mutation-induced drug resistance in lung cancer

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Evolving management for critical pulmonary stenosis in neonates and young infants

Over the years, management of critical pulmonary stenosis in young infants has evolved from surgical reconstruction of the right ventricular outflow tract and closed pulmonary valvotomy to transcatheter balloon valvoplasty. Our study aimed at evaluating how the changing policy for management had affected the immediate and long term outcomes of babies with this cardiac lesion. Interventions were made in 34 infants at a median age of 8.5 days (2-90 days). Reconstruction of the right ventricular outflow tract reconstruction was performed in 10 patients, closed pulmonary valvotomy in 13, and balloon valvoplasty in 11. Initial procedure-related mortality was 50%, 15% and 0% respectively. Multivariate analysis revealed transannular patching of the right ventricular outflow tract, and male sex, to be significant factors for death. For the 27 survivors, the ratio of right ventricular to systemic systolic pressure decreased from 1.6 ± 0.3 to 0.3 ± 0.2 after reconstruction of the outflow tract, 1.8 ± 0.5 to 0.8 ± 0.4 after closed valvotomy, and 1.8 ± 0.6 to 0.9 ± 0.3 after balloon valvoplasty. The decrease was significantly greater after patch reconstruction (p=0.025) that required no further reinterventions. The overall rate of reintervention for the survivors was 37% (10/27). The freedom from reintervention after closed valvotomy was 82%, 64% and 51% at 1, 5 and 10 years respectively. The figure remained at 78% at both 1 and 5 years (p=0.66) after balloon valvoplasty. The higher reintervention rate for closed valvotomy corresponded to the significantly greater residual gradient across the pulmonary valve noted on follow-up (p=0.01). Reinterventions included balloon dilation (n=6), reconstruction of the outflow tract (n=4), and 1 each of ligation of an arterial duct and systemic-pulmonary arterial shunting. The risk factor for reintervention was a hypoplastic right ventricle. In conclusion, transcatheter balloon valvoplasty appears to be the optimum initial approach in view of its low mortality, efficacy at relieving the obstruction, and low rate of reintervention. © Greenwich Medical Media Ltd.published_or_final_versio

Obtaining strong ferromagnetism in diluted Gd-doped ZnO thin films through controlled Gd-defect complexes

We demonstrate the fabrication of reproducible long-range ferromagnetism (FM) in highly crystalline Gdx Zn 1−xO thin films by controlling the defects. Films are grown on lattice-matched substrates by pulsed laser deposition at low oxygen pressures (≤25 mTorr) and low Gd concentrations (x ≤ 0.009). These films feature strong FM (10 μB per Gd atom) at room temperature. While films deposited at higher oxygen pressure do not exhibit FM, FM is recovered by post-annealing these films under vacuum. These findings reveal the contribution of oxygen deficiency defects to the long-range FM. We demonstrate the possible FM mechanisms, which are confirmed by density functional theory study, and show that Gd dopants are essential for establishing FM that is induced by intrinsic defects in these films