Age groups that sustain resurging COVID-19 epidemics in the United States.

After initial declines, in mid-2020 a resurgence in transmission of novel coronavirus disease (COVID-19) occurred in the United States and Europe. As efforts to control COVID-19 disease are reintensified, understanding the age demographics driving transmission and how these affect the loosening of interventions is crucial. We analyze aggregated, age-specific mobility trends from more than 10 million individuals in the United States and link these mechanistically to age-specific COVID-19 mortality data. We estimate that as of October 2020, individuals aged 20 to 49 are the only age groups sustaining resurgent SARS-CoV-2 transmission with reproduction numbers well above one and that at least 65 of 100 COVID-19 infections originate from individuals aged 20 to 49 in the United States. Targeting interventions-including transmission-blocking vaccines-to adults aged 20 to 49 is an important consideration in halting resurgent epidemics and preventing COVID-19-attributable deaths.

Inverse in silico screening for identification of kinase inhibitor targets.

Protein kinases are clinically relevant, attractive drug targets for cancer. One major problem with kinase inhibitors is broad promiscuity, causing off-target actions and side effects. In silico prediction of targets of a compound would immensely facilitate and accelerate drug development. Using a virtual "inverse" screening approach, where single compounds are docked into protein structures from a database, we identify among known targets of indirubin derivatives phosphoinositide-dependent kinase 1 (PDK1) as a target of one derivative (6BIO) in particular. This prediction is functionally supported by an in vitro kinase assay, inhibition of intracellular phosphorylation of PDK1-substrates, and inhibition of endothelial cell migration, which highly depends on PDK1. Virtual inverse screening combined with biological tests, thus, is proposed as a valuable tool for the drug discovery process and re-examination of already established kinase inhibitors.

Artificial neural network: a new diagnostic posturographic tool for disorders of stance.

OBJECTIVE: To determine the accuracy of diagnoses made with artificial neural network techniques (ANNW) that identify postural sway patterns typical for balance disorders. METHODS: Body sway was measured by means of posturography during 10 test conditions of increasing difficulty. From a database of 676 subjects 60 training cases (TCs) and 60 validation cases (VCs) were selected in which the following diagnoses had been established clinically: normal subject (NS), postural phobic vertigo (PPV), anterior lobe cerebellar atrophy (CA), primary orthostatic tremor (OT), and acute unilateral vestibular neuritis (VN). A standard 3-layer feed-forward ANNW, using the backpropagation algorithm, was trained with TCs, validated with VCs, and its accuracy tested on 5 new cases. RESULTS: ANNW differentiated the established diagnoses with an overall sensitivity and specificity of 0.93. Sensitivity and specificity were 1 for NS and OT; for PPV, 0.87 and 0.96; for CA, 1 and 0.98; and for VN, 0.8 and 0.98, respectively. New subjects were identified with ANNW output variables of the true diagnoses between 0.73 and 1. CONCLUSIONS: ANNW differentiates postural sway patterns of several distinct clinical balance disorders with high sensitivity and specificity. Once designed and tested ANNW could be considered a black box, which each examiner can apply to predict a specific diagnosis even without a clinical examination. SIGNIFICANCE: A promising diagnostic tool for disorders of upright stance in selected neurological disorders.

GlamDock: development and validation of a new docking tool on several thousand protein-ligand complexes.

In this study, we present GlamDock, a new docking tool for flexible ligand docking. GlamDock (version 1.0) is based on a simple Monte Carlo with minimization procedure. The main features of the method are the energy function, which is a continuously differentiable empirical potential, and the definition of the search space, which combines internal coordinates for the conformation of the ligand, with a mapping-based description of the rigid body translation and rotation. First, we validate GlamDock on a standard benchmark, a set of 100 protein-ligand complexes, which allows comparative evaluation to existing docking tools. The results on this benchmark show that GlamDock is at least comparable in efficiency and accuracy to the best existing docking tools. The main focus of this work is the validation on the scPDB database of protein-ligand complexes. The size of this data set allows a thorough analysis of the dependencies of docking accuracy on features of the protein-ligand system. In particular, it allows a two-dimensional analysis of the results, which identifies a number of interesting dependencies that are generally lost or even misinterpreted in the one-dimensional approach. The overall result that GlamDock correctly predicts the complex structure in practically half of the cases in the scPDB is important not only for screening ligands against a particular protein but even more so for inverse screening, that is, the identification of the correct targets for a particular ligand.

Improved cyclodextrin-based receptors for camptothecin by inverse virtual screening.

We report the computer-aided optimization of a synthetic receptor for a given guest molecule, based on inverse virtual screening of receptor libraries. As an example, a virtual set of beta-cyclodextrin (beta-CD) derivatives was generated as receptor candidates for the anticancer drug camptothecin. We applied the two docking tools AutoDock and GlamDock to generate camptothecin complexes of every candidate receptor. Scoring functions were used to rank all generated complexes. From the 10 % top-ranking candidates nine were selected for experimental validation. They were synthesized by reaction of heptakis-[6-deoxy-6-iodo]-beta-CD with a thiol compound to form the hepta-substituted beta-CDs. The stabilities of the camptothecin complexes obtained from solubility measurements of five of the nine CD derivatives were significantly higher than for any other CD derivative known from literature. The remaining four CD derivatives were insoluble in water. In addition, corresponding mono-substituted CD derivatives were synthesized that also showed improved binding constants. Among them the 9-H-purine derivative was the best, being comparable to the investigated hepta-substituted beta-CDs. Since the measured binding free energies correlated satisfactorily with the calculated scores, the applied scoring functions appeared to be appropriate for the selection of promising candidates for receptor synthesis.

Flavonoids affect actin functions in cytoplasm and nucleus.

Based on the identification of actin as a target protein for the flavonol quercetin, the binding affinities of quercetin and structurally related flavonoids were determined by flavonoid-dependent quenching of tryptophan fluorescence from actin. Irrespective of differences in the hydroxyl pattern, similar Kd values in the 20 microM range were observed for six flavonoids encompassing members of the flavonol, isoflavone, flavanone, and flavane group. The potential biological relevance of the flavonoid/actin interaction in the cytoplasm and the nucleus was addressed using an actin polymerization and a transcription assay, respectively. In contrast to the similar binding affinities, the flavonoids exert distinct and partially opposing biological effects: although flavonols inhibit actin functions, the structurally related flavane epigallocatechin promotes actin activity in both test systems. Infrared spectroscopic evidence reveals flavonoid-specific conformational changes in actin which may mediate the different biological effects. Docking studies provide models of flavonoid binding to the known small molecule-binding sites in actin. Among these, the mostly hydrophobic tetramethylrhodamine-binding site is a prime candidate for flavonoid binding and rationalizes the high efficiency of quenching of the two closely located fluorescent tryptophans. The experimental and theoretical data consistently indicate the importance of hydrophobic, rather than H-bond-mediated, actin-flavonoid interactions. Depending on the rigidity of the flavonoid structures, different functionally relevant conformational changes are evoked through an induced fit.