Performance of machine-learning scoring functions in structure-based virtual screening

Classical scoring functions have reached a plateau in their performance in virtual screening and binding affinity prediction. Recently, machine-learning scoring functions trained on protein-ligand complexes have shown great promise in small tailored studies. They have also raised controversy, specifically concerning model overfitting and applicability to novel targets. Here we provide a new ready-to-use scoring function (RF-Score-VS) trained on 15 426 active and 893 897 inactive molecules docked to a set of 102 targets. We use the full DUD-E data sets along with three docking tools, five classical and three machine-learning scoring functions for model building and performance assessment. Our results show RF-Score-VS can substantially improve virtual screening performance: RF-Score-VS top 1% provides 55.6% hit rate, whereas that of Vina only 16.2% (for smaller percent the difference is even more encouraging: RF-Score-VS top 0.1% achieves 88.6% hit rate for 27.5% using Vina). In addition, RF-Score-VS provides much better prediction of measured binding affinity than Vina (Pearson correlation of 0.56 and -0.18, respectively). Lastly, we test RF-Score-VS on an independent test set from the DEKOIS benchmark and observed comparable results. We provide full data sets to facilitate further research in this area (http://github.com/oddt/rfscorevs) as well as ready-to-use RF-Score-VS (http://github.com/oddt/rfscorevs_binary)

Nanotopographic Cell Culture Substrate: Polymer-Demixed Nanotextured Films Under Cell Culture Conditions

Modulating physical cell culture environments via nanoscale substrate topographic modification has recently been of significant interest in regenerative medicine. Many studies have utilized a polymer-demixing technique to produce nanotextured films and showed that cellular adhesion, proliferation, and differentiation could be regulated by the shape and scale of the polymer-demixed nanotopographies. However, little attention has been paid to the topographic fidelity of the polymer-demixed films when exposed to cell culture conditions. In this brief article, two polymer-demixing systems were employed to assess topographic changes in polymer-demixed films after fibronectin (FN) extracellular matrix protein adsorption and after incubation in phosphate-buffered saline at 37◦C. We showed that FN adsorption induced very small variations ( \u3c 2 nm) to the polystyrene/polybromostyrene (PS/PBrS)-demixed nanoisland textures, not substantially altering the nanotopographies given by the polymer demixing. In addition, poly(L-lactic acid)/PS (PLLA/PS)-demixed nanoisland topographies using PLLA with Mw = 50 x 103 did not show notable degradation up to day 24

Cardiovascular response to postural perturbations of different intensities in healthy young adults

The ability to regain control of balance is vital in limiting falls and injuries. Little is known regarding how the autonomic nervous system responds during recovery from balance perturbations of different intensities. The purpose of this study was to examine the cardiovascular response following a standing balance perturbation of varying intensities, quantify cardiac baroreflex sensitivity (cBRS) during standing perturbations, and to establish the stability of the cardiac baroreflex during quiet standing before and after balance disturbances. Twenty healthy participants experienced three different perturbation intensity conditions that each included 25 brief posteriorly-directed perturbations, 8–10 s apart. Three perturbation intensity conditions (low, medium, high) were given in random order. Physiological data were collected in quiet stance for 5 min before testing (Baseline) and again after the perturbation conditions (Recovery) to examine baroreflex stability. Beat-to-beat heart rate (HR) and systolic blood pressure (SBP) analysis post-perturbation indicated an immediate acceleration of the HR for 1–2 s, with elevated SBP 4–5 s post-perturbation. Heart rate changes were greatest in the medium (p = 0.035) and high (p = 0.012) intensities compared to low, while there were no intensity-dependent changes in SBP. The cBRS was not intensity-dependent (p = 0.402) but when perturbation conditions were combined, cBRS was elevated compared to Baseline (p = 0.046). The stability of baseline cBRS was excellent (ICC = 0.896) between quiet standing conditions. In summary, HR, but not SBP or cBRS were intensity-specific during postural perturbations. This was the first study to examine cardiovascular response and cBRS to postural perturbations

Do Neuropsychological Tests Have the Same Meaning in Spanish Speakers as They Do in English Speakers?

OBJECTIVE: The purpose of this study was to examine whether neuropsychological tests translated into Spanish measure the same cognitive constructs as the original English versions. METHOD: Older adult participants (N = 2,664), who did not exhibit dementia from the Washington Heights Inwood Columbia Aging Project (WHICAP), a community-based cohort from northern Manhattan, were evaluated with a comprehensive neuropsychological battery. The study cohort includes both English (n = 1,800) and Spanish speakers (n = 864) evaluated in their language of preference. Invariance analyses were conducted across language groups on a structural equation model comprising four neuropsychological factors (memory, language, visual-spatial ability, and processing speed). RESULTS: The results of the analyses indicated that the four-factor model exhibited partial measurement invariance, demonstrated by invariant factor structure and factor loadings but nonequivalent observed score intercepts. CONCLUSION: The finding of invariant factor structure and factor loadings provides empirical evidence to support the implicit assumption that scores on neuropsychological tests are measuring equivalent psychological traits across these two language groups. At the structural level, the model exhibited invariant factor variances and covariances

Quantifying Cognitive Reserve in Older Adults by Decomposing Episodic Memory Variance: Replication and Extension

The theory of cognitive reserve attempts to explain why some individuals are more resilient to age-related brain pathology. Efforts to explore reserve have been hindered by measurement difficulties. Reed et al. (2010) proposed quantifying reserve as residual variance in episodic memory performance that remains after accounting for demographic factors and brain pathology (whole brain, hippocampal, and white matter hyperintensity volumes). This residual variance represents the discrepancy between an individual's predicted and actual memory performance. The goals of the present study were to extend these methods to a larger, community-based sample and to investigate whether the residual reserve variable is explained by age, predicts longitudinal changes in language, and predicts dementia conversion independent of age. Results support this operational measure of reserve. The residual reserve variable was associated with higher reading ability, lower likelihood of meeting criteria for mild cognitive impairment, lower odds of dementia conversion in dependent of age, and less decline in language abilities over 3 years. Finally, the residual reserve variable moderated the negative impact of memory variance explained by brain pathology on language decline. This method has the potential to facilitate research on the mechanisms of cognitive reserve and the efficacy of interventions designed to impart reserve

Intraocular Lens Power Calculation after Small Incision Lenticule Extraction

With more than 1.5 million Small Incision Lenticule Extraction (SMILE) procedures having already been performed worldwide in an ageing population, intraocular lens (IOL) power calculation in post-SMILE eyes will inevitably become a common challenge for ophthalmologists. Since no refractive outcomes of cataract surgery following SMILE have been published, there is a lack of empirical data for optimizing IOL power calculation. Using the ray tracing as the standard of reference - a purely physical method that obviates the need for any empirical optimization - we analyzed the agreement of various IOL power calculation formulas derived from the American Society of Cataract and Refractive Surgeons (ASCRS) post-keratorefractive surgery online calculator. In our study of 88 post-SMILE eyes, the Masket formula showed the smallest mean prediction error [-0.36 +/- 0.32 diopters (D)] and median absolute error (0.33D) and yielded the largest percentage of eyes within +/- 0.50D (70%) in reference to ray tracing. Non-inferior refractive prediction errors and +/- 0.50D accuracies were achieved by the Barrett True K, Barrett True K No History and the Potvin-Hill formula. Use of these formulas in conjunction with ray tracing is recommended until sufficient data for empirical optimization of IOL power calculation after SMILE is available